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Low-grade Dysplasia (low-grade + dysplasia)
Selected AbstractsLow-grade dysplasia: Nonsurgical treatmentINFLAMMATORY BOWEL DISEASES, Issue 4 2003Chee Hooi Lim No abstract is available for this article. [source] Role of cytology in the diagnosis of Barrett's esophagus and associated neoplasiaDIAGNOSTIC CYTOPATHOLOGY, Issue 3 2003Reda S. Saad M.D. Abstract We studied 327 consecutive paired esophageal biopsies and brushing specimens obtained during the same endoscopic session to evaluate the role of cytology for the diagnosis of Barrett's esophagus (BE) and/or surveillance for associated dysplasia. A diagnosis of BE was based on the cytologic presence of goblet cells. Cases were reviewed and categorized into: 1) benign esophageal lesions (125 cases), with 48 cases of Candida (32 cases diagnosed by both techniques and 16 diagnosed only by cytology), 3 cases of herpes simplex with only 1 case diagnosed by cytology, and 74 cases of inflammation and/or repair; 2) benign BE (141 cases), with 74 cases (52%) diagnosed by both techniques, 11 cases by cytology only (8%), and 56 cases (40%) by histology only; 3) low-grade dysplasia (LGD, 30 cases), with 5 cases (17%) diagnosed with both specimens, one case (3%) by cytology only, and 24 cases (80%) by histology only; 4) high-grade dysplasia (HGD, 10 cases), with 8 cases (80%) diagnosed with both specimens, 1 case (10%) by cytology, and 1 case (10%) by histology; and 5) carcinomas (23 cases), with 20 cases (87%) diagnosed with both specimens, 2 cases (9%) by cytology only, and 1 case (4%) by histology only. Our results support the high degree of diagnostic accuracy of cytology for the diagnosis of Barrett's-associated HGD and/or carcinoma, and moderate sensitivity for BE. Diagn. Cytopathol. 2003;29:130,135. © 2003 Wiley-Liss, Inc. [source] Surveillance colonoscopy for colitic cancer in inflammatory bowel diseaseDIGESTIVE ENDOSCOPY, Issue 4 2003Keisuke Hata Patients with inflammatory bowel disease are known to be at increased risk for the development of colorectal cancer, especially those with long-standing extensive ulcerative colitis. Although some recommend prophylactic total proctocolectomy for these high-risk patients, surveillance colonoscopy to detect ulcerative colitis-associated colorectal cancer is, instead, generally performed. Dysplasia has been considered to be a useful marker to detect colorectal cancer at surveillance colonoscopy. High-grade dysplasia is a definite indication for total proctocolectomy, while management of low-grade dysplasia is still controversial. Patients with Crohn's disease are also considered to be at higher risk for the development of colorectal cancer, although the risk may be lower than in extensive ulcerative colitis. Molecular biology-based surveillance and chemoprevention for ulcerative colitis-associated colorectal cancer are also reviewed. [source] Recurrence of intramucosal esophageal adenocarcinoma arising in a former esophagostomy site: a unique case reportDISEASES OF THE ESOPHAGUS, Issue 6 2009J. M. Leers SUMMARY., A 75-year-old male with a long history of gastroesophageal reflux symptoms developed adenocarcinoma proximally within a long segment of Barrett's esophagus. He was taken for esophagectomy and gastric pull-up, but intraoperatively, he was found to have a marginal blood supply in the gastric tube. A temporary left-sided esophagostomy was created with the gastric tube sutured to the left sternocleidomastoid muscle in the neck. Pathology showed an intramucosal adenocarcinoma, limited to the muscularis mucosa with surrounding high-grade dysplasia and intestinal metaplasia. The proximal esophageal margin showed no tumor cells, but there was low-grade dysplasia within Barrett's esophagus. He was reconstructed after several months, and 2 years after reconstruction, the patient noticed a nodule at the former esophagostomy site. Biopsy revealed an implant metastasis of esophageal adenocarcinoma. Here, we review the literature and discuss the possible etiology. [source] The diagnosis of dysplasia and malignancy in Barrett's oesophagusHISTOPATHOLOGY, Issue 2 2000REVIEW Barrett's metaplasia is associated with an increased risk for adenocarcinoma. Adenocarcinoma develops through a multistep process characterized by defects in genes and morphological abnormalities. The early morphological changes of