Oral bexarotene for post‐transplant cutaneous T‐cell lymphoma

Organ transplant recipients receiving immunosuppression have an increased risk of developing post‐transplant lymphoproliferative diseases (PTLDs). Traditionally, PTLDs refer to Epstein‐Barr virus (EBV)‐induced B‐cell lymphoma. However, post‐transplant T‐cell lymphoma may also occur and tends to have a poorer response to reduced immunosuppressive therapy. As such, additional therapy is often needed for post‐transplant T‐cell lymphoma, including post‐transplant cutaneous T‐cell lymphoma (PT‐CTCL). We present only the third case of PT‐CTCL occurring after liver transplantation. The patient was diagnosed with stage IB mycosis fungoides (MF). His lesions were refractory to multiple skin‐directed therapies, and so he was given oral bexarotene 150 mg daily and his oral tacrolimus dose was decreased to 2 mg daily. Remarkably, his MF patches have demonstrated a complete response to oral bexarotene 75 mg daily without recurrence over 11 years of follow‐up. He developed hypertriglyceridemia with bexarotene 150 mg, so his dose was decreased to 75 mg, without loss of response. Our report is the second to describe PT‐CTCL demonstrating a long‐term complete response to oral bexarotene. Given its anti‐carcinogenic properties and favorable toxicity profile, oral bexarotene represents an appealing treatment option for PT‐CTCL refractory to skin‐directed therapies.     

Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T‐cell lymphomas

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)‐selective retinoid, were evaluated in Japanese patients with stage IIB–IVB and relapsed/refractory stage IB–IIA cutaneous T‐cell lymphomas (CTCL). This study was conducted as a multicenter, open‐label, historically controlled, single‐arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m² for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m² in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m² met the response criteria using the modified severity‐weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose‐limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m²: two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m² bexarotene. In the 13 patients at 300 mg/m², common drug‐related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment‐related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m² once daily and effective in Japanese patients with CTCL.     

Gamma‐delta T‐cell lymphoma arising in a long‐standing cutaneous plaque

The precise classification and characterization of primary cutaneous gamma‐delta T‐cell lymphoma (PCGD‐TCL) has been hindered by clinical and morphologic features that overlap with other lymphomas, especially subcutaneous panniculitis‐like T cell lymphoma (SPTCL). The recent World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification distinguishes the more aggressive PCGD‐TCL from the usually indolent SPTCL, however. We report a 30‐year‐old woman with an indurated violaceous plaque on the left cheek that had been present for several years. Biopsies showed a dense lymphocytic infiltrate involving the subcutis and dermis that consisted mostly of small and medium‐sized lymphocytes, some with irregular nuclear contours and dense chromatin. These cells were positive for TIA‐1, TCR‐gamma and CD8, but negative for beta‐F1 and granzyme‐B. Staging with positron emission tomography–computed tomography (PET/CT), CBC and bone marrow with flow cytometry identified lymphadenopathy as well as blood and marrow involvement by an abnormal TCRgd‐positive T‐cell proliferation (Ann Arbor Stage IV). The patient's history of a long‐standing lesion in this case is unusual, in that gamma‐delta T‐cell lymphomas are typically rapidly progressive neoplasms. As such, it raises the possibility of ‘transformation’ of a long‐standing inflammatory process into an overt lymphoma.     

T‐cell receptor gene rearrangement analysis of sequential biopsies in cutaneous T‐cell lymphomas with the Biomed‐2 PCR reveals transient T‐cell clones in addition to the tumor clone

Detection of a dominant T‐cell clone by T‐cell receptor (TCR) gene rearrangement analysis is often essential for the diagnosis of cutaneous T‐cell lymphomas (CTCL). The occurrence of T‐cell clones in addition to the diagnostic T‐cell clone during the course of CTCL has been reported, but the data of these studies have been contradictory. We retrospectively evaluated the data of 114 lesional skin biopsies from 26 patients with Mycosis fungoides and two patients with primary cutaneous anaplastic large cell lymphoma, which were analysed with the standardized Biomed‐2 PCR for the TCRγ and TCRβ locus. A dominant T‐cell clone was repetitively detected in 93% (26/28) of patients. Additional T‐cell clones appeared temporarily in 39% (11/28) of patients. Correlation with the clinical data did not show an association of the presence of additional T‐cell clones with age, number of treatments, progression of disease or survival. Our findings demonstrate that a persistent T‐cell clone, most likely the disease causing tumor clone, is detectable in almost all CTCL patients. In addition, transiently appearing T‐cell clones frequently occur during the course of disease. The biological relevance of these additional clones has still to be determined. However, it is important to take the possibility of additional T‐cell clones into account for diagnostic analyses.     

