Kerri E. Rieger

Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa

Importance Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating, often fatal, inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. Support and palliation are the only current therapies. Objective To evaluate the safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with RDEB. Design, Setting, and Participants Single-center phase 1 clinical trial conducted in the United States of 4 patients with severe RDEB with a measured area of wounds suitable for grafting of at least 100 cm2. Patients with undetectable type VII collagen keratinocyte expression were excluded. Interventions Autologous keratinocytes isolated from biopsy samples collected from 4 patients with RDEB were transduced with good manufacturing practice-grade retrovirus carrying full-length human COL7A1 and assembled into epidermal sheet grafts. Type VII collagen gene-corrected grafts (approximately 35 cm2) were transplanted onto 6 wounds in each of the patients (n = 24 grafts). Main Outcomes and Measures The primary safety outcomes were recombination competent retrovirus, cancer, and autoimmune reaction. Molecular correction was assessed as type VII collagen expression measured by immunofluorescence and immunoelectron microscopy. Wound healing was assessed using serial photographs taken at 3, 6, and 12 months after grafting. Results The 4 patients (mean age, 23 years [range, 18-32 years]) were all male with an estimated body surface area affected with RDEB of 4% to 30%. All 24 grafts were well tolerated without serious adverse events. Type VII collagen expression at the dermal-epidermal junction was demonstrated on the graft sites by immunofluorescence microscopy in 9 of 10 biopsy samples (90%) at 3 months, in 8 of 12 samples (66%) at 6 months, and in 5 of 12 samples (42%) at 12 months, including correct type VII collagen localization to anchoring fibrils. Wounds with recombinant type VII collagen graft sites displayed 75% or greater healing at 3 months (21 intact graft sites of 24 wound sites; 87%), 6 months (16/24; 67%), and 12 months (12/24; 50%) compared with baseline wound sites. Conclusions and Relevance In this preliminary study of 4 patients with RDEB, there was wound healing in some type VII collagen gene-corrected grafts, but the response was variable among patients and among grafted sites and generally declined over 1 year. Long-term follow-up is necessary for these patients, and controlled trials are needed with a broader range of patients to better understand the potential long-term efficacy of genetically corrected autologous epidermal grafts. Trial Registration clinicaltrials.gov Identifier: NCT01263379.

Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer

Background: Reported recurrence rates for transected nonmelanoma skin cancer (NMSC) vary widely, and few studies have addressed recurrence of tumors followed clinically or treated with nonsurgical modalities.

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

To the editor: Indeterminate cell histiocytosis (ICH) is a rare and controversial disorder first described by Wood et al[1][1] in 1985. ICH is characterized by a nonepidermotropic histiocytic infiltrate with immunohistochemical features that overlap with Langerhans cells (LCs) and non-LCs of

ALK‐negative systemic intravascular anaplastic large cell lymphoma presenting in the skin

Systemic cases of the CD30‐positive T‐cell neoplasm, anaplastic large cell lymphoma (ALCL), are typically anaplastic lymphoma kinase (ALK)‐positive. The failure to express ALK protein has been shown to portend a worse prognosis. We describe a case of ALK‐negative systemic ALCL that presented as a violaceous plaque on the scalp of a 79‐year‐old man. Interestingly, the neoplastic cells were confined largely within vascular spaces, a configuration that is exceedingly rare in the skin and is more typically seen with intravascular large B‐cell lymphoma. In addition, bcl‐2 immunohistochemical staining was strongly positive in this case, which may portend a more aggressive clinical course. To our knowledge, this report represents the first case of an ALK‐negative ALCL to present intravascularly in the skin. Therefore, the recognition of systemic anaplastic T‐cell lymphoma present within the intravascular spaces is important to avoid misdiagnosis.

Localized Cutaneous Fibrosing Disorders

This article acquaints the reader with disorders of the skin that might mimic systemic sclerosis but whose pathology is localized to the skin and/or has extracutaneous manifestations that are different than systemic sclerosis. These disorders include localized scleroderma (morphea), eosinophilic fasciitis, scleredema, scleromyxedema, nephrogenic systemic fibrosis, and chronic graft-versus-host disease. Particular emphasis is placed on clinical and histopathologic features that help the clinician differentiate between these disorders. Treatment options are briefly reviewed.

Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy

Importance To our knowledge, there have been no previous reports of eruptive keratoacanthomas (KAs) in patients receiving pembrolizumab. Objective To report the cases of 3 consecutive patients with pembrolizumab-induced eruptive KAs and their management. Design, Setting, and Participants Case report study of 3 patients from 2 centers with pembrolizumab-treated cancer who all developed eruptive KAs. Interventions All 3 patients had AK treatment with clobetasol ointment and intralesional triamcinolone; 2 patients also underwent open superficial cryosurgery. Results Three consecutive patients with cancer, 2 men and 1 woman (median age, 83 years; range 77-91 years), experienced pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset of multiple lesions on sun-exposed areas of their extremities after a median of 13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a lichenoid infiltrate was observed in the underlying dermis, predominantly composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+ (programmed cell death 1–positive) T cells, an immunophenotypic pattern also observed in other cases of anti–PD-1–induced lichenoid dermatitis. Patients were treated with clobetasol ointment and intralesional triamcinolone, alone or in combination with open superficial cryosurgery. All KAs resolved in all patients, and no new lesions occurred during close follow-up. Pembrolizumab treatment was continued without disruption in all 3 cases, and all patients had complete responses of their primary cancers. Conclusions and Relevance Pembrolizumab is used in advanced melanoma, advanced non–small-cell lung cancer, and in head and neck cancer. A variety of dermatologic immune-related adverse events including maculopapular eruption, lichenoid reactions, pruritus, and vitiligo have been described. This case series demonstrates that pembrolizumab therapy may also be associated with eruptive KAs with characteristic dermal inflammation, which improved with corticosteroid treatment (topical and intralesional) alone or in combination with cryosurgery, allowing patients to continue therapy with pembrolizumab.

PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjögren's syndrome

Objectives Autoantibodies are used clinically to phenotype and subset patients with autoimmune rheumatic diseases. We detected a novel 60 kDa autoantibody specificity by immunoblotting using a dermatomyositis (DM) patients serum. Our objective was to identify the targeted autoantigen and to evaluate disease specificity and clinical significance of this new autoantibody. Methods A new 60 kDa specificity was detected by immunoblotting HeLa cell lysates. The targeted autoantigen was identified as poly(U)-binding-splicing factor 60 kDa (PUF60) using (i) a human protein array and (ii) two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing. Anti-PUF60 antibodies were assayed by ELISA using sera from patients with primary Sjögrens syndrome (SS; n=84), systemic lupus erythematosus (SLE; n=71), DM (n=267), polymyositis (n=45), inclusion body myositis (n=45) and healthy controls (n=38). Results PUF60 was identified as a new autoantigen. Anti-PUF60 antibodies were present in 25/84 (30%) patients with SS, 6/71 (8.5%) patients with SLE and 2/38 (5.0%) control subjects (SS vs controls, p=0.002; SLE vs controls, p=0.711). Anti-PUF60 antibodies were present in 48/267 (18.0%) patients with DM versus 4/45 (8.9%) and 5/45 (11.1%) patients with inclusion body myositis and polymyositis, respectively. The antibody was significantly associated with anti-Ro52 antibodies, rheumatoid factor and hyperglobulinemia in the patients with primary SS. In patients with DM, the antibody was associated with anti-transcription intermediary factor 1 gamma seropositivity and Caucasian race. Conclusions PUF60 represents a novel autoantigen in patients with SS and DM. PUF60 antibodies are associated with distinct clinical features and different immune responses in different diseases.

Reconsidering the Diagnostic and Prognostic Utility of LN-2 for Undifferentiated Pleomorphic Sarcoma and Atypical Fibroxanthoma

Abstract:The topic of distinguishing atypical fibroxanthoma (AFX) from undifferentiated pleomorphic sarcoma (UPS), formerly malignant fibrous histiocytoma, is highly controversial. Although their clinical behavior is disparate, AFX and UPS commonly appear nearly identical on routine histopathologic examination. Although conceptually useful, subcategorization of UPS into superficial (confined to the dermis and subcutaneous tissue) and deep (involvement of fascia and deeper structures) types has not improved our ability to differentiate UPS from AFX. Numerous authors have purported LN-2 (CD74) immunopositivity as able to distinguish UPS from AFX and to predict those rare AFX likely to behave aggressively, although only a single prior study has been dedicated to evaluating this marker. We performed LN-2 staining of 14 AFX, 8 superficial UPS, and 65 deep UPS specimens using an identical protocol as described by prior authors. Of the 73 total UPS specimens, only 1 (1.4%) stained strongly with LN-2, as compared with 3 of 14 (21%) AFX (P = 0.012). One of 2 (50%) clinically aggressive AFX tumors that later exhibited both local recurrence and metastasis stained strongly for LN-2, whereas 2 of 12 (17%) of the more indolent tumors stained strongly with this marker (P = 0.40). Our data do not replicate prior reports of LN-2 as a sensitive and specific marker for UPS, or as indicative of prognosis for AFX, and therefore does not support the use of LN-2 as either a diagnostic or prognostic marker.

Ovoid Palatal Patch in Dermatomyositis: A Novel Finding Associated With Anti-TIF1γ (p155) Antibodies.

Ovoid Palatal Patch in Dermatomyositis: A Novel Finding Associated With Anti-TIF1γ (p155) Antibodies Dermatomyositis (DM) is a heterogeneous disease with a multitude of physical findings and clinical presentations, and patients with anti–transcriptional intermediary factor-1γ (TIF1γ) antibodies have distinct cutaneous features and are also at increased risk for cancer.1 We describe a novel, distinctive patch on the hard palate, which is associated with anti-TIF1γ antibodies that may identify patients at higher risk of cancer.

Basosquamous Carcinoma: Controversy, Advances, and Future Directions.

BACKGROUND Basosquamous carcinoma is a rare cutaneous neoplasm that has caused considerable controversy as to its classification, pathogenesis, and management. OBJECTIVE To review and summarize current literature on the definition, pathogenesis, incidence, and management of basosquamous carcinoma. MATERIALS AND METHODS Through December 2015, an electronic search of the Pubmed database was performed using combinations of basosquamous carcinoma and metatypical basal cell carcinoma as search terms. RESULTS A selection of 39 publications including case reports and series, retrospective studies, and systematic reviews of the literature were included. Descriptions of the definition of basosquamous carcinoma, clinical behavior, histopathological characteristics, current treatment therapies, and future advances are summarized. CONCLUSION This systematic review provides a comprehensive overview of the current understanding of basosquamous carcinoma. Further study is required to elucidate the mechanisms driving the formation of this aggressive tumor.