the process are called ,dysplasia'. Dysplasia is defined as an unequivocal neoplastic (premalignant) transformation confined within the basement membrane. For most Western pathologists malignancy is defined as invasion and characterized by a breach through the basement membrane. Japanese pathologists rely on cytological atypia and complex branching of crypts. Cytological and architectural abnormalities allow identification of dysplasia on routinely stained sections. A distinction is made between low- and high-grade dysplasia. The differential diagnosis between low-grade dysplasia and reactive changes can be difficult. Therefore a second opinion is strongly recommended, not only for high-grade dysplasia but also for low-grade. Immunohistochemistry for p53 and flow cytometry for detection of aneuploidy can support the diagnosis. Identification of dysplasia and malignancy depends on the number of biopsy samples examined. The minimum number of biopsies required has not yet been determined and depends partly on the length of the metaplastic segment. It has been proposed to sample with four quadrant biopsies at 20-mm intervals. New endoscopic techniques can increase the diagnostic yield. Endoscopically visible lesions increase the risk of finding malignancy. The time sequence for the progression of dysplasia is not known but progression from low- to high-grade and cancer has been shown to occur over a period of years although it may not be inevitable. [source] Association of hyperhomocysteinemia and folate deficiency with colon tumors in patients with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 2 2008Jean Marc Phelip Abstract Background: Folate deficiency associated with hyperhomocysteinemia might increase the risk of developing colorectal cancer. The aim of this study was to evaluate factors associated with colonic carcinogenesis, in particular, folate and homocysteinemia levels, in a cross-sectional study of patients with inflammatory bowel disease (IBD). Methods: IBD patients with carcinogenic lesions discovered during colonoscopy [dysplasia-associated lesion or masses (DALM), colorectal cancer] were included and compared with the whole population of IBD patients with a normal colonoscopy performed during the same period. The following parameters were collected at the time of colonoscopy: age, sex, type, duration, activity, and extent of the disease, treatment, smoking status, and vitamin B12, folate, and homocysteinemia levels. Univariate and multivariate analyses were performed after adjusting for the main parameters. Results: One hundred and fourteen patients [41 with ulcerative colitis (UC), 73 with Crohn's disease (CD)] were included. Twenty-six carcinogenic lesions were isolated: 18 DALM (7 high-grade and 11 low-grade dysplasia) and 8 colorectal cancers. In univariate analysis, the factors associated with carcinogenesis were: active smoking (P = 0.03), folate level < 145 pmol/L (P = 0.02), hyperhomocysteinemia > 15 ,mol/L (P = 0.003), duration of disease > 10 years (P = 0.006), and UC (P = 0.02). In multivariate analysis, patients with hyperhomocysteinemia associated with folate deficiency had 17 times as many carcinogenic lesions as patients with normal homocysteinemia whatever the folate status and duration of the disease (P = 0.01). Patients with hyperhomocysteinemia without folate deficiency had 2.5 times as many carcinogenic lesions as patients with normal homocysteinemia (P = 0.08). Conclusions: Our data suggest that in IBD patients with normal homocysteinemia, the increase in carcinogenic risk is negligible. Conversely, in patients with hyperhomocysteinemia, folate deficiency may be associated with increased colorectal carcinogenesis in IBD patients. (Inflamm Bowel Dis 2007) [source] Incidence and Prognosis of Colorectal Dysplasia in Inflammatory Bowel Disease: A Population-based Study from Olmsted County, Minnesota,INFLAMMATORY BOWEL DISEASES, Issue 8 2006Tine Jess MD Abstract Background and Aims: The risk, fate, and ideal management of colorectal dysplasia in inflammatory bowel disease (IBD) remain debated. We estimated the incidence, long-term outcome, and risk factors for progression of colorectal dysplasia (adenomas [adenoma-associated lesions or masses (ALMs)], flat dysplasia, and dysplasia-associated lesions or masses [DALMs]) in a population-based IBD cohort from Olmsted County, Minnesota. Materials and