A rare case report of hepatoblastoma in a child with ectopic adrenocorticotropic hormone syndrome

Introduction

Hepatoblastoma is the most common malignant liver tumor in children, accounting for approximately 1% of all pediatric malignancies. The majority of cases (80–90%) occur in children between 6 months and 5 years of age, with a median age at diagnosis of 18 months (1). Hepatoblastoma in older children and adults is rare, and most cases are sporadic with an unclear etiology. Previous studies have identified low birth weight and prematurity as significant risk factors for hepatoblastoma. Parental smoking, which is a known contributor to low birth weight, has also been associated with an increased risk of hepatoblastoma (2,3). Common clinical manifestations of hepatoblastoma include abdominal distension, discomfort, palpable mass, or pain, often accompanied by anorexia or weight loss. Fewer than 5% of cases present with jaundice. Paraneoplastic syndromes secondary to ectopic hormone secretion, such as ectopic adrenocorticotropic hormone (ACTH) production, are exceedingly rare in hepatoblastoma. To date, there is no standardized diagnostic or therapeutic protocol for such presentations.

This report describes a rare case of hepatoblastoma associated with ectopic ACTH syndrome in a young child. We detail the clinical and pathological findings and discuss the challenges in diagnosis and treatment. We present this case in accordance with the CARE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-42/rc).

Case presentation

The patient was a 3-year-6-month-old girl, born full-term at 38 weeks of gestation via cesarean section, with a birth weight of 3.3 kg and a normal Apgar score. Over the past three months, she experienced rapid weight gain of more than 3 kg, reaching a body weight of 20 kg at presentation. Physical examination revealed a heart rate ranging from 118 to 129 beats per minute (normal for her age: 80–120 bpm) and hypertension with blood pressure readings between 130–140/80–90 mmHg (normal: systolic 85–105 mmHg, diastolic 55–65 mmHg). Cushingoid features were evident, including increased subcutaneous fat deposition in the abdominal region, hyperpigmentation, and hirsutism predominantly on the back. Additional symptoms included polydipsia, polyuria, and constipation.

Two months prior to admission, the patient was evaluated for suspected obesity and was advised to modify her diet, which had minimal clinical effect. A pituitary magnetic resonance imaging (MRI) performed one month before admission showed no abnormalities. However, an abdominal MRI conducted two weeks before admission revealed a large mass in the left hepatic lobe, highly suspicious for malignancy (Figure 1A). MRI of the kidneys and adrenal glands showed no abnormalities (Figure 1B). There was no family history of hereditary or familial disorders.

Figure 1 Imaging and intraoperative findings of the left hepatic mass. (A) Abdominal MRI showing a large mass occupying the left lobe of the liver. (B) Abdominal MRI showing no significant abnormalities in both adrenal glands. (C,D) Intraoperative images revealing sharp liver edges with a soft texture and no signs of cirrhosis. A grayish-white mass approximately 11 cm × 10 cm × 7 cm in size was observed in the left lobe of the liver, with a firm texture. MRI, magnetic resonance imaging.

Upon admission, laboratory tests revealed significantly elevated plasma ACTH levels (432–491 pg/mL; reference range, 7.2–63.4 pg/mL) and serum cortisol levels (44.6–53.48 µg/dL; reference range, 4.26–24.85 µg/dL). Serum calcium was elevated at 3.27 mmol/L (normal range, 2.1–2.8 mmol/L), while parathyroid hormone (PTH) was decreased at 0.35 pmol/L (normal range, 1.60–6.90 pmol/L). Alpha-fetoprotein (AFP) was mildly elevated at 10.26 ng/mL (normal: ≤7 ng/mL). Repeated physical examination confirmed persistent hypertension (130/80–90 mmHg).

A preoperative multidisciplinary team (MDT) discussion concluded that the patient’s clinical presentation was consistent with Cushing’s syndrome and a hepatic mass, likely representing an embryonal tumor (most likely hepatoblastoma) with ectopic hormone secretion. The pre-treatment extent of tumor (PRETEXT) classification was PRETEXT I group. Surgical resection was considered the primary treatment strategy. Although transarterial chemoembolization (TACE) was initially proposed as a neoadjuvant measure, it was ultimately deemed unnecessary by the surgical team.

Perioperative management included strategies to prevent adrenal crises and infection. Pharmacologic interventions consisted of long-acting somatostatin analogs, mifepristone (a glucocorticoid receptor antagonist), and mitotane (an adrenal steroidogenesis inhibitor) to control hypercortisolemia-related symptoms.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The Heyou Hospital (No. 250818-EXP01). Written informed consent for publication of this case report and accompanying images could not be obtained from the patient or relatives despite all possible attempts.

