Mixed histiocytosis (Langerhans cell histiocytosis [LCH] / Erdheim-Chester disease [ECD]) developing after treatment for initial skull LCH is not well recognized. An elderly woman presented with polyuria and polydipsia five years before being diagnosed with unifocal LCH of the left temporal bone, which was surgically removed. Two years later, a first relapse occurred in the right parietal skull, confirming a BRAF V600E mutation, and she received chemotherapy. After a second relapse in the left parietal bone, a third relapse occurred in the L2 vertebra. Biopsy of the spinal lesion revealed mixed histiocytosis (LCH/ECD), which was refractory to conventional chemotherapy but successfully treated with targeted BRAF and MEK inhibitors. Spinal mixed histiocytosis may develop following multiple skull LCH relapses, and targeted therapy can be effective.
Introduction
Histiocytic disorders include LCH and non-LCH entities such as ECD. Most cases harbor MAPK pathway mutations (e.g., BRAF V600E). Skull bones are the most frequently affected sites in LCH, with temporal and facial lesions carrying a higher relapse risk. Central diabetes insipidus from pituitary stalk involvement may precede LCH diagnosis by years. "Mixed histiocytosis" (two or more histiocytic neoplasms in one patient) is increasingly recognized, with LCH/ECD mixed histiocytosis hypothesized to arise from a common progenitor cell. This report describes an elderly patient with BRAF-positive relapsed cranial LCH who later developed spinal mixed histiocytosis.
Case Presentation
A 76-year-old woman presented with lumbago in 2024, and CT revealed an L2 spine lesion, diagnosed as the third relapse of BRAF V600E-positive LCH. Her history:
2010: Polyuria and polydipsia (attributed to aging, no workup).
2015: Unifocal LCH (CD1a+, S100+) of left temporal skull – surgically excised.
2017: First relapse – right parietal skull lesion, BRAF V600E mutation confirmed, plus central diabetes insipidus (thickened pituitary stalk). Treated with 10 courses of Special C regimen (vinblastine, prednisolone, methotrexate, 6-mercaptopurine) plus desmopressin.
Later: Second relapse – left parietal skull, treated with modified Special C (methotrexate replaced by cytarabine). Achieved complete remission.
Third relapse (2024): L2 vertebral lesion on PET/CT. Biopsy of paravertebral soft tissue showed mixed histiocytosis: CD1a+ areas (LCH) and CD68+ foamy histiocytes with Touton-like giant cells (ECD).
She received modified CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) but had poor response with new lesions (left 6th rib, left femur). Cladribine (5 courses) gave partial response but caused myelosuppression. She was switched to reduced-dose dabrafenib (BRAF inhibitor, 50 mg/day) and trametinib (MEK inhibitor, 1 mg/day). All FDG-avid lesions disappeared on PET/CT.
Discussion
This case is novel because mixed histiocytosis (LCH/ECD) developed after multiple skull LCH relapses, and the spinal bone was the site of mixed disease. Although mixed histiocytosis is well recognized, it is unclear how often it develops after treatment for LCH. In this patient, the spinal recurrence showed both LCH and ECD features. The patient lacked typical ECD manifestations (long bone pain, retroperitoneal fibrosis, "hairy kidneys," coated aorta).
In reported mixed histiocytosis series (n=69), LCH/ECD was most common, with a median delay of 4 years from initial LCH diagnosis to mixed ECD diagnosis. Such cases often respond poorly to conventional therapy but show marked sensitivity to targeted BRAF/MEK inhibitors. Here, the spinal lesion was refractory to modified CHOP; cladribine gave partial remission; and complete metabolic response was achieved with dabrafenib/trametinib. However, the contribution of cladribine cannot be excluded.
Limitations: single case report; BRAF mutation analysis was only performed on the first relapsed skull lesion, not on the spinal mixed lesion; short follow-up for mixed histiocytosis.
Conclusions
This case highlights several instructive points:
Polyuria and polydipsia should prompt a thorough search for LCH lesions, as diagnosis may be delayed for years.
Skull LCH has a relatively high relapse rate; even after remission, recurrence at other skeletal sites is possible.
When LCH recurs, mixed histiocytosis should be considered in the differential diagnosis.
Routine PET/CT for systemic screening, along with thorough pathological examination and genetic testing (including BRAF mutation analysis) of all lesions, is recommended during LCH management. Targeted therapy with BRAF and MEK inhibitors can be effective for refractory mixed histiocytosis.
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The study was recently published in the Oncology Advances .
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