Anaplastic lymphoma kinase-positive primary cutaneous anaplastic large cell lymphoma--is it a new variant?

Anaplastic large cell cutaneous lymphomas are clinically and pathologically heterogeneous, CD30 + (Ki-1) lymphoproliferative disorders. The importance of anaplastic lymphoma kinase (ALK) positivity is well known in the prognosis of primary systemic anaplastic large cell cutaneous lymphomas; however, the same in primary cutaneous anaplastic large cell cutaneous lymphomas is not much clear. Herein we report a 65-year-old male with an 18-month history of minimally pruritic localized nodulo-plaque lesion over lower back. Histology revealed cutaneous large cell lymphoma and immunohistochemical staining showed positivity for CD30, CD3 and ALK. The role of ALK positivity in pcALCL is discussed in this article.     

HIV‐associated primary cutaneous anaplastic large cell lymphoma: a clinicopathological subset with more aggressive behavior? Case report and review of the literature

Human immunodeficiency virus (HIV)‐infected patients carry an increased risk of lymphomagenesis. Although the majority of HIV‐related lymphomas have a B‐cell phenotype, the incidence of peripheral T‐cell lymphomas (PTCL), including primary cutaneous subtypes, may be up to 15‐fold higher than in the general population, with anaplastic large cell lymphomas (ALCL) accounting for 18–28% of HIV‐associated PTCL. In contrast to systemic ALCL, the relation between HIV infection and primary cutaneous ALCL has been relatively neglected in the literature. We report the case of a primary cutaneous ALCL occurring in a 76‐year‐old patient with advanced HIV infection, and showing unusually aggressive course. Neither ALK1 immunohistochemical positivity nor evidence of EBV infection were detected; staging procedures at initial presentation ruled out systemic involvement. We provide a summary of the literature regarding primary cutaneous ALCL in HIV‐infected patients. We draw attention to clinicopathological features, prognostic implications and therapeutic quandaries of HIV‐related primary cutaneous ALCL. Further, we propose that a significant fraction of HIV‐associated cases might represent a more aggressive subset of primary cutaneous ALCL.     

Multiple myeloma and cutaneous anaplastic large T‐cell lymphoma in the same patient: Is there a causal relation?

Synchronous occurrence of lymphomatous proliferations of B and T lineage in the same patient is a very rare event and still poorly understood. All the cases reported in the English language literature are described as single case reports. We report a case of 49‐year‐old man, with 2‐year history of multiple myeloma, presented with a raised, erythematous and ulcerated nodule in the anterior aspect of his right thigh. Histologic examination of biopsy specimen showed a dense dermic infiltrate made of large balastic cells displaying anaplastic morphology with no epidermotropism. Immunohistochemical study showed that tumor cells stained positive with CD30, EMA and CD4, and negative for CD3, CD8, CD5, CD20, CD79a, CD138 and anaplastic lymphoma kinase 1 (ALK or Ki‐1). Tangour M, Chelly I, Haouet S, Zitouna M, Kchir N. Multiple myeloma and cutaneous anaplastic large T‐cell lymphoma in the same patient: Is there a causal relation?     

Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma with a chronic and indolent course. Is this different from peripheral T cell lymphoma?

Cutaneous T cell lymphomas most commonly have a CD4+ memory T cell phenotype and exhibit a relatively indolent course, but may in rare cases present with a CD8+ cytotoxic phenotype with a strikingly more aggressive clinical behavior. Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma is an extremely rare entity with distinct clinicopatological features. The clinical features and prognosis of the recently-described CD8+ peripheral lymphoma are very different from cytotoxic CD8+ epidermotropic lymphoma, but the histological and phenotypic characteristics are very similar. We report a new case of CD8+ epidermotropic lymphoma with a chronic course and suggest the possibility of an overlap between these two types of lymphoma.     

Notch signalling in primary cutaneous CD30+ lymphoproliferative disorders: a new therapeutic approach?

