We have identified a cohort of children with stage I PFH hepatoblastoma that can be cured with primary surgical resection; this cohort represents approximately 6% of patients with hepatoblastoma in the two studies. Both studies were conducted with rapid central pathology review and strict monitoring criteria and stopping rules to safely test the strategy. Criteria for diagnosis of PFH included a low mitotic rate of no more than two mitoses per 10 high-power microscopic fields (×400 magnification) per the report by Weinberg and Finegold.14
The PFH criteria were rigidly defined and strict because of the known benefit of cisplatin-based chemotherapy despite its toxicity. The ultimate goal is to maintain cure and reduce acute and long-term toxicity. COG has continued this strategy in its current trial AHEP0731. In this study, we have reduced chemotherapy for all well-differentiated stage I fetal histology tumors regardless of mitotic rate.
In 1970, Kasai and Watanabe13
were the first to show a relationship between histopathology and outcome in children with hepatoblastoma. Gonzalez-Crussi et al21
explored histologic subtypes and reported on five patients of total fetal histology. In their study, two patients were cured with resection alone, two patients had extrahepatic disease and did not survive, and one patient was found to have an incidental tumor noted at autopsy after death that was related to complications of Down syndrome. Lack et al22
reported on a series of 54 patients and suggested a more favorable outcome in patients with a predominantly fetal pattern. Interestingly, eight of 11 patients treated with resection alone survived, although specific follow-up and the specific histologies of these tumors were not provided. Weinberg and Finegold15
reported on 27 patients with hepatoblastoma, including six of eight patients with PFH who were without disease for more than 4 years from diagnosis. These authors refined the criteria for PFH to require ≤ 2 mitoses per 10 high-power (×400 magnification) fields and stipulated that the entire tumor exhibit fetal histology. Douglass et al10
reported on four patients with stage I PFH tumors who survived with resection alone in the Pediatric Oncology Group Studies 8696 and 8697.
Haas et al15
have conducted the most extensive analysis of fetal histology. In a series of 168 patients with hepatoblastoma, ninety patients were described as having PFH, 28 of whom were resected at diagnosis, 46 had nonmetastatic and nonresectable disease, and 16 had metastatic disease. Twenty-five patients (89%) with resected PFH were free of disease at 4 years, whereas those with unresected or metastatic PFH had no survival advantage. In this study, the number of mitoses per high-power field was not specifically evaluated.
In addition to the United States data from Haas et al15
, studies from England23
have also suggested an improved outcome for patients PFH. The International Childhood Liver Tumours Strategy Group (SIOPEL) trials 1 and 2 have not specifically addressed this issue.2,9
Uniform criteria in diagnosing, describing, centrally reviewing, and treating patients with fetal histology have been not used. The diagnostic criteria for the determination of PFH has varied, and perhaps most importantly, the SIOPEL studies have not had access to tissue from untreated tumors for analysis. Brown et al2
did not identify PFH as having an improved outcome, probably because this study relied on needle biopsy tissue with potential sampling error and an inability to reflect the entirety of the tumor. Others have based the analysis on predominant fetal histology,15,22,24
a term that is not equivalent to the PFH criteria used in this study as established by Weinberg and Finegold.14
When feasible and safe, the COG strategy has favored primary resection for hepatoblastoma in an attempt to minimize total chemotherapy exposure in the approximately 30% of newly diagnosed patients who can undergo resection at diagnosis. In a philosophy designed to decreased surgical morbidity and truncate time to chemotherapy, in contrast, SIOPEL has favored upfront chemotherapy for all patients. This study suggests that mandatory neoadjuvant chemotherapy may result in potentially unnecessary exposure to chemotherapy and potentially unnecessary chemotherapy toxicity. In a small but real cohort of patients, upfront surgical resection leads to the identification of favorable histology features that may identify some patients for whom no chemotherapy is necessary. Modern imaging techniques and application of the PRETEXT system provide us with the means to identify patients whose tumors should be safe to resect at diagnosis.
The data reported here demonstrates that clinical and pathologic features can predict outcome in hepatoblastoma and that PRETEXT can be used to predict surgical resectability.17
The one patient who underwent reoperation for resection of a microscopic positive margin was a trisegmentectomy patient who would not have met the guidelines for upfront resection in our current protocol. The surgical guidelines in our contemporary COG hepatoblastoma study (AHEP0731) recommend upfront resection in PRETEXT 1 tumors and in PRETEXT 2 tumors with a clear radiographic margin on the middle hepatic vein and portal venous bifurcation, in which margin negative resection can be anticipated by simple segmentectomy or lobectomy.
In contrast to PFH, it appears that tumors with SCU elements have an unfavorable prognosis and require more aggressive therapy.25,26
The proportion of small cells cannot be adequately evaluated from a small biopsy, and when chemotherapy is given before surgery, the histopathologic constituents of the original neoplasm may be altered. In the various series from the United States and Germany, the error rate in diagnosis of SCU from an initial pathologic reading has ranged from 10% to 16%.27,28
The errors reflect mimickry of the radiologic appearance of hepatoblastoma by some benign vascular tumors (eg, infantile hemangioma) and mesenchymal hamartomas. Biopsy is often needed because serum alpha protein may be elevated in some of the benign tumors. Alternatively, low AFP is seen in a small subset of hepatoblastoma in which the tumor is either a well-differentiated fetal hepatoblastoma, a poorly differentiated SCU hepatoblastoma or a rhabdoid tumor.26,27,29
The molecular pathogenesis of hepatoblastoma is slowly but progressively being elucidated. Activation of the canonical Wnt pathway is present in 70% to 90% of hepatoblastoma.30,31
) mutations have been identified in all hepatoblastoma subtypes. The relationship of CTNNB1
mutation type to histologic type was statistically significant (P
=.003) in a report by Lopez-Terrada et al32
Aberrant activation of the Notch pathway has also been documented in hepatoblastoma. Lopez-Terrada et al have recently demonstrated that Wnt activation is prevalent in hepatoblastoma, most significantly in predominantly embryonal and mixed histologic subtypes, whereas Notch activation was highest in PFH hepatoblastoma. Examination of Wnt versus Notch activation may be useful in the future to stratify different hepatoblastoma subtypes and identify patients for whom no additional therapy or alternative is necessary. Correlation between recently reported prognosis-associated gene expression signatures in histologic subtypes of hepatoblastoma may also be potentially useful for patient stratification.33
In summary, PFH has been identified as a good prognostic factor, and we propose that chemotherapy not be given to this group of patients with stage I disease. These results stress the importance of our continued research focus on investigating hepatoblastoma tumor biology and pathology.