Effect of warm and cold ischemia on pancreaticoduodenectomy specimen following robotic pancreaticoduodenectomy.

doi:10.21203/rs.3.rs-4713706/v1

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Research Article

Effect of warm and cold ischemia on pancreaticoduodenectomy specimen following robotic pancreaticoduodenectomy.

https://doi.org/10.21203/rs.3.rs-4713706/v1

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Background

The adoption of robotic pancreaticoduodenectomy has increased in recent years for the treatment of pancreatic head tumours and periampullary lesions. Some potential benefits seem to be demonstrated, but the impact of longer perioperative time on ischaemia and autolysis of the surgical specimen has not been analysed. The aim of this study is to evaluate the impact of robotic surgery on histological changes of the surgical specimen occurring during robotic pancreaticoduodenectomy.

Methods

A review of histopathology files was performed for all pancreatic specimens collected at our hospital from January 2022 to March 2024. Both warm ischaemia time (WIT) and cold ischaemia time (CID) were collected. Histological features related to ischaemic damage were evaluated and ischaemic changes in normal pancreatic tissue and pancreatic tumour were graded as absent, mild, moderate and severe. Univariate and multivariate analyses were performed to determine which variables were associated with moderate and severe ischaemia.

Results

Sixty surgical specimens were analysed: 20 open PD, 17 robotic PD with cold ischaemia and 23 robotic PD. Median total WIT was 182 minutes (OPD 57 minutes vs RPD 190 minutes vs RPD-CI 198 minutes; p < 0.001). Median CID was 760 minutes (740–835) in samples stored at 4ºC. Assessment of tumour regression was of poor quality in the specimens with cold ischemia. Univariate analysis showed that longer intraoperative time, male gender and cold ischaemia were associated with pancreatic tissue degradation. In multivariate analysis, cold ischaemia was the only independent factor associated with normal pancreatic tissue and tumour tissue moderate and severe degradation.

Conclusions

Prolonged ischaemia time, especially in the case of cold storage, has a strong effect on the degradation of normal and tumour tissue without affecting tumour staging.

robotic pancreaticoduodenectomy

cold ischaemia

specimen damage

warm ischaemia

Pancreatic cancer remains one of the most challenging and devastating oncological diseases. Its incidence is increasing worldwide. It is estimated that by the year 2030, pancreatic cancer could become the second most common cause of cancer-related death in the United States, surpassing both breast cancer and colorectal cancer [1]. Due to its late detection, biological aggressiveness and resistance to conventional therapies, this disease presents several clinical and therapeutic challenges. Despite advances in medical care, the overall 5-year survival rate for pancreatic cancer remains alarmingly low. Only about 10% of patients survive beyond this period [2].

Pancreaticoduodenectomy (PD), also known as the Whipple procedure, is established as the gold standard for the surgical treatment of resectable tumors in the head of the pancreas and duodenum [3]. However, this complex surgical procedure carries significant risks. These include a high rate of perioperative complications and a long postoperative recovery [4, 5]. The development of minimally invasive surgical techniques is a major focus in the field of pancreatic surgery, with the aim of improving postoperative outcomes and quality of life. In this context, robotic pancreaticoduodenectomy (RPD) has emerged as a promising alternative to conventional open pancreaticoduodenectomy [6]. RPD makes use of advanced robotic technology to perform complex resections of the pancreas with greater precision and with less trauma to the tissue [7]. Robotic surgical systems allow for more precise dissection and meticulous reconstruction with significant advantages such as three-dimensional visualisation, optical magnification, and improved instrument articulation.

These features have led to increasing adoption of RPD in surgical centers around the world, with studies indicating comparable or even superior surgical outcomes compared to open pancreaticoduodenectomy. In addition to the technical advantages, RPD has also been associated with lower rates of post-operative complications [8]. These include reduced peri-operative morbidity, lower incidence of pancreatic fistula and faster patient recovery. Also, some studies have shown higher number of yielded lymph nodes and higher rates of R0 [9]. In the context of pancreatic cancer, where reducing perioperative complications can have a significant impact on patient survival and quality of life, these findings are particularly encouraging. However, despite these potential benefits, RPD remains a complex procedure. It requires a significant learning curve and technical expertise on the part of the surgeon.