A novel xenograft model of cutaneous T‐cell lymphoma

Please cite this paper as: A novel xenograft model of cutaneous T‐cell lymphoma. Experimental Dermatology 2010; 19 : 1096–1102. Abstract: Cutaneous T‐cell lymphomas (CTCLs) are characterized by accumulation of malignant T cells in the skin. Early disease resembles benign skin disorders but during disease progression cutaneous tumors develop, and eventually the malignant T cells can spread to lymph nodes and internal organs. However, because of the lack of suitable animal models, little is known about the mechanisms driving CTCL development and progression in vivo. Here, we describe a novel xenograft model of tumor stage CTCL, where malignant T cells (MyLa2059) are transplanted to NOD/SCID‐B2m^?/? (NOD.Cg‐Prkdc^scid B2m^tm1Unc/J) mice. Subcutaneous transplantation of the malignant T cells led to rapid tumor formation in 43 of 48 transplantations, whereas transplantation of non‐malignant T cells isolated from the same donor did not result in tumor development. Importantly, the tumor growth was significantly suppressed in mice treated with vorinostat when compared to mice treated with vehicle. Furthermore, in most mice the tumors displayed subcutaneous and/or lymphatic dissemination. Histological, immunohistochemical and flow cytometric analyses confirmed that both tumors at the inoculation site, as well as distant subcutaneous and lymphatic tumors, originated from the transplanted malignant T cells. In conclusion, we describe a novel mouse model of tumor stage CTCL for future studies of disease dissemination and preclinical evaluations of new therapeutic strategies.     

Hypopigmented mycosis fungoides in childhood and adolescence: a long‐term retrospective study

Patients with hypopigmented mycosis fungoides (HMF) present at a younger age than those with classic MF. Our goal was to describe the clinical presentation, histopathologic features and long‐term outcome in patients who developed HMF before the age of 21. It was observed that among 69 pediatric patients diagnosed with MF between 1992 and 2010, 50 had HMF. Thirty‐five patients had clinical follow‐up. There were 37 males and 32 females with a mean age of 13.6 years. Most patients were African American or Hispanic and presented with multiple hypopigmented patches. All biopsies showed epidermotropism of T‐lymphocytes, whereas fibroplasia and lichenoid infiltrate were variable. All specimens tested were CD8+. Treatment modalities included topical steroids, narrow band ultraviolet B and psoralen and ultraviolet A. HMF patients were followed for <1–12 years. Most children responded to treatment, but recurrence rates were high. One patient progressed to plaque/tumor stage. Others did not progress; however, many were lost to follow‐up. We present a large cohort of children with HMF and report on the features of disease and progression. A major difference in histology of HMF was lack of fibroplasia and lichenoid infiltrate, probably because of presentation in the early patch stage. Most patients have a waxing‐and‐waning course and relapse after discontinuation of therapy, requiring repetitive treatment.     

ALK‐positive primary cutaneous T‐cell‐lymphoma (CTCL) with unusual clinical presentation and aggressive course

