Expanding the spectrum of mesenchymal neoplasms with NR1D1-rearrangement.

Undifferentiated mesenchymal neoplasms can be morphologically subclassified based on cell shape; epithelioid tumors may be diagnostically challenging, particularly since they can show morphologic and immunohistochemical overlap with epithelial neoplasms. Following the recent report of an NR1D1::MAML1 gene fusion in an undifferentiated pediatric neoplasm, we performed a retrospective archival review and identified four additional cases of undifferentiated mesenchymal neoplasms with NR1D1-rearrangement. All four tumors occurred in adult women. The tumors involved superficial and/or deep soft tissues of the extremities or abdomen. Morphologically, they showed a spectrum of overlapping features. In addition to epithelioid cells, two cases also had a prominent spindle cell component. Two cases also had admixed polygonal cells containing prominent cytoplasmic vacuoles with amorphous debris. The immunophenotype was nonspecific but all cases had at least focal keratin expression; this was extensive in two tumors. Targeted RNA-sequencing revealed two cases each with NR1D1::MAML1 and NR1D1::MAML2 gene fusions. One patient developed lung and liver metastases, and one patient required amputation due to multifocal disease and underlying bone involvement. This study confirms undifferentiated NR1D1-rearranged sarcoma represents a distinct mesenchymal neoplasm with an epithelioid morphology and potential for aggressive behavior. Further, we offer new insight into the spectrum of clinical, morphologic, immunohistochemical, and molecular findings possible in these rare neoplasms. An awareness of this entity is especially important given the potential for misclassification as a carcinoma.

Estimating time of death based on the biological clock.

The biological clock may stop at the time of death in a dead body. Therefore, the biological clock seems useful for estimating the time of death. In this study, we tried to read the biological clock in tissues from dead bodies to estimate the time of death using molecular biological techniques. At first, we examined real-time RT-PCR analysis of gene expression for mPer2 and mBmal1, which constitutes a feedback loop in the oscillation system, in the kidney, liver, and heart of mice. We could detect circadian oscillation of these gene expressions in mouse tissues even at <48 h after death. Thus, the ratio of mPer2/mBmal1 was found to be useful for estimating the time of death. We next applied this method to the liver, kidney, and heart obtained from forensic autopsy cases with less than 72 h of postmortem interval. Significant circadian oscillation of hPer2/hBmal1 ratio could be detected in these autopsy samples. We further examined gene expression for hRev-Erbα, a component of another feedback loop. The ratios of hRev-Erbα/hBmal1 showed higher amplitude of oscillation than those of hPer2/hBmal1 and are considered more suitable for estimating the time of death. In particular, a hRev/hBmal1 ratio of >50 indicated the time of death as 0200-0900 hours, and a hRev/hBmal1 ratio that considerably exceeded 75 indicated the time of death as 0200-0800 hours. On the other hand, a hRev/hBmal1 ratio of less than 25 strongly indicated the time of death as 1000-2300 hours. Taken together, these findings indicate that gene expression analyses of the biological clock could be powerful methods for estimation of the time of death.