Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy - PubMed (original) (raw)

Multicenter Study

. 2024 Jul;205(1):127-137.

doi: 10.1111/bjh.19462. Epub 2024 Apr 12.

Benjamin H Durham 2 3 4, Anne S Reiner 5, Mariko Yabe 2, Kseniya Petrova-Drus 2, Ahmet Dogan 2, Melissa Pulitzer 2, Klaus J Busam 2, Jasmine H Francis 6, Raajit K Rampal 7, Gary A Ulaner 8 9, Ryan Reddy 8 9 10, Randy Yeh 10, Vaios Hatzoglou 10, Mario E Lacouture 7, Veronica Rotemberg 7, Roei D Mazor 11, Oshrat Hershkovitz-Rokah 12 13, Ofer Shpilberg 11 14, Gaurav Goyal 15 16, Ronald S Go 16 17, Jithma P Abeykoon 17, Karen Rech 3 16, Diana Morlote 15, Shiraz Fidai 18, Vedavyas Gannamani 18, Maryam Zia 18, Omar Abdel-Wahab 4 7, Katherine S Panageas 5, Marc K Rosenblum 2, Eli L Diamond 16 19

Affiliations

Multicenter Study

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy

Joshua S Friedman et al. Br J Haematol. 2024 Jul.

Abstract

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Keywords: MAPK signalling; histiocytes; myeloid neoplasm; targeted therapy.

© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

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Conflict of interest statement

O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, Loxo Oncology/Lilly and is on the Scientific Advisory Board of Envisagenics Inc and Harmonic Discovery Inc.; O.A.-W. has received prior research funding from H3B Biomedicine, Loxo Oncology/Lilly, Minovia, and Nurix Therapeutics unrelated to the current manuscript. E.L.D discloses unpaid editorial support from Pfizer Inc and serves on an advisory board for Day One Biotherapeutics, Springworks Therapeutics, and Opna Bio, all outside the submitted work. M.E.L has a consultant role with Johnson and Johnson, Novocure, Janssen, Novartis, Deciphera, Kintara, RBC/La Roche Posay, Trifecta, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Roche, Oncoderm, Apricity and research funding from Lutris, Paxman, Novocure, OQL, Novartis and AZ, all outside the submitte work. M.Y serves as a consultant for Janssen Research and Development outside the submitted work. V.R. serves as a medical consultant for Inhabit Brands, Inc outside the submitted work. G.A.U discloses research grant and paid consultancy and speaker bureau with GE Healthcare and Lantheus, research grant and paid consultancy from Nuclidium, research grants from RazeBio and Curium, and paid consultancy with POINT Biopharma, all outside the submitted work. G.G. has served on advisory board for Opna Bio, receives royalties from UpToDate, and consulting fees from 2nd.MD.

Figures

Figure 1:

Figure 1:. Morphology and immunohistochemistry of mixed histiocytic neoplasms.

Biphenotypic ear pinna mass in a patient with mixed Erdheim-Chester Disease (ECD) and Langerhans cell histiocytosis (LCH;; A-D). A: Histologic section of non-Langerhans cell (non-LCH) lesion shows proliferation of atypical histiocytes with vesicular chromatin and prominent nucleoli (arrowhead) (x500, H&E). B: Atypical histocytes with grooved nuclei (arrow) are present in areas demonstrating LCH (x500, H&E). C: CD68 immunohistochemistry demonstrates diffuse atypical histiocytic infiltrate both in LCH lesion and non-LCH lesion. Expression of CD68 is dimmer in LCH lesion (x20, CD68 immunohistochemistry). D: CD1a shows focal Langerhans cell differentiation (x20, CD1a immunohistochemistry). A patient with disparate LCH and ECD lesions on the face is shown in panels E-L. E: Facial photograph demonstrating medial right eyelid xanthelasma and left cheek erythematous lesion (blue arrows) F: Biopsy of left cheek shows dense subcutaneous atypical histiocytic infiltrate (x100, H&E). G: Atypical histiocytes in left cheek biopsy have grooved nuclei and admixed eosinophils are present in a background, consistent with LCH (x400, H&E). H: LCH lesional cells are highlighted with CD1a (x100, CD1a immunohistochemistry) I: Right eye lid biopsy shows xanthomatous histiocytic infiltration (x200, H&E). J: Higher magnification shows xanthomatous histiocytes with abundant cytoplasm (x500, H&E). K: CD68 highlights xanthomatous histiocytes (x100, CD68 immunohistochemistry). L: CD1a is negative in right eye lid biopsy (x100, CD1a immunohistochemistry).

Figure 2:

Figure 2:. Biphenotypic Erdheim-Chester Disease / Rosai Dorfman disease (RDD) and RDD/Langerhans cell histiocytotis

Biphenotypic ECD/RDD retroperitoneal lesion is demonstrated in panels A-H. A: Histologic section shows biphasic morphology; atypical histocytes have abundant eosinophilic cytoplasm in left upper corner consistent with ECD, while histocytes have large nuclei in right corner with admixed numerous background plasma cells, consistent with Rosai-Dorfman disease (x100, H&E). B: Areas with ECD shows atypical histiocytes with abundant xanthomatous cytoplasm and occasional giant cells (x400, H&E). C: Areas with RDD shows large atypical histiocytes showing emperipolesis (x400, H&E). D: CD163 immunohistochemistry shows sheets of atypical histiocytes in the ECD component (left-upper corner), and histocytes are scattered in areas of Rosai-Dorfman disease (x100, CD163 immunohistochemistry). E: S100 Is negative in the ECD component (x400, S100 immunohistochemistry). F: S100 is expressed in component of RDD (x400, S100 immunohistochemistry). G: OCT2 Is negative in ECD component (x400, S100 immunohistochemistry). H: OCT2 highlights nuclei of histiocytes in areas of RDD (x400, OCT2 immunohistochemistry). Biphenotypic LCH/RDD lesion of the bone is presented in panels I-L. I: Histologic section shows large atypical histocytes with emperipolesis (yellow arrow) and numerous eosinophils and atypical histiocytes with grooved nuclei (arrow head and inset) (x400, H&E). J: CD68 is expressed in both components (x100, CD68 immunohistochemistry). K: Langerin expression is restricted to the LCH component (x100, Langerin immunohistochemistry).

Figure 3:

Figure 3:. Molecular profiling of patients with mixed histiocytic neoplasms:

A: Oncoprint of kinase alterations and their frequencies identified across the mixed histiocytic neoplasm patient cohort (n=27) via whole exome and targeted DNA and RNA sequencing. Each patient is represented in one column. Mixed histiocytoses diagnostic subtypes are documented in the first row. Somatic kinase driver mutations and fusions are identified in the lower rows. B: Protein diagrams of somatic kinase alterations and their protein locations uncovered in mixed histiocytosis subtypes within this study.

Figure 4:

Figure 4:. Swimmer plot of responses to observation or systemic therapy in patients with mixed histiocytic neoplasms (N=27).

Patient-level MXH diagnoses, mutations, treatments, responses, and subsequent progression events are demonstrated with a central timepoint of initiation of targeted therapy.

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