Evan C. Jones

Periocular cutaneous malignancies: a review of the literature.

Background The periocular skin is susceptible to numerous benign and malignant neoplasms. Periocular malignancies may present differently, behave more aggressively, and pose greater challenges for treatment and repair than malignancies at other cutaneous sites. Between 5% and 10% of cutaneous malignancies occur periorbitally, with basal cell carcinoma reported as the most common malignant periocular tumor, followed by squamous cell carcinoma, sebaceous gland carcinoma, cutaneous melanoma, Merkel cell carcinoma, and other rare tumors. Objective To review the current literature on cutaneous malignancies of the periocular region pertaining to etiology, incidence, clinical presentation, differential diagnosis, complications, and treatment options. Materials and methods An extensive literature review was conducted using PubMed, searching for articles on periocular and periorbital cutaneous malignancies. Conclusions Timely diagnosis and management of periocular malignancies is essential because of their proximity to and potential to invade vital structures such as the orbit, sinuses, and brain. Surgical excision remains the standard of care for the majority of periorbital malignancies, but given the sensitive anatomic location, tissue‐sparing techniques with margin control such as Mohs micrographic surgery are the preferred method for most nonmelanoma skin cancers. Depending on tumor type, other treatment modalities may include radiation, chemotherapy, cryosurgery, topical medications, and photodynamic therapy.

Periocular Squamous Cell Carcinoma

BACKGROUND We present a case report of periocular squamous cell carcinoma and a review of the literature with emphasis on early diagnosis, proper follow-up and management, reconstructive options, and new immunomodulatory therapies. OBJECTIVE The objective is to guide the dermatologist and the dermatologic surgeon in proper management and continued care of patients with periocular squamous cell carcinoma in light of its propensity for perineural involvement and regional lymphatic metastases. MATERIALS AND METHODS A MEDLINE, Ovid, and PubMed search was conducted for recent relevant articles pertaining to “periocular,” “periorbital,” “squamous cell” carcinoma, and their “surgery” “treatment” modalities. CONCLUSIONS Periocular squamous cell carcinoma is an aggressive tumor, characterized by perineural involvement and an overall rate of regional lymph node metastases reported to range from 10% to as high as 20% to 25%. Increased vigilance must be undertaken when treating these high-risk tumors. Mohs micrographic surgery or excision with frozen section analysis is the standard of care for periocular squamous cell carcinoma. Multiple options exist for the reconstruction of the postoperative defect that allow for excellent function and cosmesis. Finally, research into new immunomodulators will hopefully lead to an increased understanding of the aggressive nature of periocular squamous cell carcinoma and potential aid in the treatment of the tumor.

Loss of primary cilia in melanoma cells is likely independent of proliferation and cell cycle progression.

Elizabeth R. Snedecor1,3,9, Clifford Sung1,4,9, Alejandra Moncayo1,5, Brooke E. Rothstein1,6, Daniel C. Mockler1, Marcia G. Tonnesen2,8, Evan C. Jones2, Mayumi Fujita7, Richard A. Clark2,5, Kenneth R. Shroyer1, and Jiang Chen1,2 1Department of Pathology, Stony Brook University, Stony Brook, NY 11794 2Department of Dermatology, Stony Brook University, Stony Brook, NY 11794 3Program in Genetics, Stony Brook University, Stony Brook, NY 11794 4School of Medicine, Stony Brook University, Stony Brook, NY 11794 5Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794 6School of Medicine, Tufts University, Boston, MA 02111 7Department of Dermatology, University of Colorado Denver, Aurora, CO 80045 8Dermatology Section, Northport VA Medical Center, Northport, NY 11768

INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma

Inturned (INTU), a cilia and planar polarity effector, performs prominent ciliogenic functions during morphogenesis, such as in the skin. INTU is expressed in adult tissues but its role in tissue maintenance is unknown. Here, we report that the expression of the INTU gene is aberrantly elevated in human basal cell carcinoma (BCC), coinciding with increased primary cilia formation and activated hedgehog (Hh) signaling. Disrupting Intu in an oncogenic mutant Smo (SmoM2)-driven BCC mouse model prevented the formation of BCC through suppressing primary cilia formation and Hh signaling, suggesting that Intu performs a permissive role during BCC formation. INTU is essential for intraflagellar transport A complex assembly during ciliogenesis. To further determine whether Intu is directly involved in the activation of Hh signaling downstream of ciliogenesis, we examined the Hh signaling pathway in mouse embryonic fibroblasts, which readily responds to the Hh pathway activation. Depleting Intu blocked Smo agonist-induced Hh pathway activation, whereas the expression of Gli2ΔN, a constitutively active Gli2, restored Hh pathway activation in Intu-deficient cells, suggesting that INTU functions upstream of Gli2 activation. In contrast, overexpressing Intu did not promote ciliogenesis or Hh signaling. Taken together, data obtained from this study suggest that INTU is indispensable during BCC tumorigenesis and that its aberrant upregulation is likely a prerequisite for primary cilia formation during Hh-dependent tumorigenesis.

