Langenbeck's Archives of Surgery (2023) 408:367 https://doi.org/10.1007/s00423-023-03105-x RESEARCH Assessment of the level III of Inoue by preoperative endoscopic ultrasound and elastography: a novel approach to predict a periarterial divestment technique in borderline resectable (BR) or locally advanced (LA) pancreatic adenocarcinoma—How I do it Piero Alberti1,2 · Elizabeth Pando1,2 · Monder Abu‑Suboh3 · Miquel Masachs3 · Xavier Merino4 · Maite Salcedo5 · Teresa Macarulla6 · Joaquin Balsells2 · Ramon Charco2 Received: 26 December 2022 / Accepted: 9 September 2023 © The Author(s) 2023 Abstract Background Periarterial divestment is a surgical technique to approach borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) with arterial involvement. There are no reports in the literature regarding the role of endoscopic ultrasound and elastography (EUS-EG) in exploring the integrity of Inoue’s level III and its correlation with the periarterial divestment technique feasibility. Our research is aimed at exploring the role of EUS-EG in this scenario. Methods We describe our approach to Inoue’s level II by EUS-EG in patients with BR and LA pancreatic cancer patients after neoadjuvant chemotherapy. Results Between June 2019 and December 2020, four patients out of 25 were eligible to perform a preoperative EUS-EG. In all cases, Inoue’s level III integrity was corroborated by EUS-EG and confirmed posteriorly in the surgical scenario where a periarterial divestment technique was feasible. Vein resections were necessary in all cases, with no need for arterial resection. An R0 (> 1 mm) margin was achieved in all patients, and the histopathological assessment showed the presence of neurovascular tissue at the peripheral arterial margin. Conclusion Preoperatively, EUS-EG is a novel approach to explore the integrity of Inoue’s level III and could be helpful to preclude a periarterial divestment technique in borderline resectable or locally advanced pancreatic adenocarcinoma with arterial involvement. Keywords Periarterial divestment · Pancreatic cancer · Locally advanced pancreatic cancer · Triangle operation · Borderline pancreatic cancer Introduction * Elizabeth Pando elizabeth.pando@vallhebron.cat Borderline resectable (BR) or locally advanced (LA) pancre- atic ductal adenocarcinoma (PDAC) with arterial involve- 1 Department of Surgery, Universitat Autonoma de Barcelona, ment remains a challenge for surgical resectability [1]. In the Barcelona, Spain era of neoadjuvant therapies (NT), the proportion of patients 2 Department of Hepatopancreatobiliary and Trasplant who can undergo resection leading to better prognosis and Surgery, Hospital Vall d’Hebron, Barcelona, Spain long-term survival has increased substantially [2]. A system- 3 Digestive Endoscopy Unit, Hospital Vall d’Hebron, atic review reported a resectability rate of 28% after NT in Barcelona, Spain patients with LAPC [3]. 4 Radiology Department, Hospital Vall d’Hebron, Barcelona, Periarterial divestment is a surgical technique to approach Spain BR or LA with arterial encasement after NT by dissecting 5 Anatomopathology Department, Hospital Vall d’Hebron, the periadventitial space between the tumour and arterial Barcelona, Spain vessel, following level III of the mesopancreas, described by 6 Oncology Department, Hospital Vall d’Hebron, Vall Inoue [4]. Additionally, dissection through the neurovascular d´Hebrón Institute of Oncology, Barcelona, Spain 13 Vol.:(0123456789) 367 Page 2 of 10 Langenbeck's Archives of Surgery (2023) 408:367 level III facilitates an ‘en-bloc’ resection of the right semicir- resection (Modified Apple by) is proposed; patients not cle of the superior mesenteric artery (SMA)-nervus plexus, candidates for an exploratory laparotomy: (1) patients with obtaining cancer-free margins, avoiding arterial resections, LAPC with extended arterial involvement, considered LAPC which has been associated with high perioperative morbidity unresectable (LAPC type III) [7] with clear signs of arterial and mortality [1]. Periarterial divestment is possible when infiltration on concomitant CT, CHA, and