Kristopher McKay

Shh and p50/Bcl3 signaling crosstalk drives pathogenesis of BCCs in Gorlin syndrome

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder that is due, in large measure, to aberrant Shh signaling driven by mutations in the tumor suppressor gene Ptch1. Here, we describe the development of Ptch1+/−/SKH-1 mice as a novel model of this disease. These animals manifest many features of NBCCS, including developmental anomalies and are remarkably sensitive to both ultraviolet (UVB) and ionizing radiation that drive the development of multiple BCCs. Just as in patients with NBCCS, Ptch1+/−/SKH-1 also spontaneously develops BCCs and other neoplasms such as rhabdomyomas/rhabdomyosarcomas. Administration of smoothened inhibitors (vismodegib/itraconazole/cyclopamine) or non-steroidal anti-inflammatory drug (sulindac/sulfasalazine) each result in partial resolution of BCCs in these animals. However, combined administration of these agents inhibits the growth of UVB-induced BCCs by >90%. Employing small molecule- and decoy-peptide-based approaches we further affirm that complete remission of BCCs could only be achieved by combined inhibition of p50-NFκB/Bcl3 and Shh signaling. We posit that Ptch1+/−/SKH-1 mice are a novel and relevant animal model for NBCCS. Understanding mechanisms that govern genetic predisposition to BCCs should facilitate our ability to identify and treat NBCCS gene carriers, including those at risk for sporadic BCCs while accelerating development of novel therapeutic modalities for these patients.

A Histological Snapshot of Hypothetical Multistep Progression From Nevus Sebaceus to Invasive Syringocystadenocarcinoma Papilliferum.

Syringocystadenocarcinoma papilliferum (SCACP) is an extremely rare adnexal neoplasm, believed to arise in a preexisting nevus sebaceus of Jadassohn (NSJ) through a multistep progression process. This hypothetical process involves an NSJ giving rise to syringocystadenoma papilliferum, which then presumably undergoes malignant transformation in rare circumstances to give rise to SCACP in situ, which finally progresses to an invasive SCACP. Of the 30 SCACP cases reported so far, none have documented the process from a birthmark to the final invasive lesion, with histological evidence of each step, in a single tumor. Here, the authors report just such a case. A 74-year-old man presented with a recently enlarging birthmark on the scalp. Excisional biopsy showed an invasive SCACP, in the background of SCACP in situ, syringocystadenoma papilliferum, and NSJ. Furthermore, this tumor showed a concurrent pigmented trichoblastoma and histological evidence of lymphovascular invasion, events that have not been documented with SCACP. Interestingly, all these component lesions were present on a single histological section of this solitary tumor. Regional lymph node metastasis, a rare occurrence in SCACP, was also present in this remarkable case. The authors discuss the implications of these findings in light of the review of relevant literature.

A murine model for the development of melanocytic nevi and their progression to melanoma

Acquired melanocytic nevi are commonly found in sun exposed and unexposed human skin, but the potential for their transformation into invasive melanoma is not clear. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Nevi develop due to DNA damage initiated by dimethylbenz(a) anthracene (DMBA) followed by chronic promotion with 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA). Dysplastic pigmented skin lesions appeared in 7–9 wk with 100% penetrance. Nests of melanocytic cells appeared in a subset of skin draining lymph nodes (dLN) by 25 wk, but not in age matched controls. Immunohistochemistry, real‐time PCR, and flow cytometric analyses confirmed their melanocytic origin. Transformed cells were present in a subset of nevi and dLNs, which exhibited anchorage‐independent growth, tumor development, and metastasis in nude mice. Approximately 50% of the cell lines contained H‐Ras mutations and lost tumor suppressor p16Ink4a expression. While most studies of melanoma focus on tumor progression in transgenic mouse models where the mutations are present from birth, our model permits investigation of acquired mutations at the earliest stages of nevus initiation and promotion of nevus cell transformation. This robust nevus/melanoma model may prove useful for identifying genetic loci associated with nevus formation, novel oncogenic pathways, tumor targets for immune‐prevention, screening therapeutics, and elucidating mechanisms of immune surveillance and immune evasion.

IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations

In animal models, IL-12 and IL-23 participate in the development of malignant neoplasms of keratinocytes. However, the role of these cytokines in pigmented lesion development and their progression to melanoma has received little attention. IL-12p35, IL-23p19, and IL-12/IL-23p40 knockout mice on a C3H/HeN background, subjected to a melanomagenesis protocol, demonstrated profound differences in susceptibility to nevus initiation, transformation, tumorigenicity, and metastatic potential. IL-23 was found to be essential for melanocyte homeostasis, whereas IL-12 supported nevus development. A direct action of IL-23 on primary melanocytes, shown to be IL-23R+, demonstrated that DNA repair of damaged melanocytes requires IL-23. Furthermore, IL-23 modulated the cutaneous microenvironment by limiting regulatory T cells and IFN-γ and inhibiting IL-10 production. Neutralizing Ab to IFN-γ, but not IL-17, inhibited nevus development (p < 0.01).

CD123 immunohistochemistry for plasmacytoid dendritic cells is useful in the diagnosis of scarring alopecia.

Distinguishing types of lymphocytic scarring alopecia is often difficult because of the overlapping features. Recently, the presence of plasmacytoid dendritic cells (PDCs) in cutaneous lupus erythematosus (LE) was demonstrated and further shown to help distinguish lupus from other dermatoses.1‐6 This study aims to determine if the presence and distribution of PDCs can aid in the diagnosis of scarring alopecia.

Transepithelial elimination in sarcoidosis: a frequent finding

Transepithelial elimination is a process by which dermal materials are expelled through an active epithelial‐dermal connective tissue interaction. It has been described as a regular or sporadic occurrence in a variety of dermatologic conditions, including sarcoidosis.

Leishmaniasis Panamensis Masquerading as Myiasis and Sporotrichosis: A Clinical Pitfall

We report a case of cutaneous leishmaniasis panamensis in nonendemic Costa Rica. A 19-year-old female presented with nonhealing, unilateral eruption of erythematous papules with superficial central ulceration in a sporotrichoid pattern on right upper arm and back. Given the clinical picture and geographic locale, the patient was initially diagnosed with myiasis or human botfly infestation; however, the sporotrichoid pattern of the bites is an unlikely finding in myiasis. Peripheral blood smear, Giemsa stain, and polymerase chain reaction (PCR) were consistent for Leishmania spp. Ulceration resolved with 20-day course of IV sodium stibogluconate.

Spirochete immunostaining is not just for syphilis: diagnostic utility in borreliosis

To the Editor , The most common borreliosis and vector borne disease in North America, Europe and Asia is Lyme borreliosis, caused by Borrelia burgdorferi. The diagnosis of Lyme borreliosis relies on identification of typical clinical signs and symptoms, e.g. erythema migrans, a history of possible exposure to infected ticks and standardized laboratory tests. A 50-year-old male presented to our center with a 2-day history of a pruritic eruption on his arms that had been preceded by a week of low-grade fever and fatigue. The patient denied headaches, visual changes, sore throat, arthralgias, abdominal pain, dysuria or neurological symptoms. He worked as a veterinarian with large and small animals and had been hiking in the woods the previous week. Physical examination revealed three annular, deeply erythematous plaques with dusky centers localized on the right dorsal hand, right forearm and left forearm (Fig. 1). No enlarged lymph nodes were noted. A complete blood count (CBC) showed normal white blood cell count and thrombocytopenia. C-reactive protein (CRP) was 37.29 mg/l (ref.: <10.90 mg/l), erythrocyte sedimentation rate (ESR) was 26 (ref.: <10) and rheumatoid factor was positive. Q-fever IgG and IgM, Brucella IgG and IgM, as well as blood and wound cultures were negative. Treponemal and non-treponemal tests, Lyme antibody screening (enzyme immunoassay) and whole blood polymerase chain reaction (PCR) for B. burgdorferi DNA were negative. Biopsies showed a superficial and deep interstitial mixed infiltrate accompanied by dermal papillary edema, interface activity A

Epidermolysis bullosa nevus in a patient with recessive dystrophic epidermolysis bullosa: a case report.

We present a case of a 6-year-old girl with recessive dystrophic epidermolysis bullosa (EB) who presented with a large pigmented lesion clinically concerning for melanoma. After histological examination and fluorescent in situ hybridization analysis, diagnosis of EB nevus was performed. EB nevi are benign melanocytic neoplasms with histological findings similar to recurrent nevi occurring in all types of EB. They often mimic melanoma clinically, dermatoscopically, and histopathologically. The ability to recognize an EB nevus is essential for appropriate management of the patient. Unnecessary surgical excision in patients with already high-risk EB should be avoided. Close monitoring of these lesions is recommended because no cases of transformation to melanoma have been described.