P53 Labeling Index Research Articles

Clinicopathological comparison and assessment of Ki67, p53 and c-myc immunoexpression in carcinoma cuniculatum, verrucous carcinoma and microinvasive squamous cell carcinoma of the oral cavity

ObjectiveTo illustrate the clinicopathological comparison of carcinoma cuniculatum (CC), verrucous carcinoma (VC) and microinvasive squamous cell carcinoma (MISCC) and to compare the immunoexpression Ki67, p53 & c-myc in these entites. Material and methodsClinical and histopathological parameters observed in total 67 cases (12 cases of CC, 22 cases of VC and 27 cases of MISCC). Ki67 & p53 labelling index and c-myc immunoexpression (localization of stain (1: cytoplasmic; 2: nuclear; 3: both), intensity of stain (1: mild; 2: moderate; 3: strong) and distribution of stain in epithelium (1: basal third; 2: up to middle third; 3: up to upper third; 4: invasive islands)). ResultsCC predominantly showed keratin filled crypts, keratin microabscess, microsequestra formation and lymphocytic exocytosis. VC showed broad pushing invasive front, parakeratin plugging along with verrucous projections. Irregular infiltrating rete ridge pattern and severe cytological atypia were findings of MISCC. Ki67 LI was 12.70 % in CC, 23.34 % in VC and 28.27 % in MISCC. p53 LI was 44.167 % in CC, 30.18 % in VC and 29.51 % in MISCC. Ki67 LI showed statistically significance difference between CC and MISCC. Moderate to strong cytoplasmic immunoexpression was found in epithelium as well as in invasive islands of MISCC compared to CC and VC. ConclusionCC shows endophytic epithelium proliferation with mild to moderate dysplasia and no definite invasive front in contrast to VC. High p53 in CC basal cells correlate with more endophytic epithelial proliferation. Significant high Ki67 LI in invasive islands of MISCC supports its aggressive nature. p53, Ki67 and c-myc panel may be helpful as an adjunct in difficult cases with poorly oriented specimens.

Estrogen receptor beta expression in colitis-associated carcinoma in comparison with sporadic colonic tumor: An immunohistochemical study.

The rate of ulcerative colitis (UC)-related colorectal cancer (colitis-associated carcinoma) is increasing. Estrogen receptor (ER) beta expression has been studied separately in patients with sporadic colorectal cancer and those with colitis-associated carcinoma. However, no study has compared the expression in both of these cancer types. The present study aimed to evaluate the relationship between colitis-associated carcinoma and ERs and assess whether the expression of ER beta influences cell proliferation. This study included 45 surgically operated colitis-associated carcinomas, 43 high-grade dysplasias, 34 low-grade dysplasias, 36 sporadic colorectal cancers, 44 high-grade adenomas, and 34 low-grade adenomas. ER beta expression was evaluated with immunohistochemistry. Colitis-associated carcinoma showed significantly lower ER beta immunoexpression than sporadic colorectal lesions and high- and low-grade dysplasia. In seven colitis-associated carcinoma harboring both intensity score 3 (strong immunoexpression) and score 1 (weak immunoexpression) areas, the correlation among ER beta intensity, Ki-67, and p21 labeling index was assessed; an area with an ER beta intensity score of 3 showed a higher Ki-67 labeling index than that with score 1. In four out of the seven lesions, p21 labeling index was higher in the area of ER beta score 1 than in that of ER beta score 3. The data suggest that ER beta expression is an accelerating factor in colorectal tumors. This association may be lower in colitis-associated carcinoma than in sporadic colorectal cancer.

Correlation of Apparent Diffusion Coefficient With Proliferation and Apoptotic Indexes in a Murine Model of Fibrosarcoma: Comparison of Four Methods for MRI Region of Interest Positioning.

