Breast Cancer-Related Lymphedema Results in Impaired Epidermal Differentiation and Tight Junction Dysfunction.

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of FLG and the tight junction protein ZO-1 in skin affected by moderate lymphedema or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to those in the controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that similar to the clinical scenario, the expression of skin barrier proteins was decreased relative to that in normal skin and that colonization with Staphylococcus epidermidis bacteria amplified this effect as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

Lack of Racial Diversity in Surgery and Pathology Textbooks Depicting Diseases of the Breast.

INTRODUCTION: The lack of racial diversity depicted in medical education texts may contribute to an implicit racial bias among clinicians. This bias influences outcomes, as familiarity with the various cutaneous manifestations of disease is essential to making an accurate diagnosis. To better understand the racial disparities in breast surgery, we sought to determine the extent of skin tone representation depicted in images of breast surgery and pathology textbooks. METHODS: Textbooks were screened for color images of conditions with sufficient skin tissue present to assign the Fitzpatrick skin phototype (FSP). Figures were independently assigned an FP score (range: 1-6), and subdivided into "light skin" (FP 1-3) and "dark skin" (FP 4-6). Number of figures in each category and percentage of patients with each skin tone were calculated. RESULTS: 557 figures were included. Among 12 textbooks reviewed, seven textbooks were from the discipline of surgery, while five were pathology-related. Textbook year of publication spanned from 1996 to 2018. Overall, 533 (95.7%) figures depicted patients with light skin color versus 24 (4.3%) with dark skin color. There was no association between FP score and year of textbook publication (P = 0.69). CONCLUSIONS: Patient images in breast textbooks are overwhelmingly of light skin tones, excluding patients with darker skin tones. The dearth of images depicting dark skinned individuals did not improve over time. Inclusion of patients of color in future textbooks may help reduce racial disparities within breast cancer care.

Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease.

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.