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Journal of Pediatric Surgery
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Journal of Pediatric Surgery
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Hepatic Metastasectomy in Pediatric Patients: An Observational Study*
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Andrew M. Fleming a, b, Sara A. Mansfield a, b, Tim Jancelewicz a, b, Ankush Gosain a, b, James W. Eubanks III a, b, Andrew M. Davidoff a, b, Max R. Langham Jr. a, b, 1, Andrew J. Murphy a, b, 1, *
a St. Jude Children’s Research Hospital, Department of Surgery, Memphis, TN, USA
b The University of Tennessee Health Science Center, Department of Surgery, Memphis, TN, USA
ARTICLE INFO
Article history: Received 7 October 2023 Accepted 11 October 2023
Keywords: Germ cell tumor Wilms tumor Neuroblastoma Liver metastases
ABSTRACT
Background: The role of hepatectomy for metastatic disease in children is controversial. Rationales include potential cure, obtaining a diagnosis, and guiding chemotherapy decisions. This study examines the safety and utility of hepatic metastasectomy for children at a single institution.
Methods: After IRB approval (#22-1258), medical records were reviewed from 1995 to 2022 for children undergoing hepatic metastasectomy. En-bloc hepatectomies during primary tumor resection were excluded.
Results: Hepatic metastasectomy was performed in 16 patients for a variety of histologies. Median pa- tient age was 12.2 years [IQR 6.9-22.6], and 13/16 patients were female (81 %). Number of hepatic metastases ranged from 1 to 23 and involved between 1 and 8 Couinaud segments. Anatomic resections included 4 hemihepatectomies and 1 sectionectomy. All other resections were nonanatomic. 3/6 re- sections for germ cell tumor (GCT) revealed only mature teratoma, driving adjuvant therapy decisions. When indicated, median time to adjuvant chemotherapy was 19 days [IQR 11-22]. No patients had Clavien-Dindo Class III or higher perioperative morbidity. Three patients (1 GCT, 1 adrenocortical car- cinoma (ACC), and 1 gastric neuroendocrine tumor (GNET) experienced hepatic relapse. The patients with relapsed GCT and GNET are alive with disease at 17 and 135 months, respectively. The patient with ACC died of disease progression and liver failure. One patient with Wilms tumor experienced extrahe- patic, retroperitoneal recurrence and died. With a median follow-up of 38 months, 10-year disease- specific and disease-free survival were 77 % and 61 %, respectively.
Conclusions: Hepatic metastasectomy can be accomplished safely in children, may guide adjuvant therapy decisions, and is associated with long-term survival in selected patients.
Level of Evidence: Level IV.
Type of Study: Treatment Study, Case series with no comparison group.
@ 2023 Elsevier Inc. All rights reserved.
Abbreviations: NB, Neuroblastoma; WT, Wilms Tumor; GCT, Germ Cell Tumor; NET, Neuroendocrine Tumor; GNET, Gastric Neuroendocrine Tumor; SPN, Solid Pseudopapillary Neoplasm of the Pancreas; DSS, Disease-Specific Survival; DFS, Disease-Free Survival.
* Presented at the British Association of Paediatric Surgeons (BAPS) 69th Annual International Congress, Bruges, Belgium.
* Corresponding author. Surgery, St. Jude Children’s Research Hospital, MS 133, Room IA2305, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA. Tel .: +901 595 2911; fax: +901 595 2207.
E-mail address: andrew.murphy@stjude.org (A.J. Murphy).
1 These authors contributed equally to this work and should be denoted as co- senior authors.
1. Introduction
Cancer is the leading cause of disease-related death in children and adolescents in the United States [1]. Common extracranial malignant solid tumors in children include neuroblastoma (NB), rhabdomyosarcoma, Wilms tumor (WT), germ cell tumor (GCT), and osteosarcoma [2-6] A subset of pediatric solid tumor patients will present with distant metastatic disease [7,8]. Risk stratification schemas and therapeutic strategies for children with advanced malignancies are cancer type- and site-specific and based on multi- institutional consensus data [9-12]. The implementation of meta- stasectomy for advanced pediatric malignancies is evolving with improvements in systemic chemotherapy and surgical technique [8,13,14].
