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Primary cutaneous T-Cell lymphoma (CTCL) is a rare but heterogeneous group of extra-nodal lymphoproliferative disorders. Mycosis fungoides (MF) is the most common subset [1]. While prognosis in ear...

Adult T-cell leukemia-lymphoma (ATL) is an aggressive variant of peripheral T-cell lymphoma of CD4+ T-malignant cells caused by human T-lymphotropic virus type-1. Despite aggressive treatment with multidrug combination chemotherapies, ATL confers a poor prognosis and commonly develops resistance to conventional treatments. Areas covered: Mogamulizumab is a humanized, defucosylated monoclonal antibody that acts by targeting the CC chemokine receptor 4 (CCR4) on malignant cells of ATL. In phase I and II clinical trials, it has achieved overall response rates of 31-50% in CCR4+ malignancies. The most commonly observed hematologic and non-hematologic adverse events included lymphocytopenia, neutropenia, leukocytopenia, infusion reaction, rash, and pyrexia. Expert commentary: Mogamulizumab has shown significant efficacy in treating ATL with moderately high response rates and has been approved in Japan for use in ATL. It may serve as a bridge therapy to achieve disease control prior to allogeneic hematopoietic stem cell transplantation. It also offers potential for use in combination with conventional chemotherapy. Determining the optimal combination of mogamulizumab with conventional and novel therapies remains an important strategy to improve the prognosis of patients with ATL.

Introduction: Cutaneous T cell lymphomas are a heterogeneous group of malignancies characterized by the accumulation of malignantly transformed skin homing T cells. Mycosis fungoides, a typically indolent form of cutaneous T cell lymphoma characterized by patches, plaques, and tumors, and Sezary syndrome, a leukemic variant, make up the majority of cutaneous T cell lymphomas, and prognosis in advanced-stage disease remains poor. The defucosylated monoclonal antibody, mogamulizumab, targets the CC chemokine receptor 4 on malignant cells of cutaneous T cell lymphoma and offers a novel approach to treating advanced-stage disease.Areas covered: Mogamulizumab has shown efficacy in phase I/II clinical trials in patients with cutaneous T cell lymphoma, with overall response rates between 35–36.8%. Currently, a phase III trial is underway comparing mogamulizumab to vorinostat in the treatment of cutaneous T cell lymphoma.Expert opinion: Mogamulizumab has already been approved in Japan for the treatment of...

To demonstrate the clinical efficacy of topical 5% imiquimod for mycosis fungoides (MF) tumors.Treatment of tumor-stage MF represents a therapeutic challenge because of a limited number of effective topical therapies. Single tumors can be treated with localized radiation but may recur. Systemic therapies are also an option but are associated with serious adverse effects. Imiquimod is a topical agent whose efficacy has been documented in treating MF patches and plaques as well as one case of tumor-stage disease.We present two stage IIB MF patients, including one with large cell transformation, whose tumors were treated with imiquimod 5% cream after failing prior therapies.The MF tumors in both patients demonstrated a complete response to imiquimod 5% cream without recurrence over 8 years and 2 years of follow-up, respectively. One patient experienced application site irritation and flu-like symptoms as adverse effects.Our case series is only the second report in the literature demonstrating complete resolution of MF tumors with topical imiquimod. An additional therapeutic option for tumor-stage MF, imiquimod may represent an effective alternative to localized radiation for isolated MF tumors and warrants further investigation in the treatment of various stages of MF.

Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Constitutive activation of STAT5 and STAT3 was observed in early and late stages of CTCL, respectively. In early stages, IL-2, IL-7 and IL-15 signaling via JAK1 and JAK3 kinases is believed to be responsible for activating STAT5, while in advanced stages development of IL-21 autocrine signaling is thought to be important for STAT3 activation. Recent molecular evidence further suggests that upregulation of STAT5 in early disease stages results in increased expression of oncogenic miR-155 microRNA that subsequently targets STAT4 expression on mRNA level. STAT4 signaling is known to be critical for T helper (Th) 1 phenotype differentiation and its loss results in a switch from Th1 to Th2 phenotype in malignant T cells. During this switch the expression of STAT6 is often upregulated in CTCL. In advanced stages, activation of STAT3 and STAT5 may become completely cytokine-independent and be driven only via constitutively active JAK1 and JAK3 kinases. Further research into the molecular pathogenesis of JAK/STAT signaling in this cancer may enable us to develop effective therapies for our patients.

