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.

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.

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.

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.

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.

T-cell technology in the diagnosis & management of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a malignancy of mature, clonal, helper (CD4+) T-cells that have a propensity for localizing in the skin. This article discusses the new immunologic and molecular advances and their practical application in the management of CTCL.

Activated protein C resistance and anticardiolipin antibodies in patients with venous leg ulcers.

BACKGROUND: Hypercoagulable states, which include the presence of anticardiolipin antibodies (ACAs), have been associated with skin ulceration. Resistance to activated protein C (APC), resulting from the factor V Leiden mutation, is a common risk factor for venous thrombosis. Its prevalence among patients with venous leg ulcers is not known. OBJECTIVE: Our purpose was to determine the prevalence of factor V Leiden and ACA in patients with venous leg ulceration. METHODS: Twenty-nine consecutive patients with venous leg ulcers were studied. Resistance to APC was first determined by functional assay based on the partial thromboplastin time. Patients with an abnormally low APC ratio were then subjected to molecular analysis for confirmation of factor V Leiden. Measurements of ACA were performed by enzyme-linked immunosorbent assay. RESULTS: APC resistance was detected in 11 of 26 patients. However, only 2 of these 11 patients (7.7% overall) were found to be heterozygous for the factor V Leiden mutation. ACA was present in neither patient with the Leiden mutation but was found in 6 of 21 patients tested (29% overall). CONCLUSION: The factor V Leiden mutation, unlike ACA, may not be more prevalent in patients with venous leg ulcers than in the general population. Our results emphasize the importance of molecular analysis for factor V Leiden in patients with APC resistance.

Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides).

PURPOSE: Patients with mycosis fungoides [cutaneous T-cell lymphoma (CTCL)] may benefit from adjuvant therapy after completing total skin electron beam therapy (TSEBT). We report the results for T1/T2 CTCL patients treated with adjuvant oral psoralen plus ultraviolet light (PUVA) with respect to overall survival (OS), disease-free survival (DFS), salvage of recurrence, and toxicity. METHODS AND MATERIALS: Between 1974 and 1993, TSEBT was administered to a total of 213 patients with CTCL. Records were reviewed retrospectively, and a total of 114 patients were identified as having T1 or T2 disease. Radiotherapy was provided via a 6-MeV linac to a total of 36 Gy, 1 Gy/day, 4 days/week, for 9 weeks. Beginning in 1988, patients were offered adjuvant PUVA within 2 months of completing TSEBT. This was started at 0.5-2 J/m2, 1-2 treatments/week, with a taper over 3-6 months. Therapy then continued once per month. There were 39 T1 and 75 T2 patients. Six T1 (15%) and eight T2 (11%) patients were treated with adjuvant PUVA. A further 49% of the 114 patients received adjuvant systemic therapy, 3% received spot external beam, 4% received adjuvant ECP, 2% received topical nitrogen mustard, 22% received a combination of therapies exclusive of PUVA, and 9% received no adjuvant therapy. Patients were balanced in all subgroups based on pre-TSEBT therapy. The median age of the cohort was 58 (range 20-88), with a median follow-up time of 62 months (range 3-179). RESULTS: Within 1 month after completing of TSEBT, 97% of T1, and 87% of T2 patients had achieved a complete remission. Stratified by adjuvant therapy, none of six T1 and one of eight T2 patients who received adjuvant PUVA failed within the first 3 years after completion of TSEBT. A total of 43% of the T1 and T2 patients receiving other or no adjuvant treatment failed within the same time course. The 5-year OS for the entire cohort was 85%. Those who received PUVA had a 5-year OS of 100% versus a 5-year OS for the non-PUVA group of 82% (p < 0.10). The 5-year DFS for the entire cohort was 53%. Those who received PUVA had a 5-year DFS of 85% versus a 5-year DFS for the non-PUVA group of 50% (p < 0.02). By T stage, those with T1 receiving PUVA exhibited no relapses, whereas those with T1 not treated with PUVA had a crude relapse rate of 36%. Median DFS was not reached at 103 months for the T1 adjuvant PUVA patients versus 66 months for the non-PUVA patients (p < 0.01). For those with T2, crude relapse rates were 25% and 55%, respectively, with DFS of 60 (median DFS not reached) and 20 months (p < 0.03). The 5-year DFS for patients salvaged with PUVA was 50%. Toxicity of adjuvant and salvage PUVA therapy was acceptable, with only two patients requiring a reduction in PUVA dosage. CONCLUSION: PUVA can maintain remissions in patients with CTCL after TSEBT. There is a significant benefit in DFS but no statistically significant improvement in OS. Prospective, randomized data are needed to confirm these results. PUVA is also effective as a salvage therapy after TSEBT in early-stage patients with recurrence, with acceptable toxicity.

