Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells

Aishwarya Ravindran; Surendra Dasari; Gordon J Ruan; Cody J Artymiuk; Rong He; David S Viswanatha; Jithma P Abeykoon; Saurabh Zanwar; Jason R Young; Gaurav Goyal; Ronald S Go; Karen L Rech; Mayo Clinic-The University of Alabama at Birmingham Histiocytosis Working Group

doi:10.1016/j.modpat.2023.100268

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells

Mod Pathol. 2023 Oct;36(10):100268. doi: 10.1016/j.modpat.2023.100268. Epub 2023 Jul 4.

Affiliations

¹ Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Division of Laboratory Medicine-Hematopathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama.
² Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
³ Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
⁴ Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
⁵ Department of Radiology, Mayo Clinic, Jacksonville, Florida.
⁶ Division of Hematology-Medical Oncology, The University of Alabama at Birmingham, Birmingham, Alabama; Research Collaborator (limited tenure), Mayo Clinic, Rochester, Minnesota.
⁷ Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address: Rech.Karen@mayo.edu.

PMID: 37406859
DOI: 10.1016/j.modpat.2023.100268

Abstract

Malignant histiocytoses (MHs), or the 'M group' of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

Keywords: Langerhans cell sarcoma; MAPK pathway; histiocytic sarcoma; interdigitating dendritic cell sarcoma; malignant histiocytosis.