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1.  Overexpression of both platelet-derived growth factor-BB and vascular endothelial growth factor-C and its association with lymphangiogenesis in primary human non-small cell lung cancer 
Diagnostic Pathology  2014;9:128.
Abstract
Background
Metastatic spread of tumor through lymphatic vasculature is an important adverse prognostic factor in a variety of human cancer and tumor lymphangiogenesis requires the interplay of several growth factors. Platelet-derived growth factor (PDGF)-BB and vascular endothelial growth factor (VEGF)-C are two important molecules involving in tumor metastasis and lymphangiogenesis. Therefore, the aim of this study was to investigate the coexpression of PDGF-BB and VEGF-C in primary human non-small cell lung cancer (NSCLC) and its association with lymphangiogenesis.
Methods
Using immunohistochemical staining, PDGF-BB and VEGF-C expression were detected in 109 primary NSCLC tissues, while the lymphatic micro-vessel density (LMVD) was counted.
Results
Of 109 cases, PDGF-BB and VEGF-C overexpression was 66.97% (73/109) and 65.14% (71/109), respectively. 52 (47.7%) had overexpression of both PDGF-BB and VEGF-C (P + V+), 21 (19.3%) overexpression of PDGF-BB but low expression of VEGF-C (P + V-), 19(17.4%) overexpression of VEGF-C but low expression of PDGF-BB (P-V+) and 17(15.6%) low expression of both PDGF-BB and VEGF-C (P-V-). PDGF-BB expression was positively related to that of VEGF-C (r = 0.451, p = 0.034). LMVD in cases with P + V + was much higher than those with P-V- (p = 0.004). In addition, the patients with P + V + were younger and also had larger tumor size, more likely lymph node metastasis and worse histological differentiation than those with P-V-. Moreover, the overall survival (OS) of patients with P + V + was shorter than those with P-V- (p = 0.015).
Conclusion
Coexpression of both PDGF-BB and VEGF-C was associated with lymphangiogenesis and poor prognosis in NSCLC, and might play a critical role in NSCLC progression.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2261801312571320
doi:10.1186/1746-1596-9-128
PMCID: PMC4085714  PMID: 24972450
Platelet-derived growth factor-BB; Vascular endothelial growth factor-C; Lymphatic micro-vessel density; Non-small cell lung cancer
2.  Significant association between TAP2 polymorphisms and rheumatoid arthritis: a meta-analysis 
Diagnostic Pathology  2014;9:129.
Background
Rheumatoid arthritis (RA) is a severe chronic immune mediated inflammatory disease that has been shown to be associated with human leukocyte antigen (HLA) loci. The transporter associated with antigen processing 2 (TAP2) has been identified to play an important role in the HLA-associated diseases and immune response. The goal of our meta-analysis was to summarize the contribution of TAP2 polymorphisms to the risk of RA.
Methods
Meta-analyses were performed between RA and 3 TAP2 coding polymorphisms that comprised TAP2-379Ile > Val (rs1800454), TAP2-565Ala > Thr (rs2228396) and TAP2-665Thr > Ala (rs241447). The meta-analyses were involved with 9 studies (24 individual studies) among 973 cases and 965 controls.
Results
Meta-analyses showed that TAP2-379Ile allele was significantly associated with an increased risk of RA (p = 0.0002, odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.18-1.74). This association was further shown only in the dominant model (p = 0.006, OR = 1.59, 95% CI = 1.14-2.22). Subgroup analyses by ethnicity revealed that the association of TAP2-379Ile was significant in Asians (p = 0.03, OR = 1.38, 95% CI = 1.04-1.83). In addition, another significant association of TAP2-565Thr allele with RA was observed in Europeans (p = 0.002, OR = 1.62, 95% CI = 1.20-2.20).
Conclusions
Our meta-analyses suggested that TAP2-379Ile allele was significantly associated with a 59% increased risk in the dominant effect model. Subgroup analyses by ethnicity showed that TAP2-379-Ile increased the risk of RA by 38% in Asians and TAP2-565Thr increased the risk of RA by 38% in Europeans.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2097080313124700
doi:10.1186/1746-1596-9-129
PMCID: PMC4090395  PMID: 24972609
Rheumatoid arthritis; Polymorphism; Meta-analysis; TAP2; Ethnicity
3.  Heterogenous mismatch-repair status in colorectal cancer 
Diagnostic Pathology  2014;9:126.
Abstract
Background
Immunohistochemical staining for mismatch repair proteins is efficient and widely used to identify mismatch repair defective tumors. The tumors typically show uniform and widespread loss of MMR protein staining. We identified and characterized colorectal cancers with alternative, heterogenous mismatch repair protein staining in order to delineate expression patterns and underlying mechanisms.
Methods
Heterogenous staining patterns that affected at least one of the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 were identified in 14 colorectal cancers. Based on alternative expression patterns macro-dissected and micro-dissected tumor areas were separately analyzed for microsatellite instability and MLH1 promoter methylation.
Results
Heterogenous retained/lost mismatch repair protein expression could be classified as intraglandular (within or in-between glandular formations), clonal (in whole glands or groups of glands) and compartmental (in larger tumor areas/compartments or in between different tumor blocks). These patterns coexisted in 9/14 tumors and in the majority of the tumors correlated with differences in microsatellite instability/MLH1 methylation status.
