Int J Gastrointest Interv 2023; 12(3): 145-151
Published online July 31, 2023 https://doi.org/10.18528/ijgii230020
Copyright © International Journal of Gastrointestinal Intervention.
Ahmed Nasser1, Victoria Smith2, Niamh Campbell1, Michael Devin Rivers-Bowerman3, Ashley Elispath Stueck4, Andreu Francesc Costa3,5, Riley Arseneau4, Lauren Westhaver4, and Boris Luis Gala-Lopez2,5,*
1Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
2Department of Surgery, Dalhousie University, Halifax, NS, Canada
3Department of Radiology, Dalhousie University, Halifax, NS, Canada
4Department of Pathology, Dalhousie University, Halifax, NS, Canada
5Department of Microbiology & Immunology and Pathology, Beatrice Hunter Cancer Research Institute, QEII Health Science Centre, Dalhousie University, Halifax, NS, Canada
Correspondence to:*Department of Microbiology & Immunology and Pathology, Beatrice Hunter Cancer Research Institute, QEII Health Science Centre, Dalhousie University, 6-300 Victoria Bldg, 1276 South Park Street, Halifax, NS B3H 2Y9, Canada.
E-mail address: email@example.com (B.L. Gala-Lopez).
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Intraoperative blood salvage and autotransfusion (IBS) is considered safe in liver transplantation for hepatocellular carcinoma (HCC). However, little is known about the potential impact of the viable tumor burden on recurrence and survival. This study investigated whether the presence of viable HCC during transplantation with IBS impacted HCC recurrence and patient survival.
Methods: A retrospective study was conducted of liver transplants for patients with HCC in Atlantic Canada between 2005 and 2017. Information on locoregional treatment, IBS volume, and explant pathology was collected. Variables were analyzed to identify associations with HCC recurrence and patient survival via parametric and non-parametric tests. The Kaplan-Meier and log-rank tests were used to compare survival.
Results: Sixty-eight subjects were included. IBS was used in 44.1% of the patients, with a median volume of 711 mL. Radiographic total tumor volume correlated well with the actual tumor viable volume (TVV) (Pearson’s r = 0.82, P < 0.01), but was overestimated by 50% when compared to the actual tumor burden on explant pathology. HCC recurrence was observed in 6 patients, and IBS was used in 5. Patients receiving IBS also had more viable tumors, but not a greater TVV. Overall patient survival did not exhibit significant differences according to the presence of viable tumors, vascular invasion, or satellitosis.
Conclusion: IBS during liver transplantation was associated with significantly higher HCC recurrence in our limited series. However, the volume of viable HCC during the transplant procedure was not associated with any difference in tumor recurrence or patient survival.
Keywords: Carcinoma, hepatocellular, Liver transplantation, Operative blood salvage, Recurrence, Survival
Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancers and is the third leading cause of cancer-related death worldwide.1,2 The National Cancer Institute estimates that in 2016, 27,170 deaths in the United States were attributed to HCC. The World Health Organization has projected more than 1 million deaths due to HCC in 2030.3,4 HCC usually occurs due to chronic liver disease and cirrhosis, the causes of which vary across geographic regions due to differences in lifestyle, cultural practices, and genetic factors.5–7 Alcohol-induced cirrhosis and hepatitis C virus are the etiologies in most patients requiring liver transplantation (LT) in the West, while hepatitis B virus remains the leading cause of cirrhosis in the East.8 The prognosis for HCC can be poor, and treatment options include surgical resection, systemic therapy, locoregional treatment (LRT) and immunotherapy. These modalities can prolong survival and potentially downstage inoperable HCC.7
Orthotopic liver transplant is considered the best therapeutic approach for selected patients with underlying liver cirrhosis and non-resectable HCC.2,9 The transplant procedure is a complex surgical procedure in which intraoperative hemorrhage remains a major complication despite improvements in the management of coagulation disorders associated with liver dysfunction.10,11 Due to the risk of blood loss, intraoperative blood salvage and autotransfusion (IBS) are frequently incorporated into LT. It has been estimated that IBS is used in more than 85% of all LTs worldwide.2 This technology reduces allogeneic red cell transfusion when blood loss may exceed 500 mL in adult patients. Relative contraindications to IBS include contamination of the aspirated blood with bowel contents, infection, or tumor cells.12 During its introduction, there was significant concern about the potential to increase cancer recurrence via the dissemination of malignant cells,13 as most cases of metastatic disease result from tumor cells detaching from the primary cancer and spreading to distant sites.13,14 However, multiple studies have demonstrated that IBS is safe during surgery for HCC and other malignancies.10,15,16
To date, few studies have analyzed the impact of the actual tumor burden of HCC on cancer recurrence after LT when IBS is used during the transplant procedure. This study investigated whether using IBS during LT in patients with viable HCC was associated with higher cancer recurrence and poorer overall survival.
