Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Second Malignant Neoplasms Following Treatment for Hepatoblastoma: An International Report and Review of the Literature.

Treatment intensification has improved survival in patients with hepatoblastoma (HB); however, these treatments are associated with an increased risk of late effects, including second malignant neoplasms (SMNs). Data is limited regarding SMNs following HB treatment. Cases of SMNs following treatment for HB reported in the literature and from personal communication were analyzed to further assess this late effect. Thirty-eight patients were identified. The median age at diagnosis of HB was 16 months (range: 3 to 168 mo). All patients had received a platinum agent, and almost all had anthracycline exposure. The SMNs reported were hematopoietic malignancies (n=19), solid tumors (n=12), and post-transplant lymphoproliferative disorder (n=7). Of the 36 patients with outcome data, 19 survived. SMNs following HB treatment were primarily seen in patients with chemotherapy exposure, a history of liver transplantation, hereditary tumor predisposition syndromes, and/or a history of radiation treatment. Hematopoietic malignancies were the most common SMN reported in this cohort and were diagnosed earlier than other SMNs. Prospective collection of data through a companion late effects study or international registry could be used to further evaluate the rates and risks of SMNs as well as tumor predisposition syndromes in patients treated for HB.

Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC).

BACKGROUND: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers. PROCEDURE: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis. RESULTS: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB. CONCLUSIONS: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.

Tyrosine kinase-altered spindle cell neoplasms with EGFR internal tandem duplications.

In this study, we present two extra-renal pediatric spindle cell neoplasms with epidermal growth factor receptor (EGFR) internal tandem duplications (ITD). Histologically, these tumors demonstrated the same histologic features seen in other tyrosine kinase-altered spindle cell neoplasms, with one case showing abundant adipose tissue with cellular fibrous septae resembling lipofibromatosis and the other case showing fascicles of spindled cells resembling infantile fibrosarcoma. There was variable expression of CD34, S100, and SMA, and all cases were negative for panTRK. This case series adds to our molecular understanding of the spectrum of tyrosine kinase-altered spindle cell neoplasms and represents the first reported examples of EGFR ITDs in extra-renal tumors. The presence of EGFR alterations in the absence of gene fusions represents a potential therapeutic target and necessitates a broader testing panel for this group of tumors.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

PURPOSE: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Surgical and anesthetic management for hepatectomy in two pediatric patients with trisomy 18, pulmonary hypertension, and hepatoblastoma.

Children with trisomy 18 are surviving longer and undergoing more aggressive life-sustaining therapy. This report describes two patients with trisomy 18 and hepatoblastoma (HB) successfully resected in the setting of significant pulmonary hypertension. Forty-four previously published cases of the association between HB and trisomy 18 are reviewed. With careful multidisciplinary preoperative planning, successful resection of HB in children with trisomy 18 who have significant pulmonary hypertension is feasible. Because HB and trisomy 18 are increasing in prevalence, the need for timely liver tumor resection in the setting of pulmonary hypertension will be more common.

Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening.

Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma. All cases of hepatoblastoma in patients with FAP reported in the literature were reviewed. One hundred and nine patients were identified. Thirty-five patients (of 49 with data) were diagnosed with hepatoblastoma prior to a later diagnosis of FAP (often in association with advanced colorectal carcinoma), emphasizing a need to identify patients earlier with germline APC mutations for early colorectal carcinoma screening. Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted.

Outcomes of Patients With Relapsed Hepatoblastoma Enrolled on Children's Oncology Group (COG) Phase I and II Studies.

Data are limited regarding outcomes of patients treated for relapsed hepatoblastoma. We reviewed enrollment patterns and outcomes of patients with hepatoblastoma on Children's Oncology Group (COG) phase I/II studies. The medical literature was searched for reports of COG phase I/II studies using PUBMED as well as an inventory from the COG publications office searching manuscripts published from 2000 to 2014. Seventy-one patients with relapsed hepatoblastoma were enrolled on 23 separate COG phase I/II studies. Four studies collected α-fetoprotein (AFP) data, but none utilized AFP decline in assessing response. Most studies enrolled few patients with relapsed hepatoblastoma: 7 studies enrolled 1 patient, and another 7 studies enrolled 2 patients each. Only 9 studies enrolled 3 or more patients with relapsed hepatoblastoma. Four responses were reported. Dedicated strata and/or focus on 1 or 2 studies with compelling biological or clinical rationale for hepatoblastoma may improve accrual (and statistical significance of response data) of patients with relapsed hepatoblastoma. Prospective study of AFP decline versus RECIST response could help determine the optimal method of assessing response to identify potentially beneficial treatments in hepatoblastoma.

Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment?

Patients with Beckwith-Wiedemann Syndrome (BWS) are predisposed to developing hepatoblastoma. Clinical data were reviewed in all cases of hepatoblastoma in patients with BWS reported in the literature and from personal cases. Patients were identified by literature review using PubMed and by a search of the authors' local tumor registries. Fifty-six patients were identified. The median age of presentation with hepatoblastoma was 6 months (range birth-30 mo). Thirteen of 26 patients were born prematurely. Of 31 evaluable patients, 19 exhibited hemihypertrophy. Thirty-two of 33 patients with α-fetoprotein data reported had elevated levels at diagnosis. Overall survival was 75% (27 of 36 patients). Of 25 patients with data who survived, 24 were treated with chemotherapy and surgery (vs. only 2 of 8 who did not survive). All 9 patients with hepatoblastoma detected by routine screening with outcomes reported were surviving at the time of the reports. Overall survival was high in patients with BWS and hepatoblastoma, especially given lower stage at presentation and when treated with surgery and chemotherapy. Future prospective trials should evaluate if BWS is independently associated with outcome and if the outcome is improved by routine screening.

The RELIVE consortium for relapsed or refractory pediatric hepatoblastoma and hepatocellular carcinoma: a scoping review of the problem and a proposed solution.

Liver tumors account for approximately 2% of all pediatric malignancies. Children with advanced stages of hepatoblastoma (HB) are cured only 50-70% of the time while children with advanced hepatocellular carcinoma (HCC) have a <20% 5-year overall survival. This scoping review was performed to highlight the paucity of rigorous, reliable data guiding the management of relapsed pediatric HB or HCC. When these patients are enrolled on prospective trials, the trials are often histology-agnostic, exclude patients less than a year of age, lack a liquid formulary of the drug under study, exclude recipients of a solid organ transplant, and enroll only 1-2 patients limiting the ability to deduce efficacious regimens for current use or future study. We highlight the creation of a global pediatric consortium intended to source retrospective relapse data from over 100 institutions spanning 4 continents. The data collected from this effort will inform future relapse trials.

Outcomes for patients with congenital hepatoblastoma.

BACKGROUND: Congenital hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. PROCEDURE: We retrospectively reviewed two patients from the senior authors' personal series and 25 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94, and HB 99). We compared this series with cases of congenital hepatoblastoma previously published in the literature. RESULTS: The 3-year survival in our case series was 86% (18/21) with a follow-up of 44-230 months (median 85.5 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. Survival was comparable to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [von Schweinitz et al., Eur J Cancer 1997; 33:1243-1249]. The 2-year survival of cases reported in the literature was 0% (0/9) and 42% (10/24) for patients reported before and after 1990, respectively. CONCLUSIONS: Congenital hepatoblastoma does not appear to confer a worse prognosis. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of hepatoblastoma at this young age is much better than has been historically reported. More rigorous analysis should be conducted in future multicenter trials. It is possible that congenital hepatoblastoma should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy.

Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children's Hepatic Tumors International Collaboration (CHIC).

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.

Relapsed hepatoblastoma.

Successful treatment of recurrent hepatoblastoma (HB) relies largely on surgical resection. When tumors are responsive, chemotherapy can be used to render patients resectable. Various chemotherapeutic regimens studied in small numbers of patients on phase I/II trials have shown few responses. The best available data indicate that doxorubicin, if not given during intial treatment, and irinotecan are the most active agents in recurrent HB. Stem cell transplantation and radiation therapy have been reported in several patients with unclear successes. Advances in therapy for relapsed patients require concentrating enrollment in one or two phase I/II trials utilizing agents with promising preclinical data.

Chemotherapeutic approaches for newly diagnosed hepatoblastoma: past, present, and future strategies.

