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An 81-year-old man with blastic plasmacytoid dendritic cell neoplasm (BPDCN) involving the skin, bone marrow, and central nervous system achieved complete remission with pivekimab sunirine, intrathecal chemotherapy, and allogeneic stem cell transplant. After a localized cutaneous relapse treated with radiation and donor lymphocyte infusion, surveillance positron emission tomography/computed tomography obtained during follow-up for metastatic prostate cancer showed a new intensely fluorodeoxyglucose-avid, weakly prostate-specific membrane antigen-avid intramuscular left thigh lesion (panel A) without active skin disease. Biopsy showed skeletal muscle diffusely replaced by medium/large-sized blasts with irregular nuclei and fine chromatin (panels B-C; hematoxylin and eosin; original magnification ×4 and ×100, respectively). By immunostaining, the cells expressed TCF4/CD123, TCL1, and SOX4 (panels D-F; original magnification ×100) and showed diffuse p53 overexpression (panel G; original magnification ×100). At initial diagnosis, next-generation sequencing had revealed canonical founder alterations with biallelic TET2 mutations and copy number loss of 1p and 17p, establishing the first TP53 hit. Molecular analysis of the intramuscular relapse found the same TET2 mutations, a new TP53 missense mutation (at 78% variant allele fraction), and copy number analysis showed loss of all targeted regions of 17p (panel H), confirming biallelic TP53 inactivation. Bone marrow results remained negative.

This case highlights an unusual intramuscular relapse of BPDCN without active skin disease and illustrates stepwise TP53 progression superimposed on a background of canonical TET2 founder alterations.

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