Methods: The Rochester Epidemiology Project was used to identify cohort patients with colorectal dysplasia. Medical records were reviewed for demographic and clinical characteristics. Histology slides were reviewed by a pathologist blinded to previous pathology reports. The cumulative incidence of dysplasia was estimated, and the association between patient characteristics and recurrence/progression of dysplasia was assessed using proportional hazards regression. Results: Twenty-nine (4%) IBD patients developed flat dysplasia (n = 8), DALMs (n = 1), ALMs in areas of IBD (n = 18), or ALMs outside areas of IBD (n = 2). Among 6 patients with flat low-grade dysplasia (fLGD) who did not undergo colectomy, none progressed during a median of 17.8 (range 6,21) years of observation with a median of 3 (range 0,12) surveillance colonoscopies. Four (22%) patients with ALMs in areas of IBD who did not undergo surgery developed LGD or DALMs. Primary sclerosing cholangitis and dysplasia located proximal to the splenic flexure were significantly associated with risk for recurrence/progression of dysplasia. Conclusions: This population-based cohort study from Olmsted County, Minnesota did not confirm an increased risk of cancer related to fLGD, whereas 22% of patients with ALMs in areas of IBD developed fLGD or DALMs. [source] Patients with low-grade dysplasia should be advised to undergo colectomyINFLAMMATORY BOWEL DISEASES, Issue 4 2003Thomas A. Ullman M.D. No abstract is available for this article. [source] Genomic analysis of Barrett's esophagus after ablative therapy: Persistence of genetic alterations at tumor suppressor lociINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Mariska Hage Abstract Barrett's esophagus (BE) is a major predisposing factor for the development of esophageal adenocarcinoma. Current strategies for treatment of BE, both dysplastic and nondysplastic, include photodynamic therapy (PDT) and argon plasma coagulation (APC). However, the effect of ablative therapy at the genetic level is unclear. We performed loss of heterozygosity (LOH) analysis of BE in baseline and follow-up biopsy specimens from 21 patients with BE (17 male, 4 female) treated with PDT and/or APC. At baseline, 14 patients had intestinal metaplasia without dysplasia (MET), 4 low-grade dysplasia (LGD) and 3 high-grade dysplasia (HGD). LOH was assessed using a panel of 9 polymorphic markers for evaluation of the P53 gene on 17p, P16 on 9p, DCC and SMAD4 on 18q and the APC gene on 5q. The tissue specimens obtained at baseline (t = 0) were analysed, as well as the first (t = 1; mean interval: 4 months) and last (t = 2; mean interval: 8 months) available biopsy with residual or recurrent BE after ablation. At t = 0, allelic loss was detected of 5q in 27%, 9p in 56%, 17p in 31% and 18q in 6% of informative cases. At t = 1 (18 patients with persistent MET and 3 with LGD) and at t = 2 (8 MET, 2 LGD), the LOH patterns were not statistically different from t = 0. Further, multiple genetic lineages before and after therapy were detected in 15 cases illustrating the multiclonal nature of BE. We conclude that recurrent and/or persistent BE after ablative therapy still contains genetic alterations associated with malignant progression to cancer. Therefore, the goal of treatment should be the complete elimination of Barrett's mucosa. © 2005 Wiley-Liss, Inc. [source] Current practice compared with the international guidelines: endoscopic surveillance of Barrett's esophagusJOURNAL OF EVALUATION IN CLINICAL PRACTICE, Issue 5 2007Nassira Amamra MPH Abstract Rationale, aims and objectives, To describe the current practice for the surveillance of patients with Barrett's esophagus, to compare this practice with the national guidelines published by the French Society of Digestive Endoscopy in 1998 and to identify the factors associated with the compliance to guidelines. Method, To determine the attitudes of French hepatogastroenterologists to screening for Barrett's oesophagus, a postal anonymous questionnaire survey was undertaken. It was sent to 246 hepatogastroenterologists in the Rhone-Alpes area. We defined eight criteria allowed to assess the conformity of practices with the guidelines. We created three topics composed of several criterion. The topics analysed were ,Biopsies', ,Surveillance' and the diagnosis of high grade dysplasia. We studied the factors which could be