Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis.

Interleukin-34 (IL-34) is a newly discovered regulator of myeloid lineage differentiation, proliferation, and survival, acting via the macrophage-colony stimulating factor receptor (M-CSF receptor, c-fms). M-CSF, the main ligand for c-fms, is required for osteoclastogenesis and has been already identified as a critical contributor of the pathogenesis of giant cell tumours of bone (GCTs), tumours rich in osteoclasts. According to the key role of M-CSF in osteoclastogenesis and GCTs, the expression of IL-34 in human GCTs was first assessed. Quantitative analysis of IL-34 mRNA expression in 14 human GCTs revealed expression of this cytokine in GCTs as well as M-CSF and c-fms. Immunohistochemistry demonstrated that osteoclast-like cells exhibited a huge immunostaining for IL-34 and that mononuclear stromal cells were slightly positive for this protein. In contrast to osteoblasts, bone-resorbing osteoclasts showed very strong staining for IL-34, suggesting its potential role in the pathogenesis of GCTs by facilitating osteoclast formation. The role of IL-34 in osteoclastogenesis was then studied in murine and human models. IL-34 was able to support RANKL-induced osteoclastogenesis in the absence of M-CSF in all models. Multinucleated cells generated in the presence of IL-34 and RANKL expressed specific osteoclastic markers and resorbed dentine. IL-34 induced phosphorylation of ERK 1/2 and Akt through the activation of c-fms, as revealed by the inhibition of signalling by a specific c-fms tyrosine kinase inhibitor. Furthermore, IL-34 stimulated RANKL-induced osteoclastogenesis by promoting the adhesion and proliferation of osteoclast progenitors, and had no effect on osteoclast survival. Overall, these data reveal that IL-34 can be entirely substituted for M-CSF in RANKL-induced osteoclastogenesis, thus identifying a new biological activity for this cytokine and a contribution to the pathogenesis of GCTs.

Postmortem Investigation of Immunohistochemical Staining and Gross Description of Sarcomatoid Carcinoma of the Lung in a Patient With Extreme Leukemoid Reaction.

A 72-year-old male smoker was brought into the emergency department complaining of 4 months of progressive dyspnea and fatigue. Computed tomography angiogram of the lungs was negative for pulmonary embolism; however, a 10 cm right upper lobe mass and multiple bilateral pulmonary nodules were identified. While computed tomography scan of the head showed no lesions in the brain, there was osseous destruction of the right mandible. Records obtained from an outside hospital indicated that he had 2 prior biopsies of this lung mass that failed to show malignant cells. In addition, an outpatient positron emission tomography scan had shown increased tracer uptake in this mass as well as multiple nodules in the contralateral lung and in the left adrenal gland. This gentleman was admitted for sepsis and was started on broad-spectrum antibiotics. He continued to have respiratory compromise and required transfer to the intensive care unit for intubation and mechanical ventilation. Over the next 4 days, the patient progressed into septic shock requiring vasopressors and developed worsening respiratory failure. His white blood cell count continued to rise and peaked at 157 × 103 cells/µL. The patient's wife decided to proceed with comfort measures and the patient subsequently expired. Autopsy was consistent with sarcomatoid carcinoma, also known as giant cell carcinoma of the lung. Immunohistochemical staining was also performed, which identified several tumor markers as well as distant metastasis, hemorrhage, and multi-organ necrosis.