Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases

Abstract

BackgroundSkin involvement is frequent in ALK-positive anaplastic large cell lymphomas. The role of an insect bite as a triggering event has been postulated but not well documented. Design and MethodsWe retrospectively investigated five cases of ALK-positive anaplastic large cell lymphoma who presented with skin lesions occurring after an insect bite. Biopsies were immunostained with antibodies against CD30, ALK, T-and B-cell antigens. ResultsPersistent skin lesions developed after solitary insect bites in three patients and after multiple bites in two. Regional lymphadenopathy developed within weeks after the bite in three cases. In four cases the correct diagnosis was delayed due to misinterpretation of the findings as a reactive infiltrate in the skin (n=2) or lymph nodes (n=2); all cases subsequently showed small numbers of cells with nuclear and cytoplasmic staining for ALK. The final diagnoses were lymphohistiocytic variant (n=3) and composite common/small cell type (n=2) anaplastic large cell lymphoma. The patients were treated and three were alive at the last follow-up. Two patients died, one of pneumonia and the other of disseminated disease. ConclusionsIn these cases the sequence of events between the insect bites and the occurrence of both skin lesions and satellite lymphadenopathy suggest a direct relationship between the bite and the presentation with anaplastic large cell lymphoma. We postulate that insect bite-associated antigens could result in an influx of T lymphocytes, some bearing the t(2;5). The subsequent release of cytokines at the site of the bite could act as a 'second hit', eliciting activation of the latter cells, which would then express the oncogenic NPM-ALK protein and undergo uncontrolled proliferation.Key words: ALK-positive ALCL, NPM-ALK, skin involvement. Haematologica. 2010;95:449-455. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Lamant L, Pileri S, Sabattini E, Brugières L, Jaffe ES, and Delsol G. Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases. Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases

ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study

“…Lamant et al 29 recently reported 5 children with systemic ALK + ALCL that presented as skin lesions at the site of preceding insect bites, often with involvement of the draining local lymphnode. Thus, the skin might not only present a preferred microenvironment for ALK + ALCL but might even be the primary site of lymphomagenesis.…”

Anaplastic lymphoma kinase in human cancer

“…A single ALK lesion, although essential for transformation, requires additional genetic defects, which are however yet to be determined. The actual impact of insect bites in the pathogenesis of ALK C ALCL remains to be elucidated (Fornari et al 2009, Lamant et al 2010.…”

ALK+ALCLs induce cutaneous, HMGB-1–dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation

“…4 The subsequent release of cytokines leading to skin inflammation at the site of the bite could act as a "second hit" eliciting activation of T lymphocytes, which would then express the oncogenic NPM-ALK protein and undergo uncontrolled proliferation and transformation. 4 ALK ϩ ALCL patients also present with an inflammatory syndrome characterized by high fever, lymphadenopathy or neutrophilia, release of various circulating inflammatory chemokines such as IL-8, 5 and expression of skin-inflammatory biomarkers such as the alarmins heat-shock protein 90 (HSP90), HSP70, 6 S100A8, or A11. 7 Recent studies have highlighted a role for IL-8 in mediating cutaneous skin inflammation and human keratinocyte hyperplasia associated with acanthosis (thickening of the skin).…”

“…Our group reported 5 cases of systemic ALK ϩ ALCL in which skin lesions presented after an insect bite at the onset of the disease, postulating that bite-associated Ags could result in an influx of T lymphocytes, some of them bearing the t(2;5) translocation. 4 The subsequent release of cytokines leading to skin inflammation at the site of the bite could act as a "second hit" eliciting activation of T lymphocytes, which would then express the oncogenic NPM-ALK protein and undergo uncontrolled proliferation and transformation. 4 ALK ϩ ALCL patients also present with an inflammatory syndrome characterized by high fever, lymphadenopathy or neutrophilia, release of various circulating inflammatory chemokines such as IL-8, 5 and expression of skin-inflammatory biomarkers such as the alarmins heat-shock protein 90 (HSP90), HSP70, 6 S100A8, or A11.…”