BRAFV600E-Mutated Histiocytic Sarcoma Presenting on a Background of Clonal Cytopenia Responsive to Dabrafenib: Case Report and Review of the Literature
Authors: Mitchell Alex , Bacon Chris , Nicolle Annette , Collin Matthew 
Published: December 2024

Case: An 80-year-old man presented with a right sided 3rd and 6th cranial nerve palsy, fevers and high inflammatory markers having experienced progressive limb pain and debility over 6-8 weeks. He had previously been well with only a mild macrocytic anemia. An MRI head demonstrated a right sided cavernous sinus lesion with extension into the right side pituitary fossa and sphenoid sinus. There was also involvement of the clivus and extension along the dura posteriorly. There were several other areas of bony abnormality within the skull. He had normal serum electrophoresis and serum free light chains. Serum tumor markers including PSA, b-HCG, CEA and CA19-9 were unremarkable.

Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) demonstrated increased uptake in the skull base lesions noted on MRI and widespread skeletal bone lesions. A CT-guided iliac bone biopsy demonstrated infiltration with abundant large and pleomorphic atypical histiocytes, with prominent nucleoli and abundant eosinophilic or vacuolated cytoplasm. There was expression of CD45, CD14, CD163, CD33, trace CD68, and a high Ki67 fraction of &gt;75%. The following markers were not detected: cyclin D1, ALK, CD1a, S100, CD34, CD117, myeloperoxidase, CD123, cytokeratin (AE1/AE3), EMA, Sox10 nor desmin.

Molecular investigations identified BRAFV600E (VAF 21.5%), with clonal TET2 c.4079T&gt;C p.Leu1360Pro (VAF 43%) and ZRSR2 c.312+1G&gt;A p.(=) synonym, splicing site (VAF 71%) variants. A diagnosis of histiocytic sarcoma was made, in the context of a clonal cytopenia of uncertain significance. Of interest, these clonal variants have also been reported in blastic plasmacytoid dendritic cell neoplasm.

The patient's condition rapidly deteriorated with persistent fevers and fluctuating conscious level including episodes of unresponsiveness lasting 30-60 minutes. He was treated with a weaning course of dexamethasone 8 mg dailyand urgent radiotherapy (8Gy single fraction) to the base of skull lesion. The oral BRAF inhibitor Dabrafenib was commenced at 50% dose (75mg twice daily). Levetiracetam 500 mg twice a daywas given as anti-epileptic prophylaxis.

Over the following week, his condition rapidly improved, he became pain-free, conversant and able to feed himself although he remained bed-bound. His fever resolved, the inflammatory markers including CRP fell significantly, and there was an improvement in his hemoglobin by 10 g/L. He gave consent for research by joining the UK Histiocytosis Registry (IRAS 238319; Northumberland and North Tyneside Research Ethics Committee, United Kingdom). The patient was discharged from hospital to a nursing home where he survived taking Dabrafenib monotherapy for a further 4 months. PET-CT 2 months after starting Dabrafenib demonstrated a good partial response with complete resolution of most of his base of skull and skeletal lesions. Treatment with Dabrafenib was tolerated well with only grade 1 skin dryness managed with topical treatment.

Discussion: Histiocytic sarcoma is malignant histiocytic neoplasm with a median survival of less than 6 months. It occurs in isolation or clonally related to another hematological neoplasm. This case showed evolution from a highly clonal myelodysplastic state; association with lymphoid malignancy including acute lymphoblastic leukemia and follicular lymphoma has also been reported. Conventional chemotherapy has no proven efficacy and may result in undesirable toxicity. The recent discovery of activating mutations of the MAPK pathway in histiocytic sarcoma, offers opportunity for targeted therapy with BRAF or MEK inhibitors. In a recent series, Egan et al reported 4/21 cases with BRAF mutations, of which 2 were BRAFV600E, with others bearing mutations in NF1(6/21) and MAP2K1 (5/21). Further review of the literature identified 8 cases treated with MAPK inhibitors, including Dabrafenib. All reported patients achieved at least a partial response, and 3 cases reported a complete response. Responses were seen in all cases within 1-4 months of starting treatment. Generally, these treatments were well tolerated and associated with manageable toxicity. Although responses were not durable and 50% of cases had progressed within 12 months,the advantage of a non-toxic regimen is clear when preserving quality of life is the goal of therapy, as in this case.

Note: The use of Dabrafenib for histiocytic sarcoma is off-label