Breast implant-associated anaplastic large cell lymphoma: A review and assessment of cutaneous manifestations.

One newly recognized form of T-cell lymphoma is breast implant-associated anaplastic large cell lymphoma (biALCL), which appears in close proximity to breast implants. The number of reported cases of biALCL is increasing and warrants careful attention by clinicians to more effectively diagnose and treat affected individuals. As pertinent to dermatologists, the objective of this paper is to present the associated cutaneous features of this clinical entity along with the pathogenesis, management, and clinical outcomes. biALCL is a T-cell lymphoma in which malignant T-cells are characterized by large pleomorphic and anaplastic morphology and immunoreactivity for CD30, similar to primary cutaneous anaplastic large cell lymphomas (pcALCL). It has a favorable clinical outcome like nonimplant-associated pcALCL and involves the fibrous capsule around the implant, which creates an immunologically privileged site with a peri-implant effusion (seroma). More rare presentations are of a solitary mass. Appropriate management of biALCL is the complete surgical removal of the implant and total capsulectomy. Dermatologists should be aware of the occurrence of this entity in patients who have breast implants because patients may present specifically for breast-related cutaneous findings or have incidental cutaneous changes noted during a skin examination. The recognition and timely diagnosis of biALCL is critical to prevent progression to more advanced disease, ensure adequate treatment with removal of the implant, and avoid unnecessary aggressive systemic chemotherapy.

Cutaneous T cell lymphoma: translating immunobiology into therapeutic opportunities.

Cutaneous T cell lymphoma (CTCL) has always served as a proving ground where conceptual advances in immunology can be tested and the results translated into clinical practice. From the earliest studies that used sheep red blood cells to identify the malignant cell as a T lymphocyte to molecular demonstration of the clonalilty of the disease, basic science techniques have provided sign posts that allow us to understand the clinical features seen in the patients. We continue to apply this paradigm to develop new insights into the role of the immune system in CTCL with the goal of using this knowledge to enhance the therapeutic options available to the patient. This article will review the studies that have led to our current understanding of the immunobiology of CTCL and the new therapeutic approaches that are being tested in this disease.

Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States.

BACKGROUND: An association between Borrelia burgdorferi and cutaneous B-cell lymphoma (CBCL) has been made in several European countries. The evidence in favor of such an association has recently been based on more definitive tests for the pathogenetic role of B. burgdorferi in CBCL, including positive cultures or polymerase chain reaction (PCR) amplification of borrelial DNA from lesional skin. However, there is only one report of B. burgdorferi in four North American cases of B-cell lymphoma. METHODS: We retrieved 38 cases of primary and secondary CBCL from different geographic regions of the United States. Two separate techniques were used to detect borrelial DNA by PCR, a nested PCR method to amplify a B. burgdorferi-specific gene as well as a borrelial chromosomal Ly-1 clone amplification method. Southern blot hybridization was used for confirmation of the PCR results. RESULTS: No B. burgdorferi-specific DNA was detected in any of the 38 CBCL cases, whereas detectable PCR products were obtained with our positive controls. CONCLUSIONS: Our findings, in light of previous studies, suggest that B. burgdorferi plays a minimal role in the development or pathogenesis of CBCL in the United States. The findings also suggest that the geographic variations in the clinical manifestations of B. burgdorferi are indeed real and may be secondary to the genetic and phenotypic differences between B. burgdorferi strains present in Europe and North America.

Current treatment practice of herpes zoster.

The management of herpes zoster infection has been impacted by the development of oral and iv. antiviral therapies. There are clinical and historical features that help optimise the particular therapy course for a given patient. Additionally, there are common features of management in all patients with herpes zoster. In this review an understanding of the pathogenesis of herpes zoster is utilised as a starting point for the development of a rational approach to therapy. Clinical findings that impact decision making are emphasised and the appropriate goals for therapy are discussed.

Clinical trials and efficacy assessment in the therapy of cutaneous T cell lymphoma.

The ability of clinical trials to measure cutaneous T cell lymphoma (CTCL) has allowed physicians and regulatory reviewers to assess the response of the disease to experimental therapies. The goals of therapy are remission, palliation, and improvement of survival. Given the chronic nature of the disease, surrogate markers for survival are used in clinical trials. The surrogate markers and the validity of the surrogate markers used to date will be compared and contrasted. Tumor burden measurements by way of skin scoring are the parameters most commonly used to assess the response to therapy. Skin scoring systems have used global mapping, severity recording, or target lesions to assess any change in response to an intervention. The advantages and limitations of global and focal scoring are presented, along with examples of skin scoring systems for the five most recently completed trials for CTCL. Measures of palliation are performed via questionnaires. General and CTCL-specific questionnaires have been developed that assess both discrete and global manifestations of the disease. Those measures of palliation that have been shown to correlate with skin scoring are presented for inclusion into future studies. In addition, study terms such as relapse and freedom from relapse can now be defined with reproducible molecular techniques. Every stage of CTCL warrants further clinical trials, and guidelines for future investigations are proposed.

