POSSIBILITIES OF SURGICAL TREATMENT OF NEUROENDOCRINE NEOPLASIA OF THE PANCREATIC HEAD, INVADING THE MAIN VEINS

Mikael G. Abgaryan; Абгарян Микаэл Грантович; Alexey G. Kotelnikov; Котельников Алексей Геннадьевич; Anastasiya М. Belozerskikh; Белозерских Анастасия Михайловна; Sergey N. Berdnikov; Бердников Сергей Николаевич; Ivan N. Peregorodiev; Перегородиев Иван Николаевич; Alexander N. Polyakov; Поляков Александр Николаевич; Ivan G. Avdyukhin; Авдюхин Иван Геннадьевич

doi:10.35693/SIM690586

POSSIBILITIES OF SURGICAL TREATMENT OF NEUROENDOCRINE NEOPLASIA OF THE PANCREATIC HEAD, INVADING THE MAIN VEINS

Authors: Abgaryan M.G.¹, Kotelnikov A.G.¹, Belozerskikh A.М.¹, Berdnikov S.N.¹, Peregorodiev I.N.¹, Polyakov A.N.¹, Avdyukhin I.G.¹
Affiliations:
1. N.N. Blokhin NMRCO
Section: Original study articles
URL: https://innoscience.ru/2500-1388/article/view/690586
DOI: https://doi.org/10.35693/SIM690586
ID: 690586

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Abstract

The aim of the study was to show the possibility and relative safety of resection of the portal and/or superior mesenteric vein invaded by a tumor during surgical treatment of neuroendocrine neoplasia of the pancreatic head, as well as the possibility of simultaneous liver resection for resectable metastases in patients with stage IV disease during primary surgery and with the progression of the disease at any stage after surgical treatment.

Materials and methods: surgical treatment of 16 patients with neuroendocrine neoplasia of the pancreatic head with invasion of the superior mesenteric and/or portal vein of stages III-IV of high and moderate degree of differentiation (G1 and G2) included standard gastropancreoduodenal resection in 87.5% of cases, extended gastropancreoduodenal resection with aortocoval lymphodissection in 6.25% and pancreatectomy – 6.25%.

Results: The rate of surgical treatment in the volume of R0 was 93.8%, the rate of complications of surgical intervention of class III and above on the Clavien-Dindo scale was 43.8%, with a total rate of all complications of 75%. The main complications were gastrostasis (50.1%), erosive bleeding (18.8%), bleeding from acute gastrointestinal ulcers (18.8%), and pneumonia (18.8%). The frequency of postoperative portal and/or superior mesenteric vein thrombosis was 12.5%, pancreatodigestive anastomosis was 12.5%, biliodigestive anastomosis was 6.3%, and pancreatic fistula was 12.5%. With a median follow-up period of 62.6 months, disease progression was detected in 62.5% of patients, the median time to progression was 39.7 months, and mortality from progression was 50%. Local recurrence developed in 12.5% of patients, retroperitoneal lymph node metastases – in 6.25%, liver metastases – in 43.75%, in two cases liver resection was performed for metastases. The median overall survival was 70.1 months, the median survival without signs of disease progression was 49.2 months, 1-year survival rates were 81.2% and 78.6%, respectively, 3–year-olds were 68.2% and 63.5%, 5–year-olds were 68.2% and 36.3%, 10–year-olds were 20.55% and 18.1%.

Conclusion: the results of surgical treatment of patients with neuroendocrine neoplasia of the pancreatic head with invasion of the portal and/or superior mesenteric vein indicate the acceptability, relative safety and effectiveness of resections of these major veins.

Keywords

neuroendocrine neoplasia of the pancreas, gastropancreoduodenal resection, portal vein resection, superior mesenteric vein resection, liver metastasis resection

