A mixed histiocytosis (Langerhans cell histiocytosis (LCH)/Erdheim-Chester disease (ECD)) that develops after treatment of initial cranial LCH is poorly recognized. An elderly woman suffered from polyuria and polydipsia 5 years before being diagnosed with monofocal LCH of the left temporal bone, which was surgically removed. Two years later, the first recurrence occurred in the right parietal skull, the BRAF V600E mutation was confirmed, and he received chemotherapy. After the second recurrence in the left parietal bone, a third recurrence occurred in the L2 vertebrae. Biopsy of the spinal cord lesion revealed mixed histiocytosis (LCH/ECD), which was refractory to conventional chemotherapy but was successfully treated with targeted BRAF and MEK inhibitors. Spinal mixed histiocytosis can develop after multiple cranial LCH recurrences and targeted therapy may be effective.
introduction
Histiocytic diseases include LCH and non-LCH entities such as ECD. In most cases, MAPK pathway mutations (such as BRAF V600E) are present. The skull is the most frequently affected site in LCH, and temporal and facial lesions have a higher risk of recurrence. Central diabetes insipidus due to involvement of the pituitary stalk can develop years before diagnosis of LCH. “Mixed histiocytosis” (two or more histiocytic tumors in one patient) is increasingly recognized, and it has been hypothesized that LCH/ECD mixed histiocytosis arises from a common progenitor cell. In this report, we describe an elderly patient with BRAF-positive recurrent cranial LCH who later developed spinal cord mixed histiocytosis.
Case study
A 76-year-old woman complained of low back pain in 2024, and a CT scan revealed an L2 spinal lesion, which was diagnosed as the third recurrence of BRAF V600E-positive LCH. Her career:
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2010:Polyuria and polydipsia (due to aging, no detailed examination).
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2015: Monofocal LCH on the left side of the skull (CD1a+, S100+) – surgically removed.
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2017: First recurrence – right parietal skull lesion, BRAF V600E mutation confirmed, plus central diabetes insipidus (hypertrophic pituitary stalk). Treated with 10 courses of Special C regimen (vinblastine, prednisolone, methotrexate, 6-mercaptopurine) and desmopressin.
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later: Second recurrence – left parietal skull, treated with modified Special C (replacing methotrexate with cytarabine). Complete remission was achieved.
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Third recurrence (2024): L2 spinal lesions on PET/CT. Paravertebral soft tissue biopsy showed mixed histiocytosis, CD68+ foamy histiocytes with areas of CD1a+ (LCH) and Touton-like giant cells (ECD).
She underwent a modified CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) but had a poor response with new lesions (left 6th rib, left femur). Cladribine (5 courses) produced a partial response but caused myelosuppression. She was switched to a reduced dose of 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 recurrence of multifocal cranial LCH, and the vertebrae were the site of mixed disease. Although mixed histiocytosis is well known, it is unclear how often it occurs after treatment for LCH. In this patient, spinal recurrence showed features of both LCH and ECD. The patient did not have typical ECD symptoms (long bone pain, retroperitoneal fibrosis, “hairy kidneys,” encased aorta).
In the reported mixed histiocytosis series (n=69), LCH/ECD was the most common, with a median delay of 4 years from initial LCH diagnosis to mixed ECD diagnosis. Such cases often have little response to conventional treatments but are markedly sensitive to targeted BRAF/MEK inhibitors. Here, the spinal cord lesion was refractory to modified CHOP. Cladribine resulted in partial remission. and a complete metabolic response was achieved with dabrafenib/trametinib. However, the contribution of cladribine cannot be excluded.
Limitations: Single case report. BRAF mutation analysis was performed only for initially recurrent cranial lesions and not for mixed spinal lesions. Short-term follow-up of mixed histiocytosis.
conclusion
This case highlights several useful points.
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Polyuria and polydipsia should prompt a thorough search for LCH lesions, as diagnosis may be delayed for years.
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Cranial LCH has a relatively high recurrence rate. Even after remission, recurrence can occur in other skeletal areas.
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If LCH recurs, mixed histiocytosis should be considered in the differential diagnosis.
During LCH management, regular PET/CT for systemic screening is recommended, along with thorough pathological and genetic testing of all lesions (including BRAF mutation analysis). Targeted therapy with BRAF and MEK inhibitors may be effective in refractory mixed histiocytosis.
sauce:
Reference magazines:
Tetsuya Hamada others. (2026). Development and successful treatment of spinal mixed histiocytosis in an elderly woman after two recurrences of unifocal cranial Langerhans cell histiocytosis due to a BRAF mutation. advances in oncology. DOI: 10.14218/ona.2025.00030. https://www.xiahepublishing.com/2996-3427/OnA-2025-00030