Diffusion-weighted imaging (DWI) has demonstrated great potential in predicting the expression of tumor cell proliferation and apoptosis indexes. To evaluate the impact of four region of interest (ROI) methods on interobserver variability and apparent diffusion coefficient (ADC) values and to examine the correlation of ADC values with Ki-67, Bcl-2, and P53 labeling indexes (LIs) in a murine model of fibrosarcoma. Prospective, animal model. A total of 22 female BALB/c mice bearing intramuscular fibrosarcoma xenografts. A 3.0 T/T1-weighted fast spin-echo (FSE), T2-weighted fast relaxation fast spin-echo, and DWI PROPELLER FSE sequences. Four radiologists measured ADC values using four ROI methods (oval, freehand, small-sample, and whole-volume). Immunohistochemical assessment of Ki-67, Bcl-2, and P53 LIs was performed. Interclass correlation coefficient (ICC), one-way analysis of variance followed by LSD-t post hoc analysis, and Pearson correlation test were performed. The statistical threshold was defined as a P-value of <0.05. All ROI methods for ADC measurements showed excellent interobserver agreement (ICC range, 0.832-0.986). The ADC values demonstrated significant differences among the four ROI methods. The ADC values for oval, freehand, small-sample, and whole-volume ROI methods showed a moderately negative correlation with Ki-67 (r=-0.623; r=-0.629; r=-0.642, and r=-0.431) and Bcl-2 (r=-0.590; r=-0.597; r=-0.659, and r=-0.425) LIs, but no correlation with P53 LI (r=0.364, P=0.104; r=0.350, P=0.120; r=0.379, P=0.091; r=0.390, P=0.080). The ADC value can be used to evaluate cell proliferation and apoptosis indexes in a murine model of fibrosarcoma, employing the small-sample ROI as a reliable method. 1 TECHNICAL EFFICACY: Stage 3.

Non-invasive prediction of p53 and Ki-67 labelling indices and O-6-methylguanine-DNA methyltransferase promoter methylation status in adult patients with isocitrate dehydrogenase wild-type glioblastomas using diffusion-weighted imaging and dynamic susceptibility contrast-enhanced perfusion-weighted imaging combined with conventional MRI

To assess whether conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI) could non-invasively predict p53 and Ki-67 labelling index (LI) and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in adult isocitrate dehydrogenase (IDH) wild-type glioblastomas. The conventional MRI, DWI, and DSC-PWI results of 120 adult patients with IDH wild-type glioblastomas were reviewed retrospectively and their efficacy was analysed using chi-square tests or Fisher's exact test. Relative minimum apparent diffusion coefficient (rADCmin) and relative maximum cerebral blood volume (rCBVmax) values were compared between glioblastomas with different molecular statuses using the Mann-Whitney U-test. Receiver operating characteristic (ROC) curves and logistic regression were used to evaluate predictive performance. Glioblastomas with a high p53 LI were more likely to show a well-defined enhancement margin (p=0.047). Glioblastomas in the high-Ki-67-LI group demonstrated significantly lower rADCmin (p<0.001) and higher rCBVmax (p=0.001) values than those in the low-Ki-67-LI group. Tumours without MGMT promoter methylation showed lower rADCmin (p<0.001) and higher rCBVmax (p<0.001) values than those with it. The rCBVmax value exhibited a greater efficacy in predicting the MGMT promoter methylation status of adult IDH wild-type glioblastomas than the rADCmin value (p=0.001). The present results suggest that conventional and DWI and DSC-PWI results are influenced by the molecular status of the glioblastoma and indicate that DWI and DSC-PWI may help to identify regions of high invasiveness within heterogeneous glioblastomas.

Proliferation, apoptosis and their regulatory protein expression in colorectal adenomas and serrated lesions

BackgroundAdenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis.MethodsWe conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics.ResultsAdenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value<0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p <0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p<0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions.ConclusionsOur findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis.ClinicalTrials.gov Identifier: NCT00272324

Risk of carcinogenesis in the biliary epithelium of children with congenital biliary dilatation through epigenetic and genetic regulation.

