Introduction
Despite modern data on the possibility of R1 resection in surgical treatment of hepatoblastoma in exceptional cases, total resection is still the “gold standard” for these patients [1]. Among other things, hepatoblastoma as an embryonic tumor is characterized by fast growth that inevitably affects the details of liver resection. Extended resection is required in most cases. One of the most common procedures is extended hemihepatectomy. Children with POST-TEXT III-IV hepatoblastoma require a maximum permissible resection when liver transplantation is considered as an alternative option. These procedures may be followed by post-resection hepatic failure and various methods of surgical prevention have been proposed. Since the combined treatment of hepatoblastoma and some other liver malignancies implies timely adjuvant chemotherapy, the ALPPS procedure ensuring the earliest regenerative hypertrophy of the future liver remnant is the most attractive surgery. Some national and foreign authors reported various volumetric characteristics as indications for ALPPS. Nevertheless, liver remnant volume of 25% is considered the most common value [2—7]. At the same time, assessment of functional reserve of future liver remnant has not been described in pediatric practice while this approach became very popular in adult surgical hepatology and influenced the evolutionary trajectory of ALPPS procedure. Considering traumatic nature of this surgery and risks of complications after the first surgical stage, analysis of functional reserve of the future liver remnant in children seems to be an urgent objective. Solving of this problem can call into question advisability of such interventions in the treatment of liver tumors in children [8].
The objective was to analyze the initial data on future liver remnant volume and its function in children with liver tumors.
Material and methods
Depending on histological type of liver tumor, most patients received neoadjuvant chemotherapy in accordance with the approved treatment protocol (SIOPEL for hepatoblastoma and hepatocellular cancer, CWS-2009 for embryonic sarcoma, EU-RHAB for rhabdoid tumor). Planning the forthcoming surgery, we considered primary tumor spread to obtain resection margin free of tumor cells and pathomorphosis after neoadjuvant chemotherapy. Anatomical liver resections via open and laparoscopic approaches were preferred.
Evaluation of liver volumetric characteristics
Preoperative examination included CT volumetry with assessment of total liver volume (TLV)), future liver remnant volume (FLR-V), FLR/TLV ratio and remnant liver volume/body weight ratio (RLV-BWR) [9—12]. FLR/TLV > 25% determined sufficient volume of the future liver remnant as the most common value in adult and pediatric liver surgery. RLV-BWR ≥ 0.5 was considered as sufficient value.
99mTc-Bromesida hepatobiliary scintigraphy
Future liver remnant function (FLR-F) was quantified during 99mTc-Bromesida hepatobiliary scintigraphy. This technique was introduced at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology and described earlier [13]. According to the literature, risk of postoperative hepatic failure is minimal in adults with a threshold value ≥ 2.7 %/min/m2 obtained during 99mTc hepatobiliary scintigraphy (99mTc-Mebrofenin) [14].
Postoperative period
In postoperative period, we assessed liver function considering laboratory data and excluded postoperative liver failure. The latter was classified in accordance with the ISGLS grading system (International Study Group of Liver Surgery) criteria [15, 16].
Results
Extended liver resections for various liver neoplasms were performed in 58 patients aged 2 — 208 months (median 26 months) for the period from June 2017 to March 2021. Patients underwent combined treatment for hepatoblastoma, hepatocellular cancer, embryonic liver sarcoma, rhabdoid liver tumor, liver rhabdomyosarcoma, cholangiocellular cancer and metastatic lesions. Isolated surgical treatment was carried out in 1 patient with hepatocellular cancer, 1 patient with calcifying nodular stromal-epithelial tumor, as well as patients with benign liver neoplasms (mesenchymal hamartoma, focal nodular hyperplasia, epithelioid angiomyolipoma, hemangioma). One patient with nephroblastoma of the right kidney complicated by thrombosis of inferior vena cava, left renal and right hepatic veins and right atrium underwent on-pump right-sided nephradrenalectomy with right-sided hemihepatectomy, extirpation of inferior vena cava and right atrium repair. Characteristics of patients are shown in Table 1.
