Antibiotics and Imiquimod for Cutaneous T-Cell Lymphoma in Veterans: A Patient Population with Agent Orange Exposure.

LESSONS LEARNED: Staphylococcus aureus infection in cutaneous T-cell lymphoma (CTCL) is thought to contribute to disease progression; thus, adjunctive treatment with antibiotics warrants further investigation. This trial of antibiotic therapy followed by imiquimod in early stage CTCL was not completed because of difficulties with patient accrual. BACKGROUND: Cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin lymphoma, is a heterogeneous group of malignancies of mature memory T lymphocytes. It has an annual age-adjusted incidence of 7.5 per million persons in the U.S. population [1]. The etiology of CTCL is unknown, but epidemiological studies have reported potential associations with environmental and occupational factors, including Agent Orange exposure in Vietnam Veterans [2]. Both topical and systemic therapies have been identified as effective in CTCL; the choice of treatment is dependent on disease stage, with the overall goal of improving symptoms given the chronic and recurrent nature of the disease. Several studies have suggested that CTCL is exacerbated by the presence of Staphylococcus aureus in the skin and can be ameliorated by treatment with antibiotics [3]. METHODS: Our study was designed to assess the effects of antibiotics and imiquimod on early stage CTCL. Patients between the ages of 30-89 years with stage I and II CTCL were eligible for enrollment. They could not be receiving concurrent therapy, and the study design included a 14-day washout period after discontinuation of CTCL therapy. The washout period was followed by doxycycline 100 mg p.o. b.i.d. for 14 days and then two packets (250 mg per packet) of imiquimod 5% cream topically to the most clinically active lesions 3 days a week (Monday, Wednesday, and Friday) for 28 days. Skin lesions were measured using the modified Severity Weighted Assessment Tool (mSWAT). RESULTS: Our study enrolled only two patients with early stage CTCL because of difficulty locating patients with active CTCL able to discontinue all therapy. The two enrolled patients completed all therapy. One patient had a complete response after imiquimod, whereas the other patient had stable disease. CONCLUSION: Antibiotics and imiquimod have reported activity as single agents in CTCL; we did not enroll enough patients to assess value in the sequence of antibiotic therapy followed by imiquimod.

Methotrexate-induced Primary Cutaneous Diffuse Large B-cell Lymphoma in Patients with Erythrodermic Cutaneous T-cell Lymphoma.

is missing (Short communication).

Clustering of cutaneous T-cell lymphoma is associated with increased levels of the environmental toxins benzene and trichloroethylene in the state of Georgia.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma arising in the skin. Geographic clustering of CTCL has recently been reported, but its association with environmental factors is unknown. Benzene and trichloroethylene (TCE) are environmental toxins with carcinogenic properties. The authors investigated associations between geographic clustering of CTCL incidence in the state of Georgia with benzene and TCE exposure. METHODS: The statewide county-level incidence of CTCL within Georgia was obtained from the Georgia Cancer Registry for the years 1999 to 2015. Standardized incidence ratios (SIRs) were calculated by dividing observed cases by expected cases using national incidence rates by age, sex, and race. Clustering of CTCL was analyzed using spatial analyses. County-level concentrations of benzene and TCE between 1996 and 2014 were collected from the Environmental Protection Agency's National Air Toxics Assessment database. Linear regression analyses on CTCL incidence were performed comparing SIRs with levels of benzene and TCE by county. RESULTS: There was significant geographic clustering of CTCL in Georgia, particularly around Atlanta, which was correlated with an increased concentration of benzene and TCE exposure. Among the 4 most populous counties in Georgia, CTCL incidence was between 1.2 and 1.9 times higher than the state average, and benzene and TCE levels were between 2.9 and 8.8 times higher. CONCLUSIONS: The current results demonstrate nonrandom geographic clustering of CTCL incidence in Georgia. To the authors' knowledge, this is the first analysis to identify a correlation between geographic clustering of CTCL and environmental toxic exposures.

Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T-cell lymphoma?

