Squamous cell cancers account for more than half of all human cancers, and esophageal cancer is the sixth leading cause of cancer death worldwide. The majority of esophageal squamous cell carcinomas have identifiable p53 mutations, yet the same p53 mutations are found at comparable frequencies in pre-cancerous dysplasia, indicating that transformation requires additional somatic changes yet to be defined. Here we show that the zinc finger transcription factor KLF5 transactivates NOTCH1 in the context of p53 mutation or loss. KLF5 loss limited NOTCH1 activity and was sufficient on its own to transform primary human keratinocytes harboring mutant p53, leading to formation of invasive tumors. Restoration of NOTCH1 blocked transformation of KLF5-deficient and p53 mutant keratinocytes. While human dysplastic epithelia accumulated KLF5, KLF5 expression was lost concurrently with NOTCH1 in squamous cell cancers. Taken together, these results define KLF5 loss as a critical event in squamous cell transformation and invasion. Our findings suggest that KLF5 may be a useful diagnostic and therapeutic target in esophageal squamous carcinomas and possibly more generally in other cancers associated with p53 loss-of-function.

The authors found that reclassification with TPS improved correlation with the SD compared with previous methodologies. Specifically, TPS increased the number of high-grade urothelial carcinoma diagnoses and decreased the number of equivocal or "atypical" diagnoses. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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GATA binding protein 3 (GATA3) is a recently described immunohistochemical marker that has proven useful in the characterization of breast and urothelial carcinomas. However, the expression pattern of GATA3 in mesonephric proliferations is largely unknown. The aim of this study was to examine the immunohistochemical expression of GATA3 in cervicovaginal mesonephric lesions and compare it to its expression in endocervical and endometrial adenocarcinomas and cervicovaginal endometriosis. A cohort of 107 cases, including 33 cases of mesonephric lesions and 74 cases of nonmesonephric lesions, was selected for the study. Of 33 mesonephric lesions, 31 (94%) cases (16 remnants, 12 hyperplasias, and 3 adenocarcinomas) were strongly and diffusely positive in tumor cell nuclei for GATA3. The remaining 2 mesonephric carcinosarcomas showed focal nuclear staining and rare nuclear positivity, respectively. Of 36 endocervical adenocarcinomas, 33 (92%) were negative for GATA3 and the remaining revealed focal weak nuclear staining. Of 34 endometrial adenocarcinomas, 32 (94%) were negative, whereas 2 showed rare nuclear positivity. All 4 cases of endometriosis were negative. The benign endocervical epithelium and the benign endometrium in most cases lacked GATA3 expression, whereas the benign squamous epithelium in the majority exhibited nuclear basal and parabasal staining pattern. Our study demonstrates that GATA3 protein is expressed in most mesonephric lesions, regardless of them being benign or malignant. In contrast, GATA3 is absent in the majority of endometrial and endocervical adenocarcinomas. These results support that GATA3 immunostain can be a useful tool in differentiating mesonephric lesions from endocervical and endometrial adenocarcinomas.

Mesonephric remnants, usually located deep in the lateral cervical wall, may become hyperplastic resulting in a florid proliferation. These can be misinterpreted as malignant and confused with endocervical adenocarcinomas. Recent data have shown that PAX2 is diffusely expressed in mesonephric remnants and hyperplasias. PAX8 is a related transcription protein that is expressed in tissues of müllerian and wolffian origin. In this study, we have investigated the utility of an immunohistochemical panel comprising of PAX8, estrogen receptor (ER), and p16 in the differential diagnosis between mesonephric proliferations and cervical adenocarcinomas. A database search was conducted for cases of mesonephric remnants/hyperplasia/carcinoma of cervix and invasive cervical adenocarcinomas. Immunohistochemical stains for PAX8, ER, and p16 were performed using the avidin-biotin peroxidase technique on the most representative tissue. The search yielded 28 cases of mesonephric proliferations of cervix (15 mesonephric remnants, 12 mesonephric hyperplasias, and 1 mesonephric adenocarcinoma) and 16 cases of cervical adenocarcinomas (15 usual type and 1 adenoma malignum). Immunohistochemically, all the mesonephric proliferations, regardless of being benign or malignant, displayed a consistent staining pattern-diffusely and strongly positive for PAX8, negative for ER, and patchy cytoplasmic staining for p16. The usual type cervical adenocarcinomas exhibited a variable staining pattern with PAX8 and ER but all were strongly and diffusely positive for p16. The case of adenoma malignum was PAX8 positive, ER negative, and showed weak and patchy staining with p16. Our study suggests that a panel of immunohistochemical stains composed of PAX8, p16, and ER is useful in the distinction between mesonephric proliferations and cervical adenocarcinomas.