Background The oncogenic potential of deregulated Notch signalling has been described in several haematopoietic malignancies. We have previously reported an increased expression of Notch1 in primary cutaneous CD30+ lymphoproliferative disorders, lymphomatoid papulosis and primary cutaneous anaplastic large‐cell lymphoma (pcALCL). Objectives To investigate the functional importance of Notch signalling in cell lines derived from pcALCL. Methods Cell lines derived from pcALCL (Mac1, Mac2a and JK) were treated with different γ‐secretase inhibitors (GSIs) (GSI I, IX, XX and XXI). The effects of GSIs on cell viability, apoptosis and cell cycle progression were measured as well as the impact of GSI I on the known prosurvival pathway Akt–mTOR–FOXO3a. Results Notch family members were expressed in all investigated pcALCL cell lines. GSI I had a marked proapoptotic effect, but GSI IX, XX and XXI were much less potent. The GSI I‐triggered apoptosis was preceded by an accumulation of cells in the G2/M, cyclin B1‐controlled phase of the cell cycle accompanied by an increase in the cyclin‐dependent kinase inhibitor, p21^WAF/Cip. GSI I induced the nuclear translocation of proapoptotic FOXO3a, probably via an Akt‐independent pathway. Conclusions Notch signalling may be a future therapeutic target for the treatment of advanced pcALCL.     

Variable CD7 expression on T cells in the leukemic phase of cutaneous T cell lymphoma (Sézary syndrome)

CD7, a molecule normally expressed on 90% of normal CD4+ T cells, is often deficient on the malignant T cells of cutaneous T cell lymphoma. To investigate the clinical and biologic implications of CD7 expression, blood lymphocytes from 42 patients with the leukemic phase of cutaneous T cell lymphoma (CD4/CD8 ratio of 10 or more with evidence of a T cell clone in the blood) were analyzed for level of expression of CD7 by flow cytometry. CD7 expression by cells did not clearly segregate into two distinct subgroups that are either CD7 positive or CD7 negative as generally thought; however, nine of 17 patients with a predominantly CD4+CD7+ tumor population on early studies became CD4+CD7- over time whereas the converse situation was not observed. In addition, of three patients with evidence of large tumor cells in the blood coexisting with smaller cells, discordant CD7 expression was observed in one instance. In lymph node specimens, the percentage of cells expressing CD7 and other T cell markers did not correlate with histologic evidence of involvement. CD7 expression on blood lymphocytes also did not correlate with patients' survival nor to serum IgE levels or blood eosinophil counts, a finding suggesting that this marker does not identify functional cell subsets that produce serum interleukin-4 or -5, respectively. We speculate that the level of CD7 expression on malignant T cells may be the effect of sustained antigen stimulation in vivo analogous to what has been proposed to occur with normal T cells during aging.     

Brentuximab vedotin in CD30+ cutaneous lymphoma: How do we treat,how shall we treat? A review of the literature

Brentuximab vedotin is an antibody–drug conjugate that brings the antimicrotubule agent monomethyl auristatin E into CD30‐expressing cells. Some prior studies demonstrated good efficacy in cutaneous lymphomas. The standard therapeutic scheme is 1·8 mg kg⁻¹ every 3 weeks. The background of this work is the fact that cutaneous lymphoma has a different pathophysiology and a dynamic other than systemic lymphomas. The objectives of this review were to get an overview of the currently used therapeutic regimen, and to check whether dose reduction or modified time intervals could be of benefit in a similar way with less toxicity. Therefore, we conducted a systematic review of the literature indexed in PubMed and the Cochrane Central Register of Controlled Trials up to April 2016. The procedure was based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) criteria. The review showed that the currently used therapeutic regimen is 1·8 mg kg⁻¹ every 3 weeks. No publications of dose‐finding studies in CD30⁺ cutaneous T‐cell lymphoma (CTCL) were found. Two cases of patients, treated with a dose < 1·8 mg kg⁻¹, have been published. Brentuximab vedotin seems to be a powerful treatment option in refractory CD30⁺ CTCL, and there is a trend that dose reductions, as well as prolonged treatment intervals, work without any loss of response and with fewer side‐effects.     

Heavy metal (monoclonal) bands: A link between cutaneous T‐cell lymphoma and contact allergy to potassium dichromate,nickel and cobalt?

