The Immune Checkpoint Inhibitor LAG-3 and Its Ligand GAL-3 in Vulvar Squamous Neoplasia.

Vulvar squamous cell carcinoma (vSCC), although rare, carries significant morbidity and a high rate of recurrence. Treatment options beyond surgical excision remain limited. Lymphocyte activation gene-3 (LAG-3) and its binding partner galectin-3 (GAL-3) are an immuno-inhibitory checkpoint pair that represent potential immunotherapy targets for the treatment of vSCC. This study examined the expression of LAG-3 and GAL-3 alongside programmed cell death ligand-1 expression in invasive SCC and vulvar intraepithelial neoplasia (VIN) by immunohistochemical analysis of formalin-fixed paraffin-embedded tissue. A total of 35 cases were selected for evaluation: 13 VIN3 [human papillomavirus (HPV)-associated VIN/usual-type VIN], 2 differentiated VIN (dVIN), 16 HPV-associated vSCC, and 4 dVIN-associated vSCC. LAG-3+ tumor-infiltrating lymphocytes were identified in 91% (32/35) of cases of vulvar squamous neoplasia. Tumor cells were positive for GAL-3 in 71% of the vulvar neoplasia cases. HPV-associated vSCC was more likely to demonstrate GAL-3 tumoral positivity when compared with dVIN-associated vSCC (24/29 vs. 1/6, P=0.004). We observed co-expression of all 3 immunomarkers in 40% (14/35) of cases evaluated. In light of these findings, use of immunomodulatory drugs that target the LAG-3/GAL-3 pathway may be potentially beneficial in vSCC and efficacy may be increased when combined with anti-programmed cell death ligand-1 therapy.

Necrobiosis lipoidica associated with sarcoidosis.

We report the case of a 40-year-old African-American female with biopsy-proven pulmonary sarcoidosis who developed atrophic plaques on her shins, trunk, and scalp that were clinically and histologically consistent with necrobiosis lipoidica (NL). The lesions appeared 3 years after her diagnosis of sarcoidosis, and progressed despite chronic prednisone. Sarcoidosis and NL are granulomatous skin disorders reported to coexist in the same patient only 10 times in the literature. Including the current case, patients have been exclusively females around middle age, and have greater tendencies to develop typical cutaneous sarcoidosis. The incidence of diabetes is rare in this group. Like typical NL, NL associated with sarcoidosis tends to ulcerate, and is difficult to treat. Interestingly, there are six similar cases reported in the literature of patients with sarcoidosis who developed lesions clinically and behaviorally consistent with NL, but received a final histological diagnosis of sarcoidosis. These cases share very similar demographics and clinical features with cases of true NL associated with sarcoidosis, and often have more ambiguous histology containing features of both cutaneous sarcoidosis and NL. Comparing the two sets of cases raises the possibility of a final common disease pathway shared by these two granulomatous skin disorders.