SMA, and patients the tumour is not infiltrating across the Inoue’s level III to with a non-reconstructible portal or mesenteric vein. the adventitia; consequently, an arterial infiltration is absent. Endoscopic ultrasonography (EUS) is used to assess BR and LA pancreatic cancer definitions vascular infiltration in pancreatic cancer, and its association with elastography (EUS-EG) has been found to increase the Borderline resectable or locally advanced pancreatic adeno- diagnostic power by evaluating hardness, softness, and the carcinoma is defined according to the NCCN radiological relative movement of two tissues at the same compression definition at the time of diagnosis based on the computed level [5]. Nevertheless, there are no reports in the literature tomography multiphase scan [8]. regarding the role of EUS-EG in exploring the integrity of Inoue’s level III and its correlation with the surgical findings Neoadjuvant chemotherapy and periarterial divestment technique feasibility. Thus, we described our experience using EUS-EG as an Neoadjuvant chemotherapy consists of FOLFIRINOX approach towards arterial involvement in the settings of BR in < 75 years old and fit patients, or gemcitabine alone, or and LA pancreatic cancer after NT in order to assess the gemcitabine plus Nab-paclitaxel when the patient is not integrity of the level III of Inoue, corroborated in the surgi- fit enough to be treated with FOLFIRINOX. For BR and cal scenario with the hypothetical benefit to be a preopera- LA, the treatment duration of neoadjuvant chemotherapy tive diagnostic technique. is at least 8 cycles for FOLFIRINOX and 4 cycles for This study is aimed at showing our first case series fol- gemcitabine ± Nab-paclitaxel. lowing this novel approach. Computed tomography scan and CA 19–9 evaluation Methods CT scan and CA 19–9 levels are done at diagnosis, 2 months We describe our technique to approach the integrity of after neoadjuvant treatment and at the end of treatment. The Inoue’s level III preoperatively using EUS-EG by perform- CT scan protocol consists of a triphasic protocol with a late ing a case series report of patients with BR or LA pancre- arterial phase (35–40 s after intravenous contrast injection) atic cancer after completing neoadjuvant chemotherapy. and a late portal phase (60–70 s after intravenous contrast All patients are discussed in the pancreatic cancer multi- injection). A complete laboratory test work-up includes CA disciplinary board from our hospital, a third-level reference 19–9 and CEA levels. Patients are discussed with a multi- hospital in pancreatic cancer. Our centre performed around disciplinary board of pancreatic cancer at diagnosis every 60 pancreatic resections/year and at least 720 EUS-EG/year. 2 months and when NT is finished. CT scans are reviewed by two experts radiologist from our multidisciplinary board. Inclusion criteria Endoscopic ultrasound + elastography evaluation Inclusion criteria are patients with a RECIST 1.1 (Response Evaluation Criteria in Solid Tumours) [6] i) Patients who meet inclusion and exclusion criteria are regression or stable disease criteria who presents a critical eligible to perform an EUS-EG. arterial encasement of the common hepatic artery (CHA), ii) EUS-EG is performed the day before surgery by the superior mesenteric artery (SMA), or celiac trunk (CT), same experienced endoscopist to evaluate the integrity with suspicion of infiltration in the computed tomography of Inoue’s level III. Technical considerations include a scan (more than 90° around arterial vessels) who are can- radial EUS scope, GF-UE 160-AL5 Olympus, an Olym- didates to an exploratory laparotomy. pus EUS processor, and EU-ME2. The procedure was carried out at the clinic under monitored sedation. Exclusion criteria iii) EUS-EG protocol includes an assessment of pancreatic tumour and their relationship with vessels: Exclusion criteria are patients with isolated venous involve- ment; arterial contact of less than 90°; proper hepatic artery (1) For vessels: (a) grade of vessel contact: < 90/90– involvement, patients with infiltration