Anaplastic lymphoma kinase (ALK) expression is uncommon in primary cutaneous T‐cell‐lymphomas (CTCL). We report the case of a patient who was initially diagnosed with small plaque parapsoriasis, and eventually developed an unusual manifestation of CTCL 6 years later. The disease was characterized by aggressively ulcerating plaques and tumors of the entire skin. Histopathology revealed monoclonal proliferation of atypical T‐lymphocytes and CD30‐positive blasts with expression of ALK and identification of an ATIC‐ALK fusion protein. Extensive staging confirmed the primary cutaneous origin of the lymphoma. After failure of several conventional treatments including polychemotherapy, the patient finally achieved remission after receiving brentuximab‐vedotin, alemtuzumab and subsequent allogeneic stem cell transplantation. In the following, the patient developed inflammatory cutaneous lesions that pathologically showed no evidence for lymphoma relapse or classical cutaneous graft‐versus‐host disease. The patient responded to immunosuppression, but finally died from multi‐organ failure due to sepsis 8 months after stem cell transplantation. This is a rare instance of ALK positivity in a CTCL, most likely resembling CD30+ transformed mycosis fungoides, because it was not typical for cutaneous anaplastic large cell lymphoma (ALCL). In contrast to its role in systemic ALCL as favorable prognostic marker, ALK expression here was associated with an aggressive course.     

Systemic panniculitis‐like T‐cell lymphoma with involvement of mesenteric fat and subcutis

Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is an uncommon non‐Hodgkins primary cutaneous lymphoma that typically presents as subcutaneous nodules on the extremities or trunk. Here, we report an unusual case of systemic panniculitic T‐cell lymphoma with predominantly mesenteric extra‐cutaneous involvement and an aggressive clinical course with histopathologic and immunophenotypic features that mimic SPTCL. This case serves to expand the body of literature regarding systemic SPTCL‐like disorders with prominent extra‐cutaneous involvement.     

Long‐term efficacy and safety of bexarotene for Japanese patients with cutaneous T‐cell lymphoma: The results of a phase 2 study (B‐1201)

The present study (B‐1201 clinical trial) was conducted as a multicenter, open‐label, single‐arm phase II study to evaluate the long‐term safety, tolerability and efficacy of bexarotene. This study enrolled 10 Japanese adults aged more than 20 years with cutaneous T‐cell lymphoma (CTCL) who completed the 24‐week study period of the B‐1101 trial. The objective response rate (ORR) was 53.8% (95% confidence interval, 25.1–80.8). In the early stage (IB), the ORR was 60% (3/5 cases). In the advanced stage (IIB and IIIA), the ORR was 57.1% (4/7 cases). The median time to response was 58 days (range, 27–168). The median treatment duration was 380 days (range, 33–1674). The median duration of response (DOR) could not be reached during the study period. The longest DOR reached 1618 days at the end of the B‐1201 trial. Nine patients (56.3%) in the full analysis set (FAS) population experienced dose reduction of bexarotene. Common drug‐related adverse events in the FAS population included hypothyroidism (93.8%), hypertriglyceridemia (81.3%), hypercholesterolemia (81.3%), leukopenia (68.8%) and neutropenia (56.3%). Dose‐limiting toxicity (DLT) was present in five (38.5%) of the 13 patients in the 300 mg/m² cohort. Of the five patients, four developed grade 3 neutropenia and one developed grade 4 hypertriglyceridemia. All DLT cases recovered after the discontinuation of bexarotene. None of the five patients discontinued this trial because of DLT. The B‐1201 trial shows the long‐term safety of oral bexarotene for Japanese patients with CTCL, despite frequent dose reduction.     

Hypopigmented interface T‐cell dyscrasia: A form of cutaneous T‐cell dyscrasia distinct from hypopigmented mycosis fungoides

Hypopigmentation in cutaneous T‐cell lymphoproliferative disease should not always be equated with hypopigmented mycosis fungoides (MF). A form of hypopigmented pre‐lymphomatous T‐cell dyscrasia falling under the designation of the so‐called hypopigmented interface variant of T‐cell dyscrasia has recently been proposed. The aim of the present study was to establish hypopigmented interface T‐cell dyscrasia as its own entity apart from other T‐cell dyscrasias and MF using a patient case series. Twenty four cases of hypopigmented interface T‐cell dyscrasia were identified in the dermatopathology database of Weill Medical College of Cornell University. There were 17 females and seven males (mean age, 36 years). In children and adolescents, the patients were most commonly of African American extraction. Truncal photo‐protected areas manifesting as large solitary patches or multiple smaller macules were characteristic; disease progression to MF occurred in only one patient. The lesions responded to topical steroids and light therapy. The pathology was defined by a cell poor interface associated with degeneration of keratinocytes and melanocytes, and by lymphocytes whose nuclei showed low‐grade cerebriform atypia, and which expressed a significant reduction in CD7 and CD62L expression. In 50% of the cases, the implicated cell type was of the CD8 subset. Clonality was not identified. Hypopigmented interface T‐cell dyscrasia is a distinct entity separate from and rarely progressive to MF.     

