DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma

Abstract

DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P<0.05). TP63 rearrangement (TP63-R) was detected in three of the 66 (5%) ALK-negative ALCL cases tested and none of these cases carried the DUSP22-R. Overall survival of patients with DUSP22-R ALCL was similar to that of the patients with DUSP22-NR neoplasms regardless of International Prognostic Index score, stage, age, or stem cell transplantation status (all P>0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.

Figure 1.

Lymph node biopsy from a case with DUSP22-rearranged ALK-negative anaplastic large cell lymphoma. (A, B) The nodal architecture is effaced by sheets of monotonous, intermediate sized lymphoma cells. Some lymphoma cells show kidney-shaped nuclei (hallmark cells) (arrows, A) or central nuclear pseudoinclusions (“doughnut” cells) (arrows, B). (C-G) The lymphoma cells are strongly and diffusely positive for CD30 (C) and CD3 (D), and are negative for ALK1 (E), granzyme B (F) and EMA (G). (H) Fluorescence in situ hybridization analysis using IRF4/DUSP22 break-apart probes, ×600. The nuclei showing a DUSP22 rearrangement (with red and green split signals) are indicated by white arrow heads. (A, B) Hematoxylin-eosin stain, x600 (A) and x600 (B). (C-G) Immunohistochemistry, x400.

Figure 2.

The DUSP22-rearranged ALK-negative anaplastic large cell lymphoma shown in Figure 1 also involves bone marrow and peripheral blood. (A) This bone marrow core biopsy specimen shows a hypercellular bone marrow infiltrated by lymphoma cells in an interstitial pattern. The lymphoma cells are morphologically similar to those in the lymph node described in Figure 1. (B) The lymphoma cells in the bone marrow are positive for CD30 by immunohistochemistry. (C) Bone marrow aspirate smear showing lymphoma cells, mostly small to intermediate size, with irregular nuclear contours and basophilic cytoplasm. A lymphoma cell shows kidney-shaped nuclei. (D-G) Flow cytometric immunophenotypic analysis of the peripheral blood shows a large population (75%) of lymphoma cells (red dots) which are positive for CD45 (D), CD30 (E), CD3 (partial/decreased, E), CD8 (dim, F), and CD7 (partial, G), and negative for CD4 and CD26, immunophenotypically similar to the lymphoma cells in the lymph node described in Figure 2. The purple and blue dots represent background benign CD4⁺ and CD8⁺ T cells, respectively. (A) Hematoxylin-eosin stain, x500. (B) Immunohistochemistry, x500. (C) Wright-Giemsa stain, x1000.

Figure 3.

Flow cytometric immunophenotypic analysis of the lymph node biopsy specimen shown in Figure 1. (A-H) The lymphoma cells (red dots) are positive for CD45 (A), CD30 (B), CD3 (decreased, B), CD8 (partial, C), CD2 (D), CD7 (partial/decreased, F), and T-cell receptor (TCR) α/β (decreased, H), and negative for CD4 (C), CD5 (D), CD26 (F), CD25 (G), and TCR γ/d (H). The lymphoma cells are medium-sized by forward scatter (E). The purple and blue dots represent background benign CD4⁺ and CD8⁺ T cells, respectively.

Figure 4.

CD15 expression with three staining paterns in DUSP22-rearranged cases of ALK-negative anaplastic large cell lymphoma. (A) Golgi-like pattern. (B) Membranous/cytoplasmic pattern. (C) Combination of the Golgi-like and membranous/cytoplasmic patterns. (D) The percentage of CD15⁺ lymphoma cells in DUSP22-rearranged cases of anaplastic large cell lymphoma cases is significantly higher than that in the cases without a DUSP22 rearrangement. (A-C) Immunohistochemistry, x500. DUSP22-R: with DUSP22 rearrangement; DUSP22-NR: without DUSP22 rearrangement.

Figure 5.

Comparison of STAT3 activation (pSTAT3^Tyr705) and PD-L1 expression in ALK-negative anaplastic large cell lymphoma with or without a DUSP22 rearrangement. (A, D) Negative pSTAT3^Tyr705 (A) and PD-L1 (D) expression in a DUSP22-rearranged case. (B, E) Diffuse positivity of pSTAT3^Tyr705 (B) and PD-L1 (E) in a case without a DUSP22-rearrangement. (C, F) The percentage of pSTAT3^Tyr705-positive (C) or PD-L1-positive (F) lymphoma cells in DUSP22-rearranged cases of anaplastic large cell lymphoma is significantly lower than that in cases without a DUSP22 rearrangement. DUSP22-R: with DUSP22 rearrangement; DUSP22-NR: without DUSP22 rearrangement.

Figure 6.

DUSP22 rearrangement has no prognostic significance in patients with ALK-negative anaplastic large cell lymphoma regardless of International Prognostic Index score, stage, age, or transplantation status. (A, B) Comparison of overall survival (A) and progression-free survival (B) among the patients with ALK+ anaplastic large cell lymphoma (ALCL), DUSP22-R (all were TP63-NR) ALK-negative ALCL, DUSP22-NR/TP63-NR (triple-negative) ALK-negative ALCL, and DUSP22-NR/TP63-R ALK-negative ALCL. *P<0.05, when comparing ALK+ ALCL versus DUSP22-R ALK-negative ALCL or comparing ALK+ ALCL versus DUSP22-NR/TP63-NR ALK-negative ALCL. (C, D) Comparison of overall survival in patients with International Prognostic Index score ≥3 (C) and <3 (D). (E, F) Comparison of overall survival in patients with stage III-IV (E) and stage I-II (F) disease. (G, H) Comparison of overall survival in patients aged ≥50 years (G) and <50 years (H). (I, J) Comparison of overall survival in patients with stem cell transplantation (I) and without (J). DUSP22-R: with DUSP22 rearrangement; DUSP22-NR: without DUSP22 rearrangement; TP63-R: with TP63 rearrangement; TP63-NR: without TP63 rearrangement; IPI: International Prognostic Index; OS: overall survival; PFS: progression-free survival; SCT: stem cell transplant. (C-J) TP63-R cases were excluded.