Despite landmark advances in the management of hepatic me- tastases in adult patients, even the incidence of liver metastases in pediatric cancer remains unknown [6,15,16]. Previous estimates of the incidence of hepatic metastases are 20-30 % in patients with NB and 10-20 % in patients with WT, with data for other pediatric malignancies extrapolated from adult populations [6]. Recent data support the use of complex local control strategies for patients with primary hepatoblastoma when no evidence of disease can be attained [13]. However, the utility of hepatic resection for non- hepatic solid tumors with metastases to the liver is poorly defined in children [6,17]. The rationale for hepatic resection in this setting includes the potential for cure, obtaining tissue for a diagnosis, and guiding future chemotherapy decisions [17,18]. This study in- vestigates the safety and efficacy of hepatic metastasectomy for pediatric cancer patients at a single institution.
2. Patients and methods
A retrospective cohort analysis was performed for patients who underwent hepatic metastasectomy for advanced solid tumors at a single center between 1995 and 2022. The Institutional Review Board of St. Jude Children’s Research Hospital approved this study (IRB 22-1258), which was performed in accordance with federal law. This analysis was performed and reported according to the Strengthening the Reporting of Observational Studies in Epidemi- ology (STROBE) guidelines [19].
2.1. Setting, patients, and data sources
Patients within the current analysis were treated at St. Jude Children’s Research Hospital in Memphis, Tennessee. All patients who underwent hepatic metastasectomy between 1995 and 2022 were identified within the electronic medical record. Four patients with local extension who underwent en-bloc hepatectomy during resection of their primary tumor were excluded from analysis. Histopathologic examination of metastasectomy specimens was performed by board-certified pediatric pathologists specializing in pediatric malignancies. All patients were followed in a multidisci- plinary pediatric oncology clinic pre- and post-operatively. Identi- fication of disease persistence or relapse was performed by multidisciplinary treatment teams and was based on radiographic and/or laboratory findings depending on the primary malignancy
Hepatectomy for Non-Hepatic Malignancy N=22
En-Bloc Resection During Removal of Primary Tumor N=4
Not Part of En-Bloc Resection N=18
Non-Therapeutic Liver Biopsy Only N=2
Curative-Intent Hepatic Metastasectomy N = 16
treated. Details of the patient selection process are included in the patient selection flow diagram in Fig. 1.
The primary outcome of interest was disease-specific survival (DSS). The secondary outcomes of interest were perioperative morbidity and disease-free survival (DFS). Each patient chart was used to abstract data regarding patient characteristics (age, sex, race), disease characteristics (primary histology, disease synchro- nicity, number of hepatic metastases, number of Couinaud seg- ments involved), treatment strategies (resection performed, operative time, blood loss, use of radiofrequency ablation (RFA), use of adjuvant chemotherapy, time to continuation of adjuvant chemotherapy, receipt of adjuvant radiation), histopathology (presence of viable metastatic disease, maturity of teratoma if GCT primary, percent necrosis if GCT primary), and outcomes (periop- erative morbidity, grade of perioperative morbidity, perioperative mortality, disease progression, disease relapse, time to diseases progression/relapse, site of relapse, length of follow-up, DFS and DSS).
2.2. Statistical analysis
Statistical analyses were performed using GraphPad PRISM version 9.5.0 for macOS GraphPad Software, San Diego, California USA, www.graphpad.com. Normality of continuous data was determined using the Kolmogorov-Smirnov test. Normally distributed continuous data were reported as means and standard deviations (SD), and non-normally distributed continuous data were reported as medians and interquartile ranges (IQR). Time-to- event analyses were performed using the Kaplan-Meier method.
3. Results
3.1. Patient and tumor characteristics
After applying exclusion criteria, 16 patients were identified for analysis (Table 1). Primary histologies included GCT (n = 6), WT (n = 4), NB (n = 2) ACC (n = 1), gastric neuroendocrine tumor (GNET) (n = 1), osteosarcoma (n = 1), and solid pseudopapillary neoplasm of the pancreas (SPN) (n = 1). The majority of patients were female (13/16, 81 %), and the median patient age was 12.2 years [IQR 6.9-16.6 years]. The number of hepatic metastases ranged from 1 to 23 distinct lesions. Patients had between 1 and 8 Couinaud segments involved by disease (Fig. 2). Hepatic metastases were present at diagnosis in 50 % of patients analyzed, while the other 50 % of patients presented later with metachronous hepatic metastases.
3.2. Management of hepatic metastases
Multidisciplinary management of hepatic metastases and the rationale for resection varied by primary tumor histology and in- dividual patient disease course. Rationales for resection of GCT liver metastases included curative intent, determining response to sys- temic therapy via tumor necrosis, identification of residual imma- ture teratoma, and symptomatic treatment of growing teratoma syndrome. All other liver metastases were resected with intention to cure.