Conclusions
Heterogenous mismatch repair status can be demonstrated in colorectal cancer. Though rare, attention to this phenomenon is recommended since it corresponds to differences in mismatch repair status that are relevant for correct classification.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1771940323126788
doi:10.1186/1746-1596-9-126
PMCID: PMC4074838  PMID: 24968821
Mismatch repair; immunohistochemistry; heterogeneity; MLH1; MSH2; MSH6; PMS2
4.  Unusual presentation of primary T-cell lymphoblastic lymphoma: description of two cases 
Diagnostic Pathology  2014;9:124.
Abstract
Background
T-cell lymphoblastic lymphoma comprises approximately 85-90% of all lymphoblastic lymphomas. It often arises as a mediastinal mass, and with bone marrow involvement. Presentation at other sites without nodal or mediastinal localization is uncommon.
Case report
We describe clinical, histologic, immunohistochemical, and molecular features of two cases of primary T-cell lymphoblastic lymphoma arising respectively in uterine corpus and testis. The tumors were composed by medium to large cells, exhibiting a diffuse pattern of growth but sometimes forming indian files or pseudo-rosettes. The neoplastic cells strongly expressed TdT and T-cell markers in both uterine corpus and testis. However, the testis case also showed aberrant expression of B-cell markers, thus molecular biology was necessary to achieve a final diagnosis. T-cell receptor gene rearrangement analysis identified a T-cell origin.
Conclusions
To the best of our knowledge, only one doubtful previous case of primary uterine T-cell lymphoblastic lymphoma and no previous cases of primary testicular T-cell lymphoblastic lymphoma have been reported. Due to the morphology of neoplastic cells, a challenging differential diagnosis with all the tumors belonging to the so-called small round blue cell tumor category is mandatory. In ambiguous lineage cases, molecular biology may represent an adequate tool to confirm diagnosis.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1559880973128230
doi:10.1186/1746-1596-9-124
PMCID: PMC4078934  PMID: 24950962
Lymphoblastic lymphoma; TdT; molecular biology
5.  Silencing BMP-2 expression inhibits A549 and H460 cell proliferation and migration 
Diagnostic Pathology  2014;9:123.
Abstract
Background
Bone morphogenetic protein 2 (BMP-2) is a member of the TGF-β superfamily that is closely correlated with many malignancies, particularly lung cancer. However, the effects of silenced BMP-2 on lung cancer cell proliferation and migration are not clear.
Methods
Using quantitative real-time RT-PCR, BMP-2 mRNA expression was detected in 61 non-small cell lung cancer (NSCLC) samples. Survival curves were generated using follow-up data. Relationships between clinical or pathological characteristics and prognosis were analyzed. Cell viability assays and transwell migration assays were used to evaluate the effects of BMP-2 silencing on cell proliferation and migration of A549 and H460 cells.
Results
BMP-2 mRNA expression was higher in NSCLC tissues compared to matched adjacent normal tissues (P < 0.01). High BMP-2 expression levels were significantly associated with the occurrence of lymph node metastases and tumor stage (P < 0.05). There were significant differences in survival curves between groups with metastatic lymph nodes and non-metastatic lymph nodes, as well as between groups with low BMP-2 expression and groups with high BMP-2 expression. In addition, we observed decreased proliferation and migration rates of the NSCLC-derived cell lines A549 and H460 that were transfected with siBMP-2 (P < 0.05).
Conclusion
BMP-2 mRNA is overexpressed in NSCLC samples and is a risk factor for survival in patients with NSCLC. BMP-2 silencing can significantly inhibit A549 and H460 cell proliferation and migration.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4263254471298866
doi:10.1186/1746-1596-9-123
PMCID: PMC4070338  PMID: 24946687
Non-small cell lung cancer (NSCLC); BMP-2; siRNA; Proliferation; Migration
6.  Inter-observer variability between general pathologists and a specialist in breast pathology in the diagnosis of lobular neoplasia, columnar cell lesions, atypical ductal hyperplasia and ductal carcinoma in situ of the breast 
Diagnostic Pathology  2014;9:121.
Background
This study aimed to assess inter-observer variability between the original diagnostic reports and later review by a specialist in breast pathology considering lobular neoplasias (LN), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) of the breast.
Methods
A retrospective, observational, cross-sectional study was conducted. A total of 610 breast specimens that had been formally sent for consultation and/or second opinions to the Breast Pathology Laboratory of Federal University of Minas Gerais were analysed between January 2005 and December 2010. The inter-observer variability between the original report and later review was compared regarding the diagnoses of LN, CCL, ADH, and DCIS. Statistical analyses were conducted using the Kappa index.
Results
Weak correlations were observed for the diagnoses of columnar cell change (CCC; Kappa = 0.38), columnar cell hyperplasia (CCH; Kappa = 0.32), while a moderate agreement (Kappa = 0.47) was observed for the diagnoses of flat epithelial atypia (FEA). Good agreement was observed in the diagnoses of atypical lobular hyperplasia (ALH; Kappa = 0.62) and lobular carcinoma in situ (LCIS; Kappa = 0.66). However, poor agreement was observed for the diagnoses of pleomorphic LCIS (Kappa = 0.22). Moderate agreement was observed for the diagnoses of ADH (Kappa = 0.44), low-grade DCIS (Kappa = 0.47), intermediate-grade DCIS (Kappa = 0.45), and DCIS with microinvasion (Kappa = 0.56). Good agreement was observed between the diagnoses of high-grade DCIS (Kappa = 0.68).