Surgical procedure

A reverse L-shaped incision was made along the right subcostal margin, approximately 25 cm in length. Intraoperative exploration revealed sharp liver edges with a soft parenchymal consistency and no signs of cirrhosis. A well-circumscribed gray-white mass measuring approximately 11 cm × 10 cm × 7 cm was identified in the left hepatic lobe. The mass was firm and rubbery in texture with prominent surface vascularity. Intraoperatively, it was found to be densely adherent to the gallbladder, raising suspicion for tumor invasion, which necessitated concomitant cholecystectomy.

Following cholecystectomy, the left hepatic ligaments—including the round ligament, falciform ligament, left coronary ligament, hepatogastric ligament, hepatoduodenal ligament, and left triangular ligament—were sequentially dissected. The porta hepatis was exposed, and a rubber band was pre-placed for hepatic inflow occlusion via the foramen of Winslow. The left hepatic artery and the left portal vein branch were carefully isolated, ligated, and transected. Hepatectomy was performed along the ischemic demarcation line, and an anatomical left hemihepatectomy was successfully completed (Figure 1C,1D).

Pathological diagnosis

Gross examination

Postoperative gross pathology revealed a resected liver specimen measuring 13 cm × 12 cm × 8 cm. On sectioning, a well-demarcated, firm, gray-white lobulated tumor was identified, measuring 8.5 cm × 8 cm × 8 cm (Figure 2A).

Figure 2 The pathological examination after surgery. (A) Gross photography of the surgical resection specimen. (B) Fibrosarcoma-like mesenchymal component, with cholangiocellular epithelial component at the periphery (HE staining; 10×). (C) Adipose component with cholangiocellular epithelial component in the lower left corner (HE staining; 10×). (D) Bone tissue formation (HE staining; 10×). (E) CK (the epithelial components are positive; IHC staining; 20×). (F) ACTH (partial tumor cells are positive; IHC staining; 20×). ACTH, adrenocorticotropic hormone; CK, cytokeratin; HE, hematoxylin and eosin; IHC, immunohistochemistry.

Microscopic findings

Histologically, the tumor consisted of both epithelial and mesenchymal components. The epithelial elements formed solid nests, with areas showing tubular and papillary architecture. Frequent mitotic figures were observed (approximately 1 per 2 mm²). The mesenchymal component included spindle-shaped cells, adipocytes, and foci of mature osteoid tissue (Figure 2B-2D).

Immunohistochemical staining

Immunohistochemical staining results are summarized in Table 1. Representative images of CK and ACTH staining are shown in Figure 2E,2F.

Final diagnosis

Mixed-type hepatoblastoma involving the left hemi-liver, associated with ectopic ACTH secretion. No evidence of perineural invasion was identified, but vascular invasion was noted. Surgical margins were negative. Background liver parenchyma showed mild steatosis and bile stasis. The gallbladder was unremarkable.

Postoperative course

Approximately one week following surgery, the patient’s serum levels of ACTH, PTH, calcium, and dehydroepiandrosterone sulfate (DHEA-S) returned to within normal limits. Serum cortisol levels also declined significantly (Figure 3), and her blood pressure improved to 124/84 mmHg. Follow-up imaging, including MRI, confirmed postoperative changes consistent with left hemihepatectomy and cholecystectomy, with smooth margins of the remaining right hepatic lobe and no abnormal findings.

Figure 3 Changes in serum ACTH and cortisol levels before and after surgery. ACTH, adrenocorticotropic hormone.

The patient underwent six cycles of adjuvant chemotherapy with etoposide, carboplatin, and ifosfamide following surgery. At present, 10 months postoperatively, the patient remains in good general condition.

Discussion

Hepatoblastoma typically presents with abdominal distension, discomfort, a palpable mass, or abdominal pain, often accompanied by anorexia and weight loss. Jaundice is reported in fewer than 5% of cases. Paraneoplastic syndromes caused by ectopic hormone secretion in hepatoblastoma are exceedingly rare. Previously reported cases have described hormone production involving β-human chorionic gonadotropin (β-HCG) (4), thyroid hormones (T3, T4) (5), and a suspected case of renin secretion (6).

In 2010, Grunewald et al. published the first known case of hepatoblastoma associated with ectopic ACTH secretion in a 6-year-old child (7). That patient presented with rapid weight gain, abdominal distension, and polyuria. Imaging revealed a large hepatic mass in the right lobe, and biochemical testing showed markedly elevated ACTH levels. The patient had no response to corticotropin-releasing hormone (CRH) stimulation or dexamethasone suppression tests. Abnormalities in glucose, calcium, and PTH levels were also reported. Following radical resection of the liver tumor, histopathology confirmed mixed-type hepatoblastoma with ectopic ACTH secretion and PTH-related protein (PTHrP)-induced hypercalcemia. The child received adjuvant chemotherapy (cisplatin, etoposide, doxorubicin, and ifosfamide) and remained disease-free for 20 years, with normalization of biochemical markers.