However, when PD is performed using a minimally invasive approach, the final specimen containing the tumor sometimes is removed following the reconstruction phase (including 3 anastomoses).

In this context, the surgical specimen goes through the phenomenon of ischemia and autolysis of the surgical specimen, which may lead to microscopic degradation of the tissue. This issue may be particularly relevant as it may have an impact on the final quality and oncological evaluation of the histological and oncological assessment.

As there is no previous literature on this topic, the aim of this study is to evaluate the impact of robotic surgery on the histological changes of the surgical specimen that occur during robotic PD.

After approval by the institutional review board of our Institution with identification number HCB/2022/0095, a search of the archival histopathology files was conducted for all pancreatic specimens collected at our hospital from January 2022 to March 2024.

All consecutive patients undergoing robotic PD for pancreatic, ampullary and biliary malignancies at our institution were included in this study. Patients with preoperative pancreatitis were excluded. Patients undergoing neoadjuvant treatment were also excluded. Patients undergoing RPD receiving conversion to open surgery were also excluded.

In our Center, pancreatic specimens are examined according to the protocols provided by the College of American Pathologists the guidelines from the College of American Pathologists and final reports are issued following the cancer protocol templates [10, 11].

Surgical procedure

Surgical procedure is performed in all patients according to center protocols and mitigation strategies are used in each case based on surgeon’s experience, as previously described [5, 12]. Pancreatic neck is divided by ultrasonic energy devices, in all cases.

In open procedures, once the specimen is completely detached from the superior mesenteric vein (SMV) it is send to the pathology Department. Contrary, in minimally invasive approach once the specimen is completely detached from the SMV it is kept in the abdominal cavity until the reconstruction is completed.

Surgical time is collected in all cases.

Specimen storage

All pancreatic specimens arriving before 5PM at Pathology Department undergo fresh examination, including orientation, measuring and identification of the relevant structures and margins. Pancreatic neck margin, uncinate margin, vascular groove area and common bile duct margin are then inked with different colors [11]. Anterior and posterior free surfaces are also inked. Fixation and harvesting are performed by letting the specimen be properly fixed in formalin for 24 hours. Nontumoral tissue sections from the pancreas and the adjacent organs are also included. Several images of the specimen in both fresh (before and after inking, bivalving and sectioning) and fixed states are also taken.

If the specimen is extracted after 5PM, to mitigate the activation of enzymes producing autolysis, samples are stored at 4°C to control cold ischemia until they can be examined the following day before undergoing formalin fixing. PD surgery is not performed on Friday to avoid long-term issues with degradation.

Ischemia time measurement

Both warm (WIT) and cold (CID) ischemia time were collected. Intraoperative warm ischemia was defined as the time from complete dissection of the posterior lamina to specimen extraction; this was determined by reviewing the surgical videos of each case included. Additionally, time to arrival at pathology department for fresh examination and inking, up to formalin storage was added as warm ischemic time: this time was calculated by reviewing the electronic records.

In case of specimen extraction after 5 PM, time of cold ischemia was added. It was defined as the time between cold storage of the specimen following extraction and the formalin storage following the inking at the pathology department on the next day.

Histopathological analysis

Quality of the pathological assessment was reviewed by two dedicated pathologists with large experience in pancreatic assessment and who were blinded to the surgical approach.

All slides of every case were assessed under light microscopy. Histologic features related to ischemic damage such as cytoplasmic eosinophilia, nuclear degeneration or nuclear absence with ghost outlines of cells, karyolisis and karyorrhexis were evaluated in neoplastic cells, pancreatic parenchyma including acinar and ductal cells, and duodenal epithelium. Ischemic changes were then semi-quantitative graded as absent (0), mild (1), moderate (2) and severe (3) depending on the extent of the changes [13].