Conclusions
According to our data, the best diagnostic agreements were observed for high-grade DCIS, ALH, and LCIS. CCL without atypia and pleomorphic LCIS had the worst agreement indices.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1640072350119725.
doi:10.1186/1746-1596-9-121
PMCID: PMC4071798  PMID: 24948027
Breast cancer; Lobular neoplasia; Columnar cell lesions; Atypical ductal hyperplasia; Ductal carcinoma in situ; Inter-observer variability; Agreement
7.  Glutathione S-transferase M1 null genotype meta-analysis on gastric cancer risk 
Diagnostic Pathology  2014;9:122.
Background
Glutathione S-transferases (GSTs) have proved to be involved in the detoxifying several carcinogens and may play an important role in carcinogenesis of cancer. Previous studies on the association between Glutathione S-transferase M1 (GSTM1) polymorphism and gastric cancer (GC) risk reported inconclusive results. To get a precise result, we conducted this present meta-analysis through pooling all eligible studies.
Methods
A comprehensive databases of Pubmed, Embase, Web of Science, and the Chinese Biomedical Database (CBM) were searched for case–control studies investigating the association between GSTM1 null genotype and GC risk. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess this possible association. A χ2-based Q-test was used to examine the heterogeneity assumption. Begg’s and Egger’s test were used to examine the potential publication bias. The leave-one-out sensitivity analysis was conducted to determine whether our assumptions or decisions have a major effect on the results of present work. Statistical analyses were performed with the software program STATA 12.0.
Results
A total of 47 eligible case–control studies were identified, including 6,678 cases and 12,912 controls. Our analyses suggested that GSTM1 null genotype was significantly associated with increased risk of GC (OR = 1.186, 95% CI = 1.057-1.329, Pheterogenetiy = 0.000, P = 0.004). Significant association was also found in Asians (OR = 1.269, 95% CI = 1.106-1.455, Pheterogenetiy = 0.002, P = 0.001). However, GSTM1 null genotype was not contributed to GC risk in Caucasians (OR = 1.115, 95% CI = 0.937-1.326, Pheterogenetiy = 0.000, P = 0.222). In the subgroup analysis stratified by sources of controls, significant association was detected in hospital-based studies (OR = 1.355, 95% CI = 1.179-1.557, Pheterogenetiy = 0.001, P = 0.000), while there was no significant association detected in population-based studies (OR = 1.017, 95% CI = 0.862-1.200, Pheterogenetiy = 0.000, P = 0.840).
Conclusion
This meta-analysis showed the evidence that GSTM1 null genotype contributed to the development of GC.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1644180505119533.
doi:10.1186/1746-1596-9-122
PMCID: PMC4079641  PMID: 24948179
GSTM1; Polymorphism; Gastric cancer; Risk; Meta-analysis
8.  Association of TRPS1 gene with different EMT markers in ERα-positive and ERα-negative breast cancer 
Diagnostic Pathology  2014;9:119.
Background
Breast cancer is a heterogeneous disease consisting of different subtypes. Trichorhinophalangeal syndrome type 1 (TRPS1) gene, a GATA-type transcription factor, has been found to be highly expressed in breast cancer. Epithelial-to-mesenchymal transition (EMT) is known to play an important role in tumour invasion and metastasis. Our objective was to elucidate the different roles and clinical relevance of TRPS1 in different estrogen receptor (ER) expression subtypes of breast cancer.
Methods
An immunohistochemical study was performed. The correlation between clinicopathological features and other biomarker profiles were analysed statistically.
Result
TRPS1 expression was correlated with the patients’ age (P = 0.017). It was positively related with ERα (P < 0.001), progesterone receptor (PR) (P < 0.001) and ERβ (P = 0.001) status, but negatively associated with Ki67 (P = 0.002) and HER2 (P = 0.025) status. In ERα-positive breast cancer, TRPS1 expression was positively associated with the expression of E-cadherin (P < 0.001), β-catenin(P = 0.001), ERβ (P = 0.03), and p53 (P = 0.002) status, while in ERα-negative breast cancer, TRPS1 expression was correlated with slug (P = 0.004), vimentin (P = 0.003), smooth muscle actin (SMA) (P = 0.031), and IMP3 (P = 0.005) expression.
Conclusions
Based on our findings, we conclude that TRPS1 is positively associated with E-cadherin and β-catenin status in ERα-positive breast cancer cells, while it is also significantly associated with mesenchymal markers of EMT in ERα-negative breast cancer cells. TRPS1 can be a prognostic marker depending on the type of breast cancer.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8686515681264281
doi:10.1186/1746-1596-9-119
PMCID: PMC4069092  PMID: 24934762
TRPS1; Epithelial to mesenchymal transition; Estrogen receptor; Breast cancer
9.  A novel model for Ki67 assessment in breast cancer 
Diagnostic Pathology  2014;9:118.
