Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder and is characterized by the clonal expansion of pathological dendritic cells [1]. LCH mainly affects populations between 1 and 3 years of age [2]. The clinical course is heterogeneous, ranging from self-limited and indolent disease to rapid progression of multiorgan involvement. LCH has been redefined as being a tumour derived from haematopoietic myeloid progenitor cells. Liver involvement is observed in 10.1% to 19.8% of patients with LCH and is characterized by sclerosing cholangitis (SSC), which manifests as progressive destruction of the biliary tree by histiocytes [3]. LCH accompanied by haemophagocytic lymphoproliferative syndrome (HLH) may indirectly affect the liver. In such cases, a generalized activation of cellular immunity may lead to Kupffer cell hypertrophy and hyperplasia, with resultant hepatomegaly and elevated liver enzymes (but without direct infiltration). These indirect effects are entirely reversible with treatment [4]. The diagnosis of hepatic LCH is often difficult and delayed because of the absence of localized LCH. LCH patients with liver involvement could have a poor prognosis due to the high risk of the absence of timely and effective therapy, refractory disease, reactivation, and complications related to liver cirrhosis and portal hypertension [5]. The liver is considered a “risk organ” (RO) in LCH. For patients with liver involvement, the risk of death is three times greater than that for patients without liver involvement [6].

There have been few reports of hepatic LCH because it is a rare disorder, and its clinical characteristics and efficacy have yet to be fully investigated. Therefore, we conducted a large, single-centre, retrospective cohort study to evaluate the clinical characteristics and analyse the prognosis of paediatric patients with LCH and liver involvement, with an aim of reducing misdiagnosis and providing a treatment strategy.

In our study, patients with liver involvement accounted for 14.5% of the LCH patients in the same time, which is similar to previous reports [3]. Liver involvement is exclusively observed in patients with MS LCH, and patients may present with hypoproteinaemia, oedema, hepatomegaly, and hyperbilirubinemia [15]. We found that MS LCH patients with liver involvement were more prone to developing multisystemal symptoms such as fever, rash, splenomegaly, and abnormal ear discharge than were those without liver involvement. In terms of the involved organs, patients with liver involvement had increased frequencies of skin, lung, and hearing system involvement, as well as HLH. Currently, LCH is generally redefined as being an inflammatory myeloid neoplasia driven by activating mutations in the MAPK pathway. A French LCH cohort demonstrated that 89.2% of patients with hepatic LCH carried a BRAF V600E mutation, which is related to activation of the MAPK pathway, increased resistance to first-line treatment and increased reactivation [14]. Our study also demonstrated that the BRAF V600E mutation rate in the tissue and plasma of patients with liver involvement was greater than 70%. In addition, we also identified several rare gene mutations, such as non-V600E BRAF, MAP2K1, and ARAF. The percentage of non-V600E BRAF mutation-positive tissues in the liver group was lower than that in the nonliver group (P=0.025). Previous research has reported that patients with BRAF V600E mutations are prone to having multiple systems and organs at risk [16].

Liver involvement is associated with poor prognosis in LCH patients, especially those with SSC [17]. The 2-year OS rate in the MS LCH with liver group was significantly lower than that in the MS LCH without liver group (P<0.001). In addition, the 2-year PFS rate in the MS LCH with liver group was only 21.3% ±4.6%. Further multivariate analysis demonstrated that increased levels of ALP, γ-GGT, total bile acid, and DBIL were independent risk factors for liver progression/relapse during treatment. Thus, clinicians need to closely monitor liver function during therapy.