Anatomic resections included 4 hemihepatectomies, and 1 sectionectomy (segments II and III). All other resections were non- anatomic. For patients who underwent hepatectomy at a separate operation from their index resection, median operative time was 318 min [IQR 242-389 min] and median estimated blood loss was 375 mL [IQR 200-650 mL]. The patient with GNET underwent radiofrequency ablation of additional unresected liver lesions while undergoing hepatic metastasectomy.
| Age, Years | Sex | Histology | Number of Hepatic Metastases | Number of Segments Involved | Resections Performed | Hepatic Relapse | Follow Up, months | Vital Status |
|---|---|---|---|---|---|---|---|---|
| 16.2 | F | Germ Cell Tumor | 4 | 5 | Nonanatomic | No | 79 | NED |
| 18.3 | F | Germ Cell | 1 | 4 | Hemihepatectomy | No | 40 | NED |
| Tumor | ||||||||
| 10.6 | F | Germ Cell | 7 | 4 | Nonanatomic | No | 21 | NED |
| Tumor | ||||||||
| 15.3 | F | Germ Cell | 2 | 5 | Hemihepatectomy, | Yes | 17 | AWD |
| Tumor | Nonanatomic | |||||||
| 2.9 | F | Germ Cell | 23 | 8 | Nonanatomic | No | 36 | NED |
| Tumor | ||||||||
| 12.3 | F | Germ Cell | 2 | 5 | Hemihepatectomy | No | 150 | NED |
| Tumor | ||||||||
| 7.8 | F | Wilms | 2 | 1 | Nonanatomic | No | 49 | DOD |
| Tumor | ||||||||
| 9.1 | F | Wilms | 4 | 3 | Nonanatomic | No | 16 | NED |
| Tumor | ||||||||
| 12.1 | M | Wilms | 2 | 2 | Nonanatomic | No | 1 | NED |
| Tumor | ||||||||
| 6.6 | M | Wilms | 8 | 4 | Hemihepatectomy | No | 151 | NED |
| Tumor | ||||||||
| 1.8 | F | Neuroblastoma | 1 | 1 | Nonanatomic | No | 20 | NED |
| 1.9 | F | Neuroblastoma | 1 | 1 | Nonanatomic | No | 5 | NED |
| 15.1 | F | Adrenocortical | 6 | 3 | Sectionectomy, | Yes | 31 | DOD |
| Carcinoma | Nonanatomic | |||||||
| 22.6 | F | Gastric NET | 6 | 5 | Nonanatomic | Yes | 135 | AWD |
| 20.6 | M | Osteosarcoma | 1 | 1 | Nonanatomic | No | 63 | AWD |
| 16.7 | F | Pancreatic | 1 | 1 | Nonanatomic | No | 122 | NED |
| SPN |
“NET” = Neuroendocrine Tumor; “SPN” = Solid Pseudopapillary Neoplasm; “NED” = No Evidence of Disease; “AWD” = Alive with Disease; “DOD” = Died of Disease.
3.3. Patient outcomes
There were no perioperative deaths. One patient with a large GCT metastasis (17.2 × 13.8 x 21.0 cm in oblique anteroposterior by transverse by craniocaudal dimensions) experienced an air embolism during right hepatic mobilization, which resulted in intraoperative cardiac arrest. She underwent successful cardiopulmonary resusci- tation, completion of her hepatectomy, and had no long-term sequelae. One patient with WT presented months after initial hepa- tectomy with abdominal pain. He underwent unroofing of a biliary pseudocyst and has subsequently required banding of esophageal varices due to persistent portal hypertension (Clavien Dindo IIIb). Two patients required antibiotic treatment for wound infections, one with GCT and one with ACC (Clavien-Dindo class II).
Thirteen patients (13/16, 81 %) were noted to have viable met- astatic disease on final pathology. Of the 6 resections performed for metastatic GCT, 3/6 revealed only mature teratoma, including in one patient with growing teratoma syndrome. One patient with WT had focal anaplasia and rhabdomyoblastic/sarcomatoid fea- tures on final pathology.
For patients who received planned adjuvant therapy post- operatively, the median time from hepatectomy to initiation of chemotherapy was 19 days [IQR 11-22 days]. Treatment regimens were specific to the individual patient’s tumor histology and dis- ease course. The patient with osteosarcoma received chemotherapy 206 days after resection due to identification of bilateral pulmonary nodules.