Secukinumab is an interleukin (IL)-17 monoclonal antibody inhibiting T-helper (Th)1-mediated immune response. It has proven high efficacy for moderate to severe psoriasis but data on its long-term toxicities are limited. We describe two patients who received secukinumab for clinically presumed psoriasis, but were subsequently diagnosed with mycosis fungoides (MF) following skin biopsies triggered by skin deterioration while on secukinumab. Previous studies suggested decreased numbers of regulatory T cells (Tregs) with increasing stage of MF, which may lead to the shift in the Treg/Th17 balance towards the Th17 pathway. Theoretically, the use of IL-17 monoclonal antibodies to inhibit Th17 pathway may lead to further immunosuppression and disease progression in cutaneous T-cell lymphoma (CTCL) by shifting the balance towards Tregs, although this hypothesis has not been proven. With uncertainty over the role of IL-17 and Treg/Th17 as well as diagnostic challenges in CTCL, we recommend that patients should have a confirmatory skin biopsy prior to the commencement of biologic therapy.

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.

Linfoma cutáneo asociado a metotrexato en un paciente con artritis reumatoide / Cutaneous lymphoma associated with methotrexate in a patient with rheumatoid arthritis

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Primary Cutaneous Small/Medium CD4+ T-CELL Lymphoproliferative Disorder Occurring in a Patient With Metastatic Melanoma.

Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear. A biopsy showed a dense population of CD4 lymphocytes with a T-follicular helper cell phenotype. Molecular studies confirmed the presence of a clonal population of T cells, and the process was classified as PC-SMTCL. The patient was diagnosed with metastatic melanoma approximately 3 years before the development of the cutaneous lymphoma and had been treated with vemurafenib followed by 2 courses of IL-2. The patient's last course of IL-2 was completed in April of 2013. She developed the cutaneous lymphoma behind her ear in December of 2015. An association between PC-SMTCL and vemurafenib treatment for advanced melanoma has been reported previously in one patient; however, an association between PC-SMTCL and IL-2 treatment has not been documented. The immunostimulatory properties of IL-2 or vemurafenib may be responsible for the development of PC-SMTCL in our patient. Additionally, antigenic stimulation of the immune system by melanoma itself could contribute to clonal selection of lymphocytes.

Linear Folliculotropic CD30-Positive Lymphomatoid Drug Reaction.

We report a unique case of probable drug-induced CD30-positive lymphomatoid reaction. A 58-year-old woman presented with bilateral facial eruptions of 3 weeks duration composed of erythematosus papules in a linear distribution. The pathological features demonstrated a dense dermal and follicular infiltrate of many medium- to large-sized atypical CD30-positive lymphoid cells. The rash resolved rapidly after discontinuation of her medication 1 week later and did not recur. This case highlights the importance of clinicopathological correlation.

Methotrexate and etanercept-induced primary cutaneous CD4 positive small/medium-sized pleomorphic T-cell lymphoma.

Immunosuppressive drugs and biological agents may represent a potential risk of lymphoma development in patients with rheumatoid arthritis. But most cases are diffuse, large B-cell lymphomas. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, a provisional entity in the 2005 WHO-EORTC classification of cutaneous lymphomas, is only described in a limited number of reports. To our knowledge, our case is a rare instance of primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, after associated treatment with methotrexate and etanercept, in a patient with moderate rheumatoid arthritis who had undergone an orchidectomy incorrectly.

Methotrexate and etanercept-induced primary cutaneous CD4 positive small/medium-sized pleomorphic T-cell lymphoma

Abstract: Immunosuppressive drugs and biological agents may represent a potential risk of lymphoma development in patients with rheumatoid arthritis. But most cases are diffuse, large B-cell lymphomas. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, a provisional entity in the 2005 WHO-EORTC classification of cutaneous lymphomas, is only described in a limited number of reports. To our knowledge, our case is a rare instance of primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, after associated treatment with methotrexate and etanercept, in a patient with moderate rheumatoid arthritis who had undergone an orchidectomy incorrectly.

Cutaneous toxicities associated with vemurafenib therapy in 107 patients with BRAF V600E mutation-positive metastatic melanoma, including recognition and management of rare presentations.