of CT in whom a 180, 180–270, > 270; (b) deformity (irregularity): 13 Langenbeck's Archives of Surgery (2023) 408:367 Page 3 of 10 367 yes/no; (c) lumen reduction: no, < 50%, > 50%, contact only, three patients were excluded due to less than occlusion; (d) thrombus in the vessel: yes/no; (e) a 90° SMA, one patient had 180° CT contact and was pro- length of stenosis in mmm. posed for a modified Apple By procedure (arterial divest- (2) For Inoue’s level III evaluation, a hyperechogenic ment technique was not the chosen technique), one patient line between the vessel wall and tumour suggests had less than a 90° CT contact, and four patients had proper the integrity of Inoue’s level. Additionally, the hepatic artery involvement. presence of green lines on elastography around The mean age was 52 years, and three were female. Due vessels indicated the integrity of the vascular wall. to a delay in the surgical schedule because of the COVID- 19 pandemic, patients A and B received additional cycles Surgical technique of neoadjuvant chemotherapy than initially planned, and patient A underwent radiotherapy. Patient C was included in In our centre, we perform an SMA artery first approach [9] a clinical trial, limited to receiving no more than five cycles to determine resectability first. of FOLFIRINOX. Patient D received eight cycles of FOL- Independently of the EUS-EG evaluation results, we fol- FIRINOX according to our routine clinical practice. Tumour low an intending to treat principle. When arterial involve- marker Ca 19–9 decreased > 50% of its initial value in three ment is suspected, we reproduce the periarterial divestment patients, except in one case that remained stable. Patient’s technique previously described by experienced centres [10] and tumour characteristics are listed in Table 1. to release the tumour from the arterial vessel, avoiding arterial resection. When a periadventitial dissection is not CT scan findings feasible, we abort the procedure and perform a palliative by-pass (biliary or gastric) if necessary. In fit patients under Patients showed a partial response after NT in 2 cases, and 65 years old with no significant comorbidities, an arterial 2 showed stable disease in CT scans (Fig. 1). Regarding resection with anastomosis is offered contrary to a pallia- the relation with arterial margins, the CT scan showed the tive procedure. persistence of tumour contact around vessels, with no signs A partial (180°) or total circumferential excision of the of deformity or irregularity. Based only on the CT scan find- SMA-mesopancreas, according to the degree of arterial ings, it was not possible to determine if a potential divest- involvement, is performed. Regional lymphadenectomy is ment technique between the tumour and the adventitial plane performed as routine. Venous reconstruction is performed could be performed. according to the type of defect (tangential, terminal-ter- minal, peritoneum patch, cadaveric graft, or PTFE graft if EUS‑EG results necessary). After the surgical specimen extraction, the arterial and The median time of the procedure was 43.5 min (range: venous bed is marked to facilitate the margin evaluation for 40–60 min). In all cases, the integrity of level III of Inoue the pathologist. The pathological evaluation is performed by was corroborated by EUS-EG, visualising the integrity of an experienced pathologist in pancreatic tumours using the the hyperechoic line between the vessel and the tumour axial slicing technique [10]. We consider an R0 resection and a green line in the elastography views in all the cases, when a free margin ≥ 1 mm was achieved. compatible with a low echo area at this level (Fig. 2). The arterial encasement grades were similar to those reported Statistics and ethics by the CT scan. No occlusion or irregularity was reported. There were no potential side effects after the procedure in Descriptive statistics were performed. Our local ethical com- all patients. All patients were discharged the same day after mittee approved our prospective data register following the the procedure. Helsinki Declaration principles