This retrospective study included consecutive adult patients undergoing deceased-donor LT for HCC at our hospital, a regional tertiary care referral and transplant center, between 2005 and 2017. Our Research Ethics Board approved the study (file number: 1025307), which was conducted following the Declaration of Helsinki. Patients that were included had signed consent forms to participate in the research. Clinical information was collected from a prospectively maintained database that included pre-transplant, intraoperative, and post-transplant data. All participants had a minimum 3-year follow-up. Any subject with mortality within 30 days of LT was excluded from the study.
Pre-transplant imaging (computed tomography [CT] and magnetic resonance imaging [MRI]) was reviewed independently by two board-certified radiologists (MRB and AC), followed by a consensus to establish a unified assessment of tumor viability before and after LRT. Radiographic total tumor volume (TTV) was calculated as the sum of the individual volume of each viable tumor, assuming that the tumor had a spherical shape, as previously reported.17 The volume (
As previously described, IBS was carried out using the CATSmart Continuous Autotransfusion System (Fresenius Kabi AG).18 Briefly, blood in the surgical field was suctioned into anticoagulated lines with either heparinized saline or acid-citrate dextrose. This mixture was filtered and collected into a reservoir, where red blood cells were separated from whole anticoagulated blood through centrifugation. Red blood cells were finally washed with normal 0.9% saline and then pumped into a bag, ready for re-infusion into the patient (Fig. 1).12 The decision to use IBS during LT was at the discretion of the surgical team and was not randomized. Patients were divided into two groups according to the use of IBS during their transplant procedure.
As previously described,19 patients usually receive a treatment protocol targeting interleukin-2, consisting of a combination of basiliximab, tacrolimus, mycophenolate, mofetil, and steroids. Patients were typically switched to sirolimus for long-term maintenance.
Explant pathology slides for each patient were independently reviewed by a board-certified hepatopathologist (AS). The total number of lesions was documented, and each tumor's percentage of necrosis was calculated. Three-dimensional measurements were performed, and the actual tumor viable volume (TVV) was calculated as the sum of each viable nodule's individual volume, assuming an ellipsoid, as previously reported.20 The volume (
Categorical variables were compared using Pearson’s chi-square test. Continuous variables were expressed as mean ± standard derivation and analyzed using the Student’s
Between 2005 and 2017, 77 patients underwent deceased-donor LT for HCC. Of these, nine were excluded, four due to insufficient follow-up and five due to in-hospital mortality. As a result, 68 subjects were included in the study and divided into IBS (
Table 1 . Patients’ Baseline Characteristics.