BACKGROUND: Vemurafenib significantly improved overall survival compared with dacarbazine in patients with metastatic or unresectable BRAF V600E-positive melanoma in the BRIM-3 trial. However, vemurafenib was associated with a number of skin-related adverse events (AEs). OBJECTIVES: To investigate the incidence and management of vemurafenib-associated skin AEs. METHODS: This retrospective, observational study included adult patients with stage IIIC or IV melanoma who received vemurafenib between March 2010 and August 2013. Patients received oral vemurafenib 960 mg twice daily, with dose interruptions and reductions allowed for AE management. RESULTS: In total 107 patients were treated with vemurafenib during the study period. The most frequent clinically important skin-related AEs were rash (64%), squamoproliferative growths (41%), photosensitivity (40%) and squamous cell carcinoma (SCC) or keratoacanthoma (KA; 20%). Rare cases of granulomatous dermatitis and cutaneous T-cell lymphoma were also found. Rash was manageable with corticosteroids and dose modifications; squamoproliferative growths and SCCs/KAs were treated with cryotherapy and surgical excision, respectively. Patients were counselled regarding phototoxicity. The uncontrolled nature and retrospective design of the study, and the small patient numbers are limitations. CONCLUSIONS: Vemurafenib appears to have a predictable and manageable AE profile. Proactive management can limit the impact of AEs on patients, allowing treatment to continue despite toxicities.

Primary cutaneous small/medium CD4+ T-Cell lymphoma occurring during treatment with vemurafenib for advanced melanoma.

The discovery of BRAF mutations in 40%-60% of melanomas led to the development of BRAF inhibitors, which exhibit objective response in over 50% of patients. However, up to 98% of the patients develop at least 1 side effect. We report for the first time a patient with metastatic melanoma harboring BRAF V600E mutation that develops a primary, cutaneous small/medium CD4 T-cell lymphoma secondarily to the treatment with vemurafenib. A 54-year-old man with a history of metastatic melanoma treated with the oral BRAF inhibitor vemurafenib presents, 4 months after the initiation of the treatment, with multiple, nodular firm nonulcerated lesions on his back. Two skin biopsies from the lesions revealed a primary, cutaneous small/medium CD4 T-cell lymphoma.The extensive use of recently approved mutation-specific RAF inhibitors seems to be speeding up the emergence of unknown nonpreventable toxicities of these agents. Our patient developed a primary, cutaneous small/medium CD4 T-cell lymphoma, which presented 4 months after the commencement of vemurafenib. Although no treatment interruption is normally required, a close monitoring of the patients with advanced melanomas treated with vemurafenib seems imperative to optimize the management strategies.

Cutaneous lymphoproliferative disorders in organ transplant recipients: update 2014.

Post-transplant lymphoproliferative disorders (PTLD) are lymphoid or plasmacytic proliferations that develop after solid organ, bone marrow or stem cell transplantation. PTLD are the leading cause of cancer-related mortality and graft loss in both pediatric and adult solid organ transplant recipients (ORT). These disorders comprise a spectrum ranging from usually EBV-driven, mostly B-cell polyclonal proliferations to B- and T-cell lymphomas indistinguishable from their counterparts occurring in immunocompetent individuals. PTLD usually present in extranodal sites; isolated skin involvement of PTLD is rare. A recent multicenter European case series showed that primary cutaneous T-cell PTLD are more common than primary cutaneous B-cell PTLD, and along with its folliculotropic variant, mycosis fungoides (MF) is the most frequent form of posttransplant primary cutaneous T-cell lymphoma (CTCL). This case series also disclosed that primary cutaneous CD30+ lymphoproliferative disorders is the second most common posttransplant CTCL subtype, indicating that the spectrum of primary CTCL in OTR is similar to that in the general population. However, in contrast with the immunocompetent individuals, the prognosis of primary cutaneous CD30+ anaplastic large T-cell lymphoma is worse than posttransplant MF and than its counterpart in the general population which has an excellent prognosis. The recent case series indicated that the spectrum of primary cutaneous B-cell PTLD differs significantly from cutaneous B-cell lymphoma in the general population, with a predominance of EBV-associated forms. Currently, the best therapeutic intervention(s) for primary cutaneous PTLD remains unknown.