Mycosis fungoides (MF) is an extranodal non-Hodgkins lymphoma of T-cell origin. MF is the most common type and can be stratified as early (IA-IIA) or late (IIB or greater) stage disease. Patients with patch disease usually have a benign, chronic course. Patients with plaques have a worse prognosis and need more aggressive therapy. Topical nitrogen mustard ([NM]; mechlorethamine hydrochloride) has been used for MF since the 1950s. Complete response rates reported for stage IA are 76–80% and 35–68% for stage IB. Most common toxicities reported are irritant contact dermatitis, allergic reaction and hyperpigmentation. There is a potential for risk of non-melanoma skin cancers reported with NM use in patients who used multiple skin damaging therapies. This article focuses on the clinical trial that led to the US FDA approval of VALCHLOR™ for stage IA and IB MF in 2013 after one prior treatment (excluding NM within 2 years or carmustine therapy ever).

Th e occurrence of cutaneous T cell lymphoma (CTCL) and chronic lymphocytic leukemia (CLL) in the same patient is unusual. Of 1263 patients with biopsy-proven CTCL at a single institution, we identifi ed 14 patients with concomitant CLL. Th e overall prevalence of CLL in our CTCL population was 1.11%, higher than expected by the estimated annual incidence of CLL. A prospectively collected, previously published database of patients with mycosis fungoides (MF) and S e zary syndrome (SS) seen at M. D. Anderson Cancer Center from 1982 to 2009 [1] was queried to identify patients who also had CLL. Th is database is similar in survival outcomes and percentage of early-stage patients to other databases in America and Europe [2,3]. All patients signed M. D. Anderson Institutional Review Board approved informed consents and underwent baseline staging work-up, including skin biopsy with immunohistochemistry staining and peripheral blood examination by either a hematopathologist manually for S e zary cells or fl ow cytometry for CD4 CD26 cells.

Amaral and Garbe discuss the impressive developments in targeted therapy for non-melanoma skin cancers (NMSCs) such as basal cell carcinoma and squamous cell carcinoma [1]. Systemic targeted therap...

Vorinostat (suberoylanilide hydroxamic acid) is the first US FDA-approved histone deacetylase inhibitor for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphomas (CTCLs). In two Phase II trials, vorinostat was safe and effective at an oral dose of 400 mg/day, with an overall response rate of 24–30% in refractory advanced CTCL patients, including large-cell transformed mycosis fungoides and Sezary syndrome. Most patients with CTCL also experience significant itching relief with vorinostat therapy. Moreover, a recent follow-up study reported long-term safety and clinical benefits of vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue and thrombocytopenia. These side effects are dose-related and reversible upon cessation of therapy. Translational studies have shown that vorinostat has in vitro and in vivo anti-tumor activities against CTCL, includ...

Denileukin diftitox (DAB(389)IL-2 or Ontak) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.