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Introduction
Currently, there are relatively few publications in the literature reflecting the frequency, features and results of resections of the main veins in patients with locally advanced neuroendocrine neoplasia (NEN) of the pancreas (RV), which invades the portal and superior mesenteric veins. This can be explained by the low incidence of NEH, which is about 2% among cancers of the pancreas and gastrointestinal tract [1], however, according to McKenna and Edil [2], every tenth among pancreatic tumors is a neuroendocrine formation. In the "Practical recommendations for the drug treatment of neuroendocrine neoplasia of the gastrointestinal tract and pancreas", published in 2023, surgical treatment is recommended for the surgical process, there is no unambiguous decision on neo- and adjuvant therapy, an individual approach and discussion at a multidisciplinary consultation are necessary [3].
According to the publications of the last 10-15 years, the frequency of resection of the main vessels during surgical treatment of patients with locally advanced pancreatic NEH of high and moderate degree of differentiation (G1 and G2) is ambiguous and ranges from 5% to 25%. So, Haugvik et al. [4] performed vascular resection and reconstruction during pancreatic resection in 7 (9.3%) of 75 patients with portal vein (BB), splenic vein, or common hepatic artery and celiac trunk invasion. The activity of Titan et al. [5] significantly higher – 25.3%.
As for the complications of vascular resections, they are comparable to the complications of similar surgical treatment of pancreatic head neoplasia without vascular resections. In a study by Haugvik et al. [4] There were no grade III–IV complications on the Clavien–Dindo scale, nor mortality after resection of the main veins and arteries in 7 patients. Titan et al. [5] report that the 30-day mortality after NEN resections from resections and reconstructions of the invaded main vessels was 2%. In 2024, Nießen et al. [6] published the results of surgical treatment of NAS with resection of the portal and/or superior mesenteric vein (IBV) in 54 patients. The incidence of complications of class IIIb and above on the Clavien-Dindo scale was 27.8% and was similar to that of those operated on without vascular resection (13%, p=0.071). The incidence of thrombosis of explosives was 19%, relaparotomy – 33%, 90-day mortality – 2%.
Taking into account the urgency of the problem and the small number of publications devoted to the surgical treatment of NAS with invasion of the main veins, we present our own research results conducted at the Blokhin National Research Medical Center of Oncology of the Ministry of Health of the Russian Federation in 2001-2023.
The aim of the study was to show the possibility and relative safety of resection of tumor—invaded portal and/or superior mesenteric vein during surgical treatment of neuroendocrine neoplasia of the pancreatic head, as well as the possibility of simultaneous liver resection for resectable metastases in patients with stage IV disease during primary surgery and with the progression of the disease at any stage after surgical treatment.

Material and methods
The retrospective analysis included data from 16 patients with pancreatic nodules that invade BB and/or VBV who were examined and treated at the Blokhin National Research Medical Center of the Ministry of Health of the Russian Federation in 2001-2023. The study included 5 (31.3%) men and 11 (68.7%) women who were between 22 and 62 years old at the time of hospitalization (median 51 years). In all patients, the tumor was clinically and hormonally inactive, with a maximum size ranging from 2.5 to 7 cm (median 5.3 cm). Stage T2N1M0 was detected in 1 (6.25%) patient, T4N0M0 in 12 (75%), T4N1M0 in 2 (12.5%) and T4N1M1 in 1 (6.25%). In 3 (18.8%) cases, a high degree of tumor differentiation was diagnosed (G1) and in 13 (81.2%) – moderate (G2). The median level of Ki-67 was 8.5% in patients of the IBD+ group.The BB marker significantly exceeded that of the BBB group (14% vs 4.5%, p= 0.032). In 4 (25%) patients, tumor invasion was detected in the duodenum and in 3 (18.8%) – in the duodenum and choledochus. 9 (56.3%) people had jaundice at the time of hospitalization, requiring bile removal, and its development in the IBD+ groupBB was significantly more frequently observed compared with the group of BBB (100% vs 25%, p=0.006). Standard gastropancreoduodenal resection (GPDR) was performed in 14 (87.5%) patients, mesenteric access was used in 1 (6.25%) case, extended GPDR with aortocoval lymph dissection was performed in 1 (6.25%) patient, and pancreatectomy was performed in 1 (6.25%) patient. During standard GPDR, one patient (6.25%) underwent segmental liver resection to remove metastasis. BB resection was performed in 1 (6.2%) person, BBB – in 8 (50%), both main veins (BBB +BB) – in 7 (43.8%). In 14 (87.5%) patients, circular resection of the main veins with a length of 2 to 5 cm (median 3.5 cm) was performed. In 9 (56.3%) cases, plastic surgery was performed using an end-to-end anastomosis, in 5 (31.3%) – using a Gore-Tex synthetic prosthesis. Two (12.5%) underwent parietal resection of the main veins with a length of 1 to 3 cm (median 2.0 cm), and a parietal suture was used for plastic surgery. The duration of compression of the portal vein during the formation of an end–to-end direct anastomosis ranged from 13 to 16 minutes, and from 22 to 32 minutes when using a synthetic prosthesis. Temporary bypass shunts were not formed. Neoadjuvant therapy was not performed, 3 (18.8%) people received adjuvant treatment according to the XELOX scheme.