|Age (yr)||64.2 ± 6.3||66.7 ± 5.5||0.10|
|HBV||2 (6.7)||3 (7.8)|
|HCV||16 (53.3)||23 (60.5)|
|Alcohol||4 (13.3)||5 (13.2)|
|NASH/NAFLD||3 (10.0)||2 (5.3)|
|Others||5 (16.7)||5 (13.2)|
|Natural MELD at transplant (point)||8 (5–30)||10 (5–21)||0.48|
|Locoregional bridge therapy||23 (76.7)||33 (86.8)||0.344|
|TTV (cm3)||15.3 ± 17.6||11.5 ± 15.1||0.14|
|AFP (μg/L)||10.8 (1.0–342.0)||14.6 (2.0–3,395.0)||0.53|
|HCC recurrence||5 (16.7)||1 (2.6)||0.03*|
Table 2 . Intraoperative Hematologic Parameters.
|Platelet count (×109/L)||99.67 ± 62.2||100.2 ± 48.5||0.97|
|Platelet volume (fL)||10.8 (7.6–3.2)||9.8 (7.0–13.2)||< 0.01|
|Packed red cell volume (mL)||582.5 (0–8,925.0)||2,100.0 (0–26,250.0)||< 0.01|
|IBS volume (mL)||711.0 (75.0–5,200.0)||-||-|
Explant pathology analysis revealed that 56 (82.3%) study subjects had viable HCC. Of these, 44 (78.6%) had received bridging LRT. Only 11 patients (19.6%) receiving LRT had complete tumor necrosis (TVV = 0 cm3). Patients in the IBS group had a median of 2 (IQR, 1–14) viable tumors versus 1 (IQR, 1–4) in the non-IBS group (
Table 3 . Histopathologic Tumor Characteristics.
|Patients with viable tumors||21 (70.0)||35 (92.1)||0.05|
|Number of viable nodules||2 (1–14)||1 (1–4)||< 0.01|
|Size of largest viable nodule (cm)||2.8 (0.9–7.1)||2.7 (1.2–6.0)||0.38|
|TVV (cm3)||8.7 ± 13.0||5.7 ± 8.9||0.32|
|Vascular invasion||21 (70.0)||26 (68.4)||0.89|
|Satellitosis||9 (30.0)||10 (26.3)||0.79|
HCC recurrence was documented in 6 (8.9%) patients. Of these, 5 (83.3%) received IBS (5 out of 29 [17.2%] within the IBS group), and 1 (16.7%) in the non-IBS group (1 out of 38 [2.6%] within the non-IBS group) (
Table 4 . Summary of Six Patients Exhibiting Hepatocellular Carcinoma Recurrence after Liver Transplantation.
|ID||LRT||TTV (cm3)||AFP (μg/L)||IBS||TVV (cm3)||Vascular invasion||Satellitosis||TTR (mo)||Survival (mo)||Status|
No significant differences in patient survival were found between the IBS and the non-IBS group (log-rank,
LT is the preferred treatment for patients with early-stage HCC and liver cirrhosis. In the last decade, the proportion of cases of HCC undergoing LT has tripled, and HCC has become the leading indication for transplantation.21 Despite strict selection criteria, HCC recurrence still takes place in about 15% to 20% of these patients.22,23 Debate has continued for years about the intrinsic risk of performing IBS in cancer patients due to the theoretical risk of increased recurrence.13 IBS is frequently used in LT, which is often performed in a setting of portal hypertension, intra-abdominal varices, and clotting dysfunction associated with liver failure.2,11,24 The surgery is also highly complex, involving major blood vessel dissection, which increases the risk of potential hemorrhage and extensive allogenic blood transfusion.25,26 Numerous studies have demonstrated that IBS had no significant impact on cancer recurrence or patient survival.13,16,27–29 However, there is a paucity of data in the literature regarding the potential impact of the viable tumor burden on long-term results. Our study demonstrated that IBS could be safely used without severely impacting the outcomes after LT.