Phase II trial of 9-aminocamptothecin as a 72-h infusion in cutaneous T-cell lymphoma.

PURPOSE: To evaluate the role of 9-aminocamptothecin (9-AC), a synthetic camptothecin analog, in advanced cutaneous T-cell lymphoma (CTCL). METHODS: Eligible patients had stage IIB-IV CTCL. 9-AC was infused over 72 h at a dose of 1,100 microg/m2 per day (approximately 46 microg/m2/h) every 2 weeks, with granulocyte-colony stimulating factor (G-CSF) support. RESULTS: Twelve patients received a total of 30 cycles of 9-AC. Nine patients had stage IV disease, 5 patients had circulating Sezary cells, and 2 patients had evidence of tranformation to a large cell lymphoma. Most of the patients were heavily pretreated: 10 had received prior chemotherapy (83%), 5 of whom had received 2 or more prior regimens, including a patient who had received high-dose chemotherapy, and 7 had previously received total-skin electron beam therapy. The study was prematurely terminated due to substantial toxicity. Six patients (50%) developed an indwelling central venous catheter-related infection, 5 during a period of neutropenia. Three patients died due to sepsis 4-8 weeks after their last 9-AC treatment. Two of these patients had a previous history of bacterial sepsis. Four patients (33%) developed grade IV thrombocytopenia. Two partial responses were observed (response rate 17%), but the duration of response was brief, 4-8 weeks. CONCLUSION: 9-AC at this schedule and route of administration had activity but resulted in an unacceptable rate of complicated neutropenia and septic deaths in heavily pretreated patients with advanced CTCL who are susceptible to catheter-related infections.

Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results.

PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.

Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

Cutaneous T-cell lymphoma and cutaneous graft-versus-host disease. Two indications for photopheresis in dermatology.

Dermatologists are frequently involved in the management of cutaneous T-cell lymphoma (CTCL) and graft-versus-host disease (GVHD). The similarities of these two entities are reviewed in the context of clinical and histologic findings, pathogenesis, and therapy. Photopheresis therapy (extracorporeal photochemotherapy) is used in the treatment of both entities, and the mechanisms underlying the responses represent yet another striking similarity of these two crippling dermatologic diseases.

Future directions for pentostatin (Nipent) usage in dermatology.

Cutaneous T-cell lymphoma (CTCL) is a dynamic disease with several distinct components that make it unique from other lymphomas. The components of CTCL are reviewed to provide a background for understanding the role of pentostatin (Nipent; SuperGen, San Ramon, CA) in CTCL. In CTCL the malignant T cells mimic and eventually replace their nonmalignant counterparts. This enhances the need for targeting T cells with therapy that preferentially eliminates CTCL cells while sparing nonmalignant cells. Given the similarities of CTCL with T-cell mediated chronic inflammatory diseases, therapies used for this lymphoma also may play a role in nonmalignant disease management.

Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides.

OBJECTIVE: We compared the prognosis of patients with erythrodermic mycosis fungoides (MF) administered total skin electron beam radiation (TSEB) plus neoadjuvant, concurrent, and adjuvant extracorporeal photopheresis (ECP) with the prognosis of patients administered only TSEB. Outcomes of clinical interest include disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and cause-specific survival (CSS). METHODS: This study was a retrospective nonrandomized series. Between 1974 and 1997, a total of 44 patients with erythrodermic MF from the Department of Therapeutic Radiology, Yale University School of Medicine, and the Department of Radiation Oncology, Cancer Care Ontario, Hamilton, Ontario, were collected and analyzed as a group (Hamilton = 15, Yale = 29). These patients received TSEB consisting of 32 to 40 Gy via 4 to 6 MeV. Twenty-one patients at Yale also received ECP treatment 2 days per month for a median of 6 months. Median age was 68 years (range, 29-82 years) at the commencement of TSEB, and 66% were male. Seventy-three percent of patients had received other therapies before TSEB, including 75 courses that failed to control disease (n = 15 systemic therapy, 16 biologicals, and 44 topical therapies). At TSEB, 59% had hematologic involvement (B1), 30% were stage IVA (N3), and 13% were IVB (M1). Median follow-up was 2.2 years (range, 0.3-13.9 years) subsequent to TSEB and 3.7 years from diagnosis (range, 0.8-16.8 years). RESULTS: All patients responded to TSEB within 2 months of completion, with a cutaneous complete response rate of 73%. For the 32 complete responders the 3-year DFS was 63%. It was 49% for those 17 patients who received only TSEB compared with 81% for those 15 patients who received TSEB + ECP. Cox regression analysis demonstrated that ECP was associated with prolonged remission (DFS multivariate P =.024, adjusting for B1 and stage). The 2-year PFS, CSS, and OS for the TSEB group were 36%, 69%, and 63%, respectively, compared with 66%, 100%, and 88% for the TSEB + ECP cohort. Cox regression demonstrated that ECP was associated with CSS (multivariate P =.048, adjusting for B1 and stage). For those who progressed, a total of 49 subsequent courses of therapy were administered (n = 20 chemotherapy, 10 biologicals, and 19 topical therapies). Thirteen patients died from MF-related causes, and 8 died from other causes. Acute and chronic toxicities were consistent with those previously reported. CONCLUSION: ECP given concurrently with, or immediately after, TSEB (32-40 Gy) significantly improves both PFS and CSS for patients with erythrodermic MF compared with TSEB without the addition of ECP.