Results
Of the 16 patients, 15 (93.8%) underwent surgical treatment in the amount of R0, and 1 (6.2%) – in the amount of R2 due to the invasion of the NEN into the superior mesenteric artery and surrounding tissue. The median duration of surgical interventions was 305 minutes (from 210 to 600 minutes), the median blood loss during operations was 3000 ml (from 600 to 6500 ml).
Complications of surgical treatment were observed in 12 (75%) of 16 patients, 7 (43.8%) people had complications of class III and higher on the Clavien-Dindo scale. The incidence of early complications was 62.5% (10/16), early and late – 12.5% (2/16). 3 (18.8%) patients developed 1 complication, 2 (12.5%) had two, 4 (25%) had three, and 3 (18.7%) had four or more. Gastrostasis (50.1%), erosive bleeding (18.8%), bleeding from acute gastrointestinal ulcers (18.8%), and pneumonia (18.8%) prevailed in frequency. The types and frequency of complications depending on the volume of venous resection are shown in Table 1.
Table 1 – Types and frequency of complications depending on the volume of venous resection during surgical treatment of patients with NENE of the head of the pancreas with invasion of the main veins

Relaparotomy was performed in two (12.5%) patients due to the failure of pancreatodigistive anastomosis with erosive bleeding. Both died from complications of surgical treatment.
A pathohistological examination of the surgical material in 13 (81.3%) of the 16 patients confirmed the invasion of the pancreatic head into the surrounding tissues. Retroperitoneal extraorgan invasion was verified in 10 (62.5%) cases, perineural invasion – in 6 (37.5%), extrapancreatic lesion was detected in 3 people, intrapancreatic lesion in 2, extra– and intrapancreatic in 1. The frequency of histological confirmation of the types of deformity of BB and/or VBV according to the Nakao classification was: type A – 33.3%, Type B – 87.5%, Type C – 75%, Type D – 100%.
The median follow-up period for 16 patients was 62.6 months, with terms ranging from 0.5 to 172 months. Disease progression was detected in 10 (62.5%) people, of whom 8 died and 2 were alive at the end of the study. The median time to detection of progression was 39.7 months. (3 to 69.3 months). Local recurrence developed in 2 (12.5%) people, liver metastases – in 7 (43.75%), retroperitoneal lymph node metastases – in 1 (6.25%). With progression, all patients received antitumor treatment with analogues of prologued Sandostatin.
It should be noted that of the 7 patients with liver metastases, two underwent liver b resection against the background of antitumor treatment with analogues of prologated Sandostatin, after which they lived without symptoms of the disease for 2 years before the development of repeated progression of NES in the form of liver metastases. This:

― the patient is 22 years old. Surgical treatment of stage III NEN (T4N0M0G2) was performed in the volume of radical standard GPDR with parietal resection of the VB and plastic surgery using a parietal suture. Liver metastasis was diagnosed 53 months after surgical treatment. She did not receive additional antitumor treatment. Liver metastasis was resected and antitumor treatment with prologated Sandostatin analogues was performed after 24 months. Repeated progression of NEN in the form of metastases to the liver and retroperitoneal lymph nodes was revealed, and she died after 100.6 months. after surgical treatment;
― patient, 51 years old. She received surgical treatment for stage III NES (T4N0M0G2) in the volume of radical expanded GPDR with circular resection of the explosives with the formation of an end-to-end anastomosis, after 66 months. liver metastases have been identified. Metastasis resection was performed, antitumor treatment with analogues of prologated Sandostatin was performed, liver metastases reappeared after 23 months, death was confirmed 99.5 months after surgical treatment with NAN.

The median overall survival of 16 patients with pancreatic nodule invasion of the main veins was 70.1 [11.4; 100.1] months, the median survival without signs of disease progression was 49.2 [14; 66.7] months, 1–year survival rates were 81.2±9.8% and 78.6±11.0%, respectively, 3-year – 68.2±11.8% and 63.5±13.1%, 5-year–olds - 68.2±11.8% and 36.3±14.0%, 10–year-olds - 20.5±12.5% and 18.1±11.5%.
There were no statistically significant differences in any of the presented indicators depending on the volume of vein resection.

