Lindy P. Fox

Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole

BACKGROUND Voriconazole is a broad-spectrum antifungal agent associated with photosensitivity and accelerated photoaging. A possible link with aggressive squamous cell carcinoma (SCC) has also been reported. OBJECTIVE We sought to determine the incidence and frequency of cutaneous SCC among patients undergoing long-term treatment with voriconazole who also manifest features of chronic phototoxicity. METHODS We conducted a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole at 3 academic dermatology centers. RESULTS A total of 51 cutaneous SCC were identified in 8 patients (median age 34.5 years, range 9-54) treated with chronic voriconazole (median duration 46.5 months, range 13-60). Underlying diagnoses included graft-versus-host disease, HIV, and Wegener granulomatosis. Signs of chronic phototoxicity and accelerated photoaging included erythema, actinic keratoses, and lentigo formation. LIMITATIONS The retrospective nature of the study cannot determine the true population risk of SCC associated with voriconazole therapy. A prospective cohort study is needed. CONCLUSION A high index of suspicion for photosensitivity and SCC may be warranted with chronic voriconazole use when used in the setting of concurrent immunosuppression.

A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group

BackgroundAccurate grading of dermatologic adverse events (AE) due to epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is necessary for drug toxicity determinations, interagent comparisons, and supportive care trials. The most widely used severity grading scale, the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0), was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events. We believe a class-specific grading scale is needed to help standardize assessment and improve reporting of EGFRI-associated dermatologic AEs.MethodsThe Multinational Association of Supportive Care in Cancer (MASCC) Skin Toxicity Study Group conducted an international multidisciplinary meeting that included 20 clinicians and researchers from academic centers and government agencies. Experts from different disciplines presented current information specific to EGFRI-induced dermatologic toxicities: grading scale development, pharmacovigilance safety reporting, health-related quality of life, patient reporting, and pharmacology. Group discussions, literature reviews, and professional expertise established the theoretical foundation for the proposed grading scale.ResultsA new grading system is proposed for the most common events associated with EGFRI-induced dermatologic AEs: papulopustular reaction or acneiform rash, nail changes, erythema, pruritus, xerosis, hair changes, telangiectasias, hyperpigmentation, mucositis, flushing, radiation dermatitis, hyposalivation, and taste changes. The proposed scale maintains consistency with the grading principles and language of the existing CTCAE version 4.0 and MedDRA terminology and includes relevant patient-reported health-related quality of life factors.ConclusionsA grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.

Melanoma Associated With Long-term Voriconazole Therapy A New Manifestation of Chronic Photosensitivity

BACKGROUND Voriconazole is a triazole antifungal agent approved by the US Food and Drug Administration for serious fungal infections, including with Aspergillus, Fusarium, Pseudallescheria, and Scedosporium species. In initial clinical trials, approximately 2% of patients developed cutaneous reactions, including photosensitivity, cheilitis, and xerosis. Subsequent reports have implicated voriconazole as a cause of severe photosensitivity and accelerated photoaging, pseudoporphyria cutanea tarda, and aggressive squamous cell carcinoma. OBSERVATION We report 5 melanoma in situ lesions in the setting of extreme photosensitivity associated with long-term voriconazole therapy. CONCLUSIONS We recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photodamage. Further study of the mechanism underlying voriconazole photosensitivity and oncogenesis is warranted.

Cocaine-associated retiform purpura and neutropenia: Is levamisole the culprit?

REFERENCES 1. Miyamura Y, Suzuki T, Kono M, Inagaki K, Ito S, Suzuki N, et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 2003;73:693-9. 2. Rongioletti F, Rebora A. Acquired brachial cutaneous dyschromatosis: a common pigmentary disorder of the arm in middleaged women. J Am Acad Dermatol 2000;42:680-4. 3. Li M, Li C, Hua H, Zhu W, Lu Y, Yang L. Identification of two novel mutations in Chinese patients with dyschromatosis symmetrica hereditaria. Arch Dermatol Res 2005;297:196-200.

Subcutaneous panniculitis-like T-cell lymphoma with overlapping clinicopathologic features of lupus erythematosus: coexistence of 2 entities?

We observed 5 patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) who were unusual, in that they also exhibited features of lupus erythematosus (LE). This observation is in keeping with a recent study that reported an increased rate of autoimmune disease, including systemic lupus erythematosus (SLE), among patients with SPTCL. In all cases, attributes indicating SPTCL included an infiltrate of lymphocytes with pleomorphic nuclei involving subcutaneous lobules exhibiting a cytotoxic T-cell (CD3+/CD8+/βF1+) immunophenotype. Additionally, a high proliferation rate and a monoclonal T-cell receptor-γ gene rearrangement were observed in most cases. The manifestations of LE in these patients included a spectrum of clinical and histopathological abnormalities. Clinical manifestations of LE included, in some patients, morphologic evidence of lupus erythematosus panniculitis (LEP) with subcutaneous nodules that healed with lipoatrophy on the face. In addition, all the patients exhibited serologic and/or extracutaneous end-organ abnormalities seen in patients with SLE, with 2 patients having sufficient findings to meet American College of Rheumatology criteria for SLE. Histopathological evidence of LE included vacuolar change at the dermal-epidermal interface in 3 patients, 2 of whom also showed interstitial deposition of mucin in the reticular dermis. One of these patients also had findings of LEP in the subcutaneous lobules with clusters of CD20+ B cells partially arranged within germinal centers. In 2 patients in which neither the epidermis nor dermis was available for review, histopathological features of LE included, in one patient, a few small clusters of CD123+ plasmacytoid dendritic cells within the adipose tissue and, in the other patient, a positive direct immunofluorescence test (lupus band) on clinically uninvolved and lesional skin. Our study shows that some patients show overlap between SPTCL and LE. We suspect that these patients may suffer from both diseases concomitantly. Furthermore, patients with LE, particularly LEP, should be monitored for evolution into SPTCL with biopsy of any subcutaneous lesion that is not typical of LEP. Additionally, screening for cutaneous LE and SLE could be considered in patients with SPTCL.