Congenital biliary dilatation (CBD), defined as pancreaticobiliary maljunction (PBM) with biliary dilatation, is a high risk factor for biliary tract cancer (BTC). KRAS and p53 mutations reportedly affect this process, but the mechanisms are unclear, as is the likelihood of BTC later in life in children with CBD. We investigated potential carcinogenetic pathways in children with CBD compared with adults. The subjects of this study were nine children with CBD and 13 adults with PBM (10 dilated, 3 non-dilated) without BTC who underwent extrahepatic bile duct resections, as well as four control patients who underwent pancreaticoduodenectomy for non-biliary cancer. We evaluated expressions of Ki-67, KRAS, p53, histone deacetylase (HDAC) and activation-induced cytidine deaminase (AID) in the biliary tract epithelium immunohistochemically. The Ki-67 labeling index (LI) and expressions of KRAS, p53, HDAC, and AID in the gallbladder epithelium were significantly higher or tended to be higher in both the children with CBD and the adults with PBM than in the controls. BTC may develop later in children with CBD and in adults with PBM, via HDAC and AID expression and through epigenetic and genetic regulation.

Case Report: Long-Term Chemotherapy With Hydroxyurea and Prednisolone in a Cat With a Meningioma: Correlation of FDG Uptake and Tumor Grade Assessed by Histopathology and Expression of Ki-67 and p53

A 15.5-year-old, neutered, male, domestic shorthair cat was presented with neurologic dysfunctions. At presentation, an obtunded mental status and vestibular ataxia were identified. On neurologic examination, postural reactions were decreased-to-absent in all four limbs, and pupillary light reflexes showed bilaterally delayed results. Magnetic resonance imaging was performed, and a demarcated lesion was identified in the third ventricle. The cat was tentatively diagnosed with a brain tumor, which was suspected to be a meningioma. The cat was treated with hydroxyurea and prednisolone. Mental status was considered more alert, and ataxia improved following treatment. On the 106th day after the commencement of treatment, a 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan was performed. On the PET images, a hypermetabolic region was found in the lesion. The average standardized uptake value of FDG was 2.47, and the tumor-to-normal-tissue ratio was 1.25. The cat died 408 days following the commencement of treatment, and a grade 1 meningioma was confirmed by postmortem histopathology. Immunohistochemistry for Ki-67 and p53 was performed. The labeling indices of Ki-67 and p53 were 2.56 and 0%, respectively. This case shows that chemotherapy with hydroxyurea and prednisolone may be considered in the treatment of feline meningiomas. Furthermore, this is the first case describing the application of FDG-PET to visualize a naturally occurring meningioma in a cat.

Time-course changes in 5-fluorouracil-induced neural progenitor cell damages in the developing rat brain.

5-Fluorouracil (5-Fu) is a DNA-damaging agent and teratogenic in rodents. This study aimed to investigate its influence on neural progenitor cells (NPCs) in the developing fetal rat brain. Dams were intraperitoneally injected with 5-Fu (50 mg/kg b.w.) on gestation day 13 and its effects on fetal NPCs were observed from 3 to 72 hours after treatment (HAT), via periodic examination at six intervals. In NPCs of the fetal brain, the p53-labeling index (LI%) was markedly elevated at 3 HAT. Pyknosis and cleaved caspase-3-LI% also increased at 3 HAT, reaching peak values at 9 and 12 HAT. These parallel changes suggested the induction of apoptosis through a p53-mediated pathway. Pyknotic NPCs were distributed across the ventricular zone (VZ) of the telencephalic wall until 12 HAT, and became localized in the medial and dorsal layers at 12 and 48 HAT. Significant decreases in the numbers of mitotic NPCs and BrdU-LI% were noted from 3 HAT and 24 HAT, respectively. BrdU-positive NPCs were located in the ventral and middle layer at 24 and 48 HAT. p21-positive cells were detected at 12 and 24 HAT. The present results demonstrated that p53-mediated apoptosis was induced in all phases of the cell cycle of the NPCs in the early stage after 5-FU treatment. Furthermore, apoptosis of NPCs and suppression of cell proliferative activity are the events that take place in parallel leading to prominent reduction in the width of the telencephalic wall.

Immunohistochemical differences in gastric mucosal damage between nodular and non-nodular gastritis caused by Helicobacter pylori infection.

