Novel Pathologic Factors for Risk Stratification of Gastric “Indefinite for Dysplasia” Lesions

Background/Aims. “Indefinite for dysplasia” (IND) conditions of the stomach have high malignancy rates (22.6%–75.0%). Endoscopic resection is sometimes used for follow-up, but criteria for selecting this follow-up method are not established. We investigated pathologic factors to subclassify the IND of the stomach and select appropriate follow-up methods. Methods. In total, 123 IND cases with final diagnoses of cancer (29.3%), high-grade dysplasia (6.5%), low-grade dysplasia (11.4%), and nonneoplasm (52.8%) were randomly divided into test set ( n = 27 ) and validation set ( n = 96 ). By the image analysis, size, pleomorphism, hyperchromasia, irregularity of nuclei, and ratios of structural atypia area (SAA) to total IND area were measured in the test set. Using the validation set, consensus meetings were held for the evaluation of pathologic factors that predict the final diagnosis. Results. By image analysis, the only ratio of SAA to total IND area was associated with the final diagnosis ( p < 0.001 ). In the consensus meeting for validation, the nuclear factors, except loss of nuclear polarity ( p = 0.004 – 0.026 ), could not predict the final diagnosis. Conversely, most structural factors could predict the final diagnosis. In particular, SAA > 25 % was the most powerful predictive factor. We proposed criteria of risk stratification by using SAA > 25 % , loss of surface maturation (LOSM), and loss of nuclear polarity (LONP) (Malignancy rate; Category 0: SAA ≤ 25 % without LOSM and LONP; 0%, Category 1: SAA ≤ 25 % with any of LOSM or LONP; 15.2%–16.7%, Category 2: SAA > 25 % without LOSM and LONP; 44.4%–50.0%, Category 3: SAA > 25 % with any of LOSM or LONP 54.5%–55.6%). Conclusions. Structural atypia was more helpful than nuclear atypia and SAA > 25 % was the most powerful predictor for the diagnosis of INDs of the stomach. We propose shortening the follow-up period to six months for Category 1, endoscopic resection for Category 2 and 3, postresection follow-up periods of one year for Category 2, and six months for Category 3.

Prognostic value and reproducibility of different microscopic characteristics in the WHO grading systems for pTa and pT1 urinary bladder urothelial carcinomas

Background European treatment guidelines for pTa and pT1 urinary bladder urothelial carcinoma depend highly on stage and WHO-grade. Both the WHO73 and the WHO04 grading systems show some intra- and interobserver variability. The current pilot study investigates which histopathological features are especially sensitive for this undesired lack of reproducibility and the influence on prognostic value. Methods Thirty-eight cases of primary non-muscle invasive urothelial carcinomas, including thirteen cases with stage progression, were reviewed by three pathologists. Thirteen microscopic features were extracted from pathology textbooks and evaluated separately. Reproducibility was measured using Gwet’s agreement coefficients. Prognostic ability regarding progression was estimated by the area under curve (AUC) of the receiver operating characteristics (ROC) function. Results The best reproducible features (Gwet’s agreement coefficient above 0.60) were papillary architecture, nuclear polarity, cellular maturation, nuclear enlargement and giant nuclei. Nucleoli was the strongest prognostic feature, and the only feature with an AUC above 0.70 for both grading systems, but reproducibility was not among the strongest. Nuclear polarity also had prognostic value with an AUC of 0.70 and 0.67 for the WHO73 and WHO04, respectively. The other features did not have significant prognostic value. Conclusions The reproducibility of the histopathological features of the different WHO grading systems varied considerably. Of all the features evaluated, only nuclear polarity was both prognostic and significantly reproducible. Further validation studies are needed on these features to improve grading of urothelial carcinomas.

