Childhood Liver Cancer Treatment (PDQ®) 2/2 –Health Professional Version - National Cancer Institute

Childhood Liver Cancer Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Liver Cancer Treatment (PDQ®)–Health Professional Version

Treatment of Hepatoblastoma

Treatment options for newly diagnosed hepatoblastoma depend on the following:

• Whether the cancer is resectable at diagnosis.
• The tumor histology.
• How the cancer responds to chemotherapy.
• Whether the cancer has metastasized.

Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) I and II resectable disease before or after chemotherapy.[46,48,59]

Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 6. (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for information describing each stage.)

Table 6. Outcomes for Hepatoblastoma Multicenter Trialsa

Study	Chemotherapy Regimen	Number of Patients	Outcomes
AFP = alpha-fetoprotein; C5V = cisplatin, 5-fluorouracil (5FU), and vincristine; CARBO = carboplatin; CCG = Children’s Cancer Group; CDDP = cisplatin; CITA = pirarubicin-cisplatin; COG = Children's Oncology Group; DOXO = doxorubicin; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); HR = high risk; IFOS = ifosfamide; IPA = ifosfamide, cisplatin, and doxorubicin; JPLT = Japanese Study Group for Pediatric Liver Tumor; LR = low risk; NR = not reported; OS = overall survival; PLADO = cisplatin and doxorubicin; POG = Pediatric Oncology Group; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group; SR = standard risk; SUPERPLADO = cisplatin, doxorubicin, and carboplatin; THP = tetrahydropyranyl-adriamycin (pirarubicin); VP = vinorelbine and cisplatin; VPE+ = venous, portal, and extrahepatic involvement; VP16 = etoposide.
aAdapted from Czauderna et al.[66] and Meyers et al.[79]
bStudy closed early because of inferior results in the CDDP/CARBO arm.
INT0098 (CCG/POG) 1989–1992	C5V vs. CDDP/DOXO	Stage I/II: 50	4-Year EFS/OS:
			I/II = 88%/100% vs. 96%/96%
		Stage III: 83	III = 60%/68% vs. 68%/71%
		Stage IV: 40	IV = 14%/33% vs. 37%/42%
P9645 (COG)b 1999–2002	C5V vs. CDDP/CARBO	Stage I/II: Pending publication	1-Year EFS:
			I/II: Pending publication
		Stage III: 38	III/IV: C5V = 51%; CDDP/CARBO = 37%
		Stage IV: 50
AHEP0731 (COG) 2010–2014 [80][Level of evidence: 3iiA]	LR: C5V (2 cycles)	LR (stage I/II): 49	5-year EFS: 88%; 5-year OS: 91%
HB 94 (GPOH) 1994–1997	I/II: IFOS/CDDP/DOXO	Stage I: 27	4-Year EFS/OS:
			I = 89%/96%
		Stage II: 3	II = 100%/100%
	III/IV: IFOS/CDDP/DOXO + VP/CARBO	Stage III: 25	III = 68%/76%
		Stage IV: 14	IV = 21%/36%
HB 99 (GPOH) 1999–2004	SR: IPA	SR: 58	3-Year EFS/OS:
			SR = 90%/88%
	HR: CARBO/VP16	HR: 42	HR = 52%/55%
SIOPEL-2 1994–1998	SR: PLADO	PRETEXT I: 6	3-Year EFS/OS:
			SR: 73%/91%
		PRETEXT II: 36
		PRETEXT III: 25
	HR: CDDP/CARBO/DOXO	PRETEXT IV: 21	HR: IV = 48%/61%
		Metastases: 25	HR: metastases = 36%/44%
SIOPEL-3 1998–2006	SR: CDDP vs. PLADO	SR: PRETEXT I: 18	3-Year EFS/OS:
			SR: CDDP = 83%/95%; PLADO = 85%/93%
		PRETEXT II: 133
		PRETEXT III: 104
	HR: SUPERPLADO	HR: PRETEXT IV: 74	HR: Overall = 65%/69%
		VPE+: 70
		Metastases: 70	Metastases = 57%/63%
		AFP <100 ng/mL: 12
SIOPEL-4 2005–2009	HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B: CARBO/DOXO	PRETEXT I: 2	3-Year EFS/OS:
			All HR = 76%/83%
		PRETEXT II: 17
		PRETEXT III: 27
		PRETEXT IV: 16	HR: IV = 75%/88%
		Metastases: 39	HR: Metastases = 77%/79%
JPLT-1 1991–1999	I/II: CDDP(30)/THP-DOXO	Stage I: 9	5-Year EFS/OS:
			I = NR/100%
		Stage II: 32	II = NR/76%
	III/IV: CDDP(60)/THP-DOXO	Stage IIIa: 48	IIIa = NR/50%
		Stage IIIb: 25	IIIb = NR/64%
		Stage IV: 20	IV = NR/77%
JPLT-2 1999–2010	I: Low-dose CDDP-pirarubicin	PRETEXT I–IV: 212	5-Year EFS/OS:
			I = NR/100%
	II–IV: CITA		II = NR/89%
			III = NR/93%
			IV = NR/63%
	Metastases: High dose chemotherapy + stem cell transplant		Metastases = 32%

Treatment options for hepatoblastoma that is resectable at diagnosis

Approximately 20% to 30% of children with hepatoblastoma have resectable disease at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRETEXT I tumors and PRETEXT II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins.

Prognosis varies depending on the histologic subtype, as follows:

• Patients with well-differentiated fetal histology (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no adjuvant chemotherapy.[47,62,70]
• Patients with non–well-differentiated fetal histology, non–small cell undifferentiated hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[47,48,59,62,81]
• If any small cell undifferentiated elements are present, the 3-year survival rate is 40% to 70%.[61,62]

Treatment options for hepatoblastoma resectable at diagnosis showing non–well-differentiated fetal histology include the following:

1. Resection followed by two to four cycles of chemotherapy.

Re-resection of positive microscopic margins may not be necessary. Conclusive evidence is lacking for tumors with resection at diagnosis compared with those with positive microscopic margins resected after preoperative chemotherapy.

Evidence (gross surgical resection [with or without microscopic margins] and postoperative chemotherapy):

1. Gross surgical excision with or without microscopic margins has been followed by four courses of combination chemotherapy with cisplatin, vincristine, and fluorouracil or cisplatin and doxorubicin or cisplatin alone.[46-48,59]
   Second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic and who receive subsequent chemotherapy.[54,63]
2. In the COG AHEP0731 (NCT00980460) trial, 49 of 51 patients with stage I or stage II hepatoblastoma (without pure fetal histology) received two cycles of adjuvant chemotherapy consisting of cisplatin, fluorouracil, and vincristine.[80][Level of evidence: 3iiA]
   • The 5-year EFS rate was 88%, and the 5-year OS rate was 91%.
   • This outcome is comparable to the outcomes for children treated with four cycles after initial resection, and to the outcomes for children treated with two cycles of neoadjuvant chemotherapy before resection followed by two cycles of chemotherapy after resection.
3. There is no reliable data for local recurrence risk in patients with a positive microscopic margin status who were resected at diagnosis.[49] SIOPEL studies suggest that in patients who received preoperative chemotherapy, positive microscopic margin did not increase risk of local recurrence.[54,59,63]
   • In a European study conducted between 1990 and 1994, 11 patients had tumor found at the surgical margins after hepatic resection and two patients died, neither of whom had a local recurrence. None of the 11 patients underwent a second resection and only one patient received radiation therapy postoperatively. All of the patients were treated with four courses of cisplatin and doxorubicin before surgery and received two courses of postoperative chemotherapy.[54]
   • In another European study of high-risk hepatoblastoma, 11 patients had microscopic residual tumor remaining after initial surgery and received two to four postoperative cycles of chemotherapy with no additional surgery. Of these 11 patients, 9 survived.[63]
   • In the SIOPEL-2 study, 13 of 13 patients with microscopic positive resection margins survived.[59]
4. A randomized clinical trial demonstrated comparable efficacy with postoperative cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma.[47]
   • Although outcome was nominally higher for the children who received cisplatin/doxorubicin, this difference was not statistically significant.
   • The combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin, to which it was compared.

Results of chemotherapy clinical trials are described in Table 6.

Treatment options for hepatoblastoma of well-differentiated fetal (pure fetal) histology resectable at diagnosis include the following:

1. Complete surgical resection followed by watchful waiting or chemotherapy.[70]

Evidence (complete surgical resection followed by watchful waiting or chemotherapy):

1. In the COG prospective clinical trial (INT0098), nine children with stage I (completely resected) well-differentiated fetal histology and fewer than two mitoses per high-power field were treated with adjuvant doxorubicin for four cycles.[47]
   • At a median follow-up of 5.1 years, the EFS and OS were 100% for all nine children.
2. In the COG P9645 (NCT00003994) study, 16 patients with stage I (completely resected) tumor had well-differentiated fetal histology and received no adjuvant chemotherapy. In a retrospective PRETEXT classification of 21 of these 25 patients with adequate data, PRETEXT I, II, and III were found in 7, 10, and 4 patients, respectively.[70]
   • The EFS and OS were 100% for patients with stage I well-differentiated fetal histology, including one patient who had a second surgery to address a positive tumor margin.
3. Treatment of a small focus of undifferentiated small cell histology within an otherwise well-differentiated fetal histology tumor with aggressive chemotherapy has been reported in the following small series suggesting the importance of a thorough histologic examination of apparent well-differentiated fetal histology.[78]
   A retrospective study of 16 patients with well-differentiated fetal histology treated at multiple institutions had complete surgical resections, but also had elements of (or, in some case, predominance of) small cell histology found in the resected tumor.[78]
   • Despite receiving postoperative chemotherapy, 10 of 16 patients recurred, and 5 of these patients died of hepatoblastoma.