for human investigations. All patients signed informed consent for both EUS-EG and Surgical findings surgical intervention. All patients were explored by the artery-first approach technique. Of the different artery first approaches described Results [4, 12], the posterior approach was followed in 3 patients. In every case, Inoue’s level III was reached, and a peri- Between June 2019 and December 2020, four patients of 25 arterial divestment was possible to perform in all cases were eligible to perform a preoperative EUS-EG according (Fig. 3). In three patients with SMA involvement of fewer to the inclusion and exclusion criteria. Excluded patients than 180°, a right semicircle dissection of the SMA was were as follows: thirteen patients presented with venous performed to preserve neurovascular autonomic plexus and 13 367 13 Page 4 of 10 Table 1  Patients and tumour characteristics Case Age Sex ASA/ BMI (kg/ Pathological Neoadjuvant therapy NCCN criteria at diagnostic RECIST NCCN criteria post neoadju- EUS + EG Ca 19–9 (U/ml) Ca 19–9 (U/ml) ECOG m2) history (#cycles) + RT (grays) criteria vant therapy pre-neoadjuvant post-neoadjuvant therapy therapy Artery Vein Artery Vein A 53 Male 2/0 26.9 Type 2 FOLFIRINOX 180° SMA SMV encase- Regression < 180° SMA SMV encase- Integrity of 90 30 diabetes. (11) + RT(54 Gy) ment ment Inoue’s Explora- plane 3 tory lapa- rotomy in other centre (no resection possible) B 54 Female 2/0 21.9 None NALIRINOX (12) < 180° Porto-splenic Stable < 180° Porto-splenic Integrity of 206 21 HA +  < 180° confluence HA +  < 180° confluence Inoue’s SA encasement SA encase- plane 3 ment C 53 Female 2/0 30.3 None FOLFIRINOX (5) SMA > 270°, CT SMV > 270°, PV Stable SMA > 270°, SMV > 270°, Integrity of 370 370 180°–270°, 90°–180° CT 180°– PV Inoue’s CHA 90°–180° 270°, CHA 90°–180° plane 3 90°–180° D 47 Female 2/0 27.4 None FOLFIRINOX (8) > 180° SMA Porto- Regression < 180° SMA < 270° SMV Integrity of 8744 140 mesenteric Inoue’s confluence plane 3 encasement ASA, American Society of Anaesthesiologists; ECOG, Eastern Cooperative Oncology Group; BMI, body mass index; FOLFIRINOX, fluorouracil, irinotecan, and oxaliplatin; NALIRINOX, nanoliposomal irinotecan plus fluorouracil/leucovorin; RT, radiotherapy; SMA, superior mesenteric artery; HA, hepatic artery; SA, splenic artery; CT, celiac trunk; CHA, common hepatic artery; SMV, superior mesenteric vein; PV, portal vein; RECIST, Response Evaluation Criteria in Solid Tumours; NCCN, National Comprehensive Cancer Network; EUS, endoscopic ultrasound Langenbeck's Archives of Surgery (2023) 408:367 Langenbeck's Archives of Surgery (2023) 408:367 Page 5 of 10 367 Fig. 1  Cases A, C, and D show tumour contact with SMA before (A1, C1, and D1) and after NT (A2, C2, and D2). Case B shows tumour contact with HA before (A1) and after NT (A2). No separation plane between the tumour and vessel wall is seen. NT, neoadjuvant treatment; SMA, superior mesenteric artery; HA, hepatic artery 13 367 Page 6 of 10 Langenbeck's Archives of Surgery (2023) 408:367 Fig. 2  Diagnosis of disruption of the plane III of Inoue by endoscopic ultrasonography and elastography (EUS-EG). a1, b1, c, and d1 EUS-B mode image with hyperechoic line with no disruption (yellow arrows). a2, b2, and d3 EUS-EG image clearly depicts no disrupted plane and green line-low echo area (white arrows). b3 EUS-B Doppler mode with hyperechoic plane and no VI margin. d2 EUS-B mode with unclear a1 a2 tumour involvement b1 b2 b3 c d2 d1 13 Langenbeck's Archives of Surgery (2023) 408:367 Page 7 of 10 367 Fig. 3  Intraoperative results after resection. Case A: tangen- tial superior mesenteric vein resection with peritoneal patch reconstruction. Case B: tangential splenic vein—portal confluence resection. Case C: triangle operation and porto- mesenteric vein resection with T-T anastomosis. Case D: porto-mesenteric vein resection with TT-anastomosis and porto- splenic vein TL anastomosis A B C D avoid uncontrollable postoperative diarrhoea. In one case R0 resection in the surgical scenario while adhering to the with SMA > 270°, a complete circumferential resection