Virilizing hepatoblastomas: A systematic review and meta-analysis of case reports

INTRODUCTION

Hepatoblastoma (HB) is the most common primary liver tumor in children and accounts for 1–2% of all pediatric tumors.^[1] More than 90% of malignant hepatic neoplasms in under-5 children are HBs and the typical age of presentation is 6 months to 3 years.^[2,3] The worldwide incidence is around 0.5 ± 1.5 cases/million children with a male predominance of 2:1.^[4] HB is an embryonic tumor that arises from hepatoblasts present in the liver during embryonal life.^[5] Most HBs are asymptomatic and the most common presenting symptom is abdominal distension or an accidentally discovered abdominal mass.

Although HB has well known syndromic associations (such as Beckwith–Wiedemann syndrome, familial intrahepatic cholestasis, fetal alcohol syndrome, and Prader–Willi syndrome), paraneoplastic manifestations are extremely rare.^[6] HBs have been rarely reported to express human choriogonadotropins (hCG), clinically causing virilization and isosexual precocious puberty in boys.^[7,8] The first report of a virilizing HB was by Behrendt in 1931^[9] and since then, only 43 cases have been reported in the English literature.

We have conducted a systematic review and meta-analysis to elucidate the different aspects of this rare entity that has been reported in the literature, which includes the age at diagnosis, levels of tumor markers, extent of disease at diagnosis, treatment options, and survival.

MATERIAL AND METHODS

We performed a systematic review of the published literature on virilizing HBs by a Google scholar and PubMed search on January 9, 2024, using the search terms “hepatoblastoma” AND “precocious puberty” OR “virilizing hepatoblastoma.” We then proceeded with back-referencing (snowballing) to identify relevant citations and avoid missing any published literature on the topic. All publications on virilizing HBs in the English language were included in the study. The year of publication, study design, nationality of the patient, age of the patient, presentation, diagnostic modality, treatment, including surgery, response to treatment, and the outcome was tabulated in a pre-designed Excel sheet. Separate tables were made to summarize the individual patient details, staging and treatment modalities used, and the outcomes of virilizing HB on followup. Categorical variables were presented as percentages/proportions while continuous variables were summarized as mean (standard deviation) or median (interquartile range). No risk of bias assessment was carried out as the published articles are all case reports and no methods were used to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. The indexing status of the journals, in which these cases were published, was assessed separately to assess the certainty (and confidence) in the body of evidence collected for this review.

RESULTS

The database search showed 49 published papers on children with HB who presented with precocious puberty. After screening the title and abstract, 12 articles were excluded for not addressing the issue in question. Thirty-seven potentially relevant articles were retrieved for eligibility and full text evaluation. Out of these, 13 articles were excluded as they were in a non-English language and one was a duplicate paper [Figure 1]. On back-referencing these papers, another 11 articles were found relevant and subsequently added. Finally, a total of 34 case reports^[7,8,10-42] were included, comprising 43 children with virilizing HB [Tables 1 and 2]. This includes three cases from a paper by McArthur et al.^[21] which were personal communications to the author.

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Figure 1:

PRISMA flow diagram depicting selection of articles for the meta-analysis.

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The first such case report ever published was in a German article by Behrendt^[9] in 1931. In English literature, it was in 1952 when McNab first reported a child with HB who came with precocious puberty, in the 30^th Annual Report of the British Empire Cancer Campaign.^[11] The same patient was later reported by Jolly as a case discussion on sexual precocity.^[12] Out of the 34 published reports, 17 (50%) were published in PubMed indexed journals, 8 (23.53%) in Scopus indexed journals, and 4 (11.76%) in journals that had Medline/Embase indexing while 2 (5.88%) in non-indexed journals. The most recent comprehensive literature review (including non-English papers as well) on this topic was by Yhoshu et al.^[7] in 2019.

All reported patients are boys as β-hCG-induced precocious puberty is manifested only in boys through the action of luteinizing hormone (LH). The mean age at presentation was 2.29 ± 1.61 years. Sixteen children (16/43; 37.21%) presented with an abdominal mass in the right hypochondrium/epigastrium. Only four patients (4/43; 9.3%) had constitutional symptoms such as fever,^[26,33] vomiting,^[30] and abdominal pain.^[33,41] One patient had referred pain to the right shoulder at presentation.^[13] A detailed version of tumor staging and management strategies of the reported cases is depicted in Table 3. The overall presenting features, tumor markers, tumor characteristics, and treatment are summarized in Table 4.

The histological subtype was mentioned by 21 authors (n = 23) and the most common type was mixed epithelialmesenchymal (12/23; 52.17%), followed by pure fetal (6/23; 26.09%), embryonal (4/23; 17.39%), and pure epithelial (1/23; 4.35%) [Figure 2].