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend biopsy without an attempt to resect the tumor at diagnosis in children with PRETEXT II tumors with less than 1 cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.

Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.[82]

Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:

1. Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.
2. Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant.[48,52,83-88]
3. Transarterial chemoembolization (TACE). TACE may be used to improve resectability before definitive surgical approaches.[89,90]

In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[48,54,59] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease.[70] In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.

Patients whose tumors remain unresectable after chemotherapy should be considered for liver transplant.[48,52,83-87] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical.[60] In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with liver transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):

1. In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[48]
   • The chemotherapy was well tolerated.
   • Complete resection was obtained in 87% of children.
   • This strategy resulted in an OS rate of 75% at 5 years after diagnosis.
2. Identical results were seen in a follow-up international study (SIOPEL-2).[59]
3. The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and not involving more than three sectors.[81][Level of evidence:1iiA]
   • The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
   • The OS rates were also similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
4. In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[63]
   • In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year OS of this group was 69% (± 11%).
   • Of the 70 patients with metastases enrolled in the trial, the 3-year EFS rate was 56% and the OS rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).
5. SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients whose tumors were resected or whose livers were transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT II (27%), III (44%), and IV (26%).[55][Level of evidence: 2Dii]
   • Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.
   • Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.
   • Two patients died postoperatively.
   • There were 37 partial hepatectomies and 16 liver transplants.
   • The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection. The 3-year disease-free survival (DFS) was 76% (95% CI, 65%–87%), and the 3-year OS was 83% (95% CI, 73%–93%).
   • Of the 16 PRETEXT IV patients, 11 were downstaged after chemotherapy—6 patients to PRETEXT III, 4 patients to PRETEXT II, and 1 patient to PRETEXT I. Twelve tumors became resectable; of these, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease, the 3-year DFS was 73% (95% CI, 51%–96%), and the 3-year OS was 80% (95% CI, 60%–100%).
6. In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free.[91]
7. A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease.[92]

In the United States, unresectable tumors have been treated with chemotherapy before resection or transplant.[45-47,70] On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy.[93] Some European centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant.[60,94-96]

Chemotherapy followed by TACE followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal.[97]

Treatment options for hepatoblastoma with metastases at diagnosis

The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure is possible.[45-47] Survival rates at 3 to 5 years range from 20% to 79%.[55,63,98,99] To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial).[55][Level of evidence: 2Dii]

Treatment options for hepatoblastoma with metastases at diagnosis include the following:

1. Chemotherapy followed by reassessment of surgical resectability.
   • If the primary tumor and extrahepatic disease (usually pulmonary nodules) are resectable after chemotherapy, surgical resection followed by additional chemotherapy.
   • If extrahepatic metastatic disease is in complete remission after chemotherapy and/or surgical resection of lung nodule but the primary tumor remains unresectable, orthotopic liver transplant.
   • If extrahepatic metastatic disease is not resectable or the patient is not a transplant candidate, additional chemotherapy, TACE, or radiation therapy.

The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil [47] or doxorubicin/cisplatin [48,70,98] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported (refer to Table 6 for more information).

High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy.[100]

Evidence (chemotherapy to treat metastatic disease at diagnosis):

1. A subset of 39 patients presenting with metastases were entered on the SIOPEL-4 (NCT00077389) trial, a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Patients whose tumors were resected or livers transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors were unresectable after three cycles of chemotherapy received two additional cycles of very intensive carboplatin and doxorubicin before surgery.[55][Level of evidence: 2Dii]
   • After three cycles of chemotherapy, there was a complete response (only in the metastases) in 20 of 39 patients and a partial response in 18 of 39 patients. Nineteen of the patients who achieved a complete response were alive without disease 3 years after diagnosis.
   • Of the patients who achieved a partial response, seven patients underwent metastasectomy near the time of resection or liver transplant, with an OS of 100%. An additional seven patients with residual small pulmonary nodules underwent resection without metastasectomy; of those, six patients did well and one patient recurred.
   • Two patients with initial metastases eventually recurred.
   • Liver transplant, rather than resection alone, was needed to treat 7 of the 39 patients who presented with metastases.
   • For the subset of 39 patients presenting with metastases, the 3-year DFS was 77% (95% CI, 63%–90%), and the OS was 79% (95% CI, 66%–92%).

In patients with resected primary tumors, any remaining pulmonary metastasis is surgically removed, if possible.[98] A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor.[99][Level of evidence: 3iiA]

If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed.[55,63,70,92]

The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups,[55,63,87,92] while others have noted high rates of hepatoblastoma recurrence.[52,83,86,89] All of these studies are limited by small patient numbers; additional study is needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who underwent liver transplants and presented with metastatic disease.[55,63,101]

If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:

• Nonstandard chemotherapy agents. Nonstandard chemotherapy agents such as irinotecan, high-dose cisplatin/etoposide, or continuous-infusion doxorubicin have been used.[102-104]; [105][Level of evidence: 3iiA]
• TACE.[90,106]
• Radiation therapy.[107]

Treatment options for progressive or recurrent hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:[108]

• Site of recurrence.
• Previous treatment.
• Individual patient considerations.

Treatment options for progressive or recurrent hepatoblastoma include the following:

1. Surgical resection. In patients with hepatoblastoma that is completely resected at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease, in conjunction with an overall strategy that includes appropriate chemotherapy, may make extended disease-free survival possible.[99,108,109]
   If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[110] A retrospective study of patients in SIOPEL studies 1, 2, and 3 showed a 12% incidence of recurrence after complete remission by imaging and AFP. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year EFS was 34%, and the OS was 43%.[108][Level of evidence: 3iiA] Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[111][Level of evidence: 3iiiB]
   Enrollment in a clinical trial should be considered if all of the recurrent disease cannot be surgically removed. Phase I and phase II clinical trials may be appropriate and should be considered.
2. Chemotherapy. Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil.[112] Addition of doxorubicin to vincristine/fluorouracil/cisplatin is under clinical evaluation in the COG study AHEP0731 [NCT00980460]. Combined vincristine/irinotecan and single-agent irinotecan have been used with some success.[105]; [104][Level of evidence: 3iiiA]
   A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.[113]
3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection.[52,83,86]
4. Percutaneous ablation. Percutaneous ablation techniques may also be considered for palliation.[114]

Treatment options under clinical evaluation for hepatoblastoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• AHEP1531 (NCT03533582) (Cisplatin and Combination Chemotherapy in Treating Children and Young Adults with Hepatoblastoma or Liver Cancer After Surgery):
  This is the COG's participation in a large international trial (PHITT) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.
  • Very low-risk hepatoblastoma is defined as either: 1) a well differentiated fetal mass completely resected at diagnosis, and these patients are treated with no chemotherapy; or 2) a non–well differentiated fetal mass or incompletely resected well differentiated fetal mass, and these patients are treated with two cycles of cisplatin chemotherapy.
  • Low-risk hepatoblastoma is defined as a PRETEXT I to III tumor without any positive VPEFR annotation factors (venous involvement, portal involvement, extrahepatic spread, multifocality, and tumor rupture). These patients are treated with two cycles of cisplatin chemotherapy and then undergo resection (if possible) followed by randomization between two and four more cycles of cisplatin. If the tumor is unresectable, the patient receives two more cycles of cisplatin chemotherapy, and the tumor's resectability is reassessed. If it is still unresectable, patients undergo liver transplant.
  • Intermediate-risk hepatoblastoma is defined as a PRETEXT I to III primary tumor with a positive VPEFR annotation factor but without metastasis. Patients are randomly assigned to either four 14-day cycles of cisplatin or four 21-day cycles of C5VD (cisplatin, fluorouracil, vincristine, and doxorubicin). Transplant teams are consulted early as needed. Patients in both arms then undergo resection and receive two more cycles of their assigned chemotherapy.
  • High-risk hepatoblastoma is defined as presence of distant metastasis or AFP less than 100 or age 8 years and older. All patients are treated with three cycles of induction chemotherapy per the SIOPEL-4 trial (dose-intensive cisplatin, doxorubicin, and carboplatin). The patients aged 8 years and older or with AFP less than 100 and those whose metastases have cleared receive three cycles of carboplatin and doxorubicin. Patients with metastases that have not cleared by end of induction are randomly assigned to receive either carboplatin/doxorubicin cycles alternating with carboplatin/etoposide for six cycles or carboplatin/doxorubicin alternating with vincristine/irinotecan for six cycles.
• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

