Elaine S. Gilmore

A Distinct Entity in the Spectrum of the Cd30+ Cutaneous Lymphoproliferative Diseases: Oligolesional Nodules With Pseudoepitheliomatous Hyperplasia Followed by Spontaneous Resolution

Pseudoepitheliomatous hyperplasia (PEH) in biopsies of CD30+ anaplastic large-cell lymphoma (ALCL) is present infrequently and is of unknown prognostic value and significance. Our goal was to review the clinicopathologic features of cases of ALCL with PEH, study their course, and review the literature on the subject. Biopsy specimens of all cases of CD30+ lymphoproliferative disorders (59) were retrieved from the files of Yale Dermatopathology Laboratory over a 17-year period and reviewed. We identified 4 cases of ALCL (7%) exhibiting prominent PEH. All 4 patients presented with 1 or 2 nodules. In 2 patients, the lesions spontaneously regressed within a few months after initial diagnosis. One patient chose to have an excision in which only a small number of CD30+ cells were present. We were unable to obtain follow-up for the fourth patient. In the spectrum of CD30+ lymphoproliferative disorders, cases of ALCL with PEH are infrequent. In addition to the 4 cases described here, in our review of the literature we found 35 cases of ALCL with PEH. Most of these patients present with 1 or a few lesions. In the majority of these cases, the lesions started showing evidence of clinical spontaneous regression and even complete resolution within a few months of initial diagnosis. The clinicopathologic correlation between ALCL and PEH has not been emphasized. Because most of these cases follow a relatively benign clinical course, we recommend a more conservative approach in the clinical management of these patients.

Prevalence and characterization of pruritus in epidermolysis bullosa.

Qualitative data suggest that pruritus is a burdensome symptom in patients with epidermolysis bullosa (EB), but the prevalence of pruritus in children and adults with EB and factors that contribute to pruritus are unknown. The objective of the current study was to quantitatively identify and to characterize pruritus that EB patients experience using a comprehensive online questionnaire. A questionnaire was developed to evaluate pruritus in all ages and all types of EB. Questions that characterize pruritus were included and factors that aggravate symptoms were investigated. Patients from seven North American EB centers were invited to participate. One hundred forty‐six of 216 questionnaires were completed (response rate 68%; 73 male, 73 female; median age 20.0 years). Using a 5‐point Likert scale (1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = always), itchiness was the most bothersome EB complication (mean 3.3). The average daily frequency of pruritus increased with self‐reported EB severity. Pruritus was most frequent at bedtime (mean 3.8) and interfered with sleep. Factors that aggravated pruritus included healing wounds, dry skin, infected wounds, stress, heat, dryness, and humidity. Pruritus is common in individuals with EB and can be bothersome. Future studies will need to investigate the most effective treatments given to individuals with EB for pruritus.

PKK Suppresses Tumor Growth and Is Decreased in Squamous Cell Carcinoma of the Skin

Non-melanoma skin cancer (NMSC) represents the most common cancer in the United States. Squamous cell carcinoma (SCC) of the skin is a sub-type of NMSC that shows a greater potential for invasion and metastasis. The current study identifies the Protein Kinase C-associated Kinase (PKK), which is also known as the Receptor-Interacting Protein Kinase 4 (RIPK4), as a suppressor of tumor growth in SCC of the skin. We show that expression of PKK is decreased in human SCC of the skin compared to normal skin. Further, suppression of PKK in human keratinocytes leads to increased cell proliferation. Use of RNA interference to reduce PKK expression in keratinocytes leads to an increase in S phase and in proteins that promote cell cycle progression. Consistent with the results obtained from cell culture, there is a dramatic increased tumorigenesis after PKK knockdown in a xenotransplant model and in soft agar assays. The loss of tumor suppression involves the NF-κB and p63 pathways. NF-κB is inhibited through inhibition of IKK function and there is increased nuclear TP63 activity after PKK knockdown. This study opens new avenues both in the discovery of disease pathogenesis and for potential treatments.

Evaluation of Treatments for Pruritus in Epidermolysis Bullosa

Pruritus is a common complication in patients with epidermolysis bullosa (EB). There is limited published data about the treatments that individuals with EB use for pruritus. The objective of the current study was to determine quantitatively which treatments individuals with EB have used for pruritus and to evaluate the perceived effectiveness of these treatments in pruritus relief. A questionnaire was developed to evaluate the treatments and therapies used for pruritus in patients of all ages and for all types of EB. Questions about bathing products, moisturizers, topical products, oral medications, dressings, and alternative therapies were included. A 5‐point Likert scale (−2 = relieves itch a lot, −1 = relieves itch a little, 0 = no change, 1 = increases itch a little, 2 = increases itch a lot) was used to evaluate perceived effectiveness. Patients from seven North American EB centers were invited to participate. Greasy ointments (53.4%), lotions (45.2%), creams (40.4%), and oral hydroxyzine (39.0%) were the most frequently used treatments for pruritus. Treatments that were used frequently and perceived to be the most effective included creams (mean = −1.1), topical prescription corticosteroids (mean = −1.0), oils (mean = −0.9), oral hydroxyzine (mean = −0.9), topical diphenhydramine (mean = −0.9), and vaporizing rub (menthol, camphor, eucalyptus) (mean = −0.9). Systemic opioids (mean = 0.3), adherent bandages (mean = 0.3), and bleach baths (mean = 0.2) slightly increased pruritus. Randomized controlled trials of therapies will be necessary to develop evidence‐based recommendations for control of pruritus in individuals with EB.