10-year DSS and DFS for the entire cohort were 77 % (95 % CI 35-94 %) and 61 % (95 % CI 29-82 %), respectively. DSS and DFS for the patients with GCT and WT are depicted in Fig. 3. Median follow up for all patients was 38 months [IQR 18-111 months] (range 1-151 months). Reasons for short length of follow up in some pa- tients include patient mortality and patients lost to follow up. Hepatic relapse occurred in three patients - 1 with GCT, 1 with ACC, and 1 with GNET. The patients who experienced relapse due to
GNET and GCT are alive with disease at 135 months and 17 months, respectively. The patient with osteosarcoma experienced multiple extrahepatic recurrences and is currently alive with disease at 63 months. The patient with relapsed ACC experienced disease pro- gression, liver failure, and died 31 months after her hepatectomy. Extrahepatic, retroperitoneal relapse occurred in the patient with focally anaplastic, rhabdomyoblastic/sarcomatoid WT, who died of her disease 49 months after hepatectomy.
4. Discussion
Hepatic metastases are rare in children. The current analysis shows the safety of hepatectomy in this patient population, as well as the potential for curative-intent resection in carefully selected patients. However, this study brings to light several points of consideration when applying these data to practice.
4.1. Germ cell tumor with liver metastases
The management of metastatic GCT after receipt of systemic therapy presents a clinical dilemma. Patients with viable residual malignant germ cell tumor elements after induction chemotherapy will require intensification of systemic chemotherapy. Patients with viable residual immature teratoma would likely benefit from curative-intent resection [20]. Patients with necrotic residual le- sions or non-growing mature teratomas might not require major resections or additional chemotherapy for long term survival. Paradoxically, resection is currently required to make this deter- mination. In our experience, 50 % of patients who underwent he- patic metastasectomy for GCT had either viable residual teratoma or malignant germ cell tumor elements on final pathology. In the absence of other prognostic biomarkers, resection of metastatic disease seems reasonable for patients with metastatic GCT to determine viability of residual disease [20].
GCT-1
GCT-2
GCT-3
GCT-4
4a
2
7
8
7
8
4a
2
4a
2
7
8
7
8
4a
2
4b
3
3
3
5
4b
3
6
6
5
6
5
4b
6
5
4b
Metachronous
Metachronous
Synchronous
Metachronous
GCT-5
GCT-6
WT-1
WT-2
8
4a
2
2
7
3
7
8
4a
2
2
3
7
8
4a
3
7
8
4a
4b
4b
4b
46
3
6
5
6
5
1
6
5
6
5
Synchronous
Synchronous
Metachronous
Synchronous
WT-3
WT-4
NB-1
NB-2
4a
2
7
8
7
8
4a
2
4a
2
2
3
3
7
8
3
7
8
4a
4b
4b
4b
4b
3
6
5
6
5
6:
5
6
5
Metachronous
Metachronous
Metachronous
Synchronous
ACC-1
GNET-1
OS-1
SPN-1
4a
2
7
8
4a
2
7
8
7
8
4a
2
7
8
4a
2
3
5
4b
4b
3
4b
3
4b
3
6
6
5
6
5
6
5
Synchronous
Metachronous
Metachronous
Synchronous
4.2. Wilms tumor with liver metastases
Of the four patients who underwent hepatic metastasectomy for WT, only one experienced disease relapse and death. This is similar to the 10-year EFS rate reported by the Children’s Oncology Group (COG) for patients undergoing resection of WT metastases in the liver who were enrolled on National Wilms Studies (NWTS) 4 and 5 [18]. Though the primary liver resection group in this report had a higher rate of EFS at 10 years than the unresected group (86 % vs. 68 %), this difference was not found to be statistically significant (P = . 088) [18]. No difference in outcomes were found when comparing radiotherapy and chemotherapy to chemotherapy alone for children with WT and unresected liver metastases [18]. The current study lacks a non-operative comparator group to assess for a survival benefit. The presence of focal anaplasia and rhabdo- myoblastic/sarcomatoid features on final pathology in the child with relapse and progression may indicate differences in underly- ing disease biology. Patients with diffuse anaplastic WT more often experience disease relapse, fail to respond to conventional chemotherapy, and die of their disease, regardless of local control
strategies [21]. However, recent data suggest that patients with focal anaplasia have similar outcomes to identically treated inter- mediate risk non-anaplastic WT [22]. More work is needed to un- derstand the underlying mechanisms of treatment failure in patient populations with relapsed or treatment-refractory WT [18,21,23].
