Recurrent CLTC::SYK fusions and CSF1R mutations in juvenile xanthogranuloma of soft tissue.

Juvenile xanthogranuloma (JXG) is a histiocytic neoplasm that usually presents in the skin. Rarely, extracutaneous localizations occur; the genetic drivers of this clinical variant of JXG remain incompletely characterized. We present detailed clinicopathologic and molecular data of 16 children with extracutaneous JXG and 5 adults with xanthogranulomas confined to the central nervous system (CNS) or soft tissue. Tissue samples were obtained through the Dutch Nationwide Pathology Databank and analyzed with an innovative sequencing technique capable of detecting both small genomic variants and gene rearrangements. Targetable kinase alterations were detected in 16/16 children and 1/5 adults. Alterations included CLTC::SYK fusions in 6 children and CSF1R mutations in 7 others - all below 2 years old with soft tissue tumors. One child had a CSF1R mutation and MRC1::PDGFRB fusion. Most were treated surgically, although spontaneous regression occurred in 1/6 with CLTC::SYK and 2/7 with CSF1R mutations - underscoring that treatment is not always necessary. Tumors with CLTC::SYK fusions generally lacked Touton giant cells, but exhibited many other histologic features of JXG and concordant methylation profiles. Using multispectral immunofluorescence, phosphorylated-SYK expression was localized to CD163+ histiocytes; tumors with CLTC::SYK fusions also demonstrated mTOR activation, Cyclin D1 expression, and variable phosphorylated-ERK expression. BRAFV600E was detected in 1 child and 1 adult with CNS xanthogranulomas; both responded to BRAF inhibition. Finally, a TPM3::NTRK1 fusion or MAP2K1 deletion were detected in 2 children with systemic JXG who experienced spontaneous disease regression. This study advances the molecular understanding of histiocytic neoplasms and may guide diagnostics and clinical management.

Extensive, circumferential, epidural spinal cord compression by IgG4-related pachymeningitis.

A rare case of IgG4-related pachymeningitis is presented. The manuscript describes the multidisciplinary treatment of a rare entity in an exceptional location, prompting emergent surgical treatment. However, the correct intraoperative hypothesis led to a minimal surgical approach with fewer risks and good disease control. Finding a balance between maximising treatment outcome and minimising risks is often difficult for clinicians worldwide who encounter the same clinical dilemma. The known cases are summarised, as are radiological characteristics and common treatments.

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation.

Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage-, dendritic cell-, or monocyte-differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist-assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis-affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim-Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell-of-origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.