References

1. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Bethesda, Md: National Cancer Institute, 2012, Section 29. Also available online. Last accessed April 11, 2019.
2. Bulterys M, Goodman MT, Smith MA, et al.: Hepatic tumors. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 91-98. Also available online. Last accessed April 11, 2019.
3. Turcotte LM, Georgieff MK, Ross JA, et al.: Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: a report from the Children's Oncology Group. Pediatr Blood Cancer 61 (11): 2018-23, 2014. [PUBMED Abstract]
4. Tanimura M, Matsui I, Abe J, et al.: Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res 58 (14): 3032-5, 1998. [PUBMED Abstract]
5. McLaughlin CC, Baptiste MS, Schymura MJ, et al.: Maternal and infant birth characteristics and hepatoblastoma. Am J Epidemiol 163 (9): 818-28, 2006. [PUBMED Abstract]
6. Darbari A, Sabin KM, Shapiro CN, et al.: Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 38 (3): 560-6, 2003. [PUBMED Abstract]
7. Kamien BA, Gabbett MT: Aicardi syndrome associated with hepatoblastoma and pulmonary sequestration. Am J Med Genet A 149A (8): 1850-2, 2009. [PUBMED Abstract]
8. DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998. [PUBMED Abstract]
9. Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 137C (1): 12-23, 2005. [PUBMED Abstract]
10. Iwama T, Mishima Y: Mortality in young first-degree relatives of patients with familial adenomatous polyposis. Cancer 73 (8): 2065-8, 1994. [PUBMED Abstract]
11. Garber JE, Li FP, Kingston JE, et al.: Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 80 (20): 1626-8, 1988. [PUBMED Abstract]
12. Giardiello FM, Petersen GM, Brensinger JD, et al.: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 39 (96): 867-9, 1996. [PUBMED Abstract]
13. Ito E, Sato Y, Kawauchi K, et al.: Type 1a glycogen storage disease with hepatoblastoma in siblings. Cancer 59 (10): 1776-80, 1987. [PUBMED Abstract]
14. Ikeda H, Hachitanda Y, Tanimura M, et al.: Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review. Cancer 82 (9): 1789-96, 1998. [PUBMED Abstract]
15. Spector LG, Birch J: The epidemiology of hepatoblastoma. Pediatr Blood Cancer 59 (5): 776-9, 2012. [PUBMED Abstract]
16. Buonuomo PS, Ruggiero A, Vasta I, et al.: Second case of hepatoblastoma in a young patient with Simpson-Golabi-Behmel syndrome. Pediatr Hematol Oncol 22 (7): 623-8, 2005 Oct-Nov. [PUBMED Abstract]
17. Tan ZH, Lai A, Chen CK, et al.: Association of trisomy 18 with hepatoblastoma and its implications. Eur J Pediatr 173 (12): 1595-8, 2014. [PUBMED Abstract]
18. Trobaugh-Lotrario AD, Venkatramani R, Feusner JH: Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment? J Pediatr Hematol Oncol 36 (5): 369-73, 2014. [PUBMED Abstract]
19. Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79 (4): 274-8, 1998. [PUBMED Abstract]
20. Clericuzio CL, Martin RA: Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 11 (3): 220-2, 2009. [PUBMED Abstract]
21. Algar EM, St Heaps L, Darmanian A, et al.: Paternally inherited submicroscopic duplication at 11p15.5 implicates insulin-like growth factor II in overgrowth and Wilms' tumorigenesis. Cancer Res 67 (5): 2360-5, 2007. [PUBMED Abstract]
22. Steenman M, Westerveld A, Mannens M: Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28 (1): 1-13, 2000. [PUBMED Abstract]
23. Albrecht S, Hartmann W, Houshdaran F, et al.: Allelic loss but absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma. Int J Cancer 111 (4): 627-32, 2004. [PUBMED Abstract]
24. Clericuzio CL, Chen E, McNeil DE, et al.: Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143 (2): 270-2, 2003. [PUBMED Abstract]
25. Mussa A, Molinatto C, Baldassarre G, et al.: Cancer Risk in Beckwith-Wiedemann Syndrome: A Systematic Review and Meta-Analysis Outlining a Novel (Epi)Genotype Specific Histotype Targeted Screening Protocol. J Pediatr 176: 142-149.e1, 2016. [PUBMED Abstract]
26. Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 47 (6): 811-8, 2006. [PUBMED Abstract]
27. Hirschman BA, Pollock BH, Tomlinson GE: The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 (2): 263-6, 2005. [PUBMED Abstract]
28. Koch A, Denkhaus D, Albrecht S, et al.: Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59 (2): 269-73, 1999. [PUBMED Abstract]
29. Kalish JM, Doros L, Helman LJ, et al.: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res 23 (13): e115-e122, 2017. [PUBMED Abstract]
30. Eichenmüller M, Trippel F, Kreuder M, et al.: The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61 (6): 1312-20, 2014. [PUBMED Abstract]
31. Trevino LR, Wheeler DA, Finegold MJ, et al.: Exome sequencing of hepatoblastoma reveals recurrent mutations in NFE2L2. [Abstract] Cancer Res 73 (8 Suppl): A-4592, 2013. Also available onlineExit Disclaimer. Last accessed April 11, 2019.
32. Jia D, Dong R, Jing Y, et al.: Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 60 (5): 1686-96, 2014. [PUBMED Abstract]
33. Hiyama E, Kurihara S, Onitake Y: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [Abstract] Cancer Res 74 (19 Suppl): A-5188, 2014.
34. Yoon JM, Burns RC, Malogolowkin MH, et al.: Treatment of infantile choriocarcinoma of the liver. Pediatr Blood Cancer 49 (1): 99-102, 2007. [PUBMED Abstract]
35. Boman F, Bossard C, Fabre M, et al.: Mesenchymal hamartomas of the liver may be associated with increased serum alpha foetoprotein concentrations and mimic hepatoblastomas. Eur J Pediatr Surg 14 (1): 63-6, 2004. [PUBMED Abstract]
36. Blohm ME, Vesterling-Hörner D, Calaminus G, et al.: Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15 (2): 135-42, 1998 Mar-Apr. [PUBMED Abstract]
37. Perilongo G, Malogolowkin M, Feusner J: Hepatoblastoma clinical research: lessons learned and future challenges. Pediatr Blood Cancer 59 (5): 818-21, 2012. [PUBMED Abstract]
38. Trobaugh-Lotrario AD, Katzenstein HM: Chemotherapeutic approaches for newly diagnosed hepatoblastoma: past, present, and future strategies. Pediatr Blood Cancer 59 (5): 809-12, 2012. [PUBMED Abstract]
39. Trobaugh-Lotrario AD, Chaiyachati BH, Meyers RL, et al.: Outcomes for patients with congenital hepatoblastoma. Pediatr Blood Cancer 60 (11): 1817-25, 2013. [PUBMED Abstract]
40. Fuchs J, Rydzynski J, Von Schweinitz D, et al.: Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer 95 (1): 172-82, 2002. [PUBMED Abstract]
41. Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005. [PUBMED Abstract]
42. Czauderna P, Haeberle B, Hiyama E, et al.: The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 52: 92-101, 2016. [PUBMED Abstract]
43. Meyers RL, Maibach R, Hiyama E, et al.: Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. Lancet Oncol 18 (1): 122-131, 2017. [PUBMED Abstract]
44. Dall'Igna P, Brugieres L, Christin AS, et al.: Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
45. Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991. [PUBMED Abstract]
46. Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993. [PUBMED Abstract]
47. Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000. [PUBMED Abstract]
48. Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000. [PUBMED Abstract]
49. Meyers RL, Czauderna P, Otte JB: Surgical treatment of hepatoblastoma. Pediatr Blood Cancer 59 (5): 800-8, 2012. [PUBMED Abstract]
50. Hiyama E, Hishiki T, Watanabe K, et al.: Resectability and tumor response after preoperative chemotherapy in hepatoblastoma treated by the Japanese Study Group for Pediatric Liver Tumor (JPLT)-2 protocol. J Pediatr Surg 51 (12): 2053-2057, 2016. [PUBMED Abstract]
51. Becker K, Furch C, Schmid I, et al.: Impact of postoperative complications on overall survival of patients with hepatoblastoma. Pediatr Blood Cancer 62 (1): 24-8, 2015. [PUBMED Abstract]
52. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004. [PUBMED Abstract]
53. McAteer JP, Goldin AB, Healey PJ, et al.: Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 17 (8): 744-50, 2013. [PUBMED Abstract]
54. Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002. [PUBMED Abstract]
55. Zsiros J, Brugieres L, Brock P, et al.: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14 (9): 834-42, 2013. [PUBMED Abstract]
56. Van Tornout JM, Buckley JD, Quinn JJ, et al.: Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome: a report from the Children's Cancer Group. J Clin Oncol 15 (3): 1190-7, 1997. [PUBMED Abstract]
57. Nguyen R, McCarville MB, Sykes A, et al.: Rapid decrease of serum alpha-fetoprotein and tumor volume predicts outcome in children with hepatoblastoma treated with neoadjuvant chemotherapy. Int J Clin Oncol 23 (5): 900-907, 2018. [PUBMED Abstract]
58. Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000. [PUBMED Abstract]
59. Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004. [PUBMED Abstract]
60. D'Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007. [PUBMED Abstract]
61. De Ioris M, Brugieres L, Zimmermann A, et al.: Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer 44 (4): 545-50, 2008. [PUBMED Abstract]
62. Meyers RL, Rowland JR, Krailo M, et al.: Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 53 (6): 1016-22, 2009. [PUBMED Abstract]
63. Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010. [PUBMED Abstract]
64. Schneider DT, Calaminus G, Göbel U: Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 18 (1): 11-26, 2001 Jan-Feb. [PUBMED Abstract]
65. Nakagawara A, Ikeda K, Tsuneyoshi M, et al.: Hepatoblastoma producing both alpha-fetoprotein and human chorionic gonadotropin. Clinicopathologic analysis of four cases and a review of the literature. Cancer 56 (7): 1636-42, 1985. [PUBMED Abstract]
66. Czauderna P, Lopez-Terrada D, Hiyama E, et al.: Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 26 (1): 19-28, 2014. [PUBMED Abstract]
67. López-Terrada D, Alaggio R, de Dávila MT, et al.: Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27 (3): 472-91, 2014. [PUBMED Abstract]
68. Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 14 (6): 512-37, 1983. [PUBMED Abstract]
69. Haas JE, Muczynski KA, Krailo M, et al.: Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 64 (5): 1082-95, 1989. [PUBMED Abstract]
70. Malogolowkin MH, Katzenstein HM, Meyers RL, et al.: Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol 29 (24): 3301-6, 2011. [PUBMED Abstract]
71. Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, et al.: Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer 52 (3): 328-34, 2009. [PUBMED Abstract]
72. Rowland JM: Hepatoblastoma: assessment of criteria for histologic classification. Med Pediatr Oncol 39 (5): 478-83, 2002. [PUBMED Abstract]
73. Gunawan B, Schäfer KL, Sattler B, et al.: Undifferentiated small cell hepatoblastoma with a chromosomal translocation t(22;22)(q11;q13). Histopathology 40 (5): 485-7, 2002. [PUBMED Abstract]
74. Conran RM, Hitchcock CL, Waclawiw MA, et al.: Hepatoblastoma: the prognostic significance of histologic type. Pediatr Pathol 12 (2): 167-83, 1992 Mar-Apr. [PUBMED Abstract]
75. Zhou S, Gomulia E, Mascarenhas L, et al.: Is INI1-retained small cell undifferentiated histology in hepatoblastoma unfavorable? Hum Pathol 46 (4): 620-4, 2015. [PUBMED Abstract]
76. Vokuhl C, Oyen F, Häberle B, et al.: Small cell undifferentiated (SCUD) hepatoblastomas: All malignant rhabdoid tumors? Genes Chromosomes Cancer 55 (12): 925-931, 2016. [PUBMED Abstract]
77. Cornet M, De Lambert G, Pariente D, et al.: Rhabdoid tumor of the liver: Report of 6 pediatric cases treated at a single institute. J Pediatr Surg 53 (3): 567-571, 2018. [PUBMED Abstract]
78. Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92 (12): 3130-4, 2001. [PUBMED Abstract]
79. Meyers RL, Tiao G, de Ville de Goyet J, et al.: Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation. Curr Opin Pediatr 26 (1): 29-36, 2014. [PUBMED Abstract]
80. Katzenstein HM, Langham MR, Malogolowkin MH, et al.: Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial. Lancet Oncol 20 (5): 719-727, 2019. [PUBMED Abstract]
81. Perilongo G, Maibach R, Shafford E, et al.: Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 361 (17): 1662-70, 2009. [PUBMED Abstract]
82. Madanur MA, Battula N, Davenport M, et al.: Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 23 (6): 609-11, 2007. [PUBMED Abstract]
83. Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000. [PUBMED Abstract]
84. Molmenti EP, Wilkinson K, Molmenti H, et al.: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2 (6): 535-8, 2002. [PUBMED Abstract]
85. Czauderna P, Otte JB, Aronson DC, et al.: Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 41 (7): 1031-6, 2005. [PUBMED Abstract]
86. Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006. [PUBMED Abstract]
87. Pham TA, Gallo AM, Concepcion W, et al.: Effect of Liver Transplant on Long-term Disease-Free Survival in Children With Hepatoblastoma and Hepatocellular Cancer. JAMA Surg 150 (12): 1150-8, 2015. [PUBMED Abstract]
88. Khan AS, Brecklin B, Vachharajani N, et al.: Liver Transplantation for Malignant Primary Pediatric Hepatic Tumors. J Am Coll Surg 225 (1): 103-113, 2017. [PUBMED Abstract]
89. Xianliang H, Jianhong L, Xuewu J, et al.: Cure of hepatoblastoma with transcatheter arterial chemoembolization. J Pediatr Hematol Oncol 26 (1): 60-3, 2004. [PUBMED Abstract]
90. Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000. [PUBMED Abstract]
91. Aronson DC, Meyers RL: Malignant tumors of the liver in children. Semin Pediatr Surg 25 (5): 265-275, 2016. [PUBMED Abstract]
92. von Schweinitz D, Hecker H, Harms D, et al.: Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 30 (6): 845-52, 1995. [PUBMED Abstract]
93. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PUBMED Abstract]
94. Fuchs J, Cavdar S, Blumenstock G, et al.: POST-TEXT III and IV Hepatoblastoma: Extended Hepatic Resection Avoids Liver Transplantation in Selected Cases. Ann Surg 266 (2): 318-323, 2017. [PUBMED Abstract]
95. Hemming AW, Reed AI, Fujita S, et al.: Role for extending hepatic resection using an aggressive approach to liver surgery. J Am Coll Surg 206 (5): 870-5; discussion 875-8, 2008. [PUBMED Abstract]
96. Fonseca A, Gupta A, Shaikh F, et al.: Extreme hepatic resections for the treatment of advanced hepatoblastoma: Are planned close margins an acceptable approach? Pediatr Blood Cancer 65 (2): , 2018. [PUBMED Abstract]
97. Wang S, Yang C, Zhang J, et al.: First experience of high-intensity focused ultrasound combined with transcatheter arterial embolization as local control for hepatoblastoma. Hepatology 59 (1): 170-7, 2014. [PUBMED Abstract]
98. Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000. [PUBMED Abstract]
99. Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007. [PUBMED Abstract]
100. Karski EE, Dvorak CC, Leung W, et al.: Treatment of hepatoblastoma with high-dose chemotherapy and stem cell rescue: the pediatric blood and marrow transplant consortium experience and review of the literature. J Pediatr Hematol Oncol 36 (5): 362-8, 2014. [PUBMED Abstract]
101. Katzenstein HM, Furman WL, Malogolowkin MH, et al.: Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee. Cancer 123 (12): 2360-2367, 2017. [PUBMED Abstract]
102. Katzenstein HM, Rigsby C, Shaw PH, et al.: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 24 (9): 751-5, 2002. [PUBMED Abstract]
103. Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 41 (1): 78-80, 2003. [PUBMED Abstract]
104. Qayed M, Powell C, Morgan ER, et al.: Irinotecan as maintenance therapy in high-risk hepatoblastoma. Pediatr Blood Cancer 54 (5): 761-3, 2010. [PUBMED Abstract]
105. Zsíros J, Brugières L, Brock P, et al.: Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 48 (18): 3456-64, 2012. [PUBMED Abstract]
106. Sue K, Ikeda K, Nakagawara A, et al.: Intrahepatic arterial injections of cisplatin-phosphatidylcholine-Lipiodol suspension in two unresectable hepatoblastoma cases. Med Pediatr Oncol 17 (6): 496-500, 1989. [PUBMED Abstract]
107. Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992. [PUBMED Abstract]
108. Semeraro M, Branchereau S, Maibach R, et al.: Relapses in hepatoblastoma patients: clinical characteristics and outcome--experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 49 (4): 915-22, 2013. [PUBMED Abstract]
109. Shi Y, Geller JI, Ma IT, et al.: Relapsed hepatoblastoma confined to the lung is effectively treated with pulmonary metastasectomy. J Pediatr Surg 51 (4): 525-9, 2016. [PUBMED Abstract]
110. Matsunaga T, Sasaki F, Ohira M, et al.: Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma. Pediatr Surg Int 19 (3): 142-6, 2003. [PUBMED Abstract]
111. Yevich S, Calandri M, Gravel G, et al.: Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone. Cardiovasc Intervent Radiol 42 (1): 41-47, 2019. [PUBMED Abstract]
112. Malogolowkin MH, Katzenstein HM, Krailo M, et al.: Redefining the role of doxorubicin for the treatment of children with hepatoblastoma. J Clin Oncol 26 (14): 2379-83, 2008. [PUBMED Abstract]
113. Trobaugh-Lotrario AD, Meyers RL, Feusner JH: Outcomes of Patients With Relapsed Hepatoblastoma Enrolled on Children's Oncology Group (COG) Phase I and II Studies. J Pediatr Hematol Oncol 38 (3): 187-90, 2016. [PUBMED Abstract]
114. Liu B, Zhou L, Huang G, et al.: First Experience of Ultrasound-guided Percutaneous Ablation for Recurrent Hepatoblastoma after Liver Resection in Children. Sci Rep 5: 16805, 2015. [PUBMED Abstract]