Discussion
In our study, which included 16 patients with pancreatic head NEC with invasion of HBV and/or BB stages III-IV of high and moderate degree of differentiation (G1 and G2), the frequency of surgical treatment in the volume of R0 is high enough – 93.8%, in addition, we performed segmental liver resection to remove metastasis in a patient with IV the NAN stage. The incidence of surgical complications of class III and above on the Clavien-Dindo scale in our study was 43.8%, with a total incidence of 75% of all complications. The main complications in terms of frequency are gastrostasis (50.1%), erosive bleeding (18.8%), bleeding from an acute gastrointestinal ulcer (18.8%), and pneumonia (18.8%). The frequency of postoperative thrombosis of reconstructed main veins remained 12.5%, the failure of biliodigestive anastomosis – 6.3%, the failure of pancreatodigestive anastomosis – 12.5%, pancreatic fistula – 12.5%. Death from complications was detected in 2 (12.5%) of 16 patients. Our results are comparable to the data of Niessen et al. [6], published in 2024. Presenting an analysis of IV/VBV resections in 54 patients with pancreatic NEC, the authors reported that the incidence of complications of class IIIb and above on the Clavien-Dindo scale was 27.8%, the incidence of portal vein thrombosis was 19%, and mortality within 90 days after surgery was 2% (1 case). According to the literature, complications after vascular resections in patients with neuroendocrine tumors of the pancreas are characterized by an acceptable frequency and a low mortality rate, especially in comparison with similar interventions without vascular resection. Haugvik et al. [4] no serious complications were recorded in 7 patients after combined vascular resection. Titan et al. [5] report that the 30-day mortality rate in their study was 2% (2 patients), there is no mention of specific complications such as anastomotic thrombosis or bleeding, probably due to their rarity or absence. The full structure of complications on the Clavien-Dindo scale is also not indicated, but the authors note that 76% of patients maintained a high quality of life with ECOG <1. All this indicates an acceptable level of risk when performing vascular resections in patients with well-differentiated neuroendocrine tumors.
During the follow-up period (median 62.6 months), we recorded the progression of NES in 62.5% of patients. The median time to progression was 39.7 months, the incidence of local recurrence was 12.5%, the incidence of retroperitoneal lymph node metastases was 6.25%, and liver metastases was 43.75%. Please note that two out of 7 patients with liver metastases were successfully removed, significantly improving their quality of life. These two people lived without symptoms of the disease for 2 years before relapsing. Unlike pancreatic head adenocarcinoma, resection of operable metastases is possible and gives a good result.
Mortality from the progression of NES in our study was 50%, the median overall survival was 70.1 months, the median survival without signs of disease progression was 49.2 months, 1-year survival rates were 81.2% and 78.6%, respectively, 3-year–olds - 68.2% and 63.5%, 5-year–olds - 68.2% and 36.3%, 10-year–olds - 20.5% and 18.1%, which is comparable with the literature data. In almost all studies, long-term oncological results of pancreatic resections with vascular reconstruction in patients with highly and moderately differentiated neuroendocrine tumors indicate a favorable prognosis, especially with R0 resections and the absence of distant metastases. So, Birnbaum et al. [7] report that the median overall survival of patients with locally advanced forms of NEP was 90 months, the 5-year overall survival was 66%, and the 5-year disease–free survival was 26%. In a study by Nießen et al. [6] The 5-year overall survival rate of patients with NES who underwent IV resection was 66.7% for G1 tumors and 51.2% for G2 tumors (p=0.0008), the differences in 5-year disease–free survival rates were greater - 66.7% and 22.8%, respectively. For the entire group of patients who underwent vascular resection, the 3-year overall survival rate was 66.4%, the 5-year survival rate was 44.6%, and the 10–year survival rate reached 41.2%.
Thus, surgical treatment of patients with pancreatic head NEC with invasion of HBV and/or BB is possible, relatively safe, and can be supplemented with liver resection for operable metastases. The indicators of 5-year overall and disease-free survival reach high values, which indicates the acceptability and effectiveness of vascular resections in the case of pancreatic head NEC, provided high and moderate tumor differentiation and radical surgical treatment. Given the relatively favorable prognosis, in such patients it is possible to remove operable liver metastases with the progression of the underlying disease at any stage, which is safe and improves the quality of life.

Conclusion
The results of surgical treatment of patients with NENE of the pancreatic head with a high and moderate degree of differentiation (G1, G2) with invasion of BB and/or BBB indicate the acceptability, relative safety and effectiveness of resections of these major veins. In most patients, surgical treatment can be carried out to a radical extent, as well as supplemented with liver resection for operable metastases. Given the relatively favorable prognosis of the disease, it is possible to remove operable liver metastases even with the progression of the disease at any stage, it is safe, improves the quality of life of patients and prolongs the period without manifestations of the disease.

About the authors

Mikael G. Abgaryan

N.N. Blokhin NMRCO

Author for correspondence.
Email: abgaryan.mikael@gmail.com
ORCID iD: 0000-0001-8893-1894

Candidate of Medical Sciences, Senior Researcher, Oncologist at the Department of Abdominal Oncology No. 1 of the N.N. Trapeznikov Research Institute of Clinical Oncology named after Academician of the Russian Academy of Sciences and the Russian Academy of Medical Sciences