Gorab Is Required for Dermal Condensate Cells to Respond to Hedgehog Signals during Hair Follicle Morphogenesis

GORAB is a golgin that localizes predominantly at the Golgi apparatus and physically interacts with small GTPases. GORAB is ubiquitously expressed in mammalian tissues, including the skin. However, the biological function of this golgin in skin is unknown. Here, we report that disrupting the expression of the Gorab gene in mice results in hair follicle morphogenesis defects that were characterized by impaired follicular keratinocyte differentiation. This hair follicle phenotype was associated with markedly suppressed hedgehog (Hh) signaling pathway in dermal condensates in vivo. Gorab-deficient dermal mesenchymal cells also displayed significantly reduced capability to respond to Hh pathway activation in vitro. Furthermore, we found that the formation of primary cilium, a cellular organelle that is essential for the Hh pathway, was impaired in mutant dermal papilla cells, suggesting that Gorab may be required for the Hh pathway through facilitating the formation of primary cilia. Thus, data obtained from this study provided insight onto the biological functions of Gorab during embryonic morphogenesis of skin in which Hh signaling and primary cilia exert important functions.

Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by Maintaining the Homeostasis of Hair Follicle Stem Cells

Summary Ceramides and their metabolites are important for the homeostasis of the epidermis, but much remains unknown about the roles of specific pathways of ceramide metabolism in skin biology. With a mouse model deficient in the alkaline ceramidase (Acer1) gene, we demonstrate that ACER1 plays a key role in the homeostasis of the epidermis and its appendages by controlling the metabolism of ceramides. Loss of Acer1 elevated the levels of various ceramides and sphingoid bases in the skin and caused progressive hair loss in mice. Mechanistic studies revealed that loss of Acer1 widened follicular infundibulum and caused progressive loss of hair follicle stem cells (HFSCs) due to reduced survival and stemness. These results suggest that ACER1 plays a key role in maintaining the homeostasis of HFSCs, and thereby the hair follicle structure and function, by regulating the metabolism of ceramides in the epidermis.

Correction of Hair Shaft Defects through Allele-Specific Silencing of Mutant Krt75

Dominant mutations in keratin genes can cause a number of inheritable skin disorders characterized by intraepidermal blistering, epidermal hyperkeratosis, or abnormalities in skin appendages, such as nail plate dystrophy and structural defects in hair. Allele-specific silencing of mutant keratins through RNA interference is a promising therapeutic approach for suppressing the expression of mutant keratins and related phenotypes in the epidermis. However, its effectiveness on skin appendages remains to be confirmed in vivo. In this study, we developed allele specific siRNAs capable of selectively suppressing the expression of a mutant Krt75, which causes hair shaft structural defects characterized by the development of blebs along the hair shaft in mice. Hair regenerated from epidermal keratinocyte progenitor cells isolated from mutant Krt75 mouse models reproduced the blebbing phenotype when grafted in vivo. In contrast, mutant cells manipulated with a lentiviral vector expressing mutant Krt75-specific shRNA persistently suppressed this phenotype. The phenotypic correction was associated with significant reduction of mutant Krt75 mRNA in the skin grafts. Thus, data obtained from this study demonstrated the feasibility of utilizing RNA interference to achieve durable correction of hair structural phenotypes through allele-specific silencing of the mutant keratin genes.

Acral Petechiae and Purpuric Plaques in a 3-Year-Old Girl—Quiz Case

An 82-year-old woman presented with a 3-month history of an asymptomatic growth on the left posterior shoulder. She denied trauma, tenderness, bleeding, or pruritus associated with the lesion. The patient had a history of a nodular basal cell carcinoma on the nasal tip and had undergone cutaneous micrographic surgery in 2001 and excision of a keratoacanthoma on the left wrist in 2004. The physical examination revealed an 8 6-mm smooth, skin-colored, dome-shaped papule on the left posterior shoulder (Figure 1). A shave biopsy was performed (Figure 2 and Figure 3). What is your diagnosis?