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Figure 2:

Histopathological subtypes of virilizing hepatoblastomas. MEM: Mixed epithelial-mesenchymal, SCU: Small cell undifferentiated.

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The outcome was mentioned in 39 children [Table 5] with a median follow-up of 10 (3.75–16.5) months – 19 children (48.72%) survived [Figure 3], 4 (10.26%) developed local recurrences, and 11 (28.21%) developed metastases – lung (11/11; 100%), bone (4/11; 36.36%), brain (2/11; 18.18%), and lymph nodes (2/11; 18.18%). Twelve reports (12/43; 27.9%) mention regression of precocious puberty with treatment at a median duration of 1 (0.6–2.75) month.^{[10,16,18,20,24,27,30-32,35,36,40]}

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Figure 3:

Improving outcomes in virilizing hepatoblastomas. SIOPEL: Société Internationale d’Oncologie Pédiatrique - Epithelial liver tumor study group; PLADO: Cisplatin plus doxorubicin, PRETEXT: Pre-treatment extent.

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DISCUSSION

Hepatic tumors represent 0.5–2% of all childhood tumors and HB is the most common primary malignant hepatic tumor of infancy and childhood.^[43] The etiological factors predisposing to the development of HBs include extremely low birth weight and environmental factors such as alcohol, drug abuse during pregnancy, maternal hormonal treatment for infertility, and occupational exposure to heavy metals.^[6]

HB usually presents as a distended abdomen due to mass effect and non-specific symptoms including anorexia and weight loss. About 68% of cases present in the first 2 years of life and 90% present before 5 years of age.^[40] Metastatic disease is present at diagnosis in 10–20% of patients and the most common site is the lungs, which is also the most frequent site of relapse.^[44] HB may be associated with syndromes, including Beckwith–Wiedemann, Gardner, familial adenomatous polyposis, type 1A, glycogen storage disease, and trisomy 18.^[38]

Other than isosexual precocious puberty, paraneoplastic syndromes rarely reported as presenting manifestations in children with HB include hypertension due to a renin-producing HB,^[45] osteoporosis,^[46] hyperthyroidism,^[47] opsoclonusmyoclonus (Kinsbourne syndrome),^[48] hypoglycemia,^[6,49] ectopic adrenocorticotrophic hormone syndrome, and parathyroid hormone-related peptide-induced hypercalcemia.^[50]

The structure of tumor-related β-hCG is similar to that of LH and this β-hCG stimulates the testicular Leydig cells in boys to produce testosterone, resulting in virilization. Although a testosterone-secreting tumor can also result in a similar scenario,^[31] virilization as a paraneoplastic manifestation in HB is usually due to β-hCG-induced testosterone production as these patients have both elevated β-hCG and testosterone levels. This is supported by findings of some initial researchers who did a testicular biopsy (both antemortem and postmortem) and found interstitial cell hyperplasia in these children.^[21,22]

All reported cases are males as hCG-secreting HBs in girls do not result in similar manifestations. Female patients require both LH and FSH for ovarian estradiol production which is necessary for puberty.^[10] The only reported case of a girl with an ectopic hCG-producing HB was in a Japanese article by Endo et al. published in 1988 where the girl presented with an abdominal mass and a raised hCG was detected incidentally.^[51]

The overall outcome of children with HB was dismal before the advent of high-quality imaging techniques, better surgical techniques, and chemotherapeutic regimens. As a result, previous researchers suggested that virilizing HBs carried a worse outcome when compared to nonvirilizing tumors, which led Nakagawara et al. to propose the existence of a unique biological setup.^[8] They were able to identify separate populations of the hCG and AFP-producing cells of the primary tumor using an immunoperoxidase staining method. The hCG-positive cells were mainly moderately differentiated fetal type tumor cells whereas the AFP-positive cells were multinucleated giant cells and fetal type cells of a different variety than the hCG-positive cells.

However, as noted by Gattuso et al.,^[10] an increase in β-hCG levels in the preoperative phase is not necessarily related to a poor response to chemotherapy. It normalizes quickly after the initiation of chemotherapy and serves as a useful marker for the early detection of relapse during follow-up. Indeed, most of the reported cases in the past 30 years have survived over a considerable period of follow-up [Figure 3].

CONCLUSION

There is considerable heterogeneity among the reported cases due to a difference in eras from which these cases are reported. Largely, our way of managing HBs have evolved over the past decade due to sophisticated imaging, availability of better chemotherapy, and advances in surgical technology. Hence, any summarization of evidence gathered over the past 70 years is fallacious. This review should help the readers understand the pathophysiology behind virilizing HBs and treat these children in the same way as other HB patients as they have comparable outcomes.