Papuloerythroderma of Ofuji (PEO), a rare skin disorder fi rst described by Ofuji et al . in 1984, is a pruritic eruption of fl at-topped papules in a background of erythroderma characteristically sparing skin folds ( “ deck chair sign ” ) [1]. Th e disorder usually aff ects Asians with a mean age of 73.4 years. Classic laboratory fi ndings include peripheral eosinophilia, lymphocytopenia and increased immunoglobulin E (IgE) [2]. Malignancy is commonly associated with PEO, with some reports stating an association as high as 54.5% [3]. Non-Hodgkin lymphoma (NHL) is the second most common malignancy associated with PEO after gastric cancer [2]. We report a case of PEO complicated by a peripheral T-cell lymphoma not otherwise specifi ed (PTCL-NOS) with the uncommon phenotype of CD3 /CD4 /T-cell receptor (TCR) null. A 51-year-old Japanese male with a long history of atopic rhinitis reported a 6-year history of pruritic, red-brown papules and plaques that began on his legs and then spread to his trunk and arms but sparing skin folds (Figure 1). He also had a 5-year history of secondary Staphylococcus aureus infection of the skin treated with cephalexin and topical mupirocin. Th is was accompanied by hypereosinophilia ( 2500/L) and an elevated IgE level (1980 – 3980/L) as well as a skin biopsy that showed a lichenoid dermatitis with a normal epidermis, perivascular lymphohistiocytic infi ltrate with eosinophils and papillary dermal edema. He was given the diagnosis of severe atopic dermatitis and possibly a hypersensitivity reaction. Th e rash did not respond to any topical steroids or antihistamines. Th e extreme pruritus was temporarily controlled with steroids orally, topically and intramuscularly. His eruption fl ared after aspergillosis infection and had remission with itraconazole. However, a year later, his rash worsened, and he developed lymphadenopathy and subcutaneous nodules on his right elbow. Th e fi ne needle aspiration (FNA) of a nodule showed atypical lymphocytes with scattered eosinophils, suggestive of lymphoma. Flow cytometry demonstrated a T-cell population representing 75% of atypical lymphocytes with the abnormal phenotype: CD1( ), CD2( ), CD3( ), CD4( ), CD5(bright), CD7(partial), CD8( ), CD25( ), CD26(dim)

We have previously shown that Interferon-Inducible Protein-10 (IP-10), a cytokine chemotactic for CD4-positive lymphocytes, is overexpressed by lesional epidermal keratinocytes and probably accounts for the epidermotropism of cutaneous T-cell lymphoma (CTCL). The tax gene of human T-lymphotropic virus-I (HTLV-I) immortalizes CD4-positive lymphocytes, induces IFN-gamma, and has been detected in patients with classical CTCL who are seronegative for HTLV-I. TNF-alpha is synergistic with IFN-gamma for the induction of IP-10. We therefore decided to define the presence of tax, IFN-gamma, TNF-alpha, and IP-10 in lesions of 19 adults with classical CTCL who were seronegative for HTLV-I. Lesional mRNAs for actin, TNF-alpha, IFN-gamma, and tax were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) amplification. In addition IP-10, TNF-alpha, and IFN-gamma were detected and localized with immunocytochemistry of frozen sections. In agreement with previous observations IP-10 was overexpressed in lesional keratinocytes of all 19 patients. By RT-PCR, mRNA for IFN-gamma was detected in lesions of 8, and for TNF-alpha in lesions of 13 patients. By immunocytochemistry, TNF-alpha was expressed by lesional keratinocytes in 10 of 13 tested patients, whereas IFN-gamma was focally expressed by lesional lymphocytes and faintly by lesional keratinocytes in 9 of 13 tested patients. tax mRNA was not detected in lesions of any patient, but was easily detectable in cutaneous lesions or peripheral blood of control patients who were seropositive for HTLV-I. We conclude that TNF-alpha and IFN-gamma may cause epidermotropism by inducing IP-10. However, the tax gene of HTLV-I does not appear to be involved in the pathogenesis of classical CTCL.