In this study, the level of cell damage were analyzed immuno­histochemically to clarify the association between nodular gastritis and undifferentiated gastric cancer. Thirty patients of nodular gastritis were enrolled as the nodular gastritis group. Thirty patients of non-nodular gastritis were enrolled as the control group. They were evaluated according to the updated Sydney system and used for immunohistochemical staining (p53, Ki-67, E-cadherin, and 8-OHdG). The scores based on the updated Sydney system were significantly higher in the nodular group than in the non-nodular group for histologically assessed inflammation and activity in the gastric corpus (1.91 ± 0.77 vs 1.58 ± 0.60, p = 0.049, 0.83 ± 0.81 vs 0.44 ± 0.64, p = 0.032). On immunostaining, the detection of E-cadherin was lower in the nodular group for both the antrum (1.0 ± 0.62 vs 1.47 ± 0.85, p = 0.047) and the corpus (1.16 ± 0.81 vs 1.48 ± 0.71, p = 0.043) and the p53 labeling index of the gastric corpus was higher in the nodular group than in the non-nodular group (3.06 ± 1.94 vs 2.03 ± 1.99, p = 0.015). Nodular gastritis showed significant severe inflammation and immunohistochemical cell damage compared with non-nodular gastritis. These findings may play an important role in the oncogenesis of undifferentiated gastric cancer in nodular gastritis.

Comparative Analysis of Amide Proton Transfer MRI and Diffusion-Weighted Imaging in Assessing p53 and Ki-67 Expression of Rectal Adenocarcinoma.

The evaluation of prognostic factors in rectal carcinoma patients has important clinical significance. P53 status and the Ki-67 index have served as prognostic factors in rectal carcinoma. Amide proton transfer (APT) imaging has shown great potential in tumor diagnosis. However, few studies reported the value of APT imaging in evaluating p53 and Ki-67 status of rectal carcinoma. To investigate the feasibility of amide proton transfer MRI in assessing p53 and Ki-67 expression of rectal adenocarcinoma, and compare it with conventional diffusion-weighted imaging (DWI). Retrospective. Forty-three patients with rectal adenocarcinoma (age: 34-85 years). 3T/APT imaging using a 3D turbo spin echo (TSE)-Dixon pulse sequence with chemical shift-selective fat suppression, 2D DWI, and 2D T2 -weighted TSE. Mean tumor APT signal intensity (SImean ) and apparent diffusion coefficient (ADCmean ) were measured. Traditional tumor pathological analysis included WHO grades, pT (pathologic tumor) stages, and pN (pathologic node) stages. Expression levels of p53 and Ki-67 were determined by immunohistochemical assay. One-way analysis of variance (ANOVA); Student's t-test; Spearman's correlation coefficient; receiver operating characteristic (ROC) curve analysis. High-grade tumors, more advanced stage tumors, and tumors with lymph node involvement had higher APT SImean values: high grade (n = 15) vs. low-grade (n = 28), P < 0.001; pT2 (n = 10) vs. pT3 (n = 20) vs. pT4 (N = 13), P = 0.021; pN0 (n = 24) vs. pN1-2 (n = 19), P = 0.019. ADCmean differences were found in tumors with different pT stage: pT2 (n = 10) vs. pT3 (n = 20) vs. pT4 (N = 13), P = 0.013, but not in tumors with different histologic grade: high grade (n = 15) vs. low-grade (n = 28), P = 0.3536; or pN stage: pN0 (n = 24) vs. pN1-2 (n = 19), P = 0.624. Tumor with p53 positive status had higher APT SImean than tumor with negative p53 status (2.363 ± 0.457 vs. 2.0150 ± 0.3552, P = 0.014). There was no difference in ADCmean with p53 status (1.058 ± 0.1163 10-3 mm2 /s vs. 1.055 ± 0.128 10-3 mm2 /s, P = 0.935). APT SImean and ADCmean were significantly different in tumors with low and high Ki-67 status (1.7882 ± 0.11386 vs. 2.3975 ± 0.41586, P < 0.001; 1.1741 ± 0.093 10-3 mm2 /s vs. 1.0157 ± 0.10459 10-3 mm2 /s, P < 0.001, respectively). APT SImean exhibited a positive correlation with p53 labeling index and Ki-67 labeling index (r = 0.3741, P = 0.0135; r = 0.7048; P < 0.001, respectively). ADCmean showed no correlation with p53 labeling index, but a negative correlation with Ki-67 labeling index (r = -0.5543, P < 0.0001). ROC curves demonstrated that APT SImean had significantly higher diagnostic ability for differentiation of high Ki-67 expression of rectal adenocarcinoma than ADCmean (81.2% vs. 78.12%, 90.91% vs. 63.64; P < 0.001 vs. P = 0.017), while no difference was found in predicting p53 status (92.86% vs. 71.4%, 53.33% vs. 66.7%; P < 0.001 vs. P = 0.0471). APT SImean was related to p53 and Ki-67 expression levels in rectal adenocarcinoma. APT imaging may serve as a noninvasive biomarker for assessing genetic prognostic factors of rectal adenocarcinoma. 3 TECHNICAL EFFICACY STAGE: 2.