Abstract
Background
Ki67 is currently the proliferation biomarker of choice, with both prognostic and predictive value in breast cancer. A lack of consensus regarding Ki67 use in pre-analytical, analytical and post-analytical practice may hinder its formal acceptance in the clinical setting.
Methods
One hundred breast cancer samples were stained for Ki67. A standard estimation of Ki67 using fixed denominators of 200, 400 and 1 000 counted tumor cells was performed, and a cut-off at 20% was applied, Ki67static. A novel stepwise counting strategy for Ki67 estimation, Ki67scs, was developed based on rejection regions derived from exact two-sided binomial confidence intervals for proportions. Ki67scs was defined by the following parameters: the cut-off (20%), minimum (50) and maximum (400) number of tumor cells to count, increment (10) and overall significance level of the test procedure (0.05). Results from Ki67scs were compared to results from the Ki67static estimation with fixed denominators.
Results
For Ki67scs, the median number of tumor cells needed to determine Ki67 status was 100; the average, 175. Among 38 highly proliferative samples, the average Ki67scs fraction was 45%. For these samples, the fraction decreased from 39% to 37% to 35% with static counting of 200, 400 and 1 000 cells, respectively. The largest absolute difference between the estimation methods was 23% (42% (Ki67scs) vs. 19% (Ki67static)) and resulted in an altered sample classification. Among the 82 unequivocal samples, 74 samples received the same classification using both Ki67scs and Ki67static. Of the eight disparate samples, seven were classified highly proliferative by Ki67static when 200 cells were counted; whereas all eight cases were classified as low proliferative when 1 000 cells were counted.
Conclusions
Ki67 estimation using fixed denominators may be inadequate, particularly for tumors demonstrating extensive heterogeneity. We propose a time saving stepwise counting strategy, which acknowledges small highly proliferative hot spots.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3588156111195336
doi:10.1186/1746-1596-9-118
PMCID: PMC4069280  PMID: 24934660
Ki67; Breast cancer; Proliferation; Counting strategy; Statistical model
10.  Significance of 18 F-FDG PET and immunohistochemical GLUT-1 expression for cardiac myxoma 
Diagnostic Pathology  2014;9:117.
Cardiac tumours are relatively rare and are difficult to diagnose merely with imaging techniques. We demonstrated an unusual case of left atrial myxoma, displaying the successful detection by positron emission tomography using 2-deoxy-2-[18 F] fluoro-D-glucose (18 F-FDG PET), correlated closely to more intense and enhanced immunoreactivity with glucose transporter-1 (GLUT-1) in a substantial number of cardiac myxoma cells. Further prospective studies are needed to validate the significance of 18 F-FDG PET findings for cardiac myxoma and the association with immunohistochemical GLUT-1 expression in its tumour cells, after collecting and investigating a larger number of surgical cases examined with both of them.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2991481941253449
doi:10.1186/1746-1596-9-117
PMCID: PMC4077832  PMID: 24934577
Cardiac myxoma; 18 F-FDG PET; Immunohistochemistry; GLUT-1
11.  KRAS, EGFR, PDGFR-α, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE) 
Diagnostic Pathology  2014;9:116.
Background
CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.
Methods
We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-α and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets.
Results
Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-α gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene.
Conclusions
All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-α gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016
doi:10.1186/1746-1596-9-116
PMCID: PMC4078982  PMID: 24934485
CASTLE; Thymic carcinoma; Mutational analysis; Immunohistochemistry; Thyroid gland
12.  Low neonatal blood glucose levels in cesarean-delivered term newborns at Khartoum Hospital, Sudan 
Diagnostic Pathology  2014;9:112.
Abstract
Background
Glucose is the main source of energy for organ function in neonates. There are few published recent data on neonatal glucose levels during cesarean delivery.
Methods
A case (cesarean delivery) -control (vaginal delivery) study was conducted at Khartoum Hospital Sudan to compare blood glucose levels of term newborns born after elective cesarean delivery with those born vaginally.
Results
Cord blood glucose levels at delivery were significantly lower in women who had a cesarean delivery compared with those who delivered vaginally (99.8 ± 20.6 vs. 106.8 ± 11.1 mg/dl, P = 0.026), but there was no significant difference (97.8 ± 16.7 vs. 102.1 ± 9.6, P = 0.110) in newborn glucose levels at 2 hours after delivery between the groups. In linear regression, cesarean delivery (-6.475 mg/dl, P = 0.013) and maternal blood glucose levels at the time of delivery (+0.619 mg, P < 0.001) were significantly associated with mean cord glucose levels.
Conclusion
This study shows that cord blood glucose levels are significantly lower in cesarean-delivered neonates than vaginally-delivered neonates. In addition, cord blood glucose levels are significantly associated with cesarean delivery and maternal blood glucose levels at delivery.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2011479878124993
doi:10.1186/1746-1596-9-112
PMCID: PMC4064508  PMID: 24913607
Cord; Glucose; Cesarean delivery; Newborn; Sudan
13.  Extranodal Rosai-Dorfman disease involving the right atrium in a 60-year-old male 
Diagnostic Pathology  2014;9:115.