Our case represents the second documented instance of hepatoblastoma with ectopic ACTH secretion. Similar to Grunewald’s case, our patient exhibited features of Cushing’s syndrome, including moon facies, increased abdominal subcutaneous fat, and hirsutism. Imaging revealed a large hepatic mass, in this case located in the left lobe. Both pituitary and adrenal imaging was unremarkable. Laboratory evaluation confirmed elevated serum cortisol, ACTH, calcium, and 24-hour urinary free cortisol levels, with normal blood glucose. After multidisciplinary evaluation, the patient underwent an anatomical left hemihepatectomy with R0 resection. Postoperatively, ACTH, cortisol, and calcium levels decreased significantly, and the patient’s overall condition improved. Histopathological analysis confirmed a mixed-type hepatoblastoma, and immunohistochemistry demonstrated focal ACTH expression within tumor cells. Based on the clinical, biochemical, and pathological findings, the final diagnosis was hepatoblastoma (mixed type) with ectopic ACTH secretion. At present, the patient has completed all six cycles of adjuvant chemotherapy postoperatively with etoposide, carboplatin, and ifosfamide.

Ectopic ACTH secretion has been reported in various tumor types, including bronchial carcinoids, medullary thyroid carcinoma, pancreatic islet cell tumors (8), thymic neuroendocrine tumors (9,10), appendiceal neuroendocrine tumors (11), and prostate adenocarcinomas with neuroendocrine differentiation (12,13), as well as ovarian steroid cell tumors (14). Tumors demonstrating ACTH immunopositivity typically arise from neuroendocrine cells or contain neuroendocrine or sarcomatoid elements. From an embryological perspective, the liver is one of the earliest-developing organs and possesses strong stem cell potential. Hepatoblastoma arises from hepatic progenitor cells, which share a common embryonic origin with endocrine-active progenitor cells of the pancreas and thyroid—organs known to be involved in ectopic ACTH secretion (15,16). In our case, ACTH-positive tumor cells were primarily undifferentiated sarcomatoid cells, negative for both neuroendocrine markers and CK, suggesting stem cell-like properties that may underlie ectopic ACTH production.

Surgical resection remains the cornerstone of hepatoblastoma treatment, with adjuvant chemotherapy determined by clinical risk stratification. Patients are typically classified into five baseline risk groups based on three main criteria: PRETEXT stage, serum AFP levels, and the presence or absence of metastatic disease. Additional prognostic modifiers include PRETEXT annotations (e.g., extrahepatic spread, vascular invasion, spontaneous tumor rupture), age at diagnosis (<3 years, 3–7 years, ≥8 years), and AFP levels (≤100 ng/mL, 101–1,000 ng/mL) (17,18). In this case, the patient’s disease was classified as PRETEXT I, making her a good surgical candidate. Although low-mitotic, well-differentiated tumors with complete resection may not require chemotherapy, other histological subtypes—including mixed-type hepatoblastoma as seen here—often necessitate adjuvant therapy.

The 5th edition of the WHO Classification of Pediatric Tumors proposes a seven-factor prognostic model for hepatoblastoma, including age, AFP level, PRETEXT stage, vascular invasion, histological subtype, response to chemotherapy, and key molecular changes (e.g., CTNNB1 and TERT promoter mutations). Our patient had two poor prognostic factors: vascular invasion and low AFP level (≤100 ng/mL). Molecular markers and chemotherapy response could not be evaluated, as complete surgical resection was performed prior to systemic therapy. Notably, no small cell undifferentiated components or INI1 loss—both associated with unfavorable outcomes—were observed in this case.

The patient reported by Grunewald et al. had only one poor prognostic factor (normal AFP) and achieved long-term survival without recurrence (7). Drawing parallels from that case, we anticipate a moderately favorable prognosis for our patient. Continued monitoring and follow-up will be essential, and this case contributes to the limited but growing understanding of ectopic hormone secretion in pediatric hepatoblastoma.

Conclusions

Hepatoblastoma with ectopic ACTH secretion is extremely rare but should be considered in pediatric patients presenting with Cushingoid features and a hepatic mass. Comprehensive diagnostic evaluation and prompt surgical management are essential. This case contributes to the limited literature and may aid in future recognition and treatment of similar presentations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-42/rc

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-42/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-42/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The Heyou Hospital (No. 250818-EXP01). Written informed consent for publication of this case report and accompanying images could not be obtained from the patient or relatives despite all possible attempts.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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