Genetic Basis of Extramedullary Plasmablastic Transformation of Multiple Myeloma

Abstract

In patients with multiple myeloma, plasmablastic transformation in the bone marrow is rare and associated with poor outcomes. The significance of discordant extramedullary plasmablastic transformation in patients with small, mature clonal plasma cells in the bone marrow has not been well studied. Here, we report the clinicopathologic, cytogenetic, and molecular features of 10 such patients (male/female: 6/4, median age: 65 y, range: 48 to 76 y) with an established diagnosis of multiple myeloma in the bone marrow composed of small, mature plasma cells in parallel with a concurrent or subsequent extramedullary plasmablastic transformation. Eight patients with available survival data showed an overall aggressive clinical course with a median survival of 4.5 months after the diagnosis of extramedullary plasmablastic transformation, despite aggressive treatment and even in patients with low-level bone marrow involvement. Pathologically, the extramedullary plasmablastic myeloma were clonally related to the corresponding bone marrow plasma cells, showed high levels of CMYC and/or P53 expression with a high Ki-67 proliferation index by immunohistochemistry and harbored more complex genomic aberrations including frequent mutations in the RAS pathway and MYC rearrangements compared with their bone marrow counterparts. In summary, although genetic and immunohistochemical studies were not uniformly performed on all cases due to the retrospective nature of this study, our data suggest that discordant extramedullary plasmablastic transformation of multiple myeloma has an aggressive clinical course and is characterized by frequent mutations in the RAS pathway and more complex genomic abnormalities.

Figure 1.

Morphologic features of extramedullary tissue and bone marrow biopsies from case 1. (A&B). H&E-stained sections (100X and 400X; B, inset, 1000X) of a shoulder mass biopsy showing sheets of atypical cells with plasmablastic morphology exhibiting centrally located, prominent nucleoli, high nuclear-to-cytoplasmic ratios and abundant background mitotic figures and apoptotic bodies. (C&D) H&E -stained sections (100X and 400X) and aspirate smears (D, inset, 1000X) of a bone marrow biopsy showing scattered or clustered mature-appearing plasma cells.

Figure 2.

Immunophenotypic features of bone marrow and extramedullary tissue biopsies from case 1. (A). Plasma cells accounting for ~10% of the marrow cellularity (shown by CD138 IHC) with kappa light chain restriction (shown by kappa and lambda IHC) are shown. (B). CD138, kappa, lambda, CD56, MUM1, Ki-67, P53, CMYC, PD-L1 and PD-L2 IHC and in-situ hybridization for Epstein-Barr virus (EBER) performed on the shoulder mass biopsy are shown.

Figure 3.

FISH analysis using MYC break-apart probes (A) and SNP array analysis of bone marrow and extramedullary tissue biopsies (B, C, D). (A). MYC FISH analysis showed multiple copies of MYC in the tissue biopsy of case 1 (Left), a MYC translocation with split signal patterns in the bone marrow (Middle), and a more complex abnormal MYC signal pattern in the tissue biopsy of case 2 (Right). 5’ and 3’ MYC probes are labeled in spectrum green and spectrum red, respectively. Abnormal cells are highlighted by yellow arrows. (B). SNP array analysis of paired bone marrow (Upper) and tissue (Bottom) biopsies from case 1 showed a hyperdiploid genomic profile with gains of chromosomes 3, 5, 6, 7, 9, 15, 17 and 19 in the bone marrow and more complex alterations in the tissue, including gains of 1q, chromosome 2 and 6p, deletions of 6q and 8p, high level gain of 8q including MYC and gain of 11q. (C). SNP array analysis of paired bone marrow (Upper) and tissue (Bottom) biopsies from case 2 showed a hyperdiploid clone with gains of chromosomes 5, 6, 9, 11, 15, 17, 19, 20 and 21, gain of 3q and deletion of 19q in the bone marrow and additional alterations in the tissue, including deletion of 1p, gain of 1q, deletion of 4p, gain of 4q, loss of chromosome 13, gain of 15q, deletion of 17p including TP53 and deletion of 19q. (D). SNP array analysis of case 6 (tissue biopsy only) showed a doubling hypodiploid clone with gains of chromosomes 3, 7, 9, 11, 18 and 19, gains of 1q, 4q, 5p and 15q and copy-neutral loss of heterozygosity (allele differences, bottom part) of all disomic chromosomes/arms of the 1, 2, 4, 5, 6, 8, 10, 12, 13, 14, 15, 16, 17, 20, 21, 22 and X chromosomes. The left Y axis is a log2 ratio (−1.5–1.5), whereas the right Y axis is a smooth signal copy level (0–4).