Surgical resection is the foundation of therapy in hepatoblastoma (HB), yet most patients have unresectable tumors at diagnosis. Patients with resectable tumors have event-free survival (EFS) of 80-90% and can be cured with cisplatin, 5-fluorouracil, and vincristine. Patients whose tumors are unresectable but without overt metastases at diagnosis have EFS of 60-70%, and many can be rendered resectable without doxorubicin. Children with metastatic disease have fared poorly with 20-50% EFS, and new approaches for these patients remain desperately needed. Dose intensification of cisplatin and doxorubicin appears beneficial in high-risk patients. Future treatment strategies, which may be useful, include increasing intensity and/or duration of therapy, developing a maintenance regimen (oral irinotecan), using liver transplantation more often for patients to undergo complete resection, and identifying and incorporating novel agents. A better understanding of the biologic and pathologic factors is critical for predicting tumor behavior and developing more logical risk-based treatments.

Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee.

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.

Rhabdoid tumors of the liver: rare, aggressive, and poorly responsive to standard cytotoxic chemotherapy.

BACKGROUND: Rhabdoid tumors of the liver are rare tumors that are difficult to cure. We compiled all the cases previously reported in the literature to review clinical data, treatments, and outcomes. PROCEDURE: Patients were identified by literature review using PubMed. RESULTS: Thirty-four patients were identified. The median age at presentation was 8 months. All patients with reported AFP results exhibited normal or minimally increased serum AFP levels. All 10 tumors with reported INI1 immunohistochemistry results were reported as negative. Twenty-one patients presented with metastatic disease at diagnosis. Thirty patients died of disease or treatment complications. Most deaths occurred within 12 months after diagnosis. Five patients survived at the time of the reports with one patient alive with disease. One patient relapsed and subsequently died after the report was published. Of the four patients alive without disease, all were treated with chemotherapy, and at least three had surgery or transplantation. Two patients received radiation therapy but did not survive. CONCLUSIONS: Rhabdoid tumors of the liver are aggressive, rare tumors of the infant liver that are often associated with metastases at the time of diagnosis. Mortality is high and often occurs soon after diagnosis. Treatment with aggressive chemotherapy in combination (especially an alkylating agents doxorubicin) with complete resection may lead to improved outcomes. Therapy targeted to the INI1 mutation of these tumors is currently being investigated and may offer greater hope of cure.

Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors.

BACKGROUND: Small cell undifferentiated (SCU) histology in patients with stage I hepatoblastoma (HB) predicts an increased risk of relapse. We sought to determine the significance of SCU histology in patients with unresectable HB. PROCEDURE: Patients enrolled on the pediatric Intergroup (INT0098) trial for HB and patients from the personal consultation files of two of the authors (MF, LG) were reviewed for cases with SCU histology. These patients were compared with SCU HB patients identified by literature review. RESULTS: Eleven patients were studied. All patients with reported AFP results exhibited normal or minimally increased serum AFP levels. None of the patients survived: 10 died of disease progression, and 1 died from treatment complications. Immunostaining revealed that tumors from six of six patients tested were INI1 negative. Cytogenetic and molecular abnormalities in one patient (and two patients from the literature review) were similar to those described in rhabdoid tumors. Comparison with patients from the literature review revealed similar results except that 4 of 29 patients survived without evidence of disease. CONCLUSIONS: SCU histology in HB patients is associated with an adverse outcome. These tumors appear to be biologically different from non-SCU HB. Evaluation of patient characteristics and outcomes for children with SCU HB and/or those with low AFP levels should be determined from large cooperative group studies. In the meantime, we suggest patients with unresectable HB containing SCU elements have careful cytogenetic, molecular, and immunohistochemical evaluation to ascertain rhabdoid features and receive treatment that differs from that provided for other HB patients.

Unresectable hepatoblastoma: current perspectives.

Although rare, hepatoblastoma is the most common pediatric liver tumor. Complete resection is a critical component for cure; however, most patients will have tumors that are not resected at diagnosis. For these patients, administration of neoadjuvant chemotherapy renders tumors resectable in most patients. For patients whose tumors remain unresectable after chemotherapy, liver transplantation is indicated (in the absence of active unresectable metastatic disease). In patients whose tumors remain unresectable after conventional chemotherapy, interventional techniques may serve as a promising option to reduce tumor size, decrease systemic toxicity, decrease need for liver transplantation, and increase feasibility of tumor resection.