Follicular cutaneous T-cell lymphoma: a clinicopathological study of nine cases

Nine patients with follicular cutaneous T-cell lymphoma (CTCL), a recently described variant of lymphoma, are presented. On the basis of clinical manifestations and disease course, three groups of patients were distinguished: (i) two patients with follicular CTCL not associated with conventional lesions of mycosis fungoides (MF) and showing no evolution towards MF in follow-up periods of 3 and 6 years; (ii) one patient with follicular CTCL that evolved into conventional MF within 3 years; (iii) six patients showing conventional MF lesions either before or concurrently with the follicular lesions and thus representing follicular CTCL of the true MF type. The follicular lesions included hair-devoid patches or plaques with spiky hyperkeratotic papules (four patients), keratosis pilaris-like lesions (four), comedo-like lesions (four), follicular papules with alopecia (three) and milia-like lesions (three). Histopathological examination showed perifollicular and intrafollicular lymphocytes, without mucin deposition and with minimal or no involvement of the overlying epidermis. Significant syringotropism was also observed in three cases. Immunohistochemical analysis showed the predominance of CD4 + T cells, deletion of CD7 in some cases, Ki-67 + lymphocytes confined mainly to the follicular epithelium, and expression of keratinocyte intercellular adhesion molecule-1 exclusively in the hair follicle. T-cell receptor gamma gene rearrangement was positive in the one case studied from each group. Different treatment modalities were employed, the most commonly used as monotherapy being phototherapy: psoralen ultraviolet A in four patients, two of whom showed a complete clinical and histopathological remission, and ultraviolet B in one patient, who showed a complete remission (both clinical and histopathological). This study indicates that follicular CTCL is more common than reflected in the literature, has heterogeneous clinical manifestations, and is either an expression of or closely related to MF. The influence of the follicular involvement on the therapeutic response remains to be clarified. However, our therapeutic experience clearly suggests that some patients with follicular CTCL can benefit from phototherapy.     

Double‐positive CD4/CD8 mycosis fungoides: a rarely reported immunohistochemical profile

Mycosis fungoides (MF) represents the most common epidermotropic cutaneous T‐cell lymphoma (CTCL), and tumor cells typically express a mature T‐helper memory phenotype. A minority of MF patients display an unusual phenotype, which may be either CD4(?)/CD8(+) or double negative. Herein, we report a case of biopsy‐proven MF in a 31‐year‐old woman who presented with infiltrated plaques involving photoprotected areas of the skin. Immunohistochemical study combined with confocal microscopy revealed co‐expression of CD4 and CD8 in a subset of atypical T lymphocytes. To our knowledge, this is the second report of a CD4/CD8 dual‐positive MF.     

Controversies in the management of the cutaneous T cell lymphomas

The primary cutaneous T cell lymphomas (CTCL) encompass all malignancies of the T cell where the skin is the primary organ of involvement. The diagnosis of a CTCL variant can be detoured by a number of obstacles including the slow evolution of the disease into a classic clinical and pathologic pattern. A realistic goal of early stage treatment is to reduce the likelihood of progression to a more advanced stage, not to achieve a cure. No studies have adequately compared the different systemic agents in patients with advanced CTCL so the clinician is left to act in the best interest of the patient with what evidence is available. When using the systemic agents, a "start low and go slow" strategy may offer patients several advantages. Dermatologists are uniquely trained to diagnose and to manage all but the most advanced stage patients with CTCL.     

Generalized fixed drug eruption mimicking CD8+ cutaneous T‐cell lymphoma in HIV

We present a case of a widespread fixed drug eruption histologically mimicking CD8 positive cutaneous T‐cell lymphoma (CTCL). CTCL has several potential histological and clinical mimics, and accurate diagnosis relies on a combination of clinicopathological correlation and molecular studies. We add generalized fixed drug eruption to the list of possible CTCL mimics.