Hepatocellular Carcinoma

In This Section

• Incidence
• Risk Factors
  • Alagille syndrome
  • Hepatitis B and hepatitis C infection
  • Nonviral liver injury
• Genomics of Hepatocellular Carcinoma
• Diagnosis
• Prognosis and Prognostic Factors
• Histology
  • Fibrolamellar carcinoma
  • Hepatocellular neoplasm, not otherwise specified (NOS)
• Treatment of Hepatocellular Carcinoma
  • Treatment options for hepatocellular carcinoma that is resectable at diagnosis
  • Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis
  • Treatment options for hepatocellular carcinoma with metastases at diagnosis
  • Treatment options for hepatitis B virus (HBV)–related hepatocellular carcinoma
  • Treatment options for progressive or recurrent hepatocellular carcinoma
  • Treatment options under clinical evaluation for hepatocellular carcinoma

Incidence

The annual incidence of hepatocellular carcinoma in the United States is 0.8 cases per 1 million children between the ages of 0 and 14 years and 1.5 cases per 1 million adolescents aged 15 to 19 years.[1] Although the incidence of hepatocellular carcinoma in adults in the United States has steadily increased since the 1970s, possibly because of the increased frequency of chronic hepatitis C infection,[2] the incidence in children has not increased. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher than the incidence in children in North America. The high incidence appears to be related to the incidence of perinatally acquired hepatitis B, which can be prevented in most cases by vaccination and administration of hepatitis B immune globulin to the newborn child.[3]

Fibrolamellar hepatocellular carcinoma, a subtype of hepatocellular carcinoma that is unrelated to cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection, generally occurs in adolescents and young adults, but has been reported in infants.[4]

Risk Factors

Conditions associated with hepatocellular carcinoma are described in Table 7.

Table 7. Conditions Associated With Hepatocellular Carcinoma

Associated Disorder	Clinical Findings
Alagille syndrome [5]	Broad prominent forehead, deep set eyes, and small prominent chin. Abnormality of bile ducts leads to intrahepatic scarring.
Glycogen storage diseases I–IV [6]	Symptoms vary by individual disorder.
Hepatitis B and C [7-9]	Refer to the Hepatitis B and hepatitis C infection section of this summary for more information.
Progressive familial intrahepatic cholestasis [10,11]	Symptoms of jaundice, pruritus, and failure to thrive begin in infancy and progress to portal hypertension and liver failure.
Tyrosinemia [12]	First few months of life: failure to thrive, vomiting, jaundice.

Alagille syndrome

Alagille syndrome is an autosomal dominant genetic syndrome that is usually caused by a mutation in or deletion of the JAG1 gene. It involves the bile ducts of the liver, as well as the heart and blood vessels in the brain and kidney. Patients develop a characteristic facies.[5]

Hepatitis B and hepatitis C infection

In children, hepatocellular carcinoma is associated with perinatally acquired HBV, whereas in adults, it is associated with chronic HBV and HCV infection.[7-9] Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[3] Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene could be one mechanism that results in a shortened incubation period.[13]

Hepatitis C infection is associated with development of cirrhosis and hepatocellular carcinoma that takes decades to develop and is generally not seen in children.[9] Cirrhosis in children, compared with cirrhosis in adults, is much less commonly involved in the development of hepatocellular carcinoma, and is found in only 20% to 35% of children with hepatocellular carcinoma tumors.

Nonviral liver injury

Specific types of nonviral liver injury and cirrhosis that are associated with hepatocellular carcinoma in children include the following:

• Tyrosinemia. Tyrosinemia patients are regularly screened for hepatocellular carcinoma, even if they are treated with nitisinone.[12] Nitisinone can prevent cirrhosis and decrease the incidence of hepatocellular carcinoma, especially when administered during infancy, after neonatal screening is used to diagnose tyrosinemia.[14] As of 2014, only a minority of state screening programs had adopted a highly recommended, new, more predictive newborn screen that is much more effective in newborn children aged 24 to 48 hours.[15]
  In an Iranian study, 36 children underwent liver transplant for tyrosinemia.[16] Twenty-two children had liver nodules greater than 10 cm, and in 20 children, the nodules were cirrhotic. Median age at transplant was 3.9 years. Five of 19 children older than 2 years had hepatocellular carcinoma, and no children younger than 2 years had hepatocellular carcinoma in the resected liver.
• Aggressive familial intrahepatic cholestasis. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial intrahepatic cholestasis.[10]

Genomics of Hepatocellular Carcinoma

Genomic abnormalities related to hepatocellular carcinoma include the following:

• A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[17]
• Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma observed in older children. It is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[18]
• A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.
  TERT mutations were observed in two of four cases tested.[19] TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[20]

To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

Diagnosis

Refer to the Diagnosis subsection in the Hepatoblastoma section of this summary for more information.

Prognosis and Prognostic Factors

The 5-year overall survival (OS) rate is 42% for children and adolescents with hepatocellular carcinoma.[1] The 5-year survival for hepatocellular carcinoma may be dependent on stage; in an intergroup chemotherapy study conducted in the 1990s, seven of eight stage I patients survived and less than 10% of stage III and IV patients survived.[1,21] An analysis of Surveillance, Epidemiology, and End Results (SEER) data found a 5-year OS rate of 24%, a 10-year rate of 23%, and a 20-year rate of 8% in patients aged 19 years and younger, suggesting improved outcome related to more recent treatment. In a multivariate analysis of the SEER data, surgical resection, localized tumor, and non-Hispanic ethnicity were all associated with improved outcome. Patients who had a complete surgical resection had an OS rate of 60%, compared with an OS rate of 0% for patients who had an incomplete resection.[22][Level of evidence: 3iiiA]

Factors affecting prognosis include the following:

• Treatment-related factors:
  Cure of hepatocellular carcinoma requires gross tumor resection. However, hepatocellular carcinoma is often extensively invasive or multicentric, and less than 30% of tumors are resectable. Orthotopic liver transplant has been successful in selected children with hepatocellular carcinoma.[23,24]
• PRE-Treatment EXTent of disease (PRETEXT) group (resectability) is also a prognostic factor (refer to the Risk Stratification section of this summary for more information).
• Tumor histology:
  Refer to the Histology section of this summary for more information.

Histology

The cells of hepatocellular carcinoma are epithelial in appearance. Hepatocellular carcinoma commonly arises in the right lobe of the liver.

Fibrolamellar carcinoma

A distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults and, rarely, in infants.[4,25] This histology is characterized by a fusion transcript created by deletion of a 400 kb section of chromosome 19, which was found in 15 of 15 tumors that were tested.[18]

Fibrolamellar carcinoma is not associated with cirrhosis and was previously thought to be associated with an improved prognosis.[2,25,26] Unlike nonfibrolamellar hepatocellular carcinoma in adults, fibrolamellar hepatocellular carcinoma in older children and adults is not clearly increasing in incidence over time.[2,25] The improved outcomes of patients with fibrolamellar carcinoma in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis. However, the outcomes of patients with fibrolamellar carcinoma in recent prospective studies, when compared stage for stage and PRETEXT group to PRETEXT group, is not different from the outcomes of patients with conventional hepatocellular carcinomas.[27,28]; [29][Level of evidence: 3iiA]

Hepatocellular neoplasm, not otherwise specified (NOS)

Hepatocellular neoplasm, NOS is also known as transitional liver cell tumor. This tumor, with characteristics of both hepatoblastoma and hepatocellular carcinoma, is a rare neoplasm that is found in older children and adolescents, and has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. In the international consensus classification, these tumors are referred to as hepatocellular neoplasm, NOS.[30] The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy has not been rigorously studied but is felt to be much like that of hepatocellular carcinoma.[31]

Treatment of Hepatocellular Carcinoma

Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:

1. Whether the cancer is resectable at diagnosis.
2. How the cancer responds to chemotherapy.
3. Whether the cancer has metastasized.
4. Whether the cancer is HBV related.

Treatment options for hepatocellular carcinoma that is resectable at diagnosis

Treatment options for hepatocellular carcinoma that is resectable at diagnosis include the following:

1. Complete surgical resection of the primary tumor followed by chemotherapy.
2. Chemotherapy followed by complete surgical resection of the primary tumor.[27]
3. Complete surgical resection without chemotherapy.

Surgical resection and chemotherapy are the mainstays of treatment for resectable hepatocellular carcinoma.

Evidence (complete surgical resection followed by chemotherapy):

1. Seven of eight patients with stage I hepatocellular carcinoma who were given adjuvant cisplatin-based chemotherapy survived disease free.[21]
2. In a survey of childhood liver tumors treated before the consistent use of chemotherapy, only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived.[32] This suggests that treatment with adjuvant chemotherapy may benefit children with completely resected hepatocellular carcinoma.
3. Cisplatin and doxorubicin may be administered as adjuvant therapy because these agents are active in the treatment of hepatocellular carcinoma.[27]
4. In an analysis of SEER data for children and adolescents younger than 20 years diagnosed between 1976 and 2009, patients who underwent a complete resection had a 60% 5-year OS and those who did not have a complete resection had a 0% 5-year OS.[22][Level of evidence: 3iiiA]

Evidence (complete surgical resection without chemotherapy):

1. In a single-institution retrospective report, 12 patients with stage I hepatocellular carcinoma were treated with surgery. Ten patients received no chemotherapy and two patients received a short course of chemotherapy based on oncologist preference.[33][Level of evidence: 3iiA]
   • All 12 patients are alive without evidence of disease at a median of 54 months.

Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of cancer chemotherapy have not shown improved survival rates for pediatric patients with hepatocellular carcinoma.[27] The International Childhood Liver Tumors Strategy Group (SIOPEL) studies in Europe have observed no improvement in 5-year OS since 1990. The only long-term survivors were patients whose tumors were resectable at diagnosis, which was less than 30% of children entered in the study.[34] However, some liver transplant studies (complete resection with transplant with or without neoadjuvant chemotherapy) have shown OS rates that are superior to the SIOPEL studies.[24,35-38]

Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis

The use of neoadjuvant chemotherapy or transarterial chemoembolization (TACE) to enhance resectability or liver transplant, which may result in complete resection of tumor, is necessary for cure.

Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis include the following:

1. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor is resectable, complete surgical resection.
2. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor remains unresectable:
   • Orthotopic liver transplant.
   • Temporizing TACE followed by complete resection or liver transplant.
   • TACE alone.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection of the primary tumor):

1. In a prospective study of 41 patients who received preoperative cisplatin/doxorubicin chemotherapy, treatment resulted in some degree of decrease in tumor size, with a decrease in alpha-fetoprotein (AFP) levels in about 50% of patients. The responders had a superior tumor resectability and survival, although the OS was 28% and only those undergoing complete resection survived.[27]

Evidence (chemotherapy or TACE followed by reassessment of surgical resectability; treatment options for unresectable primary tumor after chemotherapy or TACE):

1. Patients whose primary tumor remains unresectable after chemotherapy should be considered for orthotopic liver transplant. Liver transplant has been a successful therapy for children with unresectable hepatocellular carcinoma; survival is about 60%, with most deaths resulting from tumor recurrence.[23,38-41]
2. A review of treatment for hepatocellular carcinoma in patients younger than 20 years reported to SEER revealed that 75% of patients underwent resection and 25% underwent liver transplant. The 5-year OS was 53.4% with resection and 85.3% with transplant, suggesting that the criteria for transplantation in hepatocellular carcinoma might be liberalized for overall patient benefit. This approach would benefit from prospective testing.[42]
3. TACE followed by complete surgical resection of primary tumor may be an alternative to the use of chemotherapy followed by surgical resection.
   • Studies in adults in China suggest that repeated hepatic TACE before surgery may improve the outcome of subsequent hepatectomy.[43]
   • A meta-analysis found seven randomized trials that compared resection alone versus TACE followed by resection. There was no difference in 3-year event-free survival (EFS) and OS between the two groups, but the 5-year EFS and OS favored TACE followed by resection.[44]

If the primary tumor is not resectable after chemotherapy and the patient is not a transplant candidate, alternative treatment approaches used in adults include the following:

• Sorafenib.
• TACE.
• Cryosurgery.
• Intratumoral injection of alcohol.
• Radiation therapy.

There are limited data on the use of these alternative treatment approaches in children.

Limited data from a European pilot study suggest that sorafenib was well tolerated in 12 newly diagnosed children and adolescents with advanced hepatocellular carcinoma when given in combination with standard chemotherapy of cisplatin and doxorubicin.[45] Additional study is needed to define its role in the treatment of children with hepatocellular carcinoma.

Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[43,46,47] Some local approaches such as cryosurgery, radiofrequency ablation, and TACE that suppress hepatocellular carcinoma tumor progression are used as bridging therapy in adults to delay tumor growth while on a waiting list for cadaveric liver transplant.[48] In a pediatric study of eight patients with hepatocellular carcinoma, two patients died of progressive disease without transplant. Treatment with TACE stabilized disease in six patients, for a mean of 141 days to reach transplant.[49][Level of evidence: 3iiA] Five patients were alive at the end of the observation period, and one patient died of disease.(Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

Treatment options for hepatocellular carcinoma with metastases at diagnosis

No specific treatment has proven effective for metastatic hepatocellular carcinoma in the pediatric age group.

In two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous-infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[21,27] Occasional patients may transiently benefit from treatment with cisplatin/doxorubicin therapy, especially if the localized hepatic tumor shrinks adequately enough to allow resection of disease and the metastatic disease disappears or becomes resectable.

Treatment options for hepatitis B virus (HBV)–related hepatocellular carcinoma

Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improves postoperative prognosis in children and adults treated in China.[50]

Treatment options for HBV-related hepatocellular carcinoma include the following:

1. Antiviral therapy.

Evidence (antiviral therapy):

1. In a randomized controlled trial, 163 patients post–radical hepatectomy were evaluated for response to one of three antiviral treatments.[50]
   • Antiviral treatment significantly decreased hepatocellular carcinoma recurrence, with a hazard ratio (HR) of 0.48 (95% confidence interval [CI], 0.32–0.70), and hepatocellular carcinoma–related death, with an HR of 0.26 (95% CI, 0.14–0.50), in multivariate Cox analyses.
   • Patients who received antiviral treatment had significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27–0.62) and improved liver function 6 months after surgery than did the control patients (P < .001).

Treatment options for progressive or recurrent hepatocellular carcinoma

The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.[51]

Treatment options for progressive or recurrent hepatocellular carcinoma include the following:

1. Chemoembolization temporization before transplant or immediate liver transplant, for those with isolated recurrence in the liver.[23,38,39,52]
2. Phase I and phase II clinical trials may be appropriate and should be considered.
   • Treatment with sorafenib has resulted in improved progression-free survival in adults with advanced hepatocellular carcinoma. For adult patients who received sorafenib, the median survival and time to radiologic progression were about 3 months longer than for patients who received a placebo.[53] A phase II COG trial of single-agent sorafenib has been completed in children and the study results are pending.

Treatment options under clinical evaluation for hepatocellular carcinoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• AHEP1531 (NCT03533582) (Cisplatin and Combination Chemotherapy in Treating Children and Young Adults with Hepatoblastoma or Liver Cancer After Surgery):
  This is the COG's participation in a large international trial (Pediatric Hepatic Malignancy International Therapeutic Trial [PHITT]) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.
  • Hepatocellular carcinoma that is potentially resectable is treated with complete resection without any chemotherapy if the mass appears to derive from underlying liver disease. If the hepatocellular carcinoma appears to be de novo without underlying disease, it is treated with resection followed by four cycles of cisplatin/doxorubicin.
  • Patients with hepatocellular carcinoma that is metastatic or appears unresectable at diagnosis undergo consultation with interventional radiology and liver transplant services. Patients are then randomly assigned to receive either cisplatin/doxorubicin/sorafenib for three 21-day cycles or cisplatin/doxorubicin/sorafenib alternating with gemcitabine/oxaliplatin/sorafenib for four 14-day cycles. Responding patients continue chemotherapy for the same number of cycles (3 or 4); they receive the same chemotherapy regimen to which they were originally assigned.
• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