Headaches as a Presenting Symptom of Linear Morphea en Coup de Sabre

Linear morphea en coup de sabre (ECDS) is a form of localized scleroderma that predominantly affects the pediatric population, with a median age of 10 years at presentation. The existence of neurologic findings in association with ECDS has been well described in the literature. Here we describe 4 patients with ECDS who presented with headaches, which were typical migraines in 3 of the patients. The headaches preceded the onset of cutaneous findings by at least 6 months. Our patients’ cases emphasize both the importance of recognizing headaches as a harbinger of ECDS and the necessity of performing thorough cutaneous examination in patients with unexplained headaches or other neurologic disease.

PKK deletion in basal keratinocytes promotes tumorigenesis after chemical carcinogenesis

Squamous cell carcinoma (SCC) of the skin is a keratinocyte malignancy characterized by tumors presenting on sun-exposed areas with surgery being the mainstay treatment. Despite advances in targeted therapy in other skin cancers, such as basal cell carcinoma and melanoma, there have been no such advances in the treatment of SCC. This is partly due to an incomplete knowledge of the pathogenesis of SCC. We have recently identified a protein kinase C-associated kinase (PKK) as a potential tumor suppressor in SCC. We now describe a novel conditional PKK knockout mouse model, which demonstrates that PKK deficiency promotes SCC formation during chemically induced tumorigenesis. Our results further support that PKK functions as a tumor suppressor in skin keratinocytes and is important in the pathogenesis of SCC of the skin. We further define the interactions of keratinocyte PKK with TP63 and NF-κB signaling, highlighting the importance of this protein as a tumor suppressor in SCC development.

Squamous cell carcinoma with osteoclast-like giant cells: a morphologically heterologous group including carcinosarcoma and squamous cell carcinoma with stromal changes.

Cutaneous squamous cell carcinoma (SCC) with osteoclast‐like giant cells (hereafter, osteoclastic cells) is very rare; eight cases have been reported since 2006. Whether the osteoclastic cells represents a reactive or neoplastic change remains a matter of debate. Osteoclastic cells are often observed in the sarcomatous component of cutaneous carcinosarcoma. SCC with osteoclastic cells is a heterogeneous condition that includes SCC with stromal changes containing osteoclastic cells (also known as osteoclast‐like giant cell reaction) and carcinosarcoma. In some cases, SCC with an associated osteoclast‐like giant cell reaction has been differentiated from carcinosarcoma based on the degree of cytologic atypia in non‐epithelial components. We summarized the clinical and histopathologic characteristics of 11 patients of SCC with osteoclastic cells, including our two cases of SCC with an osteoclast‐like giant cell reaction and one case of carcinosarcoma. The affected patients were old and more likely to be male (64%). Seven cases (64%) were in the head and neck. Moreover, multiple features of high risk SCC were observed, such as a tumor size greater than 2 cm (56%), moderate or poor differentiation (100%), recurrence (33%) and nodal metastasis (17%) after excision and immunosuppression (27%). Interestingly, half of the previously reported cases of SCC with osteoclastic giant cell reaction had histopathologic findings that were overlapping with those of carcinosarcoma.

Chronic social stress Ameliorates psoriasiform dermatitis through upregulation of the Hypothalamic-Pituitary-Adrenal axis

Acute stress is a physiological response of an organism to adverse conditions, contributing to survival; however, persistence through time may lead to disease. Indeed, exacerbation of inflammatory conditions such as psoriasis has been reported to follow stressors in susceptible patients. Because chronic stress cannot ethically be elicited in patients under controlled laboratory conditions, we studied genetically modified mice that naturally develop psoriasiform dermatitis, and subjected them to an ethological chronic social contact stress paradigm. Although we found elevated pro-inflammatory neuropeptide production of substance P (SP), calcitonin-gene-related peptide (CGRP) and nerve-growth factor (NGF) mRNA in the dorsal root ganglia (DRG) as well as pro-inflammatory cytokines in response to the social stressor, stress paradoxically prevented the development of the skin lesions. This effect of stress could be reversed by the treatment with glucocorticoid (GC) receptor blockers, suggesting that it was mediated through the upregulation of corticosterone secretion. Extrapolating to humans, the worsening of disease in susceptible patients with psoriasis could be attributed to a defect in the Hypothalamic-Pituitary-Adrenal (HPA) axis with an impaired production of GC during situations of adversity, thus rendering them unable to counteract the pro-inflammatory effects of chronic stressors.