3 | DISCUSSION
Despite recent advances in molecular diagnosis of histiocytic disorders, some issues remain unresolved regarding their association with ND, including pathophysiology and treatment. Although LCH, ECD, and systemic JXG have distinct clinical and pathologic features, these histiocytic disorders are categorized into the “Langerhans (L)” group, mainly because they harbor somatic mutations in the MAPK pathway, and LCH/ECD and LCH/JXG histological phenotypes can co-exist in a single case.3,9-11 The present two cases raise the possibility that patients with all disease types categorized in the L group can develop ND.
In the present cases, multiple organ systems were initially affected, which is considered to be a risk factor for developing LCH-associated ND.5 In case 1, abnormal MRI findings in the cerebellum, which were present already at onset, progressed gradually after chemotherapy, followed by development of cerebellar dysfunction and cognitive impairment. By contrast, the clinical symptoms and abnormal MRI findings in case 2 disappeared spontaneously. Such inter-patient heterogeneity has been reported for LCH-associated ND.12 Nonetheless, careful screening and long-term follow-up are required to detect development of ND in patients with systemic JCG.
One of the greatest concerns is development of effective treatments for JXG-associated ND. Monthly IVIG treatment may halt progression, but it failed to improve the disease status of ND in case 1, as reported for cases of LCH-associated ND. 12,13 One possible second-line therapy is cytarabine-containing chemotherapy, in combination with vincristine, dexamethasone, or IVIG, which has been effective for some patients with LCH-associated ND.12,14,15 Because a BRAF inhibitor may be a promising option for LCH-associated ND, 16 discovery of clinically meaningful therapeutic targets is mandatory.
In conclusion, additional studies are required to obtain more data regarding JXG-associated ND, which will serve as a starting point for further investigations and development of drugs to treat histiocytic disorder-associated ND.