Additionally, the Acinar/collagen/fat score was also determined as previously described. Briefly, the acinar cell, collagen and fat content were evaluated as a proportion of the total surface area of tissue on the slides comprising the pancreatic neck margin [14].

A final evaluation of histological assessment was provided on tumor grade, perineural invasion, lymphovascular invasion, number of total lymph nodes, metastatic lymph nodes, resection margin status and final pTNM.

Statistical analysis

All categorical data are presented as the number of cases and percentages. Chi-square and Fisher’s exact tests, when appropriate, were used to compare proportional data. Continuous nonparametric data were expressed as the median with interquartile range (IQR), while parametric data were expressed as the mean with standard deviation (SD). The Mann–Whitney U test was used for comparing nonparametric variables, and the t test was used for parametric continuous variables. For continuous variables without a standardized risk cut-off, receiver operating characteristics (ROC) curves were constructed, and the best cut-off values were determined as those showing the highest Youden’s index. Binary and linear regression analyses were performed to control for the effects of covariates on the clinical outcomes by including in the multivariate analysis all the variables that reached p values < 0.05 in the univariate analyses.

All the tests were 2-sided, and the threshold of significance was set at p < 0.05. Statistical analyses were performed using Statistical Package for Social Sciences software (IBM SPSS Statistics, version 27 for Macintosh; IBM Corp., Armonk, NY, USA).

Out of 102 robotic pancreatic resections, 60 patients fulfilled the inclusion criteria: 20 patients undergoing open PD without intraoperative warm ischemia and no cold ischemia, 17 patients undergoing robotic PD with cold ischemia, and 23 patients undergoing robotic PD with warm ischemia only. Specimen extraction was always performed following the reconstruction phase in all robotic PD, therefore prolonged warm ischemia was reported in all these cases.

The final histology were: PDAC (31), distal CCK (8), ampulla ADK (8), PNET (9), IPMN (3), duodenal ADK (1).

The baseline features of the patients included in this study are shown in table 1.

Table 1. Baseline features of patients. CI, cold ischemia; IQR, interquartile range.

	Open PD (n=20)	Robotic PD (n=23)	Robotic PD with CI (n=17)	P value
Age, years (IQR)	68 (49 - 73)	71 (59 - 78)	69 (66 - 76)	0.837
Gender, Male, n (%)	12 (60.0)	4 (17.4)	12 (70.6)	<0.001
ASA score ³3, n (%)	8 (40.0)	3 (13.0)	3 (17.6)	0.086
BMI, kg/m2 (IQR)	24 (21 - 27)	23 (20 - 26)	26 (22 - 34)	0.038
>1 comorbidity, n (%)	16 (80.0)	19 (82.6)	10 (58.8)	0.187
Indication (PDAC), n (%)	9 (45.0)	10 (43.5)	6 (35.3)	0.816
Operating time, minutes, (IQR)	276 (225 - 327)	393 (353 - 433)	516 (416 - 615)	<0.001

Ischemia time analysis

In all patients both warm (WIT) and cold (CIT) ischemia time were collected. WIT included intraoperative warm ischemia and postoperative warm ischemia (from specimen extraction to formalin storage). Median intraoperative WIT was 140 (120 - 155) minutes (all RPD patients). Median postoperative WI was 60 (52 - 65) minutes (all patients). Median total WIT was 182 min (OPD 57 min vs RPD 190 min vs RPD-CI 198 min; p<0.001). Median CID was 760 minutes (740 - 835), in specimens that were stored at 4ºC.

Pathological assessment

Ischemic damage in the pancreatic tissue and in the tumor was assessed (Table 3). Most of specimen with moderate or severe pancreatic or tumor ischemic damage belonged to RPD group undergoing cold storage. No difference was observed in terms of acinar score and pancreatic gland assessment.

Table 3. Ischemic damage of the surgical specimen. PD, pancreaticoduodenectomy; CI, cold ischemia.