Immunoexpression of p53 and ki-67 correlated with clinicopathological parameters in predicting recurrence of oral squamous cell carcinoma

Background: Prognosis of oral squamous cell carcinoma (OSCC) can be predicted by evaluating both clinicopathological parameters and molecular markers. Understanding the reasons of recurrence is important to increase the morbidity and mortality of the patient.&#x0D; Objectives: The objectives are to study the immunoexpression of p53 and Ki-67 in recurrent and non recurrent OSCC. And correlate the clinicopathological parameters among non-recurrent and recurrent OSCC to predict the prognosis of OSCC.&#x0D; Methods: Clinicopathological and immunoexpression of p53 and Ki-67 at the histologically negative margin (HNM) and invasive tumor front (ITF) were assessed in 50 cases of non-recurrent and recurrent OSCC. Overall survival and disease free survival was estimated. Statistical tests like Mann Whitney U test, t Test, Pearson correlation coefficient, Kaplan Meier curve and Log Rank test were used.&#x0D; Results: The Labelling Index (LI) of p53 and Ki-67 was marginally higher in recurrent than in non-recurrent OSCC cases. When compared with clinicopathologic parameters, non-recurrent OSCC cases showed no significance with p53 LI in margin and ITF except for site, muscle invasion, pattern of invasion (POI) and muscle invasion, whereas in recurrent OSCC cases p53 LI in HNM and ITF did not show any statistical significance except for duration. In both groups, OS and DFS was higher in patients with lesser LI while higher in the greater LI but more number of deaths occurred in this category respectively.&#x0D; Conclusion: To conclude p53 and Ki-67 positivity in the HNM and ITF of non-recurrent and recurrent OSCC was seen and thus can be an important marker for identification of high and low risk individuals.

Ki-67 labeling index and expression of p53 are non-predictive for invasiveness and tumor size in functional and nonfunctional pituitary adenomas.

It is still controversial whether an increased proliferation index is correlated with the tumor invasiveness of pituitary adenomas. A homogeneous large monocentric series of pituitary adenomas was retrospectively analyzed. The correlation between the proliferation indices (Ki-67 and p53 expression levels) and invasiveness and size of pituitary adenomas was investigated in primary operated and recurrent adenomas. Four hundred thirty-nine patients after resection of pituitary adenomas were retrospectively included (43 recurrent tumors, 196 null cell adenomas, 86 somatotroph adenomas, 55 corticotroph adenomas, 55 prolactinomas, 4 thyreotroph adenomas). The maximum tumor diameter and tumor invasiveness in Knosp grading were assessed and Ki-67 and p53 immunostaining was performed. The role of invasiveness was evaluated using a cumulative odds ordinal logistic regression. For calculating the effect of tumor size, a one-way analysis of variance (ANOVA) was conducted. Overall and in the subgroups, no significant correlation between proliferation indices and mean tumor diameter was found. No significant predictive expression value of Ki-67 and p53 on tumor invasiveness and in recurrent tumors could be demonstrated. There was a tendency that Ki-67 LI and p53 LI are higher in recurrent corticotroph adenomas and lactotroph adenomas but values did not reach the significant level. Invasive character of pituitary adenomas is neither correlated with increased Ki-67 LI nor with increased p53 expression. Proliferation parameters are independent from adenoma size at initial presentation. The partly elevated expression of Ki-67 in recurrent tumors underlines the clinical importance of the marker.