Human interferon-g inducible protein-10 (IP-10), a small basic protein secreted by interferon (INF)-g stimulated keratinocytes, is chemotactic for normal CD4-positive lymphocytes and inhibits early normal and leukemic hemopoietic progenitor proliferation. Cutaneous T-cell lymphoma (CTCL) is an indolent CD4-positive lymphoma characterized by multiple skin relapses before visceral dissemination. We investigated the role of IP-10 in the biology of CTCL by using immunocytochemistry to define IP-10 expression in normal and CTCL skin biopsies. Using purified recombinant (r) IP-10, we generated a rabbit antiserum that recognized and neutralized rIP-10 but did not cross-react with any keratinocyte proteins or any other chemokine. Immunoperoxidase staining of normal epidermis demonstrated that IP-10 was expressed by basal but not by differentiated keratinocytes. The epidermis overlying CTCL lesions was often hyperplastic, IP-10 immunostaining was enhanced compared to normal skin, and extended to the suprabasal keratinocytes in 25 of 26 patients for a frequency of 96%; and 95% confidence interval (CI) of 80% to 100%. However, IP-10 was detectable in the dermal or epidermal lymphoid infiltrates in only three of these 26 patients (12%; 95% Cl, 2% to 39%). Skin clinically free of CTCL demonstrated normal IP-10 immunostaining. In one patient who had matching biopsies performed before and after treatment, IP-10 was initially overexpressed before treatment but was normally expressed when he achieved remission. These results suggest that IP-10 may play a role in the epidermotropism of CTCL. More work is required to determine whether IP-10 stimulates or inhibits CTCL proliferation. A better understanding of the growth controls operating in CTCL may be used to develop curative therapies for this disorder.

Most skin malignancies are caused by external and often preventable environmental agents. Multiple reports demonstrated that cutaneous T-cell lymphomas (CTCL) can occur in married couples and cluster in families. Furthermore, recent studies document geographic clustering of this malignancy in Texas as well as in other areas of the United States. Multiple infectious, occupational, and medication causes have been proposed as triggers or promoters of this malignancy including hydrochlorothiazide diuretics, Staphylococcus aureus, dermatophytes, Mycobacterium leprae, Chlamydia pneumoniae, human T-Cell lymphotropic virus type 1 (HTLV1), Epstein-Barr virus (EBV), and herpes simplex virus (HSV). In this report, we review recent evidence evaluating the involvement of these agents in cancer initiation/progression. Most importantly, recent molecular experimental evidence documented for the first time that S. aureus can activate oncogenic STAT3 signaling in malignant T cells. Specifically, S. aureus Enterotoxin type A (SEA) was recently shown to trigger non-malignant infiltrating T cells to release IL-2 and other cytokines. These signals upon binging to their cognate receptors on malignant T cells are then able to activate STAT3 and STAT5 oncogenic signaling and promote cancer progression and IL-17 secretion. In light of these findings, it might be important for patients with exacerbation of their CTCL symptoms to maintain high index of suspicion and treat these individuals for S. aureus colonization and/or sepsis with topical and systemic antibiotics.

Primary cutaneous follicle center lymphoma (PCFCL) is the most common, indolent subtype of primary cutaneous B-cell lymphoma (PCBL) [1,2]. PCBL is an uncommon non-Hodgkin lymphoma that primarily in...

Epigenetic modification with small molecule histone deacetylase inhibitors has been a promising new anti-neoplastic approach for various solid and hematological malignancies, particularly cutaneous T-cell lymphoma (CTCL). Oral vorinostat was the first histone deacetylase inhibitor approved to enter the clinical oncology market for treating CTCL patients who have progressive, persistent, or recurrent disease after failing two systemic therapies. In two phase II clinical trials, oral vorinostat was found to be safe and effective at a dose of 400 mg/day, with an overall response rate of 24%-30% in heavily pretreated patients with advanced CTCL, including those with large-cell transformed mycosis fungoides and Sezary syndrome. About half of CTCL patients receiving vorinostat also experienced substantial relief in pruritus and thus a marked improvement in quality of life. A subsequent follow-up study reported long-term safety and clinical benefits of vorinostat in patients with refractory CTCL, regardless of previous treat- ment failures. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue, and thrombocytopenia. These adverse reactions are dose-related and reversible upon cessation of therapy. Preclinical studies have supported the therapeutic potential of vorinostat by demonstrating in vitro and in vivo anti-tumor activities against CTCL, including selective induction of apoptosis in malignant T cells, inhibition of angiogenesis, suppression of signal transducer and activator of transcription proteins, and up-regulation of pro-apoptotic proteins. Identification of biomarkers of response and resistance will help select CTCL patients most likely to benefit from treatment and guide the design of effective combination therapies.