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

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.

PD-L1 status in refractory lymphomas

“…Another important finding of our study was an excellent concordance between SP142 and SP263 clones using the 5% cut-off as recommended [13,24]. There are only a few studies that have analyzed the diagnostic utility and comparison of different anti-PD-L1 antibody clones [5,10,[27][28][29]. A systematic review of Carbognin et al [13] confirmed a significant difference in clinical response among solid tumors (melanoma, NSCLC, genitourinary cancers) when a 5% cut-off is used instead of 1% threshold.…”

Response to MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib in multifocal histiocytic sarcoma

“…Also, PD-L1 overexpression and PTEN mutations have been described and can be targeted nowadays. 13 However, as the disease is very rare, no clinical data of larger studies are available to date.…”

Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

“…Further mutational studies on this rare histiocytic disease should be undertaken to better characterize its pathogenesis as well as open up potential avenues for therapy. BRAF (p.V600E) [7][8][9] PIK3CA (p.E542K, p.E545K, p.A1046T, and p.H1047R) [7,34] NRAS (p.G12D, p.Q61K, p.Q61R) [7,34] KRAS (p.G12S) [34] MAP2K1 (p.K57E/N, p.Q56P, p.F68L, p.S123T/P, p.E144K, p.E51_Q58del, p.Q58_E62del, p.E102_I103del) [34] ARAF (p.S214A, p.A225 V, p.P539H) [34] BRAF fusions (RNF11-BRAF, CLIP2-BRAF) [34] KIF5B-ALK fusion [34] LMNA-NTRK fusion [34] Rosai-Dorfman disease (RDD) NRAS (p.Q61R) [34] KRAS (p.G12D) [34] SMAD4 (p.T521I) [40] MAP2K1 (p.V60M, p.D65M) [34] ARAF (p.N217K) [34] Juvenile xanthogranuloma (JXG) NRAS (p.Q61R) [34] KRAS (p.G12D) [34] MAP2K1 (p.T28I, p.L37P, p.E120Q, p.Y130C) [34] ARAF (p.N217K, p.F351L) [34] Histiocytic sarcoma BRAF (p.V600E) [8] PTEN deletion (deletion involving exon 7 (c.635-7_639del) [37], exon 6-9 [41] …”