Lymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases, including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus (SCS) have an unanticipated function in scavenging of modified low-density lipoprotein (LDL) and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new, to our knowledge, insights into the diversity of LECs in murine LNs and a rich resource for future studies into the regulation of immune responses by LN LECs.

Tumor-associated lymphatic vessels play an important role in tumor progression, mediating lymphatic dissemination of malignant cells to tumor-draining lymph nodes and regulating tumor immunity. An early, necessary step in the lymphatic metastasis cascade is the invasion of lymphatic vessels by tumor cell clusters or single tumor cells. In this review, we discuss our current understanding of the underlying cellular and molecular mechanisms, which include tumor-specific as well as normal, developmental and immunological processes “hijacked” by tumor cells to gain access to the lymphatic system. Furthermore, we summarize the prognostic value of lymphatic invasion, discuss its relationship with local recurrence, lymph node and distant metastasis, and highlight potential therapeutic options and challenges.

A 69-year-old Japanese woman with multiple brain metastases secondary to non-small-cell lung cancer was treated with radiosurgery, and subsequently started oral gefitinib. Three years later, she presented with erythematous erosive alopecia with pustules on the scalp. A biopsy specimen showed a dense perifollicular infiltration composed of lymphocytes, neutrophils and abundant plasma cells. Methicillin-resistant Staphylococcus aureus was cultured from the lesions; however, treatment with antibiotics was not effective. We diagnosed an eruption resembling erosive pustular dermatosis of the scalp. Although oral steroids did not improve the lesions, the pustules and erythema of the scalp rapidly improved within a few weeks after discontinuation of gefitinib. There have been only 11 case reports of alopecia associated with epidermal growth factor receptor (EGFR) inhibitors including our case. It is noteworthy that all cases were female, and most cases involved the parietal scalp. Moreover, the reduction or discontinuation of the EGFR inhibitors was needed in all cases with erythematous alopecia, which remained as scarring alopecia.