Abstract
Background: Langerhans Cell Histiocytosis (LCH) is a rare disease characterized by abnormal proliferation of bone marrow derived histiocytes. Although predominantly a childhood disease, LCH can occur at any age and has an incidence of one to two cases per million in adults. LCH can involve a single organ or present as disseminated disease. Sites most commonly affected are bone, skin, bone marrow and pituitary. Isolated hypothalamic LCH is a rare entity. A few reports of LCH presenting as a hypothalamic mass exist but mainly in children. Treatment of adult LCH is derived from pediatric studies, and no standard of care exists. We report a unique case of an adult with panhypopituitarism secondary to a hypothalamic mass found to be biopsy proven isolated LCH treated with Vemurafenib, a BRAF V600E inhibitor.
Clinical Case: A 66-year-old previously healthy man presented with progressively increasing confusion, cognitive decline and generalized weakness requiring hospital admission. Laboratory evaluation revealed an 8AM cortisol of 2.5 ug/dL (reference [ref] 7.0–25.0 ug/dL), ACTH of 9.3 pg/mL (ref 8–42 pg/mL), TSH of 0.106 uIU/mL (ref 0.35–5.5 uIU/mL), free T4 of 0.67 ug/dL (ref 0.7–1.25 ng/dL), LH <0.2 IU/L (ref 0.5–11 IU/L), FSH 0.6 IU/mL (ref 1–12 IU/L), total testosterone <12 ng/dL (ref 193 - 824 ng/dL), free testosterone <3.3 pg mL (ref 41.7 - 180.2 pg/mL), IGF1 41 ng/mL (ref 33–220 ng/mL) and prolactin of 31.5 ng/mL (ref 3.5–15 ng/mL). Findings were consistent with panhypopituitarism, and he was started on glucocorticoid and levothyroxine replacement therapy. MRI pituitary revealed an 18.1 x 13.8 x 15.8 mm hypothalamic mass with signal intensity alteration in the optic pathway. Patient developed polyuria with a serum sodium of 148 mmol/L (ref 136–145 mmol/L), elevated serum osmolality and low urine osmolality consistent with central DI and was started on oral DDAVP.
The patient underwent right sided neuroendoscopic intraventricular biopsy of hypothalamic mass. Pathology was consistent with LCH with immunohistochemistry staining for CD1a, Langerin and BRAFV600E, with occasional cells staining for CD68, CD163 and S100. Bone marrow biopsy was normal. A NM PET scan revealed a hypermetabolic hypothalamic mass compatible with LCH without evidence of involvement of other sites including the skeletal system. Given histopathologically confirmed BRAF-mutated LCH, treatment with Vemurafenib was initiated. Behavioral changes gradually improved, and repeat MRI brain three months after treatment revealed decrease in size of hypothalamic mass.
Conclusion: Isolated hypothalamic LCH is exceedingly rare. No clear guidelines exist for treatment of LCH in adults. BRAFV600E mutations are found in more than fifty percent of LCH cases and are associated with worse outcomes. This case demonstrates the successful use of targeted BRAF inhibitor therapy in an adult patient with BRAF mutated hypothalamic LCH.
BRAF-V600E–mutated Rosai-Dorfman-Destombes disease and Langerhans cell histiocytosis with response to BRAF inhibitor
