Ilana S. Rosman

Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma

right nipple. B, Nevoid hyperkeratosis of the nipple. Orthokeratotic hyperkeratosis, acanthosis, papillomatosis, and a sparse superficial perivascular lymphocytic infiltrate (Hematoxylin-eosin stain; original magnification:340). C andD, Syringocystadenoma papilliferum. Papillary foci in continuity with the surface squamous epithelium. These papilla had a bilayered epithelium of inner columnar cells showing decapitation secretion and outer flattened cells as well as a fibrovascular core containing abundant plasma cells. C and D, Hematoxylin-eosin stain; original magnifications: C, 340; D 3200. J AM ACAD DERMATOL VOLUME 70, NUMBER 4 Letters e85

Cutaneous effects of thiotepa in pediatric patients receiving high-dose chemotherapy with autologous stem cell transplantation

High-dose thiotepa, a polyfunctional alkylating agent used in the treatment of solid tumors in children and adults, has been reported to cause a variety of reactions in the skin, including erythema, blistering, and hyperpigmentation. Reports vary in descriptions of the prevalence, severity, and nature of cutaneous reactions to thiotepa. To further characterize the cutaneous effects of thiotepa in children, we performed a chart review of 38 pediatric patients treated with a thiotepa-based chemotherapy regimen before autologous stem cell transplantation. Although cutaneous symptoms were documented in all patients, a consistent pattern of diffuse erythema with progression to desquamation and hyperpigmentation occurred in nearly 80% of the patients. Intertriginous and occluded areas were often the initial areas to be affected. Recognition of this association will improve the care of this patient population. This study was limited by reliance on chart data and lack of follow-up by a dermatologist.

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

Tufted hair folliculitis in a woman treated with trastuzumab

Chemotherapeutic agents targeting the human epidermal receptor (HER) family are being used with increasing frequency for a variety of solid tumors. Cutaneous side effects are commonly reported with HER inhibitors, especially those agents that inhibit epidermal growth factor receptor (EGFR) or HER1. However, inhibitors of HER2 are not associated with specific skin toxicity. We present a case of tufted hair folliculitis, an inflammatory scalp condition causing scaling and pruritus, in a woman being treated with trastuzumab, a selective HER2 inhibitor. This finding has not previously been reported as a side effect of trastuzumab therapy.

First-in-human Phase 1 Clinical Study of the IL-15 Superagonist Complex ALT-803 to Treat Relapse after Transplantation

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 μg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.

Nevoid hyperkeratosis of the areola misinterpreted as mycosis fungoides.

Nevoid hyperkeratosis of the nipple and areola is a benign condition with fewer than 70 cases reported in the literature. We report a case of unilateral nevoid hyperkeratosis of the areola with intraepidermal lymphocytes that resembled Pautriers microabscesses on histological examination. This is the third report of mycosis fungoides‐like changes in nevoid hyperkeratosis of the nipple and areola. In addition, this is the first case to present immunohistochemical and T‐cell gene rearrangement studies of the intraepidermal lymphocytes. This case highlights a potential histopathological pitfall in the diagnosis of nevoid hyperkeratosis of the nipple and areola.

Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS☆☆☆

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patients mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.

Extensive tumoral melanosis associated with ipilimumab-treated melanoma

Tumoral melanosis describes a pigmented lesion clinically similar to melanoma but on histology reveals dense aggregates of melanin‐laden, benign macrophages without malignant cells. In the few reported cases so far, tumoral melanosis has arisen in the skin or lymph node of a patient with a regressed melanoma or an epithelioid tumour. As a marker of regressed primary melanoma, its discovery may prompt investigation and surveillance for undiagnosed local or metastatic disease. Here, we present a unique case of extensive tumoral melanosis arising during ipilimumab treatment of in‐transit metastases from a previously excised melanoma.

Ponatinib-induced neutrophilic panniculitis

Ponatinib is a bcr‐abl tyrosine‐kinase inhibitor (TKI) used to treat resistant and refractory chronic myeloid leukemia and Philadelphia chromosome‐positive acute lymphoblastic leukemia that express bcr‐abl. Neutrophilic panniculitis has been described in rare cases of patients on other TKIs in the same class as ponatinib. We present the first case of neutrophilic panniculitis following treatment with ponatinib and summarize the other cases of panniculitis caused by TKIs.

Cutaneous squamous cell carcinoma progression is associated with decreased GATA-3 immunohistochemical staining

The GATA family of transcription factors is an essential regulator of cellular proliferation and differentiation. In the skin, GATA‐3 is critical for epidermal stratification and maintenance of barrier function. A role for GATA‐3 in the development of human cutaneous squamous cell carcinoma (SCC) is not known. Here, we investigated GATA‐3 immunohistochemical staining in premalignant and invasive cutaneous SCC from sun‐exposed and sun‐protected skin.