Mitotic antipairing of homologous and sex chromosomes via spatial restriction of two haploid sets

Pairing homologous chromosomes is required for recombination. However, in nonmeiotic stages it can lead to detrimental consequences, such as allelic misregulation and genome instability, and is rare in human somatic cells. How mitotic recombination is prevented—and how genetic stability is maintained across daughter cells—is a fundamental, unanswered question. Here, we report that both human and mouse cells impede homologous chromosome pairing by keeping two haploid chromosome sets apart throughout mitosis. Four-dimensional analysis of chromosomes during cell division revealed that a haploid chromosome set resides on either side of a meridional plane, crossing two centrosomes. Simultaneous tracking of chromosome oscillation and the spindle axis, using fluorescent CENP-A and centrin1, respectively, demonstrates collective genome behavior/segregation of two haploid sets throughout mitosis. Using 3D chromosome imaging of a translocation mouse with a supernumerary chromosome, we found that this maternally derived chromosome is positioned by parental origin. These data, taken together, support the identity of haploid sets by parental origin. This haploid set-based antipairing motif is shared by multiple cell types, doubles in tetraploid cells, and is lost in a carcinoma cell line. The data support a mechanism of nuclear polarity that sequesters two haploid sets along a subcellular axis. This topological segregation of haploid sets revisits an old model/paradigm and provides implications for maintaining mitotic fidelity.

Recurrent Villous Adenoma with High-Grade Dysplasia Arising in a Urethral Diverticulum

Villous adenomas of the urinary tract are an uncommon, well-recognized entity, described in different locations. However, the occurrence of this lesion in the female urethral diverticulum is very unusual. We present the first case of a recurrent villous adenoma with high-grade dysplasia unassociated with adenocarcinoma, arising from a urethral diverticulum. A 75-year-old African-American female presented with urethral prolapse complaining of mild voiding difficulty, stress incontinence, and mild spotting of blood. Histological examination revealed a papillary lesion with finger-like processes lined by pseudostratified columnar epithelium with abundant goblet cells. There were focal areas with stratification to the luminal surface and loss of nuclear polarity and atypical mitoses, interpreted as villous adenoma with high-grade dysplasia. The lesion recurred at one year without evidence of malignant transformation. We also present a brief literature review of urothelial villous adenomas.

Colchicine Effect in a Colonic Hyperplastic Polyp

Colchicine effect has been described recently in gastrointestinal biopsies, where it can result in accumulation of metaphase mitoses and epithelial disorganization. We describe the case of a colonic hyperplastic polyp with colchicine effect from a 52-year-old woman who was receiving colchicine for primary biliary cirrhosis. Biopsy of the polyp revealed prominent metaphase mitoses and focal loss of nuclear polarity in the surface epithelium, features that mimicked a serrated adenoma. Distinguishing between hyperplastic polyp and serrated adenoma is important because of the different management implications and the increased potential for neoplastic progression in the latter.

Subcellular localization of Bic-D::GFP is linked to an asymmetric oocyte nucleus

Bicaudal-D (Bic-D) is essential for the establishment of oocyte fate and subsequently for polarity formation within the developing Drosophila oocyte. To find out where in the germ cells Bic-D performs its various functions we made transgenic flies expressing a chimeric Bic-D::GFP fusion protein. Once Bic-D::GFP preferentially accumulates in the oocyte, it shows an initial anterior localization in germarial region 2. In the subsequent egg chamber stages 1–6 Bic-D::GFP preferentially accumulates between the oocyte nucleus and the posterior cortex in a focus that is consistently aligned with a crater-like indentation in the oocyte nucleus. After stage 6 Bic-D::GFP fluorescent signal is predominantly found between the oocyte nucleus and the dorso-anterior cortex. During the different phases several genes have been found to be required for the establishment of the new Bic-D::GFP distribution patterns. Dynein heavy chain (Dhc), spindle (spn) genes and maelstrom (mael) are required for the re-localization of the Bic-D::GFP focus from its anterior to its posterior oocyte position. Genes predicted to encode proteins that interact with RNA (egalitarian and orb) are required for the normal subcellular distribution of Bic-D::GFP in the germarium, and another potential RNA binding protein, spn-E, is required for proper transport of Bic-D::GFP from the nurse cells to the oocyte in later oogenesis stages. The results indicate that Bic-D requires the activity of mRNA binding proteins and a negative-end directed microtubule motor to localize to the appropriate cellular domains. Asymmetric subcellular accumulation of Bic-D and the polarization of the oocyte nucleus may reflect the function of this localization machinery in vectorial mRNA localization and in tethering of the oocyte nucleus. The subcellular polarity defined by the Bic-D focus and the nuclear polarity marks some of the first steps in antero-posterior and subsequently in dorso-ventral polarity formation.