Currently, standard therapy for LCH patients with liver involvement has yet to be established. Yi et al. [8] showed that 44.4% of LCH patients with liver involvement presented with different degrees of improvement in biochemistry and imaging studies after treatment with the conventional vinblastine-prednisone-etoposide combination; moreover, two patients died of multiple organ failure secondary to worsening liver dysfunction. Our study showed that in MS LCH patients who received initial first-line therapy, patients with liver involvement had a shorter PFS (P<0.001). The treatment of 60.9% of patients in the liver group changed due to liver events during first-line treatment, thus suggesting that for patients with hepatic LCH, conventional first-line treatment was only effective for some patients, and the liver lesions in nearly 2/3 of LCH patients did not respond well to first-line treatment. There was no significant difference in the liver improvement rate between patients who were switched from first-line to second-line therapy and those who were shifted to targeted therapy (P=0.453). Among patients who received initial second-line or targeted therapy, 38.5% and 75.0%, respectively, had improved liver lesions. The therapeutic response of patients with BRAF mutations to targeted therapy may not be poor. Patients who were RO+ had worsened responses to treatment, and the level of the BRAF V600E mutation was associated with the extent of LCH disease [18]. Therefore, this type of patient may be ideal for targeted therapy. However, 39.3% and 50.8% of the patients in our study experienced different degrees of severe myelosuppression and gastrointestinal events, respectively, after second-line treatment. Thus, targeted therapy appears to be safe for reducing toxicity (to some extent). Improvements in symptoms and liver function were rapidly obtained after the patients accepted the target medicine. Nevertheless, studies have shown that half of patients experience relapse or progression, which may be attributed to reactivation of the MAPK pathway or too short a duration of targeted treatment [19, 20]. Three of the patients who received initial targeted therapy in our study relapsed, and the time from withdrawal to recurrence was short (approximately 1-3 months). Thus, the optimal strategy for targeted therapy should be extensively explored. Notably, the effectiveness of second-line treatment and targeted therapy also showed that liver involvement was reversible, and timely diagnosis and treatment could reduce liver cirrhosis.

Previous studies and liver biopsies have demonstrated that Langerhans cells have remarkable selectivity for bile ducts [21]. Studies have reported a 25% response to chemotherapy in LCH patients with SSC [22]. We found that the 2-year OS and PFS rates in the cholangitis group were significantly lower than those in the noncholangitis group (P=0.002 and 0.030, respectively). In our study, 4 patients who developed liver cirrhosis and 3 who died of sclerosis presented with bile duct involvement at disease onset. Notably, bile duct destruction is irreversible. Despite the resolution of active Langerhans cell infiltration, biliary duct injury continues to progress [4]. Caruso et al. [23] reported of a child who was diagnosed with LCH via skin and lymph node biopsies. The patient first presented with hepatomegaly but not cholangitis. On follow-up during chemotherapy, the patient had gradually increased liver enzymes and developed SSC and biliary cirrhosis. Therefore, it is necessary to identify and diagnose LCH as soon as possible and to perform early treatment to avoid irreversible liver involvement. Nevertheless, there are few studies on treating LCH patients with liver involvement. The optimal therapy remains unclear, and treatment-related side effects and economic costs still need further assessment.

Due to the fact that SSC is usually progressive, liver transplantation is a reliable salvage therapy for LCH patients with end-stage liver disease [3]. Several groups have performed orthotopic liver transplantation in children with end-stage biliary diseases secondary to LCH-related SSC, and they reported an OS of 87% with a mean follow-up time of 3.4 years [24]. Five patients who received effective chemotherapy, as reported by Chen et al. [25], underwent liver transplantation. A follow-up time of 2 to 67 months demonstrated that liver function was stable for a long period of time without serious complications or liver reactivation. Four patients received liver transplantation in our study. Their final evaluations were AD-B, with a follow-up period of approximately 18-79 months. One patient experienced intrahepatic reactivation 18 months posttransplant and then received first-line and second-line treatment. Currently, there has been no relapse after 46 months of withdrawal. The disease activity of LCH patients with end-stage liver involvement must be closely monitored after liver transplantation. Moreover, chemotherapy is still safe and effective for patients with liver reactivation posttransplantation. However, the optimal timing of liver transplantation is a matter of debate, as performing liver transplantation too early may result in the recurrence of the primary disease. Moreover, delayed transplantation may hamper optimal chemotherapy for reactivation in diseased livers [17].