It has been proposed that chronic antigenic stimulation plays a role in the pathogenesis of cutaneous T‐cell lymphoma (CTCL). By definition, antigenic stimulation triggers allergic contact dermatitis (ACD). It is therefore plausible that chronic ACD could serve as a precursor to CTCL. We report two cases of contact allergy to potassium dichromate, nickel and cobalt, where CTCL was diagnosed in one patient, and a diagnosis of CTCL is imminent in the other. We also review the literature on the diagnostic criteria for CTCL in the setting of ACD and explore potential mechanisms for the progression from ACD tos CTCL.     

CD95-mediated signals in the skin: going out with an (inflammatory) bang?

The death ligand CD95L (Fas/Apo-1-ligand) has been viewed as a proapoptotic molecule involved in the pathogenesis of T cell-mediated skin diseases including eczema. In the presence of inhibitors of caspases, CD95L induces proinflammatory genes in keratinocytes. This more pleiotropic function of CD95L as enhancer of inflammation may be equally important to apoptosis induction of keratinocytes, at least in eczema.     

Indolent CD8‐positive lymphoid proliferation on the face: part of the spectrum of primary cutaneous small‐/medium‐sized pleomorphic T‐cell lymphoma or a distinct entity?

We report two cases of a CD8‐positive lymphoid proliferation presenting as solitary lesions on the ear and nose, respectively. Histopathologically, both cases were characterized by a diffuse non‐epidermotropic dermal proliferation of clonal medium‐sized CD8‐positive T‐lymphocytes with a lymphoblast‐like appearance, having cells with large folded nuclei, prominent nucleoli and ample amphophilic or pale eosinophilic cytoplasm. Staging procedures excluded systemic involvement, and both lesions were successfully treated with localised radiotherapy without evidence of recurrence after 12 and 24 months' follow up, respectively. Previously reported cases on the ear had similar clinicopathological and immunophenotypical features, and together raise the possibility of a distinct entity, an indolent CD8‐positive lymphoid proliferation. Suchak R, O'ConnorS, McNamara C, Robson A. Indolent CD8‐positive lymphoid proliferation on the face: part of the spectrum of primary cutaneous small‐/medium‐sized pleomorphic T‐cell lymphoma or a distinct entity?     

Hepatitis C virus (HCV) in cryoglobulinaemic leukocytoclastic vasculitis (LCV): could the presence of HCV in skin lesions be related to T CD8+ lymphocytes,HLA-DR and ICAM-1 expression?

An association between mixed cryoglobulinaemia (MC) and hepatotropic viruses, chiefly hepatitis C virus (HCV), has been widely reported. The presence of HCV genomic sequences or HCV-related viral proteins in the serum, purified cryoglobulins, peripheral blood mononuclear cells and into several tissues has suggested an important triggering role for HCV in MC patients. However, only few reports investigated the presence of HCV in cutaneous vasculitis and its potential pathogenetic role. Biopsies of cutaneous purpuric lesions from 5 MC female patients (aged from 40 to 80 years) were carried out for virological and histopathological evaluation. A leukocytoclastic vasculitis pattern was found in 4/5 subjects, while the presence of HCV RNA was detected in 3/5. In only 3 cases biopsy specimens were sufficient for immunohistochemical and direct immunofluorescence (DIF) studies. Immunohistochemical evaluation was performed by means of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) immune-complexes. In the same skin specimen APAAP and DIF findings were compared with the presence/absence of HCV genomic sequences (PCR technique). In 1 MC patient, the detection of HCV-RNA was associated to a prevalent CD8+ T suppressor pattern with a perivascular and subjunctional distribution as well as an intense expression of second class (HLA-DR) and intercellular adhesion (ICAM-1) molecules on basal keratinocytes, endothelial cells and perivascular infiltrate. These findings suggest a marked inflammatory activation that spreads from endothelial cells to keratinocytes and Langerhans cells. In the 2 HCV-RNA negative specimens the scanty immunopathological staining could indicate a residual activity due to the previous inflammatory event triggered by cryoglobulins. The deposition of circulating HCV-containing immune complexes (CIC) in the skin could be the initial pathogenic event for cryoglobulinemic vasculitis; subsequently CIC could spread from the vascular bed to the perivascular tissue and then could be very rapidly eliminated. If confirmed in larger patients' series these findings could definitely demonstrate a direct role of HCV in the pathogenesis of cryoglobulinemic vasculitis.