Clinicopathologic study on a rare variant of ameloblastoma with basal cell features.

To investigate the clinical features, pathologic manifestations, and biologic behaviors of a variant of ameloblastoma with basal cell features (AM-BC). Following retrospective review of the clinical and pathological data of six cases of AM-BC, we described their histological and immunohistochemical (IHC) features and discussed the biologic behaviors, prognoses, pathogenesis, and clinical relevance of AM-BC. Direct sequencing of polymerase chain reaction products was also performed in all cases. The six cases of AM-BC involved four women and two men, aged 22-82years. Four lesions occurred in the maxilla and two in the mandible. Histologically, the basal cells tended to be arranged as unequally sized follicles, strands, or cords of odontogenic epithelium in the connective tissue stroma. Little or no stellate reticulum was present in the central portion of the nest. Expression of CKs was consistent with other histological variants of ameloblastoma (AM), but AM-BC had significantly higher p53 and Ki-67 (p<0.05) labeling indices than other histological variants of AM. Two patients had BRAF gene mutations. Ameloblastoma with basal cell features is a very rare variant of AM. Our study showed the differences and relationships that exist between AM-BC and other variants of AM, which could enhance understanding of AM-BC.

Meningiomas Display a Specific Immunoexpression Pattern in a Rostrocaudal Gradient: An Analysis of 366 Patients

Meningiomas are heterogeneous, with differences in anatomical, histopathological, and clinical characteristics. Such spatial variability in meningioma biology is thought to result from differences in the expression of critical developmental regulators. We hypothesized that the variability in meningioma biology would follow gradients such as in embryology and tested a cohort of 366 meningiomas for histopathological and immunohistochemical gradients. The medical records from 366 patients treated for meningiomas from 2003 to 2016 were retrospectively analyzed for age, gender, anatomical localization, recurrence-free survival, overall survival, histopathological diagnosis, and immunohistochemistry findings for 6 markers: epithelial membrane antigen (EMA), progesterone receptor (PR), CD34, S100, p53, and Ki-67 labeling index. EMA, PR, S100, p53, and CD34 were expressed in 94%, 73%, 49%, 26%, and 23% of the tumors, respectively. p53 expression correlated positively with Ki-67 and World Health Organization (WHO) grade (rτ= 0.31 and rτ= 0.4, respectively). PR positivity correlated inversely with S100, p53, Ki-67, and WHO grade (rτ=-0.19, rτ=-0.14, rτ=-0.15, and rτ=-0.16, respectively). All secretory meningiomas were positive for EMA and PR and negative for S100, and this pattern exhibited a rostrocaudal gradient. The overall proportion of EMA+PR+S100- cases was significantly lower in the cranial vault (30.3%) than in the skull base (45.89%; P= 0.021). The proportion of WHO grade II-III tumors was greater in cranial vault than in skull base meningiomas. Unsupervised methods detected an association between the anatomical location and tumor biology in meningiomas. Unlike the categorical associations that former studies had indicated, the present study revealed a rostrocaudal gradient in both the cranial vault and the skull base, correlating with human developmental biology.

Role of p53 and Ki-67 immunomarkers in oral premalignant lesions and squamous cell carcinoma: a hospital based study in BPKIHS

