Discussion:
Hepatic involvement in LCH is divided into two phases based on histology. The early hepatitis phase is characterised by the active infiltration of hepatic parenchyma by the Langerhans cells, predominantly damaging hepatocytes and initiating fibrosis. The damage is mediated by release of various proinflammatory cytokines released by these cells leading to apoptosis and/or necrosis of hepatocytes.4 The biopsy shows diffuse infiltration with cells which are CD 207 and CD1a positive. The second phase which may occur despite chemotherapy is a more chronic involvement, occurring as a cholangiolar burnt-out disease.4 It is characterised by hepatic parenchymal loss with progressive destruction of biliary tree leading to sclerosing cholangitis.12This phase has minimal presence of histiocytes and is also observed post-chemotherapy phase. In a large series from Argentina, sclerosing cholangitis was seen in 18% patients with multisystem LCH.18LT in LCH is mainly indicated for cirrhosis with decompensation or portal hypertension due to LCH related secondary sclerosing cholangitis. 18, 19
Among our cohort of 6 patients with LCH who underwent LT, the overall graft and patient survival was 100% after a median follow up of 3 years. In a previous series on LCH related liver disease, 6 patients had underwent LT, with a survival of 67% after a median period of 5.8 years.19 Two-thirds of their patients suffered from post-transplant lymphoproliferative disorder (PTLD), and 50% required a re-transplantation for acute refractory rejection within 3 months post LT.
In a report from King’s College London on LCH, Of the 2 patients who underwent LT with active disease, both had recurrence of LCH in the allograft liver, 5 and 60 months after LT respectively despite post-transplant chemotherapy using vinblastine, etoposide and steroids.20 In a recent population based analysis of 60 patients undergoing LT for LCH, the overall 1-year survival was 79.4%.9 Also it was noted that more than 50% patients had active extrahepatic disease at the time of LT and 8% had disease recurrence in the graft over a mean follow up period of 2 years.9 50% of the patients had acute rejection and 10% had Post transplant lymphoproliferative disorder (PTLD). Similar conclusions were drawn by the Whitington group, where 6 post-LT patients had a 5-year survival of 67%, with 33% disease recurrence and PTLD.19
None of our patients had recurrence of LCH or PTLD or T/B cell mediated rejections in the post LT period. We start these patients on tacrolimus based immunosupression, with periodic monitoring of trough levels as mentioned before.
Vinblastine which is part of the first line regimen of the LCH IV chemotherapy guidelines may worsen liver dysfunction.21,22 It is also known to cause increased systemic toxicity including peripheral neuropathy and bone marrow suppression.23 Thus, in the category 2 subset of patients, choosing the chemotherapeutic agents involves finding a fine balance between disease remission and hepatotoxicity. We used a modified chemotherapeutic protocol where vinblastine was replaced with cytarabine.17 Two of our patients with decompensated cirrhosis tolerated the drug well and completed the induction course. There is also accumulating literature evidence in this regard. The Japanese LCH 96 guidelines recommend cytarabine along with vincristine and the group from Texas children hospital use a cytarabine based chemotherapy (NCT02670707).24 Nonetheless, it is noteworthy that there is no unified protocol for treating LCH with liver disease. Many centres treat patients on case-to-case basis. In a recent series from China, of 5 patients who underwent LT the pre-LT chemotherapy regimen was different for each patient.25
The timing of LT in patients with LCH has been always a matter of scientific debate. An LT done for a rapidly worsening liver without achieving remission may lead to persistence of the disease post LT or a disease recurrence. In patients with active disease and cirrhosis with decompensation, a delay in LT may result in progressive liver failure.20 The current available scientific evidence is meagre to recommend a LT during active extrahepatic disease in patients with LCH, and it is a general recommendation that active extrahepatic malignancy is a contraindication for performing a LT. A prior analysis has shown a good outcome when a LT is done following disease remission in patients with LCH.25 Therefore, it is imperative to confirm remission before offering LT. Two of our patients who presented with active LCH and decompensated cirrhosis underwent LT after successful induction chemotherapy cycles (after 1 and 3 cycles respectively) as the hepatic dysfunction was rapidly progressing. Both these patients were confirmed to have disease remission before undergoing LT.
The major limitation of our study is the small sample size. However, this study throws light on the role and timing of LT in LCH. More evidence is needed in suggesting specific agents like BRAF inhibitors for the inducing remission of LCH in presence of an advanced liver disease, whose disease is refractory to conventional and modified chemotherapy.26 Based on our experience, we propose a treatment algorithm for LCH patients with liver involvement (Figure 2). Close monitoring by a multidisciplinary team though out the care with timely interventions when needed could be the reasons for the excellent results demonstrated in our series.