Faculty Bibliography

INTRODUCTION/UNASSIGNED:Quantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. METHODS/UNASSIGNED:We established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. RESULTS/UNASSIGNED:Here we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. DISCUSSION/UNASSIGNED:We describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

Immune-mediated regression of melanocytic neoplasms is predominantly lymphocytic, driven by CD8+ anti-tumoral T-cells and, rarely, natural killer cells. Histopathologic features of regression include effacement of the epidermis, replacement of tumor cells by a fibrotic stroma, varying degrees of chronic inflammation (usually lymphocytes) and melanophages, as well as vascular ectasia and angioplasia. The understanding of regression and the complex immune response in melanoma has led to the development of targeted immunotherapy in melanoma. Here, we report a case of near-complete regression of a melanocytic neoplasm associated with neutrophilic and eosinophilic inflammation, suggesting a non-traditional pathway of regression that has yet to be explored.

BACKGROUND:Ongoing controversy exists regarding terminology used to describe atypical melanocytic nevi. Efforts to standardize nomenclature, including the 1992 NIH consensus conference, have been largely unsuccessful. Significant advances have revealed an increasingly detailed genetic picture of melanocytic neoplasms, including strong evidence for the existence of those with "intermediate" behavior. METHODS:We sent an electronic survey to dermatopathologists (n=846) to assess trends in nomenclature usage and attitudes toward developing new consensus nomenclature for atypical melanocytic nevi. RESULTS:There were 229 complete responses (27.1% response rate). The most used/preferred nomenclature was "dysplastic nevus" (43%/39%, respectively), followed by the NIH-recommended terminology (28%/26%). Three-tier grading systems were most heavily used/preferred (79%/63%). Dermatopathologists based in New England were most likely to use the NIH terminology, whereas "dysplastic nevus" or 'other' were most used elsewhere (p=0.029). Most (76%) expressed at least "moderate" enthusiasm for developing consensus nomenclature, with 47% "very" or "extremely" enthusiastic. CONCLUSION/CONCLUSIONS:Little has changed with the wide variation in terminology for atypical melanocytic nevi. There continues to be no one dominant terminology in use. However, there is enthusiasm for standardization. A new attempt at updated consensus nomenclature may be fruitful.