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.