In our series, IBS was used in 43.3% of patients, significantly reducing the required transfusion volume of allogeneic blood products. Transfusions can be lifesaving; however, they carry a host of possible life-threatening reactions such as acute lung injury, metabolic derangements, circulatory overload, sepsis, hemolysis, anaphylaxis and, more rarely, graft-versus-host reaction.26 Since donated blood is also a scarce commodity, the use of IBS may be a feasible option in some cases.2 Thus, IBS is beneficial not only because it is cost-effective, but also because it prevents the deleterious reactions associated with allotransfusion.24
Platelets have been reported to interact with HCC cells and alter their microenvironment, promoting progression, recurrence, and metastasis.30,31 However, the real impact of platelets remains unclear, as multiple publications have reported thrombocytopenia to be both detrimental and advantageous to tumourigenesis.32 In this series, we recorded the platelet count and the mean platelet volume at the time of LT. We observed that pre-transplant platelet volume was significantly higher in the IBS group (
Overall, this cohort had a significant correlation between radiographic TTV and pathologic TVV. Nonetheless, we observed a 50% overestimation of the radiological tumor burden with respect to the actual viable HCC volume found on explant analysis. This likely resulted from the spherical volume calculation employed in the radiographic analysis, whereas the pathologic analysis used a more accurate ellipsoid assumption. Indeed, ellipsoid tumoral morphology was recently reported as a better predictor of cancer recurrence and hence, a more objective criterion for HCC patient selection for transplantation.20 Tumor necrosis post-LRT may also have been underestimated by CT/MRI, contributing to increased radiographic TTV relative to pathologic TTV.
Cancer recurrence is the main determinant of long-term success in HCC patients after LT. Our study observed a lower recurrence rate than has been reported in the literature.20,21 One of our main study variables was the presence of viable tumors on explant pathology, as this is traditionally associated with poor outcomes.34,35 In our series, subjects receiving IBS had more viable tumors on explant but did not have a larger TVV. Despite the presence of viable HCC, there was no significant difference in cancer recurrence or the survival of study participants. This observation also held true when patients underwent IBS and was independent of the existence of macro- and micro-vascular invasion or satellitosis, which supports previous reports concluding that this technology is safe in the field of transplantation.10,16,36 Interestingly, five out of six patients with cancer recurrence in this series had received IBS, but only two of those subjects had viable tumors at transplant. The one patient with recurrent HCC in the non-IBS group had a significant tumor burden, as shown by a TTV and TVV of 9.1 cm3, an AFP level of 1,786 μg/L, and the presence of vascular invasion and satellitosis. Finally, we analyzed the impact of the actual viable tumor burden on survival by stratifying TVV in different ranges. Although we observed significantly lower survival in the TVV = 5–10 cm3 stratum, this was not consistent in the group with a larger (> 10 cm3) viable tumor burden, and hence, difficult to interpret. Most likely, this finding can be attributed to a small sample size. A larger multi-center dataset may provide a more realistic answer to these questions.
New technologies may also provide alternative ways to assess HCC viability during liver transplants. One such technology is the quantification of circulating cell-free DNA (cfDNA, also known as liquid biopsy), which has shown clinical value in the field of oncology for detecting early recurrence.4,37 Although still experimental, combining IBS with cfDNA as a real-time estimator of circulating HCC cells could be an exciting area of research. Another attractive avenue of investigation would be microarray analysis and next-generation sequencing in IBS fluids to quantify gene transcription and discover genes and gene modifiers associated with HCC recurrence. Increasing clinical evidence suggests that this technique may enhance the precision of cancer prognostication in these patients.38,39
This study has addressed the concern of increased HCC recurrence and decreased survival due to the use of IBS during LT through an analysis of the real tumor burden. Although we found a statistically significantly higher risk of cancer recurrence in the IBS group, it was not linked to HCC viability. We believe our results are inconclusive due to the limited sample size, the retrospective nature of the study, and the lack of randomization in the use of IBS. Still, these findings certainly prompt larger prospective multi-center studies, in which more accurate modern technology can also be incorporated to measure circulating HCC cells at the time of transplant.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
This research has been presented at the Department of Surgery 2021 Research Symposium, Dalhousie University.
This research was supported by the Department of Surgery at Dalhousie University.
No potential conflict of interest relevant to this article was reported.
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