Biomedical subjects

Hagen Blaszyk

Publications and source records attributed to Hagen Blaszyk.

At least 19 recordsLinked to original sources

PubMed2007

Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations.

Multifocal hyperplasia of interstitial cells of Cajal (ICC hyperplasia) is a precursor of hereditary gastrointestinal stromal tumors (GISTs) in patients with germline mutations of c-KIT or PDGFRA, but precursor lesions of sporadic GISTs have not been defined yet. Small hyalinizing stromal tumors of the proximal stomach (referred to in this study as GIST tumorlets) were collected prospectively from 98 consecutive autopsies and additional cases were retrieved from surgical pathology files (total n=57). GIST tumorlets were grossly detectable in 22.5% consecutive autopsies performed in individuals older than 50 years. All lesions were located in the cardia, fundus, or proximal body, and ranged in size from 1 to 10 mm (4 mm). Similar lesions were not detected in the antrum, duodenum, and the remainder of the bowel. Histologically, the spindle cell subtype comprised all cases, with hyalinization and calcification in 57% of cases. The spindle cells were immunohistochemically positive for vimentin, CD117, and CD34. Twenty-four cases yielded sufficient DNA for subsequent molecular analysis, which showed c-KIT mutations in 11 cases (46%) and PDGFRA mutations in 1 case (4%). Sporadic GIST tumorlets of the proximal stomach are common in the general population over the age of 50 years and frequently show somatic c-KIT mutations. GIST tumorlets probably represent the grossly recognizable counterpart of sporadic ICC hyperplasia caused by somatic c-KIT or PDGFRA mutations. Early hyalinization and calcification seems to confer limited growth potential, and complete regression of such lesions is common. GIST tumorlets likely represent preclinical (preneoplastic) lesions that need additional stimuli to evolve into clinical GISTs, raising the possibility of a hyperplasia-neoplasia sequence in the development of sporadic GISTs.

Adult↗

PubMed2007

Role of the STK15 Phe31Ile polymorphism in renal cell carcinoma.

The search of inherited cancer susceptibility factors is an important subject in cancer epidemiology. Analyses of single nucleotide polymorphisms (SNP) in various genes revealed a correlation between the presence of specific allelic variants and cancer predisposition in diverse malignancies. STK15 is an important protein in control of the integrity of the mitotic spindle apparatus and genomic stability. We analysed the distribution of the functionally important T91A SNP in the STK15 gene in a cohort of renal cell carcinoma (RCC) patients and compared it to the distribution in a control group without malignancies. DNA from formalin-fixed, paraffin-embedded healthy renal tissue (RCC patients) or peripheral blood samples (control group) was isolated according to standard protocols. Allelic variant of STK15 nucleotide 91 was determined using restriction fragment length polymorphism (RFLP) analysis. Overall, 156 RCC patients and 158 patients without any malignancy were analysed. The distribution of the STK15 SNP in RCC patients (T/T, 58.97%; A/T, 36.53%; A/A, 4.49%) did not significantly differ from that of the control group (T/T, 51.27%; A/T, 41.14%; A/A, 7.59%). There was also no correlation between genotype and tumour grade or stage or other histopathological characteristics of the tumours. This first analysis of the STK15 T91A SNP in RCC patients revealed no correlation between a certain allelic variant and an increased risk for RCC.

Aurora Kinase A↗

PubMed2006

Molecular profiling of laser-microdissected matched tumor and normal breast tissue identifies karyopherin alpha2 as a potential novel prognostic marker in breast cancer.

PURPOSE: The aim of the present study was to identify human genes that might prove useful in the diagnosis and therapy of primary breast cancer. EXPERIMENTAL DESIGN: Twenty-four matched pairs of invasive ductal breast cancer and corresponding benign breast tissue were investigated by a combination of laser microdissection and gene expression profiling. Differential expression of candidate genes was validated by dot blot analysis of cDNA in 50 pairs of matching benign and malignant breast tissue. Cellular expression of candidate genes was further validated by RNA in situ hybridization, quantitative reverse transcription-PCR, and immunohistochemistry using tissue microarray analysis of 272 nonselected breast cancers. Multivariate analysis of factors on overall survival and recurrence-free survival was done. RESULTS: Fifty-four genes were found to be up-regulated and 78 genes were found to be down-regulated. Dot blot analysis reduced the number of up-regulated genes to 15 candidate genes that showed at least a 2-fold overexpression in >15 of 50 (30%) tumor/normal pairs. We selected phosphatidic acid phosphatase type 2 domain containing 1A (PPAPDC1A) and karyopherin alpha2 (KPNA2) for further validation. PPAPDC1A and KPNA2 RNA was up-regulated (fold change >2) in 84% and 32% of analyzed tumor/normal pairs, respectively. Nuclear protein expression of KPNA2 was significantly associated with shorter overall survival and recurrence-free survival. Testing various multivariate Cox regression models, KPNA2 expression remained a highly significant, independent and adverse risk factor for overall survival. CONCLUSIONS: Gene expression profiling of laser-microdissected breast cancer tissue revealed novel genes that may represent potential molecular targets for breast cancer therapy and prediction of outcome.

