Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1.

Zoran Gatalica,Jeffrey Swensen,Sherri Z Millis,Nurija Bilalovic,Juan P Palazzo,Semir Vranic,Ryan P Bender,Daniel Von Hoff,Robert J Arceci

doi:10.18632/oncotarget.4378

Abstract

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses.

Highlights

The proliferative histiocytoses encompass a broad spectrum of rare tumors with clinical behavior ranging from spontaneous regression to highly aggressive disease with fatal outcome [1]
The BRAF V600E mutation was identified in 8 out of 24 cases (33%) including 4/4 Erdheim-Chester disease (ECD) (100%) and 4/11 Langerhans cell histiocytosis (LCH) (36%) while other histiocytoses harbored no BRAF V600E mutations (Table 1)
A case of histiocytic sarcoma (HS) that was devoid of a BRAF V600E mutation harbored pathogenic, PTEN mutation (c.635-7_639del; a splice site mutation that abolishes the conserved splice region at exon 7 of PTEN gene) confirmed by the loss of PTEN protein by IHC (Figure 2C)

Summary

Introduction

The proliferative histiocytoses encompass a broad spectrum of rare tumors with clinical behavior ranging from spontaneous regression to highly aggressive disease with fatal outcome [1]. They are characterized by the accumulation and tissue infiltration of immunologically active cells, including T cells, eosinophils, macrophages and dendritic cells. Identification of the activating BRAF V600E mutation in a subset of histiocytoses (ECD and LCH, 50-100%) has opened a new avenue for the treatment of these disorders with BRAF and MEK inhibitors [1,2,3,4,5]. Studies of Bubolz et al [3] and Haroche et al [6,7] demonstrated some efficiency of the BRAF inhibitor vemurafenib in the treatment several patients with multisystemic and refractory ECD and LCH

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Conclusion