associated with the compliance with the guidelines. Results, The response rate was 81.3%. For 58.0% of the gastroenterologists, endoscopic biopsy sampling were made according to French guidelines (four-quadrant biopsies at 2 cm intervals). Agreement was 78.0% regarding the interval of surveillance for no dysplasia (every 2 or 3 years) and 78.5% regarding the low-grade dysplasia (every 6 or 12 months). For the management of high-grade dysplasia, 28.6% actually confirm the diagnosis by a second anatomopathologist and 42.0% treated by proton pump inhibitor during 2 months. Concerning the biopsies, the young gastroenterologists and gastroenterologists practising in university hospitals had a better adherence to the guidelines (Relative Risk: 2.22, 95% CI 1.25,3.95 and 3.74, 95% CI 1.04,13.47, respectively). The other factors of risk were not statistically significant. Conclusions, The endoscopic follow-up is mostly realized in accordance with the national guidelines. However, there is a wide variability in individual current practice. [source] The Vienna classification applied to colorectal adenomasJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2006Carlos A Rubio Abstract Background and Aim:, In 1999, a group of Western and Asian pathologists gathered in Vienna reached consensus regarding the classification of gastrointestinal epithelial neoplasia. In this study, that classification is applied to colorectal adenomas. Methods:, Colorectal adenomas from 1552 patients were histologically classified according to the categories listed in Vienna: category 3, low-grade dysplasia; 4.1, high-grade dysplasia; 4.2, carcinoma in situ; 4.3, suspicious of intramucosal carcinoma; 5.1, intramucosal carcinoma; and 5.2, submucosal carcinoma. The criteria used to diagnose these lesions are described in detail. Adenomas with dysplasia (categories 3 and 4.1) or with carcinoma (categories 4.2, 4.3, 5.1 and 5.2) were analyzed separately. On basis of their configuration, adenomas were classified into tubular, tubulovillous, villous, serrated, microtubular and combined phenotypes (i.e. other than tubulovillous). Results:, The highest percentage of adenomas with carcinoma was found amongst villous adenomas (29.6%), followed by combined adenomas (27.8%). Villous adenoma with carcinoma was the most frequent neoplasia at all ages; combined adenomas with carcinoma were more frequent among younger patients. In elderly patients (,60 years of age) the highest percentage of adenomas with carcinoma was recorded in villous adenomas (28.1%), followed by serrated adenomas (19.2%). Villous adenomas and combined adenomas with carcinoma were more frequent in males. Conclusion:, The Vienna classification of colorectal adenomas seems to be influenced by parameters inherent to the patient such as age and sex and by the histological phenotype of the adenoma. With the recent improvement in medical technology it is possible to laser-microdisect a defined group of neoplastic glands (such as with carcinoma in situ or with intramucosal carcinoma) for specific molecular analysis. This modern technology will permit in future the translation of histological structures into molecular terms. [source] The influence of symptom type and duration on the fate of the metaplastic columnar-lined Barrett's oesophagusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2009P. A. C. GATENBY Summary Background Prolonged gastro-oesophageal reflux resulting in columnar metaplasia of the oesophagus is the main risk factor for oesophageal adenocarcinoma. Aim To examine the duration of symptoms and associations of different symptoms with the development of columnar-lined oesophagus, dysplasia and adenocarcinoma. Methods UK multicentre cohort study of patients with columnar-lined oesophagus whose date of symptom onset (1082 patients) and/or types of symptoms reported (1681 patients) were documented. Follow-up was examined by analysis of histological reports from the registering centers. Results Symptoms of dysphagia/odynophagia and nausea/vomiting were associated with development of dysplasia. High-grade dysplasia and adenocarcinoma were associated with dysphagia/odynophagia and weight loss. Median duration from symptom onset to detection of columnar-lined oesophagus without intestinal metaplasia: 2.6 years, columnar-lined oesophagus with intestinal metaplasia: 5.0 years, indefinite changes for dysplasia: 