Unilesional cutaneous T-cell lymphoma: clinical features, therapy, and follow-up of 10 patients with a treatment-responsive mycosis fungoides variant.

Ten patients, mean age 61 years, who presented with unilesional cutaneous T-cell lymphoma (CTCL) were studied. Lesional structure and distribution were similar to disseminated CTCL. Ablative therapy was successful in all patients. The relatively benign behavior of unilesional CTCL may reflect the prognostic importance of minimal tumor burden. Locally ablative therapy in the management of localized CTCL appears effective.

The treatment of cutaneous T-cell lymphoma with a novel retinoid.

The clinical experience with bexarotene for cutaneous T-cell lymphoma (CTCL) at our center is reviewed here. Disease activity assessment was monitored every 4 weeks in all patients. Five target lesions were monitored, an area score was performed, and a CTCL-specific health assessment questionnaire was administered. Four patients with refractory plaque CTCL were treated with bexarotene gel. All target lesions disappeared after 8 weeks of therapy, with recurrences observed in untreated areas. In the follow-up period, no recurrences of the original target lesions were observed. One patient withdrew from the study. Patients with refractory patch/plaque disease were randomized to a high-dose (300 mg/m(2)) or low-dose (6.5 mg/m(2)) daily oral regimen of bexarotene. After showing disease progression, the two patients on the low-dose arm were entered into the high-dose arm after 8 weeks. Marked clinical responses were seen in all patients treated. The target lesions showed either complete disappearance or a reduction in lesion size, duration, and scale. No new lesions were noted in patients on high-dose bexarotene. Self-assessments also confirmed the palliative properties of the observed responses. All patients had hypertriglyceridemia despite the concomitant administration of atorvastatin at 60 mg/day. Dose reductions were required to maintain safe lipid levels. Four patients with erythrodermic CTCL were treated with high-dose oral therapy, and all patients showed rapid (within 2 weeks) improvement of erythroderma and symptoms.

Herpes zoster in seven disparate dermatomes (zoster multiplex): report of a case and review of the literature.

Noncontiguous multidermatomal herpes zoster is very rare in both immunocompetent and immunocompromised persons. Most of the reported cases have been limited to 2 noncontiguous dermatomes. This unique presentation has been referred to as zoster duplex unilateralis or bilateralis, depending on whether one or both halves of the body are involved. Granulomatous dermatitis at sites of herpes zoster scars, a rare isotopic response, has only been reported in persons with contiguous dermatomes of zoster. We describe an immunocompromised patient who developed herpes zoster in 7 disparate dermatomes. Three months after resolution of the zoster, the patient developed a granulomatous dermatitis in a zosteriform distribution at the sites of previous infection.

Integrins alpha4beta7 and alphaEbeta7 are expressed on epidermotropic T cells in cutaneous T cell lymphoma and spongiotic dermatitis.