Table 1. Characteristics of patients
|
Variable (n=58) |
n (%) |
|
Age, months |
26 (2—208) |
|
Gender |
|
|
Male |
47 (81%) |
|
Female |
11 (19%) |
|
Body mass, kg |
Average 18.5 (4.1—76) |
|
Tumor |
|
|
Hepatoblastoma |
35 (60%) |
|
Hepatocellular cancer |
6 (10.2%) |
|
Embryonic liver sarcoma |
7 (12.2%) |
|
Malignant germ cell liver tumor (yolk sac tumor) |
1 (1.8%) |
|
Intrahepatic cholangiocarcinoma |
1 (1.8%) |
|
Focal nodular hyperplasia |
3 (5.2%) |
|
Liver hemangioma |
3 (5.2%) |
|
Calcifying nodular stromal-epithelial tumor |
1 (1.8%) |
|
Liver angiomyolipoma |
1 (1.8%) |
|
Intraoperative data |
|
|
Surgery time, min |
350 (47—710) |
|
Blood loss, ml |
150 (0—9000) |
Surgeries
Surgical interventions, as well as volumetric and functional characteristics of the future liver remnant are shown in Table 2.
Table 2. Surgical interventions. Medians of FLR/TLV ratio (FLR-V, %) and functional reserve of the future liver remnant (FLR-F (%/min/m2) depending on the type of liver resection
|
Surgery |
n |
Remnant liver segments |
FLR-V, % |
FLR-F, %/min/m2 |
|
Right-sided hemihepatectomy |
9 |
SI, II, III, IV |
52.8 (44—76.5) |
12.2 (6.1—18.9) |
|
Left-sided hemihepatectomy |
4 |
SI, V—VIII |
62.8 (56.6—84) |
27.7 (10—30) |
|
Mesohepatectomy |
5 |
SI, II, III, VI, VII |
60 (41—91.4) |
8.8 (4.53—20.7) |
|
Extended right-sided hemihepatectomy |
23 |
SI, II, III |
35 (16.5—53.3) |
7.5 (1.8—18.7) |
|
Two-stage extended right-sided hemihepatectomy (ALPPS) |
1 |
SI, II, III |
21.5 (before stage 1) 33 (after stage 1) |
5.7 (before stage 1) 7.8 (after stage 1) |
|
Two-stage extended right-sided hemihepatectomy (ALPPS) |
1 |
SI, II, III |
30 (before stage 1) 77 (after stage 1) |
2.1 (before stage 1) 16.5 (after stage 1) |
|
Extended left-sided hemihepatectomy |
12 |
SVI, VII |
41.2 (29—66) |
13.8 (4.4—31.2) |
|
Segmentectomies |
3* |
Except for resected segments |
64.5 (63—67) |
16 (4.55—16.01) |
Note. * one patient underwent simultaneous caudate lobectomy and double segmentectomy 5, 6. Two patients underwent anatomical triple segmentectomy 4b, 5, 6. Considering the number of resected segments, we classified surgery as an extended liver resection.
Fifty-eight patients underwent extended liver resections, i.e. resection of 3 or more anatomical segments. Extended hemihepatectomies as the largest resections regarding the volume of excised liver parenchyma made up 64% (n = 37). A large volume of excised liver parenchyma was also observed in patients undergoing resections of central segments combined with other segmentectomies (n = 6, 10%). Analysis of volumetric characteristics of the liver remnant and its functional reserve in extended liver resections was the most interesting (Table 3).
Table 3. Volumetric and functional values of liver and its future remnant before extended resections (n=59)
|
Indicator |
Median number series |
|
TLV, ml |
442 (111—1921) |
|
FLR, ml |
194 (30—1099) |
|
FLR/TLV, % |
44.5 (16.5—91.4) |
|
RLV-BWR |
1.5 (0.4—3.8) |
|
Hepto-biliary scintigraphy (FLR-F), %/min/m2 |
10.14 (1.8—30) |
Relationship of volumetric and functional characteristics of FLR
Considering the accepted threshold values of volume (25%) and functional reserve (2.7 %/min/m2) of the future liver remnant, it is obvious that the greatest risk of post-resection liver failure should be in patients with decrease of both indicators. However, there were no similar cases (Fig. 1).
Distribution of volumetric (FLR-V) and functional (FLR-F) indicators of the future liver remnant after extended liver resections (n=58).
Note. FLR-V and FLR-F are indicated after the 1st stage of ALPPS.
○ — patients with FLR-F below the threshold value undergoing liver resection
○ — patients with FLR-V below the threshold value undergoing liver resections.
○ — patients with sufficient FLR-V and FLR-F undergoing liver resection.