of principles of periarterial divestment, thus avoiding arterial the mesopancreas at this level was necessary to complete resections. specimen resection (Table 2). Recently, neoadjuvant regimes have increased the Simultaneous complex venous vascular resection was needed in tumour resection rate in BR and LA pancreatic cancer. all cases, with a venous patch from the peritoneum in one. FOLFIRINOX is one of the most promising agents, with reported resection rates between 25 and 60% in the best Histopathological findings series [3, 13]. The major surgical challenge in BR and LA lies in the arterial encasement by the tumour. Com- Surgical margins (R0 ≥ 1 mm) were achieved for all patients. puted tomography predicts resectability with an accuracy The analysis of the anatomopathological specimens focused of around 95% [14, 15]; however, this falls dramatically on the periarterial tissue revealed the presence of neural hyper- after the neoadjuvant treatment, where periarterial strand- trophy and small calibre vessels in cases A, B, and D (Fig. 4). ing makes identifying unresectable disease less accurate Peritumoral fat and small calibre vessel were found in case C. with a positive predictive value of only 25% [16]. Previous No viable tumoral cells were seen in the arterial margins and reports described indirect findings on CT scan suggesting periarterial tissue. Those findings are consistent with surgical the absence of arterial wall invasion (‘halo sign’) and pre- dissection through the adventitial plane, including the neu- cluding a periarterial divestment technique [17, 18]. How- rovascular plexus around major vessels (AMS, CT, or HA). ever, this assessment has not been validated in prospective studies. In our cohort, the ‘halo sign’ was not assessed pro- spectively. Therefore, based on CT scan alone, pre-surgical Discussion arterial encasement evaluation and potential resectability, remain problematic, and patients should undergo operative This study is the first preliminary report in the literature exploration after NT to assess arterial infiltration [10]. exploring the EUS-EG as a valuable tool in exploring the On the other hand, the literature did not provide strong integrity of the level III of Inoue, followed by a successful evidence favouring a routine arterial resection in pancreatic 13 367 Page 8 of 10 Langenbeck's Archives of Surgery (2023) 408:367 cancer due to the lack of survival benefit in these patients, Pancreas the higher mortality rates, and significant postoperative com- consist- Portal (1.200) Hard Hard ency plications [1, 19]. Portal (1000) Soft Soft The knowledge of the mesopancreas concept and its levels of dissection has gained interest in the last few years. Inoue R. Hepatic (900) Portal (900) Doppler + described three levels of dissection through the mesopan- creas, postulating that level III is the level to perform a free Vein Vascular flow (ml/min) margin and radical surgery in pancreatic adenocarcinoma [4]. Additionally, the concept of periarterial divestment or Hepatic (245) Hepatic (270) periadventitial dissection technique is only possible when Doppler + the tumour is divided from the arterial adventitia; this is only Artery possible in cases without infiltration of the tumour through the arterial wall. The periarterial divestment technique has a prominent role in cases of complex LA tumours, avoiding Tangential SMV (perito- porto-splenic resection tion (T-T anastomosis) Porto-mesenteric resec- Venous resection (type confluence (primary (T-T and LT anasto- arterial resections and its consequent risk for postoperative Porto-mesenteric and Tangential SV portal of reconstruction) complications. In conjunction, the mesopancreas concept and the periarterial divestment technique help surgeons neal patch) PD, pancreaticoduodenectomy; DP, distal pancreatectomy; TP, total pancreatectomy; SMV, superior mesenteric vein; SV, splenic vein increase the possibility of tumour removal and free margin mosis) raffia) resections, especially in BR and LA tumours. Previous reports have explored the role of EUS-EG in predicting resecability [20, 