4.3. Neuroblastoma with liver metastases
Approximately 30 % of patients with metastatic NB have liver metastases, with rates up to 80 % in stage MS NB [6,24]. Patient “NB- 1” in the current analysis underwent neoadjuvant chemotherapy and right adrenalectomy for high-risk NB, with resolution of all residual metastatic disease except for a persistent avid focus in segment VII of the liver. There are currently no guidelines for pa- tients with persistent liver disease and chemotherapy responsive extrahepatic metastases [6]. For patient “NB-1,” hepatic meta- stasectomy was curative. The decision to resect an isolated NB liver metastases was made by a multidisciplinary care team considering the chemosensitivity of other metastatic sites and balancing sur- gical risks against toxicities of more aggressive chemotherapy [6].
A
Germ Cell Tumor
100
Probability of Survival
50
Disease-Specific Survival
0
Disease-Free Survival
0
12
24
36
48
60
72
84
96
108
120
B
Wilms Tumor
100
Probability of Survival
50
Disease-Specific Survival
0
Disease-Free Survival
0
12
24
36
48
60
72
84
96
108
120
Months From Hepatic Metastasectomy
Number at Risk
DSS
4
3
2
2
2
2
2
2
2
2
2
DFS
4
3
2
2
2
2
2
2
2
2
2
| Months From Hepatic Metastasectomy | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Number at Risk | ||||||||||
| DSS 6 | 6 | 4 | 4 | 2 | 2 | 2 | 1 | 1 | 1 | 1 |
| DFS 6 | 6 | 4 | 4 | 2 | 2 | 2 | 1 | 1 | 1 | 1 |
Fig. 3. Disease-specific survival and disease-free survival for patients undergoing hepatic metastasectomy for (A) germ cell tumor and (B) Wilms tumor. “DSS” = Disease-Specific Survival; “DFS” = Disease-Free Survival.
Patients with MS disease often experience spontaneous resolution of their liver metastases, while others may have complete resolu- tion with chemotherapy emphasizing the case by case decision making that is so important in this group [24-26].
4.4. Other histologies with liver metastases
ACC is rare in young patients, and pediatric-specific data are sparse [27]. Disease stage and older patient age predict worse event-free survival [27]. Retrospective studies of adult patients have associated resection of ACC liver metastases with improved overall survival [28,29]. Whether these data can be extrapolated to
young patients with germline TP53 mutations, which drive the majority of pediatric ACC cases, is unknown [27]. Our solitary pa- tient with metastatic osteosarcoma experienced extrahepatic relapse, consistent with the limited data previously published on this subject [17].
Complete resection is necessary for survival in osteosarcoma [30]. Consequently, aggressive surgical approaches have been employed for pulmonary metastatic disease with high-quality long- term pulmonary function data [31,32]. The data supporting hepatic resection for this histology are unclear, mandating individualized clinical decision-making. NET are exceedingly uncommon in chil- dren, and minimal improvements to overall survival have been
observed in this population over the past three decades [33]. Accordingly, current treatment strategies are modeled after analo- gous tumors in adult patients [6]. In older populations, aggressive, early resection is associated with improved survival [34]. More experience is needed to determine the ultimate role of meta- stasectomy for NET in children [6]. For SPN, metastatic disease is fortunately rare, but hard to predict [35]. Clinical presentations differ between children and adults [35]. Though few data are available to guide clinical decision-making, complete surgical resection, when feasible, seems to be associated with long term cure [36].
4.5. Limitations
The current analysis has several limitations, most of which are intrinsic to its retrospective nature and the study of rare diseases. The lack of a non-operative comparator group precludes analysis of potential survival benefit. The likelihood of selection bias is high, as there are not currently meaningful selection criteria for hepatic metastasectomy in children. The small number of patients and the single-institutional study design may limit the ability of these findings to be generalized to other patient populations. Patient safety and benefit profiles demonstrated in this study require a high level of expertise in pediatric liver surgery that may not be available in all institutions.
5. Conclusions
Hepatic metastasectomy can be performed safely in children for a variety of histologies. Resection of GCT liver metastases can both diagnose and cure residual immature teratoma, as well as identify any residual viable malignant germ cell tumor elements. Though selection criteria are not defined, hepatic metastasectomy can be associated with long term cure in children with WT and NB. Data surrounding other histologies are limited, mandating multidisci- plinary, individualized treatment plans.
Financial support statement
This work was supported by the American Lebanese Syrian Associated Charities (ALSAC)/St. Jude Children’s Research Hospital.
Conflicts of interest
The authors have no conflicts of interest to disclose.
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