Rosai-Dorfman disease (RDD) involving the cardiovascular system is extremely rare; to our knowledge, there are only 9 cases in the literature. Here, a case of a 60-year-old male with RDD involving the right atrium is presented. A comprehensive literature review was undertaken to summarize the clinical and pathologic features of this disorder.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2143194139120169.
doi:10.1186/1746-1596-9-115
PMCID: PMC4067074  PMID: 24916611
Rosai-Dorfman disease; Right atrium; Differential diagnosis
14.  Association of CYP1B1 L432V polymorphism with urinary cancer susceptibility: a meta-analysis 
Diagnostic Pathology  2014;9:113.
Abstract
Background
The Cytochrome P450 1B1 (CYP1B1) is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates. Previous studies have reported the existence of CYP1B1 L432V missense polymorphism in prostate, bladder and renal cancers. However, the effects of this polymorphism on the risk of these cancers remain conflicting. Therefore, we performed a meta-analysis to assess the association between L432V polymorphism and the susceptibility of urinary cancers.
Methods
We searched the PubMed database without limits on language for studies exploring the relationship of CYP1B1 L432V polymorphism and urinary cancers. Article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of these associations. Simultaneously, publication bias was estimated by funnel plot and Begg’s test with Stata 11 software.
Results
We observed a significant association between CYP1B1 L432V polymorphism and urinary cancers. The overall OR (95% CI) of CC versus CG was 0.937 (0.881-0.996), the overall OR (95% CI) of CC versus CG + GG was 0.942 (0.890-0.997). Furthermore, we identified reduced risk for CC versus other phenotypes in both prostate and overall urinary cancers, when studies were limited to Caucasian or Asian patients.
Conclusions
This meta-analysis suggests that the CYP1B1 L432V polymorphism is associated with urinary cancer risk.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3108829721231527
doi:10.1186/1746-1596-9-113
PMCID: PMC4067118  PMID: 24913727
CYP1B1; Polymorphism; Urinary cancer; Susceptibility; Meta-analysis
15.  Quantification of myocardial fibrosis by digital image analysis and interactive stereology 
Diagnostic Pathology  2014;9:114.
Background
Cardiac fibrosis disrupts the normal myocardial structure and has a direct impact on heart function and survival. Despite already available digital methods, the pathologist’s visual score is still widely considered as ground truth and used as a primary method in histomorphometric evaluations. The aim of this study was to compare the accuracy of digital image analysis tools and the pathologist’s visual scoring for evaluating fibrosis in human myocardial biopsies, based on reference data obtained by point counting performed on the same images.
Methods
Endomyocardial biopsy material from 38 patients diagnosed with inflammatory dilated cardiomyopathy was used. The extent of total cardiac fibrosis was assessed by image analysis on Masson’s trichrome-stained tissue specimens using automated Colocalization and Genie software, by Stereology grid count and manually by Pathologist’s visual score.
Results
A total of 116 slides were analyzed. The mean results obtained by the Colocalization software (13.72 ± 12.24%) were closest to the reference value of stereology (RVS), while the Genie software and Pathologist score gave a slight underestimation. RVS values correlated strongly with values obtained using the Colocalization and Genie (r > 0.9, p < 0.001) software as well as the pathologist visual score. Differences in fibrosis quantification by Colocalization and RVS were statistically insignificant. However, significant bias was found in the results obtained by using Genie versus RVS and pathologist score versus RVS with mean difference values of: -1.61% and 2.24%. Bland-Altman plots showed a bidirectional bias dependent on the magnitude of the measurement: Colocalization software overestimated the area fraction of fibrosis in the lower end, and underestimated in the higher end of the RVS values. Meanwhile, Genie software as well as the pathologist score showed more uniform results throughout the values, with a slight underestimation in the mid-range for both.
Conclusion
Both applied digital image analysis methods revealed almost perfect correlation with the criterion standard obtained by stereology grid count and, in terms of accuracy, outperformed the pathologist’s visual score. Genie algorithm proved to be the method of choice with the only drawback of a slight underestimation bias, which is considered acceptable for both clinical and research evaluations.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9857909611227193
doi:10.1186/1746-1596-9-114
PMCID: PMC4072260  PMID: 24912374
Cardiac; Fibrosis; Quantification; Digital; Stereology
16.  Radiological and pathological characteristics of giant cell tumor of bone treated with denosumab 
Diagnostic Pathology  2014;9:111.
Abstract
We describe a case of giant cell tumor of the proximal tibia with skip bone metastases of the ipsilateral femur in a 20-year-old man. After the neoadjuvant treatment with denosumab, plain radiographs and computed tomography showed marked osteosclerosis and sclerotic rim formation, and 18F-FDG PET/CT showed a decreased standardized uptake value, whereas magnetic resonance imaging showed diffuse enhancement of the tumor, nearly the same findings as those at pretreatment. Pathological findings of the surgical specimen after the denosumab treatment showed benign fibrous histiocytoma-like features with complete disappearance of both mononuclear stromal cells and multinuclear osteoclast-like giant cells.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1090602085125068
doi:10.1186/1746-1596-9-111
PMCID: PMC4057823  PMID: 24906559
Giant cell tumor of bone; Denosumab; Neoadjuvant chemotherapy; Receptor activator of nuclear factor-κB ligand (RANKL); Plain radiograph; MRI; 18F-FDG PET/CT; Benign fibrous histiocytoma
17.  Cyto-histopathological and outcome features of the prepuce squamous cell carcinoma of a mixed breed dog 
Diagnostic Pathology  2014;9:110.
