Targeted Therapy Treats Mixed Histiocytosis Following Multiple Skull Relapses

Mixed histiocytosis (Langerhans compartment histiocytosis [LCH] / Erdheim-Chester illness [ECD]) processing aft curen for first skull LCH is not good recognized. An aged female presented pinch polyuria and polydipsia 5 years earlier being diagnosed pinch unifocal LCH of nan near temporal bone, which was surgically removed. Two years later, a first relapse occurred successful nan correct parietal skull, confirming a BRAF V600E mutation, and she received chemotherapy. After a 2nd relapse successful nan near parietal bone, a 3rd relapse occurred successful nan L2 vertebra. Biopsy of nan spinal lesion revealed mixed histiocytosis (LCH/ECD), which was refractory to accepted chemotherapy but successfully treated pinch targeted BRAF and MEK inhibitors. Spinal mixed histiocytosis whitethorn create pursuing aggregate skull LCH relapses, and targeted therapy tin beryllium effective.

Introduction

Histiocytic disorders see LCH and non-LCH entities specified arsenic ECD. Most cases harbor MAPK pathway mutations (e.g., BRAF V600E). Skull bones are nan astir often affected sites successful LCH, pinch temporal and facial lesions carrying a higher relapse risk. Central glucosuria insipidus from pituitary stalk engagement whitethorn precede LCH test by years. "Mixed histiocytosis" (two aliases much histiocytic neoplasms successful 1 patient) is progressively recognized, pinch LCH/ECD mixed histiocytosis hypothesized to originate from a communal progenitor cell. This study describes an aged diligent pinch BRAF-positive relapsed cranial LCH who later developed spinal mixed histiocytosis.

Case presentation

A 76-year-old female presented pinch lumbago successful 2024, and CT revealed an L2 spine lesion, diagnosed arsenic nan 3rd relapse of BRAF V600E-positive LCH. Her history:

• 2010: Polyuria and polydipsia (attributed to aging, nary workup).

• 2015: Unifocal LCH (CD1a+, S100+) of near temporal skull – surgically excised.

• 2017: First relapse – correct parietal skull lesion, BRAF V600E mutation confirmed, positive cardinal glucosuria insipidus (thickened pituitary stalk). Treated pinch 10 courses of Special C regimen (vinblastine, prednisolone, methotrexate, 6-mercaptopurine) positive desmopressin.

• Later: Second relapse – near parietal skull, treated pinch modified Special C (methotrexate replaced by cytarabine). Achieved complete remission.

• Third relapse (2024): L2 vertebral lesion connected PET/CT. Biopsy of paravertebral soft insubstantial showed mixed histiocytosis: CD1a+ areas (LCH) and CD68+ foamy histiocytes pinch Touton-like elephantine cells (ECD).
  She received modified CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) but had mediocre consequence pinch caller lesions (left 6th rib, near femur). Cladribine (5 courses) gave partial consequence 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 vanished connected PET/CT.

Discussion

This lawsuit is caller because mixed histiocytosis (LCH/ECD) developed aft aggregate skull LCH relapses, and nan spinal bony was nan tract of mixed disease. Although mixed histiocytosis is good recognized, it is unclear really often it develops aft curen for LCH. In this patient, nan spinal recurrence showed some LCH and ECD features. The diligent lacked emblematic ECD manifestations (long bony pain, retroperitoneal fibrosis, "hairy kidneys," coated aorta).

In reported mixed histiocytosis bid (n=69), LCH/ECD was astir common, pinch a median hold of 4 years from first LCH test to mixed ECD diagnosis. Such cases often respond poorly to accepted therapy but show marked sensitivity to targeted BRAF/MEK inhibitors. Here, nan spinal lesion was refractory to modified CHOP; cladribine gave partial remission; and complete metabolic consequence was achieved pinch dabrafenib/trametinib. However, nan publication of cladribine cannot beryllium excluded.

Limitations: azygous lawsuit report; BRAF mutation study was only performed connected nan first relapsed skull lesion, not connected nan spinal mixed lesion; short follow-up for mixed histiocytosis.

Conclusions

This lawsuit highlights respective instructive points:

1. Polyuria and polydipsia should punctual a thorough hunt for LCH lesions, arsenic test whitethorn beryllium delayed for years.

2. Skull LCH has a comparatively precocious relapse rate; moreover aft remission, recurrence astatine different skeletal sites is possible.

3. When LCH recurs, mixed histiocytosis should beryllium considered successful nan differential diagnosis.
   Routine PET/CT for systemic screening, on pinch thorough pathological introspection and familial testing (including BRAF mutation analysis) of each lesions, is recommended during LCH management. Targeted therapy pinch BRAF and MEK inhibitors tin beryllium effective for refractory mixed histiocytosis.