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Deregulation of multiple signaling pathways and downstream transcription factors, including receptor tyrosine kinases, nuclear factor\u2013kappa B (NF-\u03baB), and Janus kinase\/signal transducer and activator of transcription (JAK\/STAT), is a further hallmark of HRS cells. These cells harbor genetic lesions that contribute to or cause increases in the activity of transcription factors of the NF-\u03baB and STAT families. HRS cells are found within a mixed reactive cellular infiltrate and interact with these nonmalignant cells in a complex fashion that appears to be essential for HRS cell survival and proliferation. 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