Sézary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain).

Sézary syndrome (SS) is a leukemic variant of low-grade cutaneous T-cell lymphomas (CTCLs). The clonal T cells in this lymphoproliferative disorder are poorly characterized. Using antibodies against the variable region of the T-cell receptor (TCR V alpha/beta), we identified four predominant T-cell clones (two V beta 8+ clones, one V beta 5.1+, and one V alpha 2(a)+) in peripheral blood mononuclear cells (PBMC) of SS patients. Their phenotype was CD3+, CD4+, CD5+, CD45RO+. Clonal T cells were purified, and cytokine transcription and secretion was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by hybridization with biotinylated probes and enzyme-linked immunosorbent assays (ELISAs). The interleukin-10 (IL-10) PCR product was cloned and sequenced and found to be identical to the published cDNA sequence. The presence of accessory factor-1 (AF-1, or interferon-gamma [IFN-gamma] receptor beta-chain) encoding mRNA was assessed by RT-PCR and immunostaining using serum of rabbits immunized with the extracellular domain of a recombinant human AF-1 protein followed by APAAP staining. Clonal T cells transcribe and secrete mainly T-helper 2 cytokines (IL-10, -5, and -13). mRNA from purified SS clones but not mRNA from SS total PBMC was positive for AF-1 in an agarose gel and/or after hybridization. AF-1 transcription was associated with membrane-bound immunoreactivity for AF-1 in SS clones. SS-derived T-cell clones display T-helper 2 cytokines. This weakens cell-mediated immunosurveillance, and explains the clinical and immunologic abnormalities in SS patients. The T-helper 2 cytokine spectrum of all clones investigated is associated with overexpression of AF-1. This suggests that AF-1 is a potential marker for these clones (and eventually other T-helper 2 lymphocytes) and might represent a target for treatment of the disease.

Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma.

BACKGROUND: Recurrent cutaneous T-cell lymphoma (CTCL) is managed with a variety of modalities. Repeat treatment with additional courses of total skin electron beam therapy (TSEBT) has not been formally evaluated. OBJECTIVE: Our purpose was to evaluate the efficacy and toxicity of additional TSEBT for recurrent CTCL. METHODS: A total of 14 patients were treated with TSEBT and received at least two courses, with five of those patients receiving a third course. Patients were offered additional TSEBT if they suffered recurrence despite other therapy if the extent of the recurrence precluded localized radiation. The median follow-up was 36 months. RESULTS: The median dose for the entire group was 57 Gy. Thirteen patients (93%) achieved a complete response (CR) after the initial course. After the second course, 12 patients (86%) had a CR; of the five patients who underwent a third course, three (60%) achieved a CR. The median disease-free interval after the first course of therapy for those with a CR was 20 months and 11.5 months after the second course. Median survival after the second course was 15 months. All patients had xerosis, pruritus, desquamation, mild erythema, epilation, and anhidrosis of the skin. CONCLUSION: Patients with recurrent CTCL recalcitrant to other forms of therapy or too diffuse for treatment with localized radiation fields are candidates for additional TSEBT. This therapy is effective and well tolerated with an acceptable risk profile.

Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy.

PURPOSE: To evaluate the impact of systemic adjuvant therapies on relapse-free (RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL) patients treated with total skin electron beam therapy (TSEBT). METHODS AND MATERIALS: Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9 weeks; 6 MeV electrons) was administered with curative intent to a total of 163 CTCL (mycosis fungoides) patients using six fields supplemented by orthovoltage boosts (120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120 kvp, 2 Gy x 3). In this group, all patients who achieved a clinical complete response or a good partial response were offered one of two competing regimens of either adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal photochemotherapy (ECP). RESULTS: When the results for the group who achieved a complete response (CR) to TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 5-10 years) and not improved by either adjuvant regimen. However, T3 and T4 patients who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years) or adjuvant ECP (100% at 3 years) had better overall survival than those who received neither adjuvant regimen (approximately 50% at 5 years). The difference between the OS curves for those who received ECP vs. those who received no adjuvant therapy approached statistical significance (p < 0.06), while a significant survival benefit from the addition of chemotherapy for TSEBT complete responders was not observed. Neither adjuvant therapy provided benefit with respect to relapse free survival after TSEBT. CONCLUSIONS: These results suggest that an adjuvant nontoxic regimen of extracorporeal photochemotherapy may prolong survival in advanced stage CTCL patients who have achieved a complete remission after TSEBT. The combination of doxorubicin/cyclophosphamide had no significant impact on overall survival in those patients who achieved CR to TSEBT, and neither adjuvant therapy had an impact on relapse free survival for all T-stages. Such results are the basis for the current development of a prospective, randomized trial studying the impact of ECP after TSEBT in patients with advanced stage CTCL.