Open PD

(n=20)

Robotic PD

(n=23)

Robotic PD with CI (n=17)

P value

Pancreatic Ischemic damage

Absent
Mild
Moderate
Severe

17 (85.0)

3 (15.0)

0 (0)

15 (65.2)

7 (30.4)

1 (4.3)

0 (0)

2 (11.8)

6 (35.3)

3 (17.6)

6 (35.3)

<0.001

Tumor Ischemic damage

Absent
Mild
Moderate
Severe

18 (90.0)

2 (10.0)

0 (0)

15 (62.5)

7 (30.4)

0 (0)

1 (4.3)

6 (35.3)

3 (17.6)

4 (23.5)

<0.001

Pancreatic assessment

Acinar score
Collagen score
Fat score

72 (35 - 93)

7.5

10 (5 - 25)

75 (65 - 90)

10 (5 - 20)

65 (57 - 87)

5.0

20 (10 - 30)

0.551

0.503

0.197

Pathological features related to tumor stage are shown in table 4.

Table 4. Pathological outcomes of the extracted specimens. CI, cold ischemia; T, tumor stage; N, nodal stage.

Open PD

(n=20)

Robotic PD

(n=23)

Robotic PD with CI (n=17)

P value

perineural invasion

lymphovascular invasion

number of total lymph nodes

metastatic lymph nodes

resection margin status (R0)

Tumor

pT1

pT2

pT3

pT4

PN0

pN1

pT2

15 (75.0)

14 (70.0)

23 (15 - 31)

2 (0 -4)

15 (75.0)

2 (10.0)

3 (15.0)

8 (40.0)

5 (25.0)

2 (10.0)

6 (30.0)

12 (52.2)

14 (60.9)

12 (9 - 26)

1 (0 - 2)

17 (73.9)

2 (8.7)

10 (43.5)

9 (39.1)

2 (8.7)

0 (0)

2 (8.7)

11 (47.8)

9 (39.1)

1 (4.3)

10 (58.8)

17 (10 - 25)

1 (0 - 2)

14 (82.4)

3 (17.6)

5 (29.4)

6 (35.3)

2 (11.8)

1 (5.9)

3 (17.6)

6 (35.3)

4 (23.5)

0.295

0.744

0.235

0.567

0.680

0.440

0.258

Assessment of surgical specimen histholological quality was also analyzed. There was no difference between groups when analyzing tumor size, perineurial invasion, lymphovascular invasion, lymph node assessment. Other features were poorly assessed in the group of RPD with CI without reaching statistical significance, table 5. Macroscopic and microscopic differences are shown in figures 1 and figure 2.

Table 5. Surgical specimen assessment quality. Specimens with good quality for different lithological features are noted.

	Open PD (n=20)	Robotic PD (n=23)	Robotic PD with CI (n=17)	P value
Histology, good quality, n (%)	20 (100)	23 (100)	16 (94.1)	0.276
Resection margin, good quality, n (%)	20 (100)	23 (100)	15 (88.2)	0.198
TNM assessment, good quality, n (%)	20 (100)	23 (100)	15 (88.2)	0.198
R category, good quality, n (%)	20 (100)	23 (100)	16 (94.1)	0.276

Univariate and multivariate analysis

Ischemic damage was grouped as follows: none and mild vs moderate and severe. Since cold ischemic time had very little difference between patients, it was analysed as a categorical variable (cold storage). ROC curves were constructed to determine cut-off values for BMI and total warm ischemia time.

The ROC curve showed an optimal BMI at 27 (AUC 80.5%, p=0.022; sensitivity and specificity of 71% and 79% respectively) and total WIT at 150 minutes (AUC 76.1%, p=0.023; sensitivity and specificity of 80% and 77% respectively).

Factors associated with ischemic changes in the normal pancreatic tissue and in the tumor were assessed by univariate and multivariate analysis. Cold storage was the only factor independently associated with ischemic damage. Results are shown in Table 6 and Table 7.