Abstract
Background
Squamous cell carcinomas (SCCs) are uncommon, high-grade tumors, predominantly composed of round cells in the prepuce. The aim of this study is to better define the clinicopathologic features of this neoplasm.
Case report
We conducted cyto-histopathologic analysis on the manifestations of the prepuce SCC by H & E staining in a terrier mix dog. Grossly, tumor was large, multiple erythematous patch, and ulcerated masses frequently affecting the prepuce and deeply invading to distal prepuce out from the ventro-lateral of penis and the tumor covered by a necrotic discharge. Cytological evaluation of fine-needle aspirates from the cutaneous mass from the prepuce comprised of round nuclei, coarse chromatin pattern, distinct nucleoli and nuclear pleomorphism. Furthermore, the neoplastic cells were pleomorphic, round to caudate in shape, exhibiting prominent anisokaryosis and anisocytosis with rare mitotic features. Microscopically, the lesions were predominantly composed of atypical round cells disposed in interlacing fascicles. Frequent findings include keratin formation, horn pearls, mitoses and cellular atypia. The cells showed distinct borders, ranged from polygonal to round or elongate and had moderate amounts of eosinophilic cytoplasm.
Conclusion
The histopathologic features coupled with the cytopathology findings led to a diagnosis of squamous cell carcinoma. To the authors’ knowledge, this is the first time that multiple erythematous plaques have undergone malignant transformation in a terrier mix dog.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5748771971272873
doi:10.1186/1746-1596-9-110
PMCID: PMC4080768  PMID: 24903567
Histopathology; Cytology; Dog; Prepuce; Tumour
18.  Bilateral ovarian metastatic squamous cell carcinoma arising from the uterine cervix and eluding the Mullerian mucosa 
Diagnostic Pathology  2014;9:109.
Bilateral ovarian metastasis from invasive squamous cell carcinoma of the cervix is a rare phenomenon with very few clinically significant cases described in the literature. Ovarian metastases when present are usually seen in association with bulky, advanced cervical squamous cell carcinomas with extensive involvement of the uterus.
We describe a 48 year old woman with clinically normal cervix whose hysterectomy and bilateral salpingo-oophorectomy performed for abnormal uterine bleeding, demonstrated high grade squamous intraepithelial lesion, moderately differentiated squamous cell carcinoma involving the deeper stroma of the uterus and bilateral ovarian metastases. Gross examination of the cervical canal and the uterine cavity did not show tumor while well circumscribed pearly white metastatic deposits were distinguished within the parenchyma of both the ovaries. Microscopy ascertained high grade squamous intraepithelial lesion with malignant cells invading the deeper cervical stroma and disseminating further as lymphovascular tumor emboli within the myometrium of the corpus uteri without involving the endometrium. Both the fallopian tubes exhibited lymphovascular tumor emboli without epithelial involvement while the parenchyma of both the ovaries showed metastatic deposits.
Although an isolated case of endophytic squamous cell carcinoma of the cervix with extensive lymphovascular invasion of the corpus uteri, both the fallopian tubes and bilateral ovarian deposits without involving either the endometrium or the tubal mucosa does not form a paradigm, this case brings to light the capricious behavior of cervical squamous cell carcinoma.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1214687069122755
doi:10.1186/1746-1596-9-109
PMCID: PMC4071803  PMID: 24899394
Cervical cancer; Endophytic tumor; Bilateral ovarian metastasis; Ovarian squamous cell carcinoma
19.  An unusual case of Acanthamoeba Polyphaga and Pseudomonas Aeruginosa keratitis 
Diagnostic Pathology  2014;9:105.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5168343391150859
A 56-year-old woman with a history of disposable soft contact lens wear was referred to our university eye center for a corneal ulcer. Based on the microbial culture, the initial diagnosis was bacterial keratitis, which was unresponsive to topical fortified antibiotics. The patient was then examined using in vivo confocal microscopy, which revealed Acanthamoeba infection. This case emphasizes the need to suspect Acanthamoeba infection in soft contact lens wearers who present with progressive ulcerative keratitis or progressively worsening corneal ulcers that are not responsive to the usual antimicrobial therapy. It is also important to consider the possibility of a coinfection with bacterial and Acanthamoeba species.
doi:10.1186/1746-1596-9-105
PMCID: PMC4051961  PMID: 24894486
Contact lens; Acanthamoeba species; Pseudomonas aeruginosa
20.  Association between OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and breast cancer risk: a meta-analysis 
Diagnostic Pathology  2014;9:108.
Background
The base excision repair (BER) pathway removes DNA damage caused by ionizing radiation, reactive oxidative species and methylating agents. OGG1 and APE1 are two important genes in the BER pathway. Many epidemiological studies have evaluated the association between polymorphisms in the two BER genes (OGG1 Ser326Cys and APE1 Asp148Glu) and breast cancer risk. However, the results are inconsistent.