References

1. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Bethesda, Md: National Cancer Institute, 2012, Section 29. Also available online. Last accessed April 11, 2019.
2. El-Serag HB, Davila JA, Petersen NJ, et al.: The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139 (10): 817-23, 2003. [PUBMED Abstract]
3. Chang MH, Chen TH, Hsu HM, et al.: Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems. Clin Cancer Res 11 (21): 7953-7, 2005. [PUBMED Abstract]
4. Cruz O, Laguna A, Vancells M, et al.: Fibrolamellar hepatocellular carcinoma in an infant and literature review. J Pediatr Hematol Oncol 30 (12): 968-71, 2008. [PUBMED Abstract]
5. Keeffe EB, Pinson CW, Ragsdale J, et al.: Hepatocellular carcinoma in arteriohepatic dysplasia. Am J Gastroenterol 88 (9): 1446-9, 1993. [PUBMED Abstract]
6. Siciliano M, De Candia E, Ballarin S, et al.: Hepatocellular carcinoma complicating liver cirrhosis in type IIIa glycogen storage disease. J Clin Gastroenterol 31 (1): 80-2, 2000. [PUBMED Abstract]
7. Ni YH, Chang MH, Hsu HY, et al.: Hepatocellular carcinoma in childhood. Clinical manifestations and prognosis. Cancer 68 (8): 1737-41, 1991. [PUBMED Abstract]
8. Tsukuma H, Hiyama T, Tanaka S, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328 (25): 1797-801, 1993. [PUBMED Abstract]
9. González-Peralta RP, Langham MR, Andres JM, et al.: Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 48 (5): 630-5, 2009. [PUBMED Abstract]
10. Knisely AS, Strautnieks SS, Meier Y, et al.: Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44 (2): 478-86, 2006. [PUBMED Abstract]
11. Alonso EM, Snover DC, Montag A, et al.: Histologic pathology of the liver in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 18 (2): 128-33, 1994. [PUBMED Abstract]
12. van Spronsen FJ, Bijleveld CM, van Maldegem BT, et al.: Hepatocellular carcinoma in hereditary tyrosinemia type I despite 2-(2 nitro-4-3 trifluoro- methylbenzoyl)-1, 3-cyclohexanedione treatment. J Pediatr Gastroenterol Nutr 40 (1): 90-3, 2005. [PUBMED Abstract]
13. Park WS, Dong SM, Kim SY, et al.: Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59 (2): 307-10, 1999. [PUBMED Abstract]
14. de Laet C, Dionisi-Vici C, Leonard JV, et al.: Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis 8: 8, 2013. [PUBMED Abstract]
15. De Jesús VR, Adam BW, Mandel D, et al.: Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs. Mol Genet Metab 113 (1-2): 67-75, 2014 Sep-Oct. [PUBMED Abstract]
16. Bahador A, Dehghani SM, Geramizadeh B, et al.: Liver Transplant for Children With Hepatocellular Carcinoma and Hereditary Tyrosinemia Type 1. Exp Clin Transplant 13 (4): 329-32, 2015. [PUBMED Abstract]
17. Vilarinho S, Erson-Omay EZ, Harmanci AS, et al.: Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol 61 (5): 1178-83, 2014. [PUBMED Abstract]
18. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014. [PUBMED Abstract]
19. Eichenmüller M, Trippel F, Kreuder M, et al.: The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61 (6): 1312-20, 2014. [PUBMED Abstract]
20. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 4: 2218, 2013. [PUBMED Abstract]
21. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 20 (12): 2789-97, 2002. [PUBMED Abstract]
22. Allan BJ, Wang B, Davis JS, et al.: A review of 218 pediatric cases of hepatocellular carcinoma. J Pediatr Surg 49 (1): 166-71; discussion 171, 2014. [PUBMED Abstract]
23. Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006. [PUBMED Abstract]
24. Vinayak R, Cruz RJ, Ranganathan S, et al.: Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015). Liver Transpl 23 (12): 1577-1588, 2017. [PUBMED Abstract]
25. Eggert T, McGlynn KA, Duffy A, et al.: Fibrolamellar hepatocellular carcinoma in the USA, 2000-2010: A detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database. United European Gastroenterol J 1 (5): 351-7, 2013. [PUBMED Abstract]
26. Mayo SC, Mavros MN, Nathan H, et al.: Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective. J Am Coll Surg 218 (2): 196-205, 2014. [PUBMED Abstract]
27. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002. [PUBMED Abstract]
28. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97 (8): 2006-12, 2003. [PUBMED Abstract]
29. Weeda VB, Murawski M, McCabe AJ, et al.: Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 49 (12): 2698-704, 2013. [PUBMED Abstract]
30. López-Terrada D, Alaggio R, de Dávila MT, et al.: Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27 (3): 472-91, 2014. [PUBMED Abstract]
31. Prokurat A, Kluge P, Kościesza A, et al.: Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin. Med Pediatr Oncol 39 (5): 510-8, 2002. [PUBMED Abstract]
32. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey--1974. J Pediatr Surg 10 (3): 329-37, 1975. [PUBMED Abstract]
33. D'Souza AM, Shah R, Gupta A, et al.: Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma. Pediatr Blood Cancer 65 (11): e27293, 2018. [PUBMED Abstract]
34. Murawski M, Weeda VB, Maibach R, et al.: Hepatocellular Carcinoma in Children: Does Modified Platinum- and Doxorubicin-Based Chemotherapy Increase Tumor Resectability and Change Outcome? Lessons Learned From the SIOPEL 2 and 3 Studies. J Clin Oncol 34 (10): 1050-6, 2016. [PUBMED Abstract]
35. Kelly D, Sharif K, Brown RM, et al.: Hepatocellular carcinoma in children. Clin Liver Dis 19 (2): 433-47, 2015. [PUBMED Abstract]
36. Malek MM, Shah SR, Atri P, et al.: Review of outcomes of primary liver cancers in children: our institutional experience with resection and transplantation. Surgery 148 (4): 778-82; discussion 782-4, 2010. [PUBMED Abstract]
37. Ismail H, Broniszczak D, Kaliciński P, et al.: Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients? Pediatr Transplant 13 (6): 682-92, 2009. [PUBMED Abstract]
38. Pham TA, Gallo AM, Concepcion W, et al.: Effect of Liver Transplant on Long-term Disease-Free Survival in Children With Hepatoblastoma and Hepatocellular Cancer. JAMA Surg 150 (12): 1150-8, 2015. [PUBMED Abstract]
39. Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000. [PUBMED Abstract]
40. Bilik R, Superina R: Transplantation for unresectable liver tumors in children. Transplant Proc 29 (7): 2834-5, 1997. [PUBMED Abstract]
41. Romano F, Stroppa P, Bravi M, et al.: Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma. Pediatr Transplant 15 (6): 573-9, 2011. [PUBMED Abstract]
42. McAteer JP, Goldin AB, Healey PJ, et al.: Surgical treatment of primary liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 17 (8): 744-50, 2013. [PUBMED Abstract]
43. Zhang Z, Liu Q, He J, et al.: The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcinoma. Cancer 89 (12): 2606-12, 2000. [PUBMED Abstract]
44. Yu T, Xu X, Chen B: TACE combined with liver resection versus liver resection alone in the treatment of resectable HCC: a meta-analysis. Chinese-German J Clin Oncol 12 (11): 532-6, 2013.
45. Schmid I, Häberle B, Albert MH, et al.: Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer 58 (4): 539-44, 2012. [PUBMED Abstract]
46. Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Semin Surg Oncol 14 (2): 171-4, 1998. [PUBMED Abstract]
47. Lencioni RA, Allgaier HP, Cioni D, et al.: Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228 (1): 235-40, 2003. [PUBMED Abstract]
48. Lubienski A: Hepatocellular carcinoma: interventional bridging to liver transplantation. Transplantation 80 (1 Suppl): S113-9, 2005. [PUBMED Abstract]
49. Weiss KE, Sze DY, Rangaswami AA, et al.: Transarterial chemoembolization in children to treat unresectable hepatocellular carcinoma. Pediatr Transplant 22 (4): e13187, 2018. [PUBMED Abstract]
50. Yin J, Li N, Han Y, et al.: Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 31 (29): 3647-55, 2013. [PUBMED Abstract]
51. Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000. [PUBMED Abstract]
52. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004. [PUBMED Abstract]
53. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PUBMED Abstract]

Undifferentiated Embryonal Sarcoma of the Liver

In This Section

• Incidence
• Diagnosis
• Histology
• Prognosis and Prognostic Factors
• Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver
• Treatment Options Under Clinical Evaluation for Undifferentiated Embryonal Sarcoma of the Liver

Incidence

Undifferentiated embryonal sarcoma of the liver (UESL) is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.[1]

Diagnosis

UESL presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. Widespread infiltration throughout the liver and pulmonary metastasis is common. It may appear solid or cystic on imaging, frequently with central necrosis.

Distinctive features are characteristic intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2] Many UESL tumors contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of INI1 expression by immunohistochemistry to help rule out rhabdoid tumor of the liver.

It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma because they share some common clinical and pathologic features but treatment differs between the two, as shown in Table 8.[1] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)

Table 8. Diagnostic Differences Between Undifferentiated Embryonal Sarcoma of the Liver and Biliary Tract Rhabdomyosarcomaa

	Undifferentiated Embryonal Sarcoma of the Liver	Biliary Tract Rhabdomyosarcoma
aAdapted from Nicol et al.[1]
Age at Diagnosis	Median age 10.5 y	Median age 3.4 y
Tumor Location	Often arises in the right lobe of the liver	Often arises in the hilum of the liver
Biliary Obstruction	Unusual	Frequent; jaundice is a common presenting symptom
Treatment	Surgery and chemotherapy	Surgery (usually biopsy only), radiation therapy, and chemotherapy

Histology

Distinctive histologic features are intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2]

Strong clinical and histological evidence suggests that UESL can arise within preexisting mesenchymal hamartomas of the liver, which are large benign multicystic masses that present in the first 2 years of life.[1] In a report of 11 cases of UESL, 5 arose in association with mesenchymal hamartomas of the liver, and transition zones between the histologies were noted.[3] Many mesenchymal hamartomas of the liver have a characteristic translocation with a breakpoint at 19q13.4 and several UESLs have the same translocation.[4,5] Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.[4]

Prognosis and Prognostic Factors

The overall survival (OS) of children with UESL appears to be substantially better than 50% when combining reports, although all series are small and most may be selected to report successful treatment.[6]; [7][Level of evidence: 3iiA]; [8-17][Level of evidence: 3iiiA]

The Childhood Cancer Database, which does not provide central review of pathology or reliable details of nonsurgical treatment, reported on 103 children with UESL diagnosed between 1998 and 2012. The 5-year OS was 86% for all patients and 92% for those treated with combination surgery and chemotherapy. A multivariate analysis of the nonsurgical data revealed statistically significant poorer outcomes for patients with tumors larger than 15 cm. Seven of ten children who presented with metastases and ten of ten children who underwent orthotopic liver transplant survived at least 5 years, but details of their treatment were not presented.[18]

Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver

UESL is rare. Only small series have been published regarding treatment.[19]

Treatment options for UESL include the following:

• Surgical resection and chemotherapy.
• Liver transplant, for unresectable tumors.