Table 6. Factors associated with pancreatic ischemic damage. Univariate and multivariate analysis for normal pancreatic tissue ischemia is shown. OR, Odds ratio; CI, confidence interval; ASA, American Society of Anesthesiologists Classification; BMI, body mass index, PDAC, pancreatic ductal adenocarcinoma

	Pancreatic tissue ischemic damage
Variables	Univariate analysis			Multivariate analysis
Variables	OR	95% CI	P value	OR	95% CI	P value
Male gender	14.684	1.722-125.239	0.014	15.702	0.847-290.968	0.064
ASA≥III	3.162	0.365-27.432	0.296
BMI>27	3.000	0.341-26.427	0.091
Cold storage	47.250	5.236-426.425	<0.001	57.848	3.358-996.610	0.005
PDAC	0.545	0.126-2.356	0.417
Intraoperative ischemia>150 min	9.000	1.918-42.236	0.005	2.077	0.150-28.759	0.584

Table 7. Factors associated with tumor ischemic damage. Univariate and multivariate analysis for humoral tissue ischemia is shown. Results from hierarchical logistic regression analyses on the association between the variables of interest and ischemic damage of pancreatic tissue. OR, Odds ratio; CI, confidence interval; ASA, American Society of Anesthesiologists Classification; BMI, body mass index, PDAC, pancreatic ductal adenocarcinoma

	Tumor tissue ischemic damage
Variables	Univariate analysis			Multivariate analysis
Variables	OR	95% CI	P value	OR	95% CI	P value
Male sex	10.33	1.183 - 90.256	0.035	5.920	0.577-60.711	0.134
ASA>III	2.33	0.262-20.792	0.448
BMI≥27	2.200	0.243-19.897	0.483
Cold storage	29.4	3.23-266.89	0.003	21.318	2.244-202.544	0.008
PDAC	0.818	0.177 - 3.792	0.798
Intraoperative ischemia>150 min	3.857	0.750-19.844	0.106

This is the first study to describe the effects of warm and cold ischemia on pancreaticoduodenectomy specimens after minimally invasive surgery. We were able to demonstrate cold ischemia can have a detrimental effect on the microscopic structure of pancreatic and peripancreatic tissue. Although we have not been able to show that the evaluation of the pancreatic specimen is really compromised, the macroscopic and especially the microscopic features of the specimen can certainly be damaged. This clearly affect the quality of the pathological evaluation of the tumor, especially in samples that have been stored at low temperatures.

Minimally invasive surgery for PD is increasing and may offer some potential benefits to patients compared to open surgery [6]. However, there is no previous literature analyzing the effect of warm ischemia time on the pancreatic specimen in minimally invasive procedures.

However, an accurate histopathological analysis of the specimen is crucial for determining the best post-operative treatment and assessing the patient's prognosis, as high-quality human tissue samples are the basis for diagnosing diseases and identifying therapies [10]. For the pancreas, ischemia is an almost inevitable factor in sampling due to its deep location and extensive anatomical structure [15]. In addition, the abundance of digestive enzymes in pancreatic tissue poses a major challenge to sample handling.

To date, the effect of cold ischaemia time (CIT) is well known in several organs. In breast cancer, hormone receptor expression decreases with increasing CIT, making it difficult to assess subtype classification [16]. In ovarian cancer, a CIT greater than 2 hours leads to poorer sample quality [17]. When analysing the effects of CIT at the cellular level, significant morphological changes occur during tissue degradation, including altered intensity of nuclear staining and loss of cell border definition. In addition, some cell surface receptors such as epidermal growth factor receptor (EGFR) are highly sensitive to CIT [18]. There are no reports in the pancreatic tissue. We showed that prolonged cold storage has a direct effect on developing moderate to severe ischemic changes in the pancreatic parenchyma by reducing cell viability. This important effect in pancreatic tissue compared to other organs is probably due to the presence of digestive enzymes. Some authors hypothesise that the timing also has negative effects on molecular characteristics, including nucleotide integrity, global gene expression, protein abundance and post-translational modifications [15]. On the other hand, ischemia also affects the viability of tumor cells in pancreatic neoplasms: this does not seem to prevent obtaining a definitive histopathological diagnosis, although it does reduce the possibility of performing more detailed analyses, such as translational studies.