19.3 years and low-grade dysplasia: 30.0 years. One tenth of patients had developed high-grade dysplasia at 9.6 years and one tenth had developed adenocarcinoma at 13.8 years from symptom onset. Conclusions In patients with columnar-lined oesophagus, symptoms of dysphagia/odynophagia and nausea/vomiting were associated with a higher risk of development of dysplasia and adenocarcinoma. There is a trend for longer duration of symptoms to the detection of dysplasia. [source] Effects of long-term cyclo-oxygenase 2 selective and acid inhibition on Barrett's oesophagusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2007A. LANAS Summary Background There is an overexpression of cyclo-oxygenase 2 (COX-2) in Barrett's oesophagus (BO). Aim To determine the long-term effect of a COX-2 inhibitor on cellular mechanisms involved in BO. Methods A randomized controlled trial was conducted in BO patients allocated to continue the usual proton pump inhibitor (PPI) alone treatment, or PPI combined with rofecoxib (25 mg/day) for 6 months. Cell proliferation index and COX-2 expression in BO glands was determined in biopsy specimens at baseline and after treatment. Cell apoptosis, cyclin D1, p53 and vascular endothelial growth factor (VEGF) expression was also explored in a subset of patients. Student- t test and the U-Mann,Whitney test were used for quantitative and ordinal variables. Results Of 62 patients, 58 completed the study. A higher proportion of patients on rofecoxib + PPI exhibited a decrease in COX-2 expression compared to those treated with PPI alone, but cell proliferation index was not affected. Unlike PPI alone, rofecoxib + PPI was associated with an increase in the apoptotic cell index, a decrease in p53 cell staining and VEGF expression in mucosal vessels. No effect on low-grade dysplasia or cyclin D1 was observed. Conclusions The addition of rofecoxib to PPI therapy does not affect cell proliferation index in BO cells after 6 months of therapy, but does reduce COX-2 and VEGF expression and increases cell apoptosis. [source] Bottom-up cell proliferation with cyclin A and p27Kip1 expression in ulcerative colitis-associated dysplasiaPATHOLOGY INTERNATIONAL, Issue 1 2006Tetuo Mikami To analyze the cell kinetics of ulcerative colitis (UC)-associated dysplasia, cyclin A, cyclin D1, cyclin E, cdk2, cdk4, p21Waf1, and p27Kip1 were immunohistochemically examined, in comparison with sporadic tubular adenomas. Immunohistochemical labeling indices for each marker in formalin-fixed paraffin-embedded tissue sections were assessed in a total of 23 low-grade dysplasias, 27 high-grade dysplasias, and 14 invasive adenocarcinomas associated with UC. For comparison, 21 sporadic tubular adenomas with low-grade dysplasia, 33 with high-grade dysplasia, and 21 invasive adenocarcinomas were also examined. In UC-associated dysplasias, cyclin A and p27Kip1 were located in the lower parts of the crypts and p21Waf1 in the upper regions. In tubular adenomas, cyclin A, cdk4, p27Kip1, and p21Waf1 were all expressed in the upper parts of the crypts. The expression levels of cyclin D1, cyclin E, and cdk2 were low. The cell proliferation zone in UC-associated dysplasia is located towards the bases of the crypts with the strong expression of cyclin A and p27Kip1, in contrast to tubular adenomas, which have their cell proliferation zone in the upper parts of neoplastic crypts. It is considered that tumorigenesis with UC-associated dysplasia is of the bottom-up type, related to altered expression of cyclin A and p27Kip1. [source] Over-expression of polycomb group protein EZH2 relates to decreased expression of p16INK4a in cholangiocarcinogenesis in hepatolithiasis,THE JOURNAL OF PATHOLOGY, Issue 2 2008M Sasaki Abstract Polycomb group protein EZH2 and Bmi1 are reportedly involved in the progression of malignant tumours. We examined the participation of EZH2 in multi-step cholangiocarcinogenesis in hepatolithiasis with respect to tumour suppressor gene p16INK4a. We examined 20 hepatolithiatic livers with intrahepatic cholangiocarcinoma (ICC) and 10 histologically normal livers. Neoplastic biliary lesions were classified into biliary intraepithelial neoplasm (BilIN-1, 2 and 3) and invasive carcinoma. We selected 15 foci of invasive carcinoma, 8 BilIN-3 (carcinoma in situ), 12 BilIN-2 (high-grade dysplasia), 32 BilIN-1 (low-grade dysplasia) and 37 non-neoplastic biliary