Tools that reduce the number of surgical biopsies performed on benign skin lesions have the potential to improve patient care. The non-invasive pigmented lesion assay (PLA) gene expression test is such a tool. It helps rule out melanoma and the need for surgical biopsies of atypical pigmented skin lesions with a NPV >99%. Analyses of ∼15,000 PLA samples in the real-world routine use setting of over 600 US dermatology offices demonstrated that 87% were PLA(-). A real-world utility study in 381 cases demonstrated that 99% of PLA(-) cases were monitored, while all PLA(+) cases were surgically biopsied demonstrating that clinicians follow the guidance of the test. With efforts to validate the PLA beyond histopathology, we found that we can identify somatic mutations in three genes known to be drivers of melanoma development (BRAF, NRAS and the TERT promoter) in PLA samples. Mutations in adhesive patch PLA samples were concordant with mutations in biopsies. The frequency of mutations in melanoma samples was 77% and statistically higher than the 14% found in non-melanoma samples (p<0.0001). TERT promoter mutations were the most prevalent mutation type in PLA(+) melanomas (79%). Eighty-six percent of non-melanomas had no mutations and 97% of histopathologically confirmed melanomas were PLA and/or mutation positive (n=103). Mutation frequencies were similar in 519 additional prospectively collected real-world PLA samples, with 88% of PLA(-) samples having no mutations. Combining gene expression and mutation analyses enhances the ability to non-invasively detect early melanoma.

Several polyomaviruses, including Human Polyomavirus 6 (HPyV6) and Human Polyomavirus 7 (HPyV7), are shed chronically from human skin. HPyV6 has been detected in the lymph node of a patient with Angiolymphoid Hyperplasia with Eosinophilia (ALHE), and HPyV7 has been strongly linked to a pruritic skin eruption with a characteristic histology in two immunosuppressed transplant recipients. We screened skin biopsies—14 cases of ALHE and 6 cases of pruritic eruptions showing "peacock plumage" on histology—by PCR for human polyomaviruses. Low levels of HPyV6 or 7 DNA were detected in several cases of ALHE, but neither virus could be detected by immunohistochemistry (IHC). Interestingly, several pruritic and dyskeratotic dermatoses were strongly positive for HPyV 6 or 7 by PCR. These cases were further analyzed by IHC, electron microscopy (EM), immunofluorescence, quantitative PCR, and sequencing. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 infected keratinocytes. High viral copy number in lesional skin, the expression of viral proteins by IHC in dyskeratotic keratinocytes, and the identification of intact virions by EM and sequencing support a role for active viral infections in these skin diseases. In conclusion, we report that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a unique histologic pattern and describe these entities as "HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses (H6PD and H7PD)."

G has been deeply intrigued with the relationship between skin and microbes for many years, and the perspective that drew him in from the start became the overarching framework for his expanding body of research. “I became fascinated with our ability to survive in dangerous environments,” he recalls. “There are literally billions of pathogens on the earth, and the skin is very frequently damaged and broken. Yet relatively few of the organisms in our environment have any potential to be skin pathogens, and the ability of a microbe to cause an infection is an infrequent event. So,” he continues, “I’ve always been more interested in understanding why we are healthy than why we are sick. I believe that a better understanding of how we maintain our health will improve our ability to control and improve it.” Gallo first documented the presence of antimicrobial peptides in the skin. They had been found in the gut, and he was convinced they also formed part of the skin’s innate immune system. He found the cathelicidins about 20 years ago, then provided he clinical and economic burdens caused by wounds—those that heal with impairing scars and those that heal slowly or not at all—are substantial, global, and continue to grow (see box on page 8). Strides in delineating the myriad molecular factors involved in normal and pathological tissue repair have not translated to significant advances in patient care. Despite the use of multimodality regimens to treat hypertrophic scar formation—including corticosteroid injections, laser and radiation therapies, and scar revision surgeries—outcomes remain poor. And chronic wounds remain notoriously challenging.

This chapter reviews the most frequently seen deep fungal infections in the human immunodeficiency virus (HIV)-infected popu­lation, and highlights their significance in light of their accompanying high mortality rates in the immunocompromised population. Cryptococcus neoformans, an encapsulated yeast-like fungus, is the second most common opportunistic fungal infection in HIV-positive patients with Candida albicans being the most common. The most common presentation of cutaneous cryptococcosis is umbilicated flesh-colored papules or nodules that are similar in appearance to lesions of molluscum contagiosum. Infection withC. neoformans occurs via inhalation of small diameter organisms which go on to enter the respiratory passages.C. neoformans infection is diagnosed by culturing the organism from clinical specimens or by organism visualization on histopathologic exam. Diagnosis of histoplasmosis can be established via culture, fungal stain, antigen detection, or serologic testing for antibodies. Definitive diagnosis can be established if the organism is isolated from a clinical specimen.