21]. However, none of these Arterial reports were approached from the surgeon’s perspective, in resec- tion No No No No which the integrity of level III of Inoue must be found to predict an effective periarterial divestment technique. Fur- Blood loss (ml) Need for transfu- thermore, these reports were conducted in an upfront sur- Yes (2) None None None sion gery scenario without considering the effect of neoadjuvant treatment. The critical aspect that gives EUS-EG an advantage over CT scan in evaluating BR and LA tumours lies in its abil- ity to differentiate ‘soft’ tissues around vessels (identified 1000 2000 900 by a hyperechogenic line or green lines in EG) from solid 80 areas (identified by hypoechoic areas or blue lines in EG). This ability is essential in planning a periarterial divestment Case Tumour location Surgery Arterial approach Inoue plane Surgical op. time (min) technique. 540 270 600 555 In this regard, the Dutch Pancreatic Cancer Group has conducted a study on intra-operative ultrasound (IOUS) in the context of LA pancreatic cancer following neoadju- vant treatment with FOLFIRINOX, showing an additional Posterior/inferior III III III Posterior/inferior III value of IOUS in determining vascular involvement and has been used for other tumours to determine resectabil- ity during surgical exploration with promising results. In Posterior this multicentre study, IOUS was helpful during surgical Anterior exploration of LA pancreatic cancer after FOLFIRINOX chemotherapy as it changed the resectability status based on CT scan in approximately one-third of the patients [22]. It is essential to acknowledge that intra-operative ultrasound PD DP PD TP requires an exploratory laparotomy, which can be considered Table 2  Surgical aspects Head-uncinated Head-uncinated Head-uncinated a drawback. In our cohort, the histopathological evaluation of the arte- rial margins identified neurovascular tissue corresponding Body to the neurovascular plexus in agreement with the achieve- ment of a periarterial divestment technique. Also, neural hypertrophy was found as a frequent pattern (independent A D B C 13 Langenbeck's Archives of Surgery (2023) 408:367 Page 9 of 10 367 Fig. 4  Histopathological samples of periarterial tissue, showing neural hypertrophy and oedema in cases A, B and C A B C of the use of neoadjuvant chemotherapy); this finding has Funding Open Access Funding provided by Universitat Autonoma de been reported in pancreatic cancer tumours, more frequently Barcelona. at the peripheral, and is probably explained by the promotion Declarations of a ‘neural’ tumoral microenvironment by tumoral cells itself, which also contributes to tumour progression [23, 24]. Competing interests The authors declare no competing interests. Open Access This article is licensed under a Creative Commons Attri- Limitations of EUS‑EG bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, Based on our experience, one limitation of EUS-EG is pre- provide a link to the Creative Commons licence, and indicate if changes vious surgical procedures, such as exploratory laparotomy were made. The images or other third party material in this article are with previous arterial wall dissection or previous palliative included in the article's Creative Commons licence, unless indicated by-pass surgery, due to oedema, fibrosis, and rigidity of otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not the duodenal wall when introducing the endoscope. permitted by statutory regulation or exceeds the permitted use, you will It is crucial to address that EUS-EG is an operator- need to obtain permission directly from the copyright holder. To view a dependent technique, requiring a highly experienced copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. endoscopist to perform a meticulous evaluation of vessels according to our strategy. Moreover, the distal common hepatic artery and proper hepatic artery are particularly difficult to assess by endo- References scopic ultrasound, which is one of the main limitations of the technique. 1. 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