Morphological Markers of Chromosomal Instability

Cancer is characterized by genomic complexity and chromosomal instability (CIN). Atypical mitosis and nuclear atypia such as micronuclei have been reported as morphological characteristics of chromosomal instability. An atypical mitotic figure is defined as anything other than the typical form of normal mitosis, including multipolar, ring, dispersed, asymmetrical, and lag-type mitoses. A micronucleus is defined as the small nucleus that forms whenever a chromosome or its fragment is not incorporated into one of the daughter nuclei during cell division. A telomere plays a key role in chromosomal instability. Telomere dysfunction induces fusion of chromatids and chromosome missegregation and this phenomenon can be observed as abnormal mitotic figures and micronuclei. Detection of morphological markers of chromosomal instability using pathological specimens, even small biopsy or cytological specimens, may provide valuable information concerning the prognosis of cancers. Here, we discuss morphological assessment of chromosomal instability using routine pathological specimens

hTERT promoter polymorphism, -1327C\u3eT, is associated with the risk of epithelial cancer

Telomeres are repetitive nucleotide sequences that cap the end of eukaryotic chromosomes. Attrition of these structures has been associated with carcinogenesis in many tissues, and therefore, they are essential for chromosome stabilization. Telomeres are maintained by telomerase complexes, of which human telomerase reverse transcriptase (hTERT) is an essential component. A functional polymorphism, -1327C\u3eT (rs2735940), located in the promoter of the hTERT gene is associated with telomere length in peripheral blood leukocytes. We hypothesized that this polymorphism might affect susceptibility to various epithelial malignancies. The -1327C\u3eT polymorphism was examined in 1,551 consecutive autopsy cases (mean age, 80.3 years), and we focused on its effect on the risks of overall and each primary malignancies. The polymorphism was further studied in 391 clinical prostate cancer patients who were diagnosed via prostate biopsy, using autopsy cases as controls. In the autopsy cases, the risk of epithelial malignancy, after adjusting for age, sex, smoking, and drinking habits, was significantly lower for the TT genotype than the CC (reference) genotype (adjusted odds ratio = 0.61, 95% CI = 0.42-0.90). Among primary malignancies, latent prostate cancer, colorectal cancer, and lung cancer were the most strongly associated with the polymorphism. In the study using clinical prostate cancer patients, susceptibility to clinical prostate cancer was lower for -1327 T carriers than for -1327 T non-carriers, but this finding was not significant. The data suggest that the hTERT promoter polymorphism, -1327C\u3eT, is an independent factor influencing the risk of various epithelial malignancies in elderly Japanese

Accelerated telomere shortening in adrenal zona reticularis in patients with prolonged critical illness

BackgroundThe number of patients with prolonged critical illness (PCI) has been increasing in many countries, and the adrenal gland plays an important role in maintaining homeostasis during PCI. Chronic disease burden is reportedly associated with shorter telomere lengths in human tissues. Telomere shortening in human somatic cells is largely dependent on cell divisions, and critically short telomeres lead to cellular dysfunction and aging. However, the association between PCI and telomere lengths in human adrenal cells is poorly understood. In this study, we investigated this association to assess whether the burden of PCI could accelerate the aging process in adrenal cells.MethodsAdrenocortical tissues from patients who died after PCI usually show a diffuse pattern of intracellular cholesterol ester depletion (i.e., lipid depletion). This study examined near-normal adrenal glands obtained from autopsied patients who died suddenly (control group) and lipid-depleted adrenal glands obtained from autopsied patients who died after PCI (PCI group). The control group included 7 men aged 80 to 94 years (mean age: 85.3 years) and 7 women aged 84 to 94 years (mean age: 87.7 years). The PCI group included 10 men aged 71 to 88 years (mean age: 78.8 years) and 8 women aged 77 to 95 years (mean age: 85.6 years). By using quantitative fluorescence in situ hybridization, relative telomere lengths (RTLs) were determined in the parenchymal cells of the three adrenocortical zones (zona glomerulosa, zona fasciculata, and zona reticularis [ZR]) and in the chromaffin cells of the medulla. The number of adrenal parenchymal cells was determined by immunohistochemistry and digital image analysis.ResultsRTLs in ZR cells were significantly shorter in the PCI group than in the control group for both men and women (P = 0.0001 for men and P = 0.0012 for women). However, RTLs in the remaining three types of adrenal cells did not differ between the control and PCI groups for both men and women. The number of ZR cells was higher in the PCI group than in the control group for both men and women (P < 0.0001 for both men and women). The proportion of the number of ZR cells to the total number of adrenocortical parenchymal cells was also higher in the PCI group than in the control group (P < 0.0001 for both men and women). The Ki-67 proliferation index in ZR cells was higher in the PCI group than in the control group (P = 0.0039 for men and P = 0.0063 for women).ConclusionsThis study demonstrated ZR cell-specific telomere shortening in patients with adrenal lipid depletion who died after PCI. Our results suggest that the reactive proliferation of ZR cells accelerates the telomere shortening and aging process in ZR cells in these patients. The results of our study may contribute to the understanding of adrenal aging during PCI

Mucinous cystadenocarcinoma of the breast: A case report and review of the literature

We report a case of mucinous cystadenocarcinoma (MCA) of the breast in a 96-year-old woman. This is an extremely rare variant of primary breast carcinoma that bears a striking resemblance to MCAs of the ovary and pancreas. The macroscopic appearance and secretion pattern (cytologic findings) resembled cystic hypersecretory carcinoma. However, microscopically, the epithelial cells were quite different from those of cystic hypersecretory carcinoma. In the present study as well as in the literature, MCAs tend to occur more frequently in elderly women. Immunohistochemical findings suggest that they may develop independently of estrogenic stimulation. Although MCAs show high proliferative activity, the prognosis was favorable in the present case as well as in the reported cases. Because MCAs appear to have a distinct pathogenesis and biologic behavior, they should be distinguished from ordinary mucinous carcinomas, cystic hypersecretory carcinomas, and carcinomas of other histologic subtypes