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Arrhythmogenic cardiomyopathy (AC) has traditionally been regarded as a rare disease with variably penetrant autosomal-dominant inheritance. Recent years have revealed that AC is actually a spectrum of disease with prevalence much higher than previously thought. Diagnosis can be quite challenging because of highly variable clinical presentation, even among family members sharing a mutation. Unlike other cardiomyopathies, AC has a concealed phase during which patients have arrhythmias in the absence of structural heart disease but remain at risk of sudden cardiac death. Importantly, it is in the setting of sudden cardiac death that pathologists are most likely to encounter AC. It is critical that these findings not be overlooked, as family members of the deceased may also be affected and could potentially avoid such a dismal outcome. With time, advances in ancillary studies are likely to expand the role for pathologists in AC diagnosis. [ABSTRACT FROM AUTHOR]

• When used in combination, SOX10 and GATA3 detect nearly all mammary carcinomas. • Though regarded as a marker of triple negative breast cancer, SOX10 is also frequently expressed when ER expression is low. • SOX10 co-expression may be useful for cases with weak GATA3 expression in establishing a breast primary. The complementary coverage of different subsets of breast cancer by GATA3 and SOX10 makes their use in combination appealing for routine clinical use, but study of these markers has been largely limited to cases with high or absent ER expression. Here we report SOX10 and GATA3 immunostaining in parallel using a tissue microarray containing 246 invasive breast carcinoma cases with a range of ER expression. GATA3 and SOX10 were positive in 93 % (229/246) and 15 % (38/246) of cases overall and in 63 % (24/38) and 74 % (28/38) of triple negative breast carcinomas (TNBC), respectively; SOX10 was positive in 15 of the 17 cases that lacked GATA3 expression (88 %). SOX10 was also positive in 3 % (6/196) of ER + cases, including 50 % of cases with low ER (3/6), 20 % with intermediate ER (3/15), and 0 % with high ER (n = 175), so that ER-low cases more strongly resembled TNBC than those with high ER expression. GATA3 expression was lower in cases that co-expressed SOX10 in comparison to those that were positive for GATA3 alone. Less than 1 % (2/246) of cases were negative for both GATA3 and SOX10. Therefore, SOX10 is a useful adjunct to GATA3 in the detection of TNBC and cases with low ER expression and/or reduced GATA3 intensity relative to that typical of breast cancers with higher ER expression. Moreover, given such high sensitivity, metastatic tumors lacking either GATA3 or SOX10 are unlikely to be of breast origin. Additional study is necessary to determine the extent to which SOX10 may also improve specificity and to characterize its biologic significance in breast cancers with low ER expression. [ABSTRACT FROM AUTHOR]

Approximately 40% of vulvar squamous cell carcinoma (vSCC) cases are etiologically associated with high-risk human papillomaviruses (HPVs) of the alpha genera (α-HPV) that cause other anogenital cancers; however, the etiology of α-HPV-negative vSCC is poorly understood. HPVs of the beta genera (β-HPV) are risk factors for cutaneous squamous cell carcinoma (cSCC) and may be related to carcinomas originating in other cutaneous sites such as the vulva. In this study, we investigate the presence of β-HPVs, with an emphasis on p16-negative squamous lesions adjacent to vSCC. We subjected 28 vulvar squamous intraepithelial lesions adjacent to vSCC for comprehensive HPV genotyping, p16 and p53 immunohistochemistry, and consensus morphology review. Selected cases were subjected to qPCR and RNA in situ hybridization. Clinical data were obtained from medical records. β-HPV DNA was detected in eight of ten p16-negative lesions and three of fourteen p16-positive high-grade squamous intraepithelial lesions. The HPV DNA loads in vulvar squamous intraepithelial lesions ranged between less than 1 HPV DNA copy per cell to more than 100 HPV DNA copies per cell. This is, to the best of our knowledge, the first report of the association of p16-negative vulvar intraepithelial squamous lesions with detection of β-HPVs. These findings expand possible etiologic mechanisms that may contribute to p16-negative lesions of the vulva. [ABSTRACT FROM AUTHOR]