T-cell responses in photoimmune therapy.

The extracorporeal inactivation of a lymphocyte rich buffy coat suspension with ultraviolet A light and 8 methoxypsoralen can lead to dramatic clinical improvements following reinfusion of the damaged cells. This therapy is reviewed in the context of the disease it is most commonly used for: cutaneous lymphoma. Studies with cutaneous lymphoma patients have shown an active immune response against purified tumor cells. In addition a mouse model for an impact of therapy on a T-cell lymphoma has demonstrated results that parallel those from clinical studies in humans. The impact of photoimmune therapy on in vivo and in vitro T-cell responses to cutaneous lymphoma is discussed.

Cutaneous cryptococcosis in a patient with cutaneous T cell lymphoma receiving therapy with photopheresis and methotrexate.

Photopheresis is being used with increasing frequency as therapy for patients with neoplastic and dermatologic diseases and is being evaluated as therapy for patients with AIDS. We describe a patient with advanced cutaneous T cell lymphoma who developed pulmonary and cutaneous cryptococcosis after receiving therapy with photopheresis and biweekly methotrexate. We consider the potential roles of cutaneous T cell lymphoma, methotrexate, and photopheresis as predisposing factors in the development of serious cryptococcal infections.

Skin-selective lymphocyte homing mechanisms in the pathogenesis of leukemic cutaneous T-cell lymphoma.

The concept of skin-associated lymphoid tissue embraces those cells and functions that are integrated in the cutaneous host defense. Recently, it has been possible to identify those circulating T-cells that are skin associated. These cells display the cell-surface phenotype of memory T cells (CD45RO+) and express the cutaneous lymphocyte antigen, a tissue-selective homing receptor involved in directing T-cell traffic to inflamed skin. To investigate the participation of this skin-associated T-cell subset in the pathogenesis of cutaneous T-cell lymphoma, we studied 16 patients with erythrodermic cutaneous T-cell lymphoma for the presence of these surface proteins on circulating cells. Results were compared with eight patients in remission and eight with minimal patch-plaque cutaneous T-cell lymphoma. The mean expression of both CD45RO and cutaneous lymphocyte antigen were significantly greater in the erythrodermic patients than in the other two patient groups. Expression of these markers was shown to be on the cells of the malignant clone by two-color flow cytometry. These results demonstrate that the malignant cells of cutaneous T-cell lymphoma express the markers of skin homing lymphocytes and that their levels are increased in the erythrodermic cutaneous T-cell lymphoma patients. Moreover, the findings suggest a critical role for the skin-selective homing receptor cutaneous lymphocyte antigen in the pathogenesis of cutaneous T-cell lymphoma.

Idiopathic CD4+ lymphocyte deficiency. Report of an unusual case associated with atopic dermatitis and allergic contact dermatitis and review of the literature.

BACKGROUND: Idiopathic CD4+ lymphocyte deficiency is a newly described entity of apparently non-human immunodeficiency virus-associated helper T-cell depletion. The clinical spectrum continues to evolve, but, to date, it has included patients ranging from those with minimal symptoms to those who have died with acute opportunistic infections. Several individual cases have been previously reported, many with distinctive, primarily infectious, cutaneous manifestations. OBSERVATIONS: We describe a patient with idiopathic CD4+ lymphocyte deficiency distinguished by a unique clinical presentation of atopic dermatitis exacerbated by contact urticaria and allergic contact dermatitis. She has a persistent markedly diminished CD4+ lymphocyte count (absolute count less than 50), no serologic evidence of, or risk factors for, human immunodeficiency virus infection, and no history of opportunistic infections. CONCLUSIONS: We present a possible new cutaneous manifestation of idiopathic CD4+ lymphocyte disease and summarize the previously reported cases, with an emphasis on the cutaneous features.