Background: As most of the oral squamous cell carcinoma develop from precursor premalignant lesions, it would be helpful if the malignant transformation is detected early in premalignant state. The objective of the research was to study the role of immunohistochemical expression of p53 and Ki-67 in oral premalignant lesion and squamous cell carcinoma.Materials and Methods: The expression of immunomarkers p53 and Ki67 were studied on formalin fixed paraffin embedded tissue sections from human oral squamous mucosal lesion for duration of 1 year. Results: Of total 36 cases, 80% cases of keratosis without dysplasia showed basal pattern of p53 staining while 47.1% cases of squamous cell carcinoma showed p53 staining in all layers of epithelium. The median p53 Labelling Index of squamous cell carcinoma was more than those of keratosis with and without dysplasia though the result was statistically non-significant. 50.0% cases of keratosis without dysplasia and 83.3% cases of keratosis with dysplasia displayed Ki-67 immunostaining confined to basal and suprabasal layer whereas 94.1% cases of squamous cell carcinoma showed Ki-67 positivity in all layers of epithelium. Median Ki-67 Labelling Index increased from keratosis without dysplasia to keratosis with dysplasia to squamous cell carcinoma, difference being statistically significant. A positive and insignificant correlation was observed between p53 and Ki-67 Labelling Index.Conclusion: Increased expressions of Ki-67 and p53 in oral squamous cell carcinoma compared to premalignant lesion suggest that they may be useful indicator of malignant transformation in dysplastic lesion.

Botryoid odontogenic cyst. Exploration of proliferative activity, apoptosis and expression of TP53 and BCL2 compared to the histologically identical lateral periodontal and gingival cysts

The botryoid odontogenic cyst (BOC) is a rare, locally more aggressive variant of the usually indolent lateral periodontal cyst (LPC) and gingival cyst (GC). A recent case of BOC provided an opportunity for an exploratory study on the causes of its more aggressive behavior. The limited objective was to see if the BOC was sufficiently different from the other cysts to warrant an investment in a large study. Sections of neutral buffered formalin fixed, paraffin-embedded tissues from the BOC and archival specimens of four GCs, four LPCs and three odontogenic keratocysts (OKCs) were stained using immunohistochemistry for Ki-67, a marker of proliferating cells, caspase-3, a marker of cells undergoing apoptosis, tumor suppressor p53, and the apoptosis inhibitor BCL2. The mean labeling index (LI) of immunoreactive cyst epithelial cells was computed for each antibody and type of cyst. Compared to the LPCs and GCs, the BOC exhibited a moderately larger Ki-67/caspase-3 LI difference, which indicates that the BOC had a net higher rate of growth. We found a much higher level of LI, therefore likely dysregulation of p53. We also found a much higher LI of BCL2. The LIs of p53 and BCL2 in the BOC were similar to and more than twice that of the OKCs, respectively. Although meaningful statistical analysis was precluded by our use of only one case of BOC and a small number of the other cysts, the high p53 and very high BCL2 labeling indices of the BOC offer a potential explanation for its reportedly more aggressive behavior that clearly is worthy of further investigation.

Metaplastic Carcinoma with Chondroid Differentiation Arising in Microglandular Adenosis.

Microglandular adenosis (MGA) of the breast is a rare, benign proliferative lesion but with a significant rate of associated carcinoma. Herein, we report an unusual case of metaplastic carcinoma with chondroid differentiation associated with typical MGA. Histologically, MGA showed a direct transition to metaplastic carcinoma without an intervening atypical MGA or ductal carcinoma in situ component. The immunohistochemical profile of the metaplastic carcinoma was mostly similar to that of MGA. In both areas, all the epithelial cells were positive for S-100 protein, but negative for estrogen receptor, progesterone receptor, HER2/neu, and epidermal growth factor receptor. An increase in the Ki-67 and p53 labelling index was observed from MGA to invasive carcinoma. To the best of our knowledge, this is the first case of metaplastic carcinoma with chondroid differentiation arising in MGA in Korea. This case supports the hypothesis that a subset of MGA may be a non-obligate morphologic precursor of breast carcinoma, especially the triple-negative subtype.

Stage I lung adenocarcinoma: the value of quantitative CT in differentiating pathological subtypes and predicting growth of subsolid nodules.