Pancreatic and ampullary cancers remain highly morbid diseases for which accurate clinical predictions are needed for precise therapeutic predictions. Patient-derived cancer organoids have been widely adopted; however, prior work has focused on well-level therapeutic sensitivity. To characterize individual oligoclonal units of therapeutic response, we introduce a low-volume screening assay, including an automated alignment algorithm. The oligoclonal growth response was compared against validated markers of response, including well-level viability and markers of single-cell viability. Line-specific sensitivities were compared with clinical outcomes. Automated alignment algorithms were generated to match organoids across time using coordinates across a single projection of Z-stacked images. After screening for baseline size (50 μm) and circularity (>0.4), the match efficiency was found to be optimized by accepting the diffusion thresholded with the root mean standard deviation of 75 μm. Validated well-level viability showed a limited correlation with the mean organoid size (R = 0.408), and a normalized growth assayed by normalized changes in area (R = 0.474) and area (R = 0.486). Subclonal populations were defined by both residual growth and the failure to induce apoptosis and necrosis. For a culture with clinical resistance to gemcitabine and nab-paclitaxel, while a therapeutic challenge induced a robust effect in inhibiting cell growth (GΔ = 1.53), residual oligoclonal populations were able to limit the effect on the ability to induce apoptosis (GΔ = 0.52) and cell necrosis (GΔ = 1.07). Bioengineered approaches are feasible to capture oligoclonal heterogeneity in organotypic cultures, integrating ongoing efforts for utilizing organoids across cancer types as integral biomarkers and in novel therapeutic development. [ABSTRACT FROM AUTHOR]

The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: K14E6/E7 transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with Mus musculus papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age (K14E6/E7) or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated K14E6/E7 mice. [ABSTRACT FROM AUTHOR]

The papillomavirus E5 gene contributes to transformation and tumorigenesis; however, its exact function in these processes and viral pathogenesis is unclear. While E5 is present in high-risk mucosotropic HPVs that cause anogenital and head and neck cancers, it is absent in cutaneous HPVs and the recently discovered mouse papillomavirus (MmuPV1), which causes papillomas and squamous cell carcinomas of the skin and mucosal epithelia in laboratory mice. We infected K14E5 transgenic mice, which express the high-risk mucosotropic HPV16 E5 gene in stratified epithelia, with MmuPV1 to investigate the effects of E5 on papillomavirus-induced pathogenesis. Skin lesions in MmuPV1-infected K14E5 mice had earlier onset, higher incidence, and reduced frequency of spontaneous regression compared to those in non-transgenic mice. K14E5 mice were also more susceptible to cervicovaginal cancers when infected with MmuPV1 and treated with estrogen compared to non-transgenic mice. Our studies support the hypothesis that E5 contributes to papillomavirus-induced pathogenesis. [ABSTRACT FROM AUTHOR]

Invasive breast carcinomas (IBC) that strongly express SOX10 are almost always negative for androgen receptor (AR). Furthermore, this SOX10+/AR- subset of IBC is nearly always estrogen receptor and progesterone receptor negative (ER-/PR-), being most commonly seen in triple negative breast carcinomas (TNBC), but also in a small subset of HER2+/ER-/PR- IBC. Following our previous work demonstrating the expression of SOX10 in a subset of IBC with "low positive" ER expression (i.e. 1–10 % ER+ staining based on CAP guidelines, here referred to as "ER-low"), we sought to investigate the expression of both SOX10 and AR in a larger cohort of ER-low tumors. As our previous work also revealed occasional SOX10 expression in IBC with >10 % ER+ staining, we also included tumors with any percentage of ER staining, as long as the staining intensity was weak (this subset is referred to as "ER-weak"). We screened cases of HER2-/ER+ IBC diagnosed at our institution over a 10 year period, identified both ER-low and ER-weak tumors and stained both groups with SOX10 and AR. Strong SOX10 expression was seen in 12/25 (48 %) ER-low tumors and 13/24 (54 %) ER-weak tumors. ER staining in the SOX10+ subset of ER-weak tumors ranged from 15 %−80 % (median 25 %). As expected, AR was negative in all but 1 of the SOX10+ tumors in both groups. While case numbers in these groups were too small for a meaningful statistical analysis, we did note that all SOX10+/AR- tumors within both the ER-low and ER-weak groups were histologic grade 3. The presence of a SOX10+/AR- profile in a significant subset of ER-low tumors confirms the findings of our previous work and provides further support for the proposed functionally ER negative status of this group. Furthermore, the fact that the same SOX10+/AR- profile is seen in a roughly equal subset of ER-weak tumors suggests that a wider range of ER staining may be acceptable as "low positive" in SOX10+/AR- tumors, as long as the ER staining is of weak intensity. However, given the small number of cases in this single institution study, we emphasize the need for larger studies to establish the biological and clinical significance of this tumor subset. [ABSTRACT FROM AUTHOR]