Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload

Abstract

Background The advent of techniques for the assessment of iron overload (liver T2*‐MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. Methods We performed a retrospective analysis of the liver T2*‐MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. Results Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate‐to‐severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI‐T2* values in affected patients were statistically lower than healthy controls (P < .001). Conclusions We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.

Pediatric Primary Hepatic Tumors: Diagnostic Considerations

“…Focal nodular hyperplasia (FNH) is the second most common benign liver tumor in pediatrics, with an estimated incidence of 0.02% in childhood, comprising 2-4% of all pediatric liver tumors [110][111][112]. FNH is more common in adulthood; however, in the pediatric cohort, the median age reported is 8.7 years and is most commonly diagnosed around the age of six to ten, with rare case reports in infants [111,[113][114][115].…”

“…It is well reported that survivors of childhood cancers-specifically, extrahepatic solid tumors such as Wilms' tumor and neuroblastoma, as well as hematopoietic stem cell transplant (HSCT) recipients-are at increased risk of development of FNH. It is estimated that the incidence within this specific population is between 5% and 12% [110]. The mean time to develop FNH after treatment has been estimated to be between four and 12 years post therapy, with a shorter interval time period for those individuals who underwent chemotherapy along with HSCT [91].…”

“…The exact pathophysiology has yet to be determined, but FNH is thought to develop as a hyperplastic response of the hepatic parenchyma secondary to circulatory disturbances or via hepatic proliferation induced by vascular injuries such as thrombosis, vascular hyperplasia, or high sinusoidal pressure [116,117]. Cattoni et al reported a potential association in the development of FNH between iron overload after HSCT, as well as a causal role of estro-progestins in patients receiving hormone replacement therapy after HSCT [110].…”

Hormonal replacement therapy in adolescents and young women with chemo- or radio-induced premature ovarian insufficiency: Practical recommendations

“…Liver focal nodular hyperplasia (FNH) is an incidental finding frequently reported in these patients, with an estimated incidence remarkably higher than the general population. As HT plays a potential contributory effect on the onset of this condition [77], the use of transdermal 17βE may be associated with a reduction of its incidence, though no specific trials have been carried out so far. In addition, also patients with chronic iatrogenic hepatic toxicity may benefit from the avoidance of "hepatic first-passage effect" and transdermal route could be preferred in these cases.…”

Late Effects After Haematopoietic Stem Cell Transplantation in ALL, Long-Term Follow-Up and Transition: A Step Into Adult Life

“…Although advances in the supportive care and monitoring of long-term survivors have dramatically improved in the last decades, iron overload is still a challenging issue and may be associated with late sequelae such as liver fibrosis, hepatic focal nodular hyperplasia, heart failure, hypogonadism and diabetes ( 158 , 159 ).…”