Methods
We searched the electronic databases including PubMed, Embase and Cochrane library for all eligible studies for the period up to February 2014. Data were extracted by two independent authors and pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.
Results
A total of 17 studies including 9,040 cases and 10,042 controls were available for OGG1 Ser326Cys polymorphism and 7 studies containing 2,979 cases and 3,111 controls were included for APE1 Asp148Glu polymorphism. With respect to OGG1 Ser326Cys polymorphism, we did not find a significant association with breast cancer risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and menopausal status, statistical significant increased breast cancer risk was found in Asian populations (Cys/Cys vs. Ser/Ser: OR = 1.157, 95% CI 1.013–1.321, P = 0.011; Cys/Cys vs. Ser/Cys + Ser/Ser: OR = 1.113, 95% CI 1.009–1.227, P = 0.014) and postmenopausal patients (Cys/Cys vs. Ser/Cys + Ser/Ser: OR = 1.162, 95% CI 1.003–1.346, P = 0.024). In subgroup analysis according to quality score, source of control, and HWE in controls, no any significant association was detected. With respect to APE1 Asp148Glu polymorphism, no significant association with breast cancer risk was demonstrated in the overall and stratified analyses.
Conclusions
The present meta-analysis suggests that the OGG1 Ser326Cys polymorphism may be a risk factor for breast cancer in Asians and postmenopausal patients. Further large and well-designed studies are needed to confirm this association.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1156934297124915
doi:10.1186/1746-1596-9-108
PMCID: PMC4064811  PMID: 24893568
Breast cancer; OGG1; APE1; Polymorphism; Meta-analysis
21.  Giant pelvic angiomyofibroblastoma: case report and literature review 
Diagnostic Pathology  2014;9:106.
Angiomyofibroblastoma (AMF) is a rare, benign, soft-tissue tumor, which predominantly occurs in the vulvovaginal region of middle-aged women. It is clinically important to distinguish an AMF from other stromal cell lesions. Here, we report the case of a 32-year-old woman with a rare, giant pelvic AMF, which showed a benign clinical course. The tumor was located in the cul-de-sac of Douglas. It was well demarcated, hypocellular, edematous and composed of spindle-shaped and oval stromal cells aggregating around thin-walled blood vessels. The tumor cells had abundant eosinophilic cytoplasm, and expressed estrogen receptors, progesterone receptors and desmin. Mitotic figures were absent. It is important to distinguish AMFs from aggressive angiomyxomas because both occur at similar sites but show different clinical behaviors. Most AMFs and aggressive angiomyxomas have the same immunohistochemical phenotype. The well-circumscribed borders of AMF are the most important characteristic that distinguish it from aggressive angiomyxomas. AMFs rarely recur after complete surgical excision.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5510813471244189.
doi:10.1186/1746-1596-9-106
PMCID: PMC4066829  PMID: 24894537
Angiomyofibroblastoma (AMF); Aggressive angiomyxoma (AAM); Pelvis
22.  The NQO1 Pro187Ser polymorphism and breast cancer susceptibility: evidence from an updated meta-analysis 
Diagnostic Pathology  2014;9:100.
Background
NAD(P)H: quinone oxidoreductase 1 (NQO1) plays a central role in catalyzing the two-electron reduction of quinoid compounds into hydroquinones. The NQO1 Pro187Ser polymorphism was found to correlate with a lower enzymatic activity, which may result in increased incidence of carcinomas including breast cancer. Previous studies investigating the association between NQO1 Pro187Ser polymorphism and breast cancer risk showed inconsistent results. We performed a meta-analysis to summarize the possible association.
Methods
All studies published from January 1966 to February 2014 on the association between NQO1 Pro187Ser polymorphism and breast cancer risk were identified by searching electronic databases PubMed, EMBASE, Cochrane library, and Chinese Biomedical Literature database (CBM). The association between NQO1 Pro187Ser polymorphism and breast cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).
Results
Ten studies with 2,773 cases and 4,076 controls were finally included in the meta-analysis. We did not observe a significant association between NQO1 Pro187Ser polymorphism and breast cancer risk when all studies were pooled into the meta-analysis. In subgroup analysis by ethnicity, significant increased breast cancer risk was found in Caucasians (Ser/Pro vs. Pro/Pro: OR = 1.145, 95% CI = 1.008–1.301, P = 0.038; Ser/Ser + Ser/Pro vs. Pro/Pro: OR = 1.177, 95% CI = 1.041–1.331, P = 0.009). When stratified by source of control, significant increased breast cancer risk was found in population-based studies (Ser/Pro vs. Pro/Pro: OR = 1.180, 95% CI = 1.035–1.344, P = 0.013; Ser/Ser + Ser/Pro vs. Pro/Pro: OR = 1.191, 95% CI = 1.050–1.350, P = 0.007). However, in subgroup analyses according to menopausal status, quality score, and HWE in controls, no any significant association was detected.
Conclusions
Our meta-analysis provides the evidence that the NQO1 Pro187Ser polymorphism contributed to the breast cancer susceptibility among Caucasians. Further large and well-designed studies are needed to confirm this association.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1248639991252504
doi:10.1186/1746-1596-9-100
PMCID: PMC4041044  PMID: 24884893
NQO1; Polymorphism; Breast cancer; Meta-analysis
23.  Immunohistochemical assessment of a unique basal pattern of p53 expression in ulcerative-colitis-associated neoplasia using computer-assisted cytometry 
Diagnostic Pathology  2014;9:99.
