Faculty Bibliography

OBJECTIVES:While the incidence of cutaneous melanoma has dramatically increased in recent years, oral malignant melanoma (OMM) remains a rare form of noncutaneous melanoma with poor survival. PRAME (PReferentially expressed Antigen in MElanoma) is reported to have diagnostic and some prognostic utility in cutaneous melanomas and some head and neck malignancies. We sought to explore the diagnostic utility of PRAME in OMM. METHODS:A total of ten specimens from eight unique cases of OMM were identified from the Oral Pathology Biopsy Service (OPBS) at University of Washington School of Dentistry between 2005 and 2019. For all cases, standard histology and immunohistochemistry stains were performed, including a stain against PRAME. The diagnoses were reviewed and confirmed by two pathologists. Clinical and epidemiologic features were described. RESULTS:Patient ages ranged from 55 to 82. The group consisted of five males and three females. All eight cases were located on the hard palate. Six cases represented invasive melanoma while two were early melanoma in situ. PRAME immunohistochemistry was successfully performed on seven of eight cases: six were positive (86%), one was negative (14%) and one case lacked sufficient tissue for staining. CONCLUSIONS:Our results suggest that PRAME immunohistochemistry may be useful in the diagnosis of OMM, including early melanoma in situ. Further studies with clinical follow-up and a larger number of cases are needed to explore prognostic value as well as the ability to distinguish between benign, intermediate and malignant melanocytic proliferations of the oral cavity.

Several mutations and gene fusions involved in the mitogen-activated protein kinase (MAPK) pathway have been reported in histiocytic neoplasms including Langerhans cell histiocytosis and non-Langerhans-cell histiocytosis (NLCH). We identified a GAB2::BRAF fusion in a cutaneous lesion from a 22-year-old woman who presented with central diabetes insipidus and red/brown papules on her face, oral mucosa, axilla, and groin. Skin biopsy showed a CD68+, S100-, and CD1a- histiocytic proliferation consistent with NLCH, best clinically classified as xanthoma disseminatum. Next-generation sequencing identified a GAB2::BRAF fusion involving exon 2 of GAB and exon 10 of BRAF. This case implicates a novel fusion in the MAPK signaling pathway, not previously reported in histiocytic neoplasms, as a possible driver of NLCH. Our findings underscore the utility of performing molecular studies on skin biopsy specimens with NLCH to help identify potential targets for therapy.

Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies.

CD4⁺ T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4⁺ T cells infiltrating human melanoma. Conventional CD4⁺ T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13⁺ CD4⁺ T cells in the tumor correlated with the transcriptional states of CD8⁺ T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor-specific CD4⁺ T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.

Dermatology heavily relies on photographs in its literature to depict diseases and demonstrate treatment modalities. Previous studies have established that general medical and dermatology textbooks have limited photographic representation of individuals with skin of color (SOC), even those diseases highly prevalent in these populations. As the US population continues to grow and diversify, there is an increase in individuals with SOC seeking cosmetic and procedural services. We set out to investigate the current trends of SOC representation in the surgical and cosmetic sections of current dermatology textbooks.

Cutaneous ganglioneuromas (GNs) are exceptionally uncommon tumors, and many reported cases describe association with overlying epidermal hyperplasia that may be interpreted as seborrheic keratosis (SK) or SK-like proliferation. We report 5 cases of cutaneous GN in adult patients; all of which were discovered incidentally in the immediate vicinity of epidermal hyperplasia. A review of the literature demonstrates the current-although likely imperfect-understanding of the etiopathogenesis of both SK and GN in the skin. We explore the putative pathophysiologies of other common, well-characterized skin lesions and, taking them into account, provide rationale for the coexistence of cutaneous GN with overlying SK and SK-like epidermal changes. However, we ultimately acknowledge a dilemma of causality and, given the rarity of their co-occurrence, objectively question whether occasional cameo appearances by GN lying subjacent to SK and SK-like hyperplasia may be due merely to chance.

Talimogene laherparepvec (T-VEC) has become an increasingly popular treatment option for surgically non-resectable, recurrent melanoma, usually of cutaneous metastases. The complete response (CR) rate has been reported to be ~20% with a median of ~9 months to achieve it. In real-world practice, decrease of tumor size often occurs rapidly within the first 2-3 months, while improvement of the pigmentation takes several more months. Such clinical observation of lasting pigmentation could be explained by tumorous melanosis-a histopathological term referring to the presence of a melanophage-rich inflammatory infiltrate without remaining viable tumor cells. Herein, we report six patients with metastatic cutaneous melanoma who were treated with T-VEC. Biopsies were performed after observing clinical responses in the injected tumors. Pathological evaluation demonstrated non-viable or absent tumor tissue with tumorous melanosis in all cases. To accurately assess response to therapy and potentially decrease unnecessary additional T-VEC treatments, serial biopsy of 'stable' lesions should be considered to assess the presence or absence of viable tumor.

Melanoma is a deadly skin cancer with rapidly increasing incidence worldwide. The discovery of the genetic drivers of melanomagenesis in the last decade has led the World Health Organization to reclassify melanoma subtypes by their molecular pathways rather than traditional clinical and histopathologic features. Despite this significant advance, the genomic and transcriptomic drivers of metastatic progression are less well characterized. This review describes the known molecular pathways of cutaneous and uveal melanoma progression, highlights recently identified pathways and mediators of metastasis, and touches on the influence of the tumor microenvironment on metastatic progression and treatment resistance. While targeted therapies and immune checkpoint blockade have significantly aided in the treatment of advanced disease, acquired drug resistance remains an unfortunately common problem, and there is still a great need to identify potential prognostic markers and novel therapeutic targets to aid in such cases.