ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes

Castellar, Edgardo R. Parrilla; Jaffe, Elaine S.; Said, Jonathan; Swerdlow, Steven H.; Ketterling, Rhett P.; Knudson, Ryan A.; Sidhu, Jagmohan S.; Hsi, Eric D.; Karikehalli, Shridevi; Jiang, Liuyan; Vasmatzis, George; Gibson, Sarah E.; Ondrejka, Sarah L.; Nicolae, Alina; Grogg, Karen L.; Allmer, Cristine; Ristow, Kay M.; Wilson, Wyndham H.; Macon, William R.; Law, Mark E.; Cerhan, James R.; Habermann, Thomas M.; Ansell, Stephen M.; Doğan, Ahmet; Maurer, Mathew S.; Feldman, Andrew L.

doi:10.1182/blood-2014-04-571091

Cited by 411 publications

(317 citation statements)

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“…A recent study by our group identified DUSP22 and TP63 rearrangements in 30% and 8% of systemic ALK-negative ALCLs, respectively [29]. These rearrangements were mutually exclusive of each other, and were uniformly absent in ALK-positive ALCLs.…”

Section: Chromosomal Rearrangements In Alk-negative Alclmentioning

confidence: 94%

Genetics of anaplastic large cell lymphoma

Zeng

Feldman

2015

Leukemia & Lymphoma

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Anaplastic large cell lymphoma (ALCL) comprises a group of T-cell non-Hodgkin lymphomas unified by common morphologic and immunophenotypic characteristics, but with a spectrum of clinical presentations and behaviors. Early identification of anaplastic lymphoma kinase (ALK) gene rearrangements in some ALCLs led to recognition of ALK as an important diagnostic and prognostic biomarker, and a key driver of ALCL pathobiology. Rearrangements and other genetic abnormalities of ALK subsequently were identified in diverse other human malignancies. Recent clinical, pathologic, and genetic data have begun to shed light on ALK-negative ALCLs, revealing significant heterogeneity within this more ill-defined entity.

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Section: Chromosomal Rearrangements In Alk-negative Alclmentioning

confidence: 94%

Genetics of anaplastic large cell lymphoma

Zeng

Feldman

2015

Leukemia & Lymphoma

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“…Study group 1 consisted of 108 systemic ALCLs (77 ALK-negative, 31 ALK-positive) assessed in our previous study. 4 One ALK-positive ALCL from that study was not available for review. Four ALK-negative ALCLs that had been assessed previously but not reported because of lack of clinical outcome data were included in the present study.…”

Section: Methodsmentioning

confidence: 99%

“…3 We recently showed, however, that ALK-negative ALCL is a genetically and a clinically heterogenous entity. 4 Thirty percent of cases bear rearrangements of the DUSP22-IRF4 locus on 6p25.3 ( DUSP22 rearrangements), 5,6 and these cases have favorable outcomes similar to those of ALK-positive ALCL. A smaller fraction of patients (~8%) have rearrangements of TP63 7 and have very poor outcomes, whereas the remaining cases lack rearrangements of ALK , DUSP22 , and TP63 (“triple-negative” ALCLs) and have intermediate outcomes.…”

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confidence: 99%

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

King¹,

Dao²,

McPhail³

et al. 2016

American Journal of Surgical Pathology

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106

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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.

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“…4,5 cWithout including the single case (Figures 1f–i) identified retrospectively in a previous biopsy from a patient with mycosis fungoides with large-cell transformation that demonstrated both p63 protein expression and TP63 rearrangement.…”

Section: Figurementioning

confidence: 99%