Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements

Abstract

Systemic anaplastic large cell lymphomas (ALCLs) are classified into ALK-positive and ALK-negative types. We recently reported that ALK-negative ALCLs are genetically heterogenous. The largest subset, representing 30% of cases, had rearrangements of the DUSP22 locus. These cases had favorable outcomes similar to ALK-positive ALCL, and superior to other ALK-negative ALCLs. Here, we examined the morphologic features of these cases in more detail. First, we conducted blinded review of hematoxylin and eosin slides of 108 ALCLs from our previous study, scoring cases for the presence of 3 histologic patterns and 5 cell types. Cases then were unblinded and re-reviewed to understand these features further. DUSP22-rearranged ALCLs were more likely than other ALK-negative ALCLs to have so-called doughnut cells (23% vs. 5%; P = 0.039), less likely to have pleomorphic cells (23% vs. 49%; P = 0.042), and nearly always (95%) had areas with sheet-like growth (common pattern). To examine the reproducibility of these findings, we conducted blinded review of hematoxylin and eosin slides of 46 additional ALK-negative ALCLs using a 0 to 3 scoring system to predict likelihood of DUSP22 rearrangement, the results of which correlated strongly with subsequent findings by fluorescence in situ hybridization (P < 0.0001). Although all ALCLs share certain morphologic features, ALCLs with DUSP22 rearrangements show significant differences from other ALK-negative ALCLs, typically showing sheets of hallmark cells with doughnut cells and few large pleomorphic cells. These morphologic findings and our previous outcome data suggest that ALK-positive ALCLs and DUSP22-rearranged ALCLs represent prototypical ALCLs, whereas ALCLs lacking rearrangements of both DUSP22 and ALK require further study.

No TP63 rearrangements in a selected group of primary cutaneous CD30+ lymphoproliferative disorders with aggressive clinical course

“…For positive staining, a cutoff value of 30% was used. 9 For the FISH probes, DNA was isolated from bacterial artificial chromosome clones: RP11-718B1, RP11-179O12, and RP11-24F1 proximal and RP11-791J2, RP11-10K11, and RP11-204624 distal of the TP63 gene, purchased from the BACPAC resources center, Children's Hospital Oakland Research Institute, California, and based on the probe design as used by Vasmatzis et al 10 The isolated DNA was labeled using nick translation either with digoxigenin-or biotin-coupled dideoxynucleotides as haptens. FFPE whole-tissue sections were deparaffinized in xylene, pretreated in 10 mM citric acid buffer, digested in 0.4% pepsin in 0.02M HCL, and codenatured and hybridized with the designed probes.…”

The 2016 revision of the World Health Organization classification of lymphoid neoplasms

“…97 the locus containing DUSP22 and IRF4 in chromosome 6p25 tends to be relatively monomorphic, usually lack cytotoxic granules, and have been reported to have a superior prognosis, whereas a small subset with TP63 rearrangements are very aggressive ( Figure 6A). [103][104][105] Interestingly, the same locus in 6p25 has also been implicated in lymphomatoid papulosis (LYP) and primary cutaneous ALCL. 106,107 LYP is a clinically diverse disorder, and in recent years a number of new pathological and clinical variants have been described.…”

Adult systemic anaplastic large-cell lymphoma: recommendations for diagnosis and management

“…The majority of sALCLs stain positively for the cytotoxic markers TIA1, granzyme B, and perforin, though these may be absent in ALK− ALCLs with DUSP22 rearrangements (see below) [23,24]. About 80% of ALK+ ALCLs stain positively for epithelial membrane antigen (EMA), compared to half that in ALK− cases [12].…”

“…When present, ALK− ALCLs with DUSP22 rearrangements had OS rates similar to ALK+ ALCLs, while TP63 rearrangements carried a worse prognosis; these findings were independent of the intensity of treatment received [23]. While the relative rarity of TP63 rearrangements make this group of patients difficult to characterize definitively, DUSP22 -rearranged ALCLs have consistent morphologic and phenotypic features in addition to their favorable prognostic features, suggesting the possibility that these cases might represent a distinct clinicopathologic entity [23,24]. The pathogenetic role of DUSP22 rearrangements remains to be demonstrated.…”