Purpose: CLIC4, a member of a family of intracellular chloride channels, is regulated by p53, c-Myc, and tumor necrosis factor-a. Regulation by factors involved in cancer pathogenesis, together with the previously shown proapoptotic activity of CLIC4, suggests that the protein may have a tumor suppressor function. To address this possibility, we characterized the expression profile, subcellular localization, and gene integrity of CLIC4 in human cancers and determined the functional consequences of CLIC4 expression in tumor epithelium and stromal cells. Experimental Design: CLIC4 expression profiles were analyzed by genomics, proteomics, bioinformatics, and tissue microarrays. CLIC4 expression, as a consequence of crosstalk between stroma and epithelium, was tested in vitro by coculture of breast epithelial tumor cells and normal fibroblasts, and the functional consequences of CLIC4 expression was tested in vivo in xenografts of human breast tumor cell lines reconstituted with CLIC4 or mixed with fibroblasts that overexpress CLIC4 transgenically. Results: In cDNA arrays of matched human normal and tumor tissues, CLIC4 expression was reduced in renal, ovarian, and breast cancers. However, CLIC4 protein levels were variable in tumor lysate arrays. Transcript sequences of CLIC4 from the human expressed sequence tag database and manual sequencing of cDNA from 60 human cancer cell lines (NCI60) failed to reveal deletion or mutations in the CLIC4 gene. On matched tissue arrays, CLIC4 was predominantly nuclear in normal human epithelial tissues but not cancers.With advancing malignant progression, CLIC4 staining became undetectable in tumor cells, but expression increased in stromal cells coincident with up-regulation of a-smooth muscle actin, suggesting that CLIC4 is up-regulated in myofibroblasts. Coculture of cancer cells and fibroblasts induced the expression of both CLIC4 and a-smooth muscle actin in fibroblasts adjacent to tumor nests. Introduction of CLIC4 or nuclear targeted CLIC4 via adenovirus into human breast cancer xenografts inhibited tumor growth, whereas overexpression of CLIC4 in stromal cells of xenografts enhanced tumor growth. Conclusion: Loss of CLIC4 in tumor cells and gain in tumor stroma is common to many human cancers and marks malignant progression. Up-regulation of CLIC4 in tumor stroma is coincident with myofibroblast conversion, generally a poor prognostic indicator. Reactivation and restoration of CLIC4 in tumor cells or the converse in tumor stromal cells could provide a novel approach to inhibit tumor growth.

Several clinical and histopathologic variants of mycosis fungoides (MF) have been well described, including the often elusive interstitial MF. Differentiation from other inflammatory disorders, such as interstitial granuloma annulare (GA) and inflammatory morphea, may be extremely difficult. We report a case of MF and GA coexisting in a 54-year-old woman who initially presented to clinic in 2000 with slightly scaly patches on the trunk and extremities, histopathologically diagnostic of MF. A second biopsy taken a few months later revealed an interstitial infiltrate that was initially interpreted as interstitial MF. Over the following 10 years, additional biopsies revealed features of conventional MF. In 2009, a new biopsy showed unequivocal features of interstitial GA. Reevaluation of the original biopsy, diagnostic of "interstitial MF," revealed that this, too, could be better classified as interstitial GA than interstitial MF. Our case illustrates that MF and interstitial GA may coexist simultaneously, thus representing a pitfall in the histopathologic diagnosis of MF. Given the similarities in clinicopathologic presentation, dermatologists and dermatopathologists should be cautious not to inadvertently misinterpret GA as interstitial MF.

A case of harlequin ichthyosis with compound heterozygous mutations in ABCA12 was successfully managed with intensive neonatal care and endotracheal intubation and without oral retinoids. The individual's appearance improved dramatically during hospitalization and at discharge resembled congenital ichthyosiform erythroderma.