Some authors have suggested that tissue handling methods may also influence the quality of pancreatic specimens [15, 19]. In our study, all samples were handled according to the same protocol, so this is unlikely to have a direct effect in our sample.

According to the literature and our results, avoiding cold storage would be necessary to improve the quality of surgical specimens, and if not possible at least a reduction of cold ischemia should be attempted. An earlier start of surgery should be promoted, especially during the learning curve or when high difficulty is expected.

Otherwise, the effect of WIT has not been well studied in the context of pathological specimen analysis. Previous reports on head and neck squamous cell carcinoma specimens have shown that ex vivo warm ischaemia time is an important determinant of tissue quality, which may explain the inconsistent results of biomarkers [20]. Otherwise, extensive studies have analysed the effect of WIT in solid organ transplantation, showing inferior outcomes when the organ is exposed to higher WIT [21]. Regarding WIT, our data suggest that intraoperative ischaemia may also have an effect on normal pancreatic tissue and tumour tissue. Some organisational efforts could be made to ensure the handling of the specimen once it has been removed from the patient. To date, some surgical groups harvest the specimen immediately after retroportal lamina dissection [22], but many groups harvest the specimen after the reconstruction phase, as doing so earlier could prolong the surgical procedure, force pneumoperitoneum exsufflation and robot redocking. According to our results, retrieval of the surgical specimen after complete detachment should be recommended in order to avoid an increase in warm ischemia. Some groups recommend the use of a Pfannenstiel incision with gel port placement for using it as assistance port and for specimen retrieval. In fact, following the results of our study, we changed our policy to immediate specimen extraction following the dissection phase.

Organisational issues are usually behind the cold ischaemia time, such as the time at which the surgical specimen is taken or the availability of staff in the pathology team. Therefore, CIT is usually long because it is associated with the collection of the specimen from the operating theatre after office hours. Therefore, the goal should be to eliminate cold ischaemia of surgical specimens by improving circulation. Our study shows that by avoiding cold ischaemia and making some changes to the surgical technique, we could significantly improve the quality of the specimen obtained by minimally invasive surgery. However, the final quality is likely to be inferior to that of specimens obtained by open surgery. There are several limitations to the study. It is a retrospective study, therefore the data used were originally measured for other purposes and may be inconsistent. Also, not all relevant factors may have been recorded. The sample size of the study is small, so we do not have evidence of the reproducibility of our findings, which would need to be validated in a larger cohort of patients. In addition, we were not able to assess whether poor histological assessment has an oncological impact on the patient; however, this would need to be studied for each histological subtype.

In conclusion, prolonged ischemia time, especially in case of cold storage, has a severe effect on the degradation of normal and tumour tissue. Although this does not affect tumour staging, it could clearly impair the possibility to perform molecular analyses.

Further studies are needed to validate our findings and the oncologic impact of our findings.

Ethics approval : Approval of the institutional review board of our Institution with identification number HCB/2022/0095 was obtained.

Informed Consent Statement: Patient consent was waived due to the retrospective nature of the study and the non-interference of the study with clinical management.

Consent for publication: All authors gave their consent for publication.

Availability of data and materials: No new data was created during this study.

Conflicts of Interest The authors declare no conflicts of interest.

Funding: This research received no external funding.

Authors' contributions: A.F conceptualized the work; A.F, C.G and M.C defined the methodology; C.G and I.A prepares the original draft; K.L and C.G curated the data, C.G and F.A did the formal analysis; A.F and M.C reviewed the draft writing; A.F supervised all the work. All authors have read and agreed to the published version of the manuscript.

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No competing interests reported.

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19 Jul, 2024
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18 Jul, 2024
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Effect of warm and cold ischemia on pancreaticoduodenectomy specimen following robotic pancreaticoduodenectomy.

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Abstract

Background

Methods

Results

Conclusions

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Introduction

Methods

Surgical procedure

Specimen storage

Ischemia time measurement

Histopathological analysis

Statistical analysis

Results

Discussion

Declarations

References

Additional Declarations

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Version 1