Biomarkers, Tumor↗

PubMed2006

High frequency of FGFR3 mutations in adenoid seborrheic keratoses.

FGFR3 germline mutations cause autosomal dominant skeletal disorders including achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, and Crouzon syndrome. Somatic mutations of FGFR3 have been identified in bladder cancer, multiple myeloma, and other neoplasms. FGFR3 mutations have also been detected in 40% of seborrheic keratoses (SKs) of the hyperkeratotic and acanthotic subtype, which are very common benign skin tumors. Using a multiplex SNaPshot assay that covers 11 activating FGFR3 mutations, we investigated a series of 27 SKs of the adenoid subtype. Mutations were detected in 23 of 27 (85%) adenoid SKs. R248C mutations were the most frequent mutation type. In two SKs, the A393E mutation was found, which has not been described in acanthotic and hyperkeratotic SKs so far. Three adenoid SKs displayed two simultaneous FGFR3 mutations. Adenoid SKs seem to be characterized by a higher frequency of FGFR3 mutations than hyperkeratotic and acanthotic SKs. The mechanism for the high rate of somatic FGFR3 mutations in these benign skin tumors remains elusive, but UV light exposure may play a potential role, especially in the R248C mutations.

Aged↗

PubMed2006

Nuclear and cytoplasmic Maspin expression in primary non-small cell lung cancer.

AIM: To investigate whether nuclear and cytoplasmic Maspin expression is associated with distinct clinicopathological parameters and TP53 expression in a representative series of primary non-small cell lung cancer (NSCLC). METHODS: Tissue microarrays (n=487) were used to immunohistochemically analyse expression of Maspin and TP53. Cytoplasmic and nuclear expression of Maspin was scored on the basis of the percentage of positive tumour cells. Univariate analysis of clinicopathological variables potentially affecting tumour-specific survival was performed. RESULTS: Immunohistochemical Maspin expression (nuclear and cytoplasmic) was informative in 72.3% (352/487) of cases. Cytoplasmic and nuclear Maspin immunoreactivity in >or=10% of tumour cells was detected in 37.8% (133/352) and 65.3% (230/352) of informative cases, respectively. Nuclear and cytoplasmic Maspin staining was observed more frequently in primary squamous cell carcinomas than in other lung cancer types. Only nuclear Maspin immunoreactivity was significantly associated with positive TP53 staining. Cytoplasmic or nuclear Maspin expression was not associated with tumour-specific survival. CONCLUSION: Maspin expression was found both in the nucleus and the cytoplasm of NSCLC, more frequently in squamous cell carcinomas. However, no association with tumour-specific survival could be demonstrated.

Biomarkers, Tumor↗

PubMed2006

Variability of grade and stage in simultaneous paired liver biopsies in patients with hepatitis C.

BACKGROUND: Grading and staging of liver biopsies in patients with chronic hepatitis remains an inexact "gold standard" that is influenced by variabilities in scoring systems, sampling, observer agreement and expertise. Spatial disease variability relative to markers of the adequacy of biopsy has not been studied previously. METHODS: Paired liver biopsy specimens were obtained from the right and left hepatic lobes of 60 patients with chronic hepatitis C. Histological grade and disease stage were assessed according to the Ludwig scoring system, and scores were evaluated in relation to differences in size and number of portal tracts in all paired samples. RESULTS: The relative difference (%) in aggregate biopsy size and number of portal tracts was similar between paired samples with and without a difference in grade. Paired samples with a difference in stage showed a larger relative difference in biopsy size (p = 0.09) and in the number of portal tracts (p = 0.016). CONCLUSIONS: Our study shows a difference of one grade or one stage in 30% of paired liver biopsies, due to a combination of sampling variability and observer variability. Acknowledgment of "built-in" variability in grading and staging chronic hepatitis C by both clinicians and pathologists is essential for managing the individual patient with chronic hepatitis C.

Adult↗

PubMed2006

Focal myointimal hyperplasia of mesenteric veins is associated with previous trauma in surgical specimens.

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare and poorly understood disease that occurs in the rectosigmoid colon of predominantly young, previously healthy, male patients. This disease is often confused with chronic idiopathic inflammatory bowel disease clinically, and pathologists may miss the diagnosis unless elastin stains are performed because diseased veins may readily be mistaken for arteries. The etiology of IMHMV is unclear, but a traumatic pathomechanism resulting in arterialization of the veins has been proposed. Review of bowel resection specimens (n=68) for non-neoplastic disease within a 1-year period in patients younger than 50 years of age revealed