The generally accepted approach is resection of the primary tumor mass in the liver when possible.[18] Use of aggressive chemotherapy regimens seems to have improved the OS of patients with UESL. Neoadjuvant chemotherapy can be effective in decreasing the size of an unresectable primary tumor mass, resulting in resectability.[8-11] Most patients are treated with chemotherapy regimens used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.[6]; [7,20][Level of evidence: 3iiA]; [8-16][Level of evidence: 3iiiA]

Evidence (surgical resection and chemotherapy):

1. In the only prospective series treating patients with UESL, which came from the Italian and German Soft Tissue Sarcoma Cooperative Groups, patients were treated with (1) conservative surgery or (2) biopsy followed by neoadjuvant chemotherapy consisting of varying combinations of vincristine, cyclophosphamide, dactinomycin, doxorubicin, and ifosfamide. Disease evaluation, usually after four cycles of chemotherapy, was followed by second-look surgery when appropriate to try to remove residual primary tumor followed by additional and/or adjuvant chemotherapy.[12]
   • Ten of 17 patients survived in their first complete remission, and one patient survived in third complete remission.
2. In a single-center retrospective report, five patients with UESL were treated with surgery and adjuvant chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Four patients were stage I and one patient was stage II. One patient received abdominal radiation for tumor rupture.[17][Level of evidence: 3iiiA]
   • All patients are alive (range, 5–19 years), with 100% event-free survival and OS.

Liver transplant has occasionally been used to successfully treat an otherwise unresectable primary tumor.[14,16,18,21]

Treatment Options Under Clinical Evaluation for Undifferentiated Embryonal Sarcoma of the Liver

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation or chemotherapy (ifosfamide/etoposide) and radiation in pediatric and adult patients newly diagnosed with unresected, intermediate-risk and high-risk nonrhabdomyosarcomatous STS. Subsequently, this trial will compare the rates of near complete pathologic response (>90% necrosis) of: (1) preoperative pazopanib plus chemoradiation versus preoperative chemoradiation alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive (i.e., histologies of undifferentiated sarcoma, synovial sarcoma, and embryonal sarcoma of the liver) adult and pediatric nonrhabdomyosarcomatous STS; and (2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous STS.
• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

References

1. Nicol K, Savell V, Moore J, et al.: Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children's Oncology Group study. Pediatr Dev Pathol 10 (2): 89-97, 2007 Mar-Apr. [PUBMED Abstract]
2. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001. [PUBMED Abstract]
3. Shehata BM, Gupta NA, Katzenstein HM, et al.: Undifferentiated embryonal sarcoma of the liver is associated with mesenchymal hamartoma and multiple chromosomal abnormalities: a review of eleven cases. Pediatr Dev Pathol 14 (2): 111-6, 2011 Mar-Apr. [PUBMED Abstract]
4. Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005. [PUBMED Abstract]
5. O'Sullivan MJ, Swanson PE, Knoll J, et al.: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: report of a case and review of the literature. Pediatr Dev Pathol 4 (5): 482-9, 2001 Sep-Oct. [PUBMED Abstract]
6. Walther A, Geller J, Coots A, et al.: Multimodal therapy including liver transplantation for hepatic undifferentiated embryonal sarcoma. Liver Transpl 20 (2): 191-9, 2014. [PUBMED Abstract]
7. Ismail H, Dembowska-Bagińska B, Broniszczak D, et al.: Treatment of undifferentiated embryonal sarcoma of the liver in children--single center experience. J Pediatr Surg 48 (11): 2202-6, 2013. [PUBMED Abstract]
8. Chowdhary SK, Trehan A, Das A, et al.: Undifferentiated embryonal sarcoma in children: beware of the solitary liver cyst. J Pediatr Surg 39 (1): E9-12, 2004. [PUBMED Abstract]
9. Baron PW, Majlessipour F, Bedros AA, et al.: Undifferentiated embryonal sarcoma of the liver successfully treated with chemotherapy and liver resection. J Gastrointest Surg 11 (1): 73-5, 2007. [PUBMED Abstract]
10. Kim DY, Kim KH, Jung SE, et al.: Undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. J Pediatr Surg 37 (10): 1419-23, 2002. [PUBMED Abstract]
11. Webber EM, Morrison KB, Pritchard SL, et al.: Undifferentiated embryonal sarcoma of the liver: results of clinical management in one center. J Pediatr Surg 34 (11): 1641-4, 1999. [PUBMED Abstract]
12. Bisogno G, Pilz T, Perilongo G, et al.: Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer 94 (1): 252-7, 2002. [PUBMED Abstract]
13. Urban CE, Mache CJ, Schwinger W, et al.: Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients. Cancer 72 (8): 2511-6, 1993. [PUBMED Abstract]
14. Okajima H, Ohya Y, Lee KJ, et al.: Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure. J Pediatr Surg 44 (2): e33-8, 2009. [PUBMED Abstract]
15. Weitz J, Klimstra DS, Cymes K, et al.: Management of primary liver sarcomas. Cancer 109 (7): 1391-6, 2007. [PUBMED Abstract]
16. Plant AS, Busuttil RW, Rana A, et al.: A single-institution retrospective cases series of childhood undifferentiated embryonal liver sarcoma (UELS): success of combined therapy and the use of orthotopic liver transplant. J Pediatr Hematol Oncol 35 (6): 451-5, 2013. [PUBMED Abstract]
17. Mathias MD, Ambati SR, Chou AJ, et al.: A single-center experience with undifferentiated embryonal sarcoma of the liver. Pediatr Blood Cancer 63 (12): 2246-2248, 2016. [PUBMED Abstract]
18. Shi Y, Rojas Y, Zhang W, et al.: Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database. Pediatr Blood Cancer 64 (4): , 2017. [PUBMED Abstract]
19. Techavichit P, Masand PM, Himes RW, et al.: Undifferentiated Embryonal Sarcoma of the Liver (UESL): A Single-Center Experience and Review of the Literature. J Pediatr Hematol Oncol 38 (4): 261-8, 2016. [PUBMED Abstract]
20. Merli L, Mussini C, Gabor F, et al.: Pitfalls in the surgical management of undifferentiated sarcoma of the liver and benefits of preoperative chemotherapy. Eur J Pediatr Surg 25 (1): 132-7, 2015. [PUBMED Abstract]
21. Kelly MJ, Martin L, Alonso M, et al.: Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child. J Pediatr Surg 44 (12): e1-3, 2009. [PUBMED Abstract]

Infantile Choriocarcinoma of the Liver

In This Section

• Treatment Options for Infantile Choriocarcinoma of the Liver
• Treatment Options Under Clinical Evaluation for Infantile Choriocarcinoma of the Liver

Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta during gestation and presents with a liver mass in the first few months of life. Metastasis from the placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often unstable at diagnosis because of hemorrhage of the tumor.

Clinical diagnosis may be made without biopsy on the basis of tumor imaging of the liver associated with extremely high serum beta-hCG levels and normal alpha-fetoprotein (AFP) levels for age.[1]

Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large multinucleated syncytia formed from the cytotrophoblasts.[2]

Treatment Options for Infantile Choriocarcinoma of the Liver

Treatment options for infantile choriocarcinoma of the liver include the following:

1. Surgical resection.[1]
2. Chemotherapy followed by surgical resection.

Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Often surgical removal of the primary tumor is performed after neoadjuvant chemotherapy.[1]

Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate, and many women, including those with distant metastases, are cured with single-agent chemotherapy. Maternal and infantile choriocarcinoma both come from the same placental malignancy. The combination of cisplatin, etoposide, and bleomycin, as used in other pediatric germ cell tumors, has been effective in some patients and is followed by resection of residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.[1]

Treatment Options Under Clinical Evaluation for Infantile Choriocarcinoma of the Liver

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

References

1. Yoon JM, Burns RC, Malogolowkin MH, et al.: Treatment of infantile choriocarcinoma of the liver. Pediatr Blood Cancer 49 (1): 99-102, 2007. [PUBMED Abstract]
2. Olson T, Schneider D, Perlman E: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2011, pp 1045-1067.

Vascular Liver Tumors

Careful attention to the clinical history, physical exam, laboratory evaluation, and radiologic imaging is essential for an appropriate diagnosis of vascular liver tumors. If there is any doubt about the accuracy of the diagnosis, a biopsy should be performed.

The different diagnoses of vascular tumors of the liver include the following:

• Benign tumors.
  • Focal congenital hemangiomas (refer to the Congenital Hemangiomas section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).
  • Multiple or diffuse infantile hemangiomas (refer to the Infantile Hemangioma section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).
• Malignant tumors.
  • Epithelioid hemangioendothelioma (refer to the Epithelioid Hemangioendothelioma section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).
  • Angiosarcoma (refer to the Angiosarcoma of the Soft Tissue section of the PDQ summary on Childhood Vascular Tumors Treatment for more information).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Changes to This Summary (10/04/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview for Childhood Liver Cancer

The Other Treatment Approaches subsection was extensively revised.

Hepatoblastoma

Added text to state that in an exploratory study of 34 children with hepatoblastoma, the rate of decrease in alpha-fetoprotein and tumor volume, but not in Response Evaluation Criteria In Solid Tumors I measurements, following two courses of treatment after diagnosis was predictive of event-free survival and overall survival (cited Nguyen et al. as reference 57).

Revised Table 6 to include the outcome results of the AHEP0731 trial (cited Katzenstein et al. as reference 80 and level of evidence 3iiA).

Added text about the treatment and outcome results of the AHEP0731 trial.

Revised text to state that percutaneous ablation techniques may also be considered for palliation.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood liver cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Liver Cancer Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
• Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/child-liver-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389232]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

• Updated: October 4, 2019