The aim of this study was to investigate feasibility of quantitative computed tomography (CT) measurements in predicting invasiveness and growth of nodular ground glass opacities (nGGOs).A set of 203 patients (group A) with nGGOs that were confirmed stage-I adenocarcinomas and 79 patients (group B) with nGGOs that were completely followed up were included. Lesions diameters, volume (VOL), maximum (MAX), mean (MEN), and standard deviation (STD) of CT attenuation were measured. P53 labeling index (LI) was evaluated through immunohistochemistry in group-A patients. Multivariate linear stepwise regressions were performed based on group-A lesions to calculate P53-LI prediction from CT measurements. The receiver operating characteristic (ROC) curve analyses were performed to assess the performance of P53-LI prediction in predicting invasiveness and growth of nGGOs. The Cox regression analysis was conducted to identify correlation between P53-LI Prediction and volume doubling time (VDT) of lesions in group B.Diameter, VOL, MEN, STD, and the P53 LI showed significant differences between lesions of different pathological invasiveness (P < .01). By multivariate linear regressions, MEN and STD were identified as independent variables indicating P53 LI (P < .001); thus, an equation was established to calculate P53-LI Prediction as: P53LI Prediction = 0.013 × MEN + 0.024 × STD + 9.741 (R square = 0.411, P < .001). The P53-LI Prediction showed good performance, similar as the actual one, in differentiating pathological invasiveness of nGGOs. In addition, the P53-LI Prediction demonstrated excellent performance in predicting growth of nGGOs (AUC = 0.833, P < .001) and independently forecasted VDT of nGGOs (β = 1.773, P < .001).The P53-LI Prediction that was calculated from preoperative quantitative CT measurements of nGGOs indicates lesions’ invasiveness and allows for predicting growth of nGGOs.

P53 and ki67 as biomarkers in determining response to chemoprevention for oral leukoplakia.

We performed a randomized controlled chemoprevention trial of oral leukoplakia by administrating a low dose of beta-carotene and vitamin C supplements. 17% of subjects in the experimental arm (4/23) demonstrated clinical remission (complete or partial response) at completion of the trial. The objective of this study was to determine whether baseline expression of p53 and ki67 demonstrated any differences between those responding or not responding to our intervention. A secondary objective was to elucidate any relationship between dietary factors and clinical responses. For this biomarker study, we included all subjects in the experimental group (n = 23) who were non-smokers. Among 16 who completed the trial for 1 year of supplementation, there were four responders and 12 non-responders at 1-year follow-up. Following immuno-staining for p53 and ki67, the percentage of positive cell nuclei were analyzed as labeling index (LI). Expression of p53 was greater in basal layers than in para-basal layers. Mean para-basal LI of p53 was higher in non-responding (26.0) than in responding subjects (11.2) (P = 0.028). ki67 LIs were not significantly different in the two groups. Expression of p53 was inversely related to clinical response to the supplements. Other biomarkers that may recognize subject's responsiveness to chemoprevention require further study.

PITX1 is a novel predictor of the response to chemotherapy in head and neck squamous cell carcinoma.

The pituitary homeobox 1 (PITX1) protein is essential for developmental processes in humans. Previously, PITX1 was identified as a possible tumor suppressor gene in various types of human carcinoma. However, the association between PITX1 and human head and neck squamous cell carcinoma (HNSCC) remains to be elucidated. Immunohistochemical analysis was performed to examine the expression levels of PITX1 in 47 cases of HNSCC, and in 4 control cases. The expression of p53 was also examined in these cases. The labeling indices (LIs) were calculated, and the correlations between clinical factors (chemosensitivity, prognosis and the degree of differentiation) and the LIs were assessed. The PITX1 LI in HNSCC was 27.4±14.5%, which was significantly lower compared with the LIs of the control samples: 76.9±6.97% (P<0.05). Additionally, the PITX1 LIs were 39.9±6.2, 26.9±16.9 and 24.2±11.8% in the complete response (CR), partial response (PR), stable disease or progressive disease (SD/PD) groups, respectively. The PITX1 LI in the CR group revealed the highest result between the all groups, and it was significantly greater compared with that in the SD/PD group (P<0.01). The p53 LIs were 24.5±19.9, 25.7±16.9 and 19.8±13.8 in the CR, PR and SD/PD groups, respectively (P>0.05). Neither the PITX1 nor the p53 LIs were a statistically significant indicator of the prognosis. PITX1 is a candidate tumor suppressor gene and a possible predictive biomarker of chemosensitivity of human HNSCC.