Cyclin D1 expression in Rosai-Dorfman disease: a near-constant finding that is not invariably associated with mitogen-activated protein kinase/extracellular signal-regulated kinase pathway activation.

Activating mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway have been shown in nearly half of the cases of Rosai-Dorfman disease (RDD). Cyclin D1, a key cell cycle regulator, constitutes a major downstream target of the MAPK/ERK pathway. In this study, we aim to further understand the pathogenesis of RDD by assessing the lesional histiocytes for cyclin D1, p-ERK, Ki-67, and BCL-2 by immunohistochemistry. We assessed 35 samples of RDD and a control group of histiocyte-rich reactive lesions. Cyclin D1 was expressed in about 90% of cases of RDD. Cyclin D1 was positive in 25-95% (median, 85%) of lesional histiocytes, was moderately/strongly expressed in 97% of cyclin D1-positive cases, and was significantly higher than in control specimens. p-ERK was positive in 16 of 30 (53%) cases of RDD and was negative in all controls. All p-ERK-positive RDD cases had concurrent cyclin D1 expression, whereas more than a third of cyclin D1-positive cases were negative for p-ERK. Ki-67 was low in RDD (median, 3%). BCL-2 was positive in lesional histiocytes in nine of 10 RDD cases assessed. Overall, these findings point to unexpected, potential roles of these molecules in the pathogenesis of RDD. Overexpression of cyclin D1 in the absence of ERK phosphorylation in a subset of RDD cases opens the possibility of oncogenic mechanisms bypassing ERK and supports the notion that cyclin D1 overexpression in RDD is multifactorial. Moreover, the observed lack of correlation between cyclin D1 with Ki-67 proliferative index suggests that prosurvival actions of cyclin D1 are, at least in part, cell cycle independent. Finally, expression of BCL-2 and the low Ki-67 index suggest that RDD might be driven by antiapoptotic rather than proproliferative oncogenic mechanisms.

Mitochondria in aneurysms and dissections of the human ascending aorta.

Factors causing the weakness that underlies thoracic aorta aneurysms and dissections are not well known. Based on the findings of apoptosis and ischemic-like necrosis, we hypothesized a possible role for mitochondrial disturbances in the pathogenesis of these diseases. To evaluate if mitochondria at the aortic medial layer are damaged, samples of ascending aortas with aneurysms (n = 6), acute dissections (n = 5), and hypertensive (n = 9) and normotensive controls (n = 7) were analyzed by transmission electron microscopy. Number of mitochondria, areas of cytoplasm, and areas of mitochondria were measured, and area percentage of the cytoplasm corresponding to mitochondria, their number by unit of area, and their mean area were calculated in randomly taken photographs. Data were compared using one-way analysis of variance or Kruskal-Wallis tests. Significant differences (P ≤ 0.05) were found in the number of mitochondria and their mean area, showing opposite results: the number increased and the mean area decreased from normotensive controls to hypertensive controls to acute dissections to aneurysms, although post hoc tests showed that only the differences between the aneurysms and either both controls (number of mitochondria/mm2: 10.37 in normotensive controls, 15.61 in hypertensive controls, and 43.67 in aneurysms) or normotensive controls only (mean area: 2800.15 in normotensive controls vs 894.91 µm2 in aneurysms) were significant. In conclusion, there are more, smaller mitochondria in ascending aorta aneurysms. This pattern possibly corresponds to dysfunctional mitochondria, indicating that alterations in the dynamics of these organelles may play a role in the pathogenesis of thoracic aorta aneurysms and dissections.