Objective The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in HNSCC. We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors. Study Design Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. 50 patients were enrolled, and 39 completed a full treatment course. Metformin was titrated to standard diabetic dose (2000 mg/day) for a course of 9 or more days prior to surgery. Level of Evidence 4 Methods Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB) and monocarboxylate transporter 4 (MCT4) as well as the TUNEL apoptosis assay and Ki-67 IHC were performed in pre- and post-metformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels was also performed in three subjects. Results Metformin was well tolerated. The average treatment course was 13.6 days. Post-treatment specimens showed a significant increase in stromal CAV1 (p<0.001) and GALB (p<0.005) and tumor cell apoptosis by TUNEL assay (p<0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold post-metformin (p<0.05) as measured by MSI. Conclusions Metformin increases markers of reduced catabolism and increased senescence in stromal cells and increased carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment. Trial Registration ClinicalTrials.gov Identifier NCT02083692.

The term ‘Langerhans cell microgranuloma’ (LCM) was introduced a decade ago to draw attention to focal collections of these cells within the epidermal layer that develops during certain immune reactions. In spite of a growing awareness of this phenomenon during the past decade, few reports have focused on the development and phenotype of LCM. In this commentary, we review the historical development of the concept of LCM, demonstrate the salient immunomorphologic characteristics of LCM, and advance a hypothesis to explain their sequential evolution and formation.