The mutational landscape of histiocytic sarcoma associated with lymphoid malignancy

Abstract

Histiocytic sarcoma and tumors with dendritic cell differentiation (HDT) are uncommon neoplasms often with an aggressive clinical course that may occur in association with another hematologic malignancy or mediastinal germ cell tumor (secondary HDT, sHDT). Previous studies have shown mutations in the RAS/MAPK pathway in HDT and have demonstrated a clonal relationship between HDT and associated lymphoid malignancies through common translocations or identical immunoglobulin or T-cell receptor gene rearrangements. We performed whole exome sequencing on 16 cases of sHDT to further evaluate the spectrum of mutations that occur in sHDT in the context of an associated lymphoid malignancy, including cases associated with follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma, B- and T-cell acute lymphoblastic leukemia/lymphoma and peripheral T-cell lymphoma, NOS. In addition, we assessed the clonal relationship between the HDT and the associated lymphoid malignancy in three cases for which matched samples were available. We found mutations in RAS/MAPK pathway genes in 14/16 cases of sHDT associated with diverse mature and precursor B-cell and T-cell neoplasms, involving KRAS (8/16), BRAF (2/16), NRAS (2/16), MAP2K1 (1/16), and NF1 (1/16). In addition, we note that FL-associated sHDT frequently shares a similar mutational profile to the associated malignancy, identifying mutations in CREBBP or KMT2D in all cases and "aberrant" somatic hypermutation in 5/6 cases. Our study confirms the role of the RAS/MAPK pathway in the pathogenesis of sHDT, provides further evidence of a common neoplastic precursor and, in the case of FL, gives additional insight into the stage in lymphomagenesis at which transdifferentiation may occur.

Fig. 1. Mutational profile of sHDT.

Cases are divided according to the associated malignancy. Each row represents a gene and each column represents a sample.

Fig. 2. sHDT associated with FL.

a Histological features of FL grade 3B (H&E, original magnification ×40) and HS, biopsy composite with FL (left) and the sequenced biopsy at 7 months (right) (original magnification ×200). The FL is positive for PAX5 (original magnification ×100) and negative for CD68 (original magnification ×100). Both HS biopsies are negative for PAX5 (original magnification ×100) and positive for CD68, which is more focal in the biopsy at 7 months (original magnification ×100, left; original magnification ×200, right). b The FL and HS share identical clonal IG arrangements. c Comparison of the mutational profiles of clonally related FL and HS.

Fig. 3. sHDT associated with T-ALL.

a Copy number analysis of T-ALL showing LOH at chromosome 4q. (BAF: B allele frequency). b Copy number analysis of HS showing gain of chromosome 20. Both cases have LOH at chromosome 9p. c Mutational and copy number comparison for clonally related T-ALL and HS. d Photomicrograph of the T-ALL and HS (original magnification ×400).

Fig. 4. sHDT associated with T-ALL.

a Copy number analysis of the T-ALL showing LOH at chromosome 9p and 17p, with gain of chromosome 18 (BAF: B allele frequency). b Copy number analysis of IDCT showing LOH at chromosome 9p and gain of chromosome 12. c Mutational and copy number comparison for clonally related T-ALL and IDCT.

Fig. 5. Copy number analysis of sHDT.

a Copy number alterations across entire cohort, with recurrent losses of chromosome 9p at CDKN2A. b Illustrative example of FISH in two cases confirming homozygous deletion of CDKN2A (CEP 9 – Aqua; chromosome 9p.21 – Orange). c View of chromosome 9 in a case with homozygous deletion of CDKN2A (arrow). Copy number alterations are represented in the top panel and B-allele frequencies in the bottom panel (Nexus 9.0, BioDiscovery).