In our sample, post-resection liver failure occurred in 2 patients (Table 4). None of the other 56 patients had liver failure.
Table 4. Characteristics of patients with insufficient volume and function of the future liver remnant
|
Patient |
Age, months |
Body weight, kg |
Surgery |
FLR-V, % |
FLR-F, %/min/m2 |
RLV-BWR |
SGLS grade of liver failure |
|
1 |
23 |
11.5 |
eRHHE (ALPPS) |
21.5 (before stage 1) 33 (after stage 1) |
5.7 (before stage 1) 7.8 (after stage 1) |
1.4 (before stage 1) 2.2 (after stage 1) |
No |
|
2 |
15 |
8.5 |
eRHHE, segmentectomy 1, atypical resection S2 |
19.8 |
13.8 |
1.9 |
No |
|
3 |
43 |
12.9 |
eRHHE |
21 |
13.6 |
0.8 |
No |
|
4 |
27 |
14.3 |
eRHHE, segmentectomy 1 |
16.5 |
4.78 |
0.4 |
Grade A |
|
5 |
158 |
36.6 |
eRHHE |
43 |
1.8 |
0.9 |
Grade B |
|
6 |
3 |
4.1 |
eRHHE (ALPPS) |
30 (before stage 1) 77 (after stage 1) |
2.1 (before stage 1) 16.5 (after stage 1) |
0.7 (before stage 1) 3.5 (after stage 1) |
No |
Note. eRHHE — extended right-sided hemihepatectomy.
Discussion
Fast growth of liver malignancies and their dimensions often determine the need for extended liver resections in children. However, another feature of pediatric patients is predominant stability of key indicators affecting development of post-resection liver failure (Table 3). Significant differences in TLV, FLR-V, their ratio, as well as RLV-BWR and FLR-F from those in adults may be associated with absent diffuse liver lesions, low hepatic toxicity of chemotherapeutic drugs used in most current protocols. Moreover, children have significantly higher reparative potential of liver.
There are no literature data on post-resection liver failure in children. Nevertheless, the future liver remnant volume < 25% is considered to be an indication for surgical prevention of liver failure including ALPPS procedure [8].
Information on liver failure in children who underwent liver resection is absent in the literature. Nevertheless, the volume of the future liver remnant of less than 25% is considered an indication for surgical prophylaxis of liver failure, including ALPPS surgery [8]. The rarity of indications for these interventions is clearly demonstrated in this manuscript and Table 2.
In our sample, extended right-sided hemihepatectomies made up 43%. Among these patients, we would like to emphasize those with low FLR-V accompanied by normal functional characteristics of liver. This group included all patients with the future liver remnant volume < 25% (patients 1—4) (Table 4). Of these, only the first one with FLR-F higher than the allowable value underwent ALPPS procedure. Others underwent single-stage extended liver resections. This circumstance is explained by the fact that the first patient underwent ALPPS surgery at initial stage of hepatobiliary scintigraphy research.
On the contrary, functional reserve of the future liver remnant was below the threshold value in patients 5 and 6 with sufficient volumetric characteristics (Table 4). Post-resection liver failure grade B occurred only in the 5th patient. There was the largest intraoperative blood loss in this patient. This fact together with low functional reserve of the future liver remnant could contribute to liver failure. Considering higher sensitivity of functional characteristics of the future liver remnant, we performed ALPPS surgery in the 6th patient with sufficient FLR-V (30 ml) and favorable postoperative outcome.
The 4th patient deserves a special attention. This one with extremely low volume of the future liver remnant (16.5%) and high quantitative indicators obtained during scintigraphy (almost 2 times higher than the accepted thresholds for adults) underwent a single-stage surgery. Postoperative laboratory data were classified as ISGLS grade A without clinically significant disorders.
Conclusion
Considering initial data on liver functional reserve obtained during 99mTc hepatobiliary scintigraphy in children with liver tumors, we can make the following conclusions:
1. Future liver remnant function is the most sensitive method to predict post-hepatectomy liver failure in children compared to volumetric characteristics of the future liver remnant and their relation to the patient's body weight.
2. Threshold FLR-V in children is below 25% and probably below 16.5%.
Further study of sensitive indicators of volume and function of the future liver remnant is needed to determine new indications for two-stage liver resections in children.
The authors declare no conflicts of interest.