Xanthogranulomas associated with hematologic malignancy in adulthood

Although xanthogranulomatosis (XG), defined as multiple xanthogranulomas occurring simultaneously, was originally described in infants and children, a number of adult cases have been reported. Adult XG, which generally presents in the absence of hyperlipidemia, has many similarities to the childhood variant. Among the similarities are reports of the simultaneous development of XG and hematologic disorders. Herein we report a case of XG in a 45-year-old man with B-cell acute lymphoblastic leukemia and review the literature regarding the association of XG and hematologic disorders in adults. We propose that xanthogranulomas seen in children and adults bear many similarities, clinically and histopathologically, and share an association with hematologic malignancies.

Keratitis, ichthyosis, and deafness (KID) syndrome: A review of infectious and neoplastic complications

Keratitis, ichthyosis, and deafness (KID) syndrome is a rare genodermatosis associated with mutations in the connexin 26 gene. Although characterized by this clinical triad, KID syndrome predisposes to a heterogeneous spectrum of cutaneous manifestations and complications, both infectious and neoplastic in nature. Chronic mucocutaneous candidiasis and/or superinfection of skin lesions commonly occur and warrant aggressive therapeutic intervention. Benign neoplasms, namely trichilemmal tumors, have also been reported and can herald malignant growth and invasive disease. Squamous cell carcinoma of both mucosa and skin, especially acral sites, occurs in approximately 15% of patients. The pathogenesis of KID syndrome can be at least partially explained by the role of connexin 26 in intercellular communication and carcinogenesis, but the precise mechanism of disease remains unclear. Treatment strategies, which have ranged from antifungals and antibiotics to systemic retinoids, pose an ongoing challenge given the spectrum of disease. A review of the literature, with a particular focus on infection and malignancy associated with KID syndrome, and updates on the pathogenesis of disease, is discussed.

Calcium may preferentially deposit in areas of elastic tissue damage

BACKGROUND Cutaneous calcification is an acquired disorder whereby insoluble, amorphous calcium salts deposit in the skin. Classically, cutaneous calcification is categorized as metastatic, dystrophic, idiopathic, or iatrogenic. OBJECTIVE The purpose of this study was to further elucidate the underlying pathogenic mechanism for cutaneous calcification. METHODS Three cases of cutaneous calcification, including clinical characteristics and associated histopathology, were reviewed. Previous reports of cutaneous calcification were searched for in the published literature and included. RESULTS Calcium is distributed within areas of underlying tissue damage (ie, locus minoris resistentiae), and in our cases, occurred specifically at sites of chronic actinic damage and intravenous extravasation tissue injury. LIMITATIONS A small number of clinical cases and previously published reports were reviewed. CONCLUSION We hypothesize that cutaneous calcification may preferentially occur at anatomic sites where tissue integrity has been compromised (ie, locus minoris resistentiae). We suggest one potential mechanism: that cutaneous calcification occurs within dermis that contains damaged elastic fibers. Pseudoxanthoma elasticum may serve as a possible genetic disease model for this process.

20q– Clonality in a Case of Oral Sweet Syndrome and Myelodysplasia

We report the case of a patient with myelodysplasia who had Sweet syndrome of the oral cavity. An atypical myeloid immunophenotype was present in the gingival biopsy specimen and in a concurrent bone marrow specimen. Fluorescence in situ hybridization performed on the gingival biopsy specimen demonstrated the same del(20q) cytogenetic abnormality present in the bone marrow, confirming the presence of a clonally related myeloid proliferation in both tissues. This is the first reported case of Sweet syndrome and myelodysplasia in which the chromosomal abnormality was identified in the neutrophilic infiltrate, confirming the neutrophilic infiltrate to be clonally related to the underlying myeloid neoplasm.

IgM-λ paraproteinemia with associated cutaneous lymphoplasmacytic infiltrate in a patient who meets diagnostic criteria for POEMS syndrome

POEMS is a rare multisystem paraneoplastic syndrome featuring polyneuropathy, organomegaly, endocrinopathy, a monoclonal protein, and skin changes. In the relatively few reported biopsies of POEMS-associated cutaneous hyperpigmentation, the most common skin finding seen in patients with the disorder, only a non-specific inflammatory infiltrate has been demonstrated histologically. We present the case of a 79-year-old man with polyneuropathy, autoimmune thyroiditis, pancytopenia, and a history of lymphadenopathy who presented to the inpatient dermatology service with cutaneous hyperpigmentation. A skin biopsy of a hyperpigmented area showed a cutaneous lymphoplasmacytic infiltrate, prompting further investigation. A monoclonal IgM-lambda paraprotein was subsequently identified, leading to administration of combination chemotherapy for a diagnosis of POEMS syndrome. The novel finding of a lymphoplasmacytic infiltrate in POEMS-associated hyperpigmentation suggests a diagnostic role for skin biopsy in these patients.