epithelia from these livers. Expression of p16INK4a, EZH2 and Bmi1 were surveyed in these foci. P16INK4a promoter methylation was examined in microdissected tissues. Taking advantage of two cell lines of CC (HuCTT-1 and TFK-1) and small interfering RNA (siRNA), the effects of the knockdown of EZH2 on p16INK4a methylation of CC cells were examined. Expression of p16INK4a, which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma, while EZH2 expression showed step-wise increase from BilIN-1, -2 and -3 to invasive carcinoma (p < 0.01). P16INK4a promoter hypermethylation was related to aberrant expression of EZH2. The knockdown of EZH2 in cultured CC cells decreased p16INK4a methylation and decreased binding of EZH2 to the p16INK4a gene promoter. The latter suggested that direct binding of EZH2 is involved in the regulation of the p16INK4a gene. Our data suggest that over-expression of EZH2 may induce hypermethylation of p16INK4a promoter followed by decreased expression of p16INK4a in the multi-step cholangiocarcinogenesis through intraepithelial neoplasm in hepatolithiasis. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasiasINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Ivy F.L. Tsui Abstract Genetic alteration in oral premalignant lesions (OPLs), the precursors of oral squamous cell carcinomas (OSCCs), may represent key changes in disease initiation and development. We ask if DNA amplification occurs at this early stage of cancer development and which oncogenic pathways are disrupted in OPLs. Here, we evaluated 50 high-grade dysplasias and low-grade dysplasias that later progressed to cancer for gene dosage aberrations using tiling-path DNA microarrays. Early occurrences of DNA amplification and homozygous deletion were frequently detected, with 40% (20/50) of these early lesions exhibiting such features. Expression for 88 genes in 7 recurrent amplicons were evaluated in 5 independent head and neck cancer datasets, with 40 candidates found to be overexpressed relative to normal tissues. These genes were significantly enriched in the canonical ERK/MAPK, FGF, p53, PTEN and PI3K/AKT signaling pathways (p = 8.95 × 10,3 to 3.18 × 10,2). These identified pathways share interactions in one signaling network, and amplification-mediated deregulation of this network was found in 30.0% of these preinvasive lesions. No such alterations were found in 14 low-grade dysplasias that did not progress, whereas 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multitarget FISH showed that amplification of EGFR and CCND1 can coexist in single cells of an oral dysplasia, suggesting the dependence on multiple oncogenes for OPL progression. Taken together, these findings identify a critical biological network that is frequently disrupted in high-risk OPLs, with different specific genes disrupted in different individuals. © 2009 UICC [source] Bottom-up cell proliferation with cyclin A and p27Kip1 expression in ulcerative colitis-associated dysplasiaPATHOLOGY INTERNATIONAL, Issue 1 2006Tetuo Mikami To analyze the cell kinetics of ulcerative colitis (UC)-associated dysplasia, cyclin A, cyclin D1, cyclin E, cdk2, cdk4, p21Waf1, and p27Kip1 were immunohistochemically examined, in comparison with sporadic tubular adenomas. Immunohistochemical labeling indices for each marker in formalin-fixed paraffin-embedded tissue sections were assessed in a total of 23 low-grade dysplasias, 27 high-grade dysplasias, and 14 invasive adenocarcinomas associated with UC. For comparison, 21 sporadic tubular adenomas with low-grade dysplasia, 33 with high-grade dysplasia, and 21 invasive adenocarcinomas were also examined. In UC-associated dysplasias, cyclin A and p27Kip1 were located in the lower parts of the crypts and p21Waf1 in the upper regions. In tubular adenomas, cyclin A, cdk4, p27Kip1, and p21Waf1 were all expressed in the upper parts of the crypts. The expression levels of cyclin D1, cyclin E, and cdk2 were low. The cell proliferation zone in UC-associated dysplasia is located towards the bases of the crypts with the strong expression of cyclin A and p27Kip1, in contrast to tubular adenomas, which have their cell proliferation zone in the upper parts of neoplastic crypts. It is considered that tumorigenesis with UC-associated dysplasia is of the bottom-up type, related to altered expression of cyclin A and p27Kip1. [source] | ||||||||||||||||||||||