Integrin alpha4beta7 has been associated with tissue-specific homing of malignant and inflammatory lymphocytes to gastrointestinal mucosa, whereas integrin alphaEbeta7 has been associated with intraepithelial lymphocytes in both the gut and the skin. This prompted us to examine the expression of alpha4beta7 on skin-infiltrating lymphocytes in 12 cases of patch/plaque stage cutaneous T cell lymphoma (CTCL) and in 4 cases of spongiotic dermatitis, which also display intraepidermal T cell accumulation. alpha4beta7 was found to be expressed on 64.8+/-7.4% of intraepidermal and 39.1+/-5.0% of intradermal T lymphocytes in CTCL. There was a significant positive correlation (r=0.58) between the degree of epidermotropism and the percentage of intraepidermal T cells expressing alpha4beta7. Similar findings were observed in spongiotic dermatitis, indicating that this result is not unique to malignant T cells. We evaluated staining of T cells in the same specimens for presence of alphaEbeta7 and observed a strong correlation between the expression of both beta7 integrins in each specimen. Staining with antibodies directed against the known ligands of alpha4beta7 was also performed on skin biopsies from CTCL patients. There was significantly increased dermal microvascular endothelial expression of vascular cell adhesion molecule-1 in lesional compared with nonlesional skin, and in nonlesional skin compared with skin of normal control subjects. Dermal and epidermal expression of the CS-1 domain of fibronectin was present but not increased in lesional biopsies compared with nonlesional or normal controls, whereas expression of mucosal addressin cell adhesion molecule-1 was not detectable in any skin biopsy specimens. In summary, alpha4beta7, like alphaEbeta7, is expressed at high levels on epidermotropic T cells and may interact with endothelial cell vascular cell adhesion molecule-1 as part of stepwise recruitment of lymphocytes from the blood to the epidermis.

Extracorporeal photochemotherapy in human and murine graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) is an immunotherapy that has found a role in the therapy of cutaneous T cell lymphoma, a disease of mature activated T cells. Graft-versus-host disease (GVHD) is also mediated by activated T cells, and thus often responds to therapies that target T cells. Murine models for both GVHD and ECP can be combined to study the impact of this immunotherapy on GVHD. In this paper we present a patient with GVHD who demonstrated a beneficial therapeutic response to treatment with ECP. The findings of this case are compared with the observations from a murine model for GVHD-ECP. The potential mechanisms of ECP in the treatment of GVHD are discussed. along with the similarities observed with ECP in the treatment of other conditions.

A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma.

Annular epidermolytic ichthyosis is a distinct phenotypic variant of bullous congenital ichthyosiform erythroderma that has recently been described in two separate kindreds. Individuals with this variant present with bullous ichthyosis in early childhood and hyperkeratotic lichenified plaques in the flexural areas and extensor surfaces at later ages. Characteristically, they also develop intermittent bouts of annular and polycyclic, erythematous, scaly plaques on the trunk and proximal extremities. We now describe a third kindred with annular epidermolytic ichthyosis. Molecular analysis of this family revealed a novel mutation resulting in an isoleucine to threonine substitution at residue 107 (codon 446) within the highly conserved helix termination motif at the end of the rod domain of keratin 10.

Cutaneous T-cell lymphoma: centuries of controversy.

Two hundred years have passed since the description of mycosis fungoides by Alibert. During this time, the disease has been the focus of intense controversy and research, with these two intimately intertwined. In this article, the major components of the controversies surrounding cutaneous T-cell lymphoma are examined. The next millenium will see the resolution of these controversies and the fruition of continued research into this condition.

Advances in the management of cutaneous T-cell lymphoma.

This article focuses on the management of specific T-cell components of cutaneous T-cell lymphomas. Advances in the management of these lymphomas are evaluated and classified. New treatment strategies and therapies are discussed.

Tumor-specific peptides in cutaneous T-cell lymphoma: association with class I major histocompatibility complex and possible derivation from the clonotypic T-cell receptor.

We wished to identify and characterize tumor-associated class I peptides which could potentially serve as immunogens for an immunoprotective CD8 response in cutaneous T-cell lymphoma (CTCL). Candidate idiotypic peptides were identified from the third complementarity determining region (CDR3) of the clonotypic T-cell receptor (TCR) expressed on malignant T cells and native class I peptides were identified from CTCL cells. Idiotypic peptides were designed by sequencing of patients' CDR3 and identifying 9 amino acid peptides that could be accommodated in the peptide-binding motif of the class I alleles. Three candidate idiotypic peptides were synthesized and tested by measuring release of tumor necrosis factor-alpha (TNF-alpha) from autologous CD8 cells. Native peptides were acid-eluted from class I molecules on CTCL lymphocytes, fractionated, tested in the TNF-alpha assay and sequenced. Two unique idiotypic peptides were specifically recognized by autologous CD8 cells from CTCL patients. In addition, a native peptide eluted from class I molecules of CTCL tumor cells was identified, in the protein data base, as a novel molecule with partial sequence homology to the conserved portion of the patient's TCR. This homology was used to construct an extended native peptide sequence that was immunogenic for CD8 cells from both CTCL patients. Our results demonstrate that peptides derived from the TCR can be used as tumor-specific immunogens that are recognized by CD8 cells. Moreover, novel class I peptides isolated from the tumor cell also serve as immunogens. These peptides might form the basis of an anti-tumor vaccine for immunotherapy of CTCL.