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L. Prieto-Torres et al.
by the simultaneous presence of dermic CD30+ large cells and intraepidermal infiltrate by CD30+ small cells with a pagetoid reticulosis pattern.10,54 The clinical behavior and prognosis of cases with DUSP22 rearrangements is simi- lar to that of cases without such rearrangements.55 Currently, clinical presentation and staging remain essen- tial to differentiate cases of pcALCL with DUSP22 rearrangement from LyP with this molecular alteration, because the two entities have similar histological fea- tures.54 DUSP22 rearrangements have also been described in rare cases of CD30-rich tumoral MF.56
Expression of the chemokine receptor gene CCR8 is asso- ciated with DUSP22 rearrangements in ALCL.57 It has been proposed that the higher level of expression of this skin- homing chemokine receptor may explain the lower tenden- cy of pcALCL to disseminate to extracutaneous sites.58
The pathways activated after DUSP22-IRF4 rearrange- ments in peripheral T-cell lymphomas have recently been investigated by Mélard et al.59 They found a tumor suppres- sor function for DUSP22, with the restored expression of DUSP22 promoting apoptosis and impairing soft agar clonogenicity.59 Negative regulation of the interleukin- 6/leukemia inhibitory factor/signal transduction and activa- tor of transcription (STAT)-3 pathway has been found in
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experimental studies.60 Consistent with these findings, DUSP22 (also known as JKAP) knockout mice develop inflammation and autoimmunity.61
ALK-positive primary cutaneous anaplastic large cell lymphoma
Cutaneous involvement in cases of systemic ALK+ ALCL is generally indicative of a bad prognosis (relative risk: 2) and occurs in 26% of pediatric ALK+ ALCL cases.62 In con- trast, ALK+ pcALCL cases seem to have a more favorable outcome. Only a few cases of ALK+ pcALCL have been reported, the largest series being that described by Oschlies et al.,63 in which six pediatric patients with ALK+ pcALCL had a favorable clinical course, comparable to that of patients with ALK– pcALCL. Other ALK+ primary cuta- neous cases occurred in adults and had peculiar features, such as cytoplasmic ALK expression and a lack of ALK translocation.64 To date, no ALK fusion partners exclusive to the primary cutaneous cases have been reported. It is important to stage patients with ALK+ pcALCL carefully because cutaneous lesions triggered by insect bites can be the first manifestation of systemic ALK+ ALCL.65 The authors postulated that insect bite-associated antigens may attract T lymphocytes to the skin, some of which bear the ALK translocation t(2;5). The subsequent release of differ- ent cytokines at the site of the bite could act as a “second hit” and activate T cells, which may express the oncogenic NPM-ALK protein and initiate deregulated growth.65
Primary cutaneous anaplastic large cell lymphoma with TP63 rearrangements
In 2012, Vasmatzis et al. described two of 19 pcALCL that carried TP63 rearrangements,27 both of which had an unusual, aggressive clinical behavior, analogous to that of systemic ALCL with TP63 rearrangements.51 Subsequent work by the same group also identified a case of aggressive MF with a TP63 translocation.66 In both series, TP63 translo- cations were associated with strong TP63 protein expres- sion detectable by immunohistochemistry, but this was not a specific finding since the protein was also expressed in cases without a TP63 translocation. Schrader et al. reviewed a series of 17 cases of aggressive LyP and pcALCL. They found no cases with a TP63 translocation, and confirmed the lack of specificity of the TP63 immunohistochemistry.28
NPM1-TYK2 gene fusion and oncogenic STAT3 activation Mutations on the JAK1/STAT3 pathway are common in systemic ALK– ALCL.67,68 However, these mutations have been found in only 5% of pcALCL, which is further evi- dence of the distinct molecular pathogenesis of the two entities. Whole-transcriptome sequencing done in pcALCL revealed the NPM1-TYK2 gene fusion, which encodes a protein containing an intact catalytic domain in TYK2 and an oligomerization domain of NPM. It was present in two (1 LyP, 1 pcALCL) of the cases of primary cutaneous CD30+ lymphoproliferative disorders studied (n=47) and was not found in other mature T-cell neo- plasms (n=151). Both cases showed nuclear STAT5 expres- sion. This defective kinase activates the STAT signaling pathway (STAT1/3/5), implying that TYK2 could be a
therapeutic target in this subset of patients.69
Epigenetic abnormalities in primary cutaneous anaplastic large cell lymphoma
Epigenetic abnormalities, including histone tail post- translational modifications and DNA methylation, are a
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Figure 3. ALK-positive primary cutaneous anaplastic large cell lymphoma. (A) Clinical picture of a large ulcerated tumor located on the back. (B) Fluorescence in situ hybridization image showing an ALK reciprocal translocation with gain of one or two copies of the ALK gene. (C,D) Hematoxylin & eosin stain showing the morphology of large T cells (E,F) (x40), with CD30 positivity and (G,H) (x40), nuclear and cytoplasmic ALK positivity in tumor T cells.
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haematologica | 2019; 104(2)