Background
The basal pattern of p53 expression, defined as its immunoreactivity confined to the basal half of the glands, is associated with early neoplastic lesions in ulcerative colitis (UC). However, their clinical utility of this finding is limited by the use of “visual estimation” (approximate immunoreactivity on the basis of scanning the stained slide, without formal counting). This study was designed to analyze the basal pattern of p53 using computer-assisted cytometry and to identify the optimal cutoff value for discriminating between UC-associated early-stage neoplasia and regenerative atypia.
Methods
The specimens were obtained from eight UC patients undergoing colectomy and were classified according to the criteria by the Research Committee of Inflammatory Bowel Disease of the Ministry of Health and Welfare in Japan. Patients with classes UC-IIa (indefinite for dysplasia, probably regenerative), UC-IIb (indefinite for dysplasia, probably dysplastic), and UC-III (definitive dysplasia) were enrolled in the study. Based on the percentage of immunoreactive cells in the basal half of the crypt with visual estimation, basal positivity of p53 was classified into three categories: grade 1 (1 - 9%), grade 2 (10 - 19%), and grade 3 (≥20%). Next, crypts classified as grade 3 by visual estimation were analyzed by computer-assisted image analysis.
Results
Using visual estimation, grade-3 p53 basal positivity was observed in 46.0% of UC-IIa crypts (128 of 278), 61.9% of UC-IIb crypts (39 of 63), and 94.2% of UC-III crypts (81 of 86). Using image analysis, the median p53 basal positivities were 30.3% in UC-IIa, 52.3% in UC-IIb, and 65.4% in UC-III (P ≤0.002). A receiver operating characteristics curve was generated to determine the method’s diagnostic utility in differentiating UC-IIa from UC-III. In this cohort, the sensitivity was 0.78; the specificity was 0.98; the negative predictive value was 87.4%; the positive predictive value was 95.5%, and the accuracy was 90.2% with a cutoff value for p53 basal positivity of 46.1%.
Conclusions
Our findings indicate that assessing p53 basal positivity by image analysis with an optimal threshold represents an alternative to visual estimation for the accurate diagnosis of UC-associated early-stage neoplasia.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3588120501252608
doi:10.1186/1746-1596-9-99
PMCID: PMC4047002  PMID: 24886509
Ulcerative colitis; p53; Immunohistochemistry; Computer-assisted cytometry; Dysplasia
24.  Association between STAT3 gene Polymorphisms and Crohn’s disease susceptibility: a case–control study in a Chinese Han population 
Diagnostic Pathology  2014;9:104.
Background
Crohn’s disease (CD) is an immune-related disease with genetic predisposition. This study aimed to investigate the association of three polymorphisms in the signal transducer and activator of transcription 3 (STAT3) gene with CD risk in a Chinese population.
Methods
We conducted a hospital-based case–control study involving 232 CD patients and 272 controls. Genotyping was performed using polymerase chain reaction with sequence-specific primer method. Statistical analyses were conducted using logistic regression and genotype risk scoring.
Results
Significant differences were found between patients and controls in allele/genotype distributions of rs744166 (Pallele = 0.0008; Pgenotype = 0.003) and allele distributions of rs4796793 (P = 0.03). The risk for CD associated with the rs744166-A mutant allele decreased by 37% [95% confidence interval (CI): 0.48–0.83] under the additive model, 39% (95% CI: 0.43–0.81) under the dominant model and 57% (95% CI: 0.24–0.77) under the recessive model. Carriers of the rs4796793-G mutant allele exhibited 25% (95% CI: 0.58–0.98; P = 0.03) and 47% (95% CI: 0.30–0.95) decreased risks of developing CD under the additive and recessive models, respectively.
Conclusions
STAT3 rs744166 and rs4796793 polymorphisms may be associated with CD occurrence and used as a predictive factor of CD in Chinese Han populations.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2169674321122294
doi:10.1186/1746-1596-9-104
PMCID: PMC4047544  PMID: 24885273
STAT3; Polymorphism; Crohn’s diseases; Susceptibility; Association study
25.  Erythrodermic psoriasis with bullous pemphigoid: combination treatment with methotrexate and compound glycyrrhizin 
Diagnostic Pathology  2014;9:102.
We report a case of erythrodermic psoriasis with bullous pemphigoid (BP) in a 68-year-old male. The patient had a history of psoriasis for 35 years and tense, blisterlike lesions for 4 months. He presented with diffuse flushing, infiltrative swelling, and tense blisterlike lesions on his head, trunk, and limbs. This patient was successfully treated by a combination of methotrexate and compound glycyrrhizin. We also discuss the clinical manifestations, histopathological features, and differentiation of erythrodermic psoriasis with BP and present a review of the pertinent literature.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1853737109114076
doi:10.1186/1746-1596-9-102
PMCID: PMC4047554  PMID: 24885087
Erythrodermic psoriasis; Bullous pemphigoid; Methotrexate; Compound glycyrrhizin

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