Cushing syndrome as presenting symptom of calcifying nested stromal–epithelial tumor of the liver in an adolescent boy: a case report

We report the case of an adolescent patient with Cushing syndrome due to an ACTH-producing CNSET of the liver. While incidental cases such as the aforementioned hormone-producing hepatoblastoma (suggesting neuroendocrine differentiation) [9], and combined HCC and carcinoid [10] have been reported, overall, liver tumors producing hormones are rare. The differential diagnosis includes carcinoids, combined or coexisting HCC and neuroendocrine carcinoma, metastatic neuroendocrine tumor, metastatic primitive gonadal stromal tumor [5], and cystadenomas/cystadenocarcinomas with ovarian-like stroma [12]. These latter tumors express alpha-inhibin and are reactive to estrogen and progesterone receptors suggesting a common early fetal origin of the cystadeno(carcino)ma and ovarian-like stroma [12]. A special property of the liver tumor in our patient is that it produced a polypeptide hormone (ACTH). ACTH-producing tumors are more common in the thymus, thyroid, bronchus, lung, adrenals, and pancreas than in the liver [13, 14]. Localizations often suggest a neural crest origin [14]. These tumors may also produce insulin and catecholamines. Most likely, the CNSET in our patient belonged to this group.

Cushing syndrome has an annual incidence of two to five cases per million, of which children make up 10 % [15]. Ectopic ACTH-producing tumors account for 1 % of Cushing syndrome causes in adolescents [15]. Given the low incidence of primary hepatic ACTH-producing tumors, liver locations of ACTH-producing tumors are more likely to represent metastases from neuroendocrine tumors originating in other abdominal organs than primary tumors, rendering primary liver tumors causing Cushing syndrome as reported here extremely rare.

Surgical resection is the treatment of choice [13]. Cushing syndrome dissolves after complete resection of the causative tumor [13]. Liver transplant has been incidentally reported in the treatment of CNSET; two patients died of postoperative complications and consecutive lung metastases, respectively; another was without evidence of disease at 2-year follow-up [46]. The role of chemotherapy is unclear [1]. Histologic and immunological features of CNSET suggest a potential role for treatment directed at neuroendocrine tumors. A recent study shows altered mesenchymal–epithelial transition with deletions in the beta-catenin gene, suggesting another potential targeting route [7].

In general, in ectopic ACTH syndrome, histology of the causative tumor, dissemination of disease and control of hypercortisolemia influence morbidity and mortality [13]. In a series of 43 patients with ectopic ACTH-induced Cushing syndrome, median survival was 32 months with overall mortality rate of 63 % [14]. Progression of the causative malignancy and systemic infection were the leading causes of death [14].

CNSET has been suggested to have low malignant potential [1, 5, 7]. In that perspective, the level of aggression in treatment warranted is unclear. However, local recurrence after resection and re-recurrence after treatment of recurrence with radiofrequency ablation have been described [15]. Recently, extrahepatic lymph node and lung metastases were reported [4, 6]. However, the patient we present here is alive and well 13 years after complete resection. With few reported cases, the biological behavior of CNSET is difficult to predict.

Larger series through international collaboration such as Children’s Hepatic tumors International Collaboration (CHIC) of the Société Internationale d’Oncologie Pédiatrique – Epithelial Liver Tumor Study Group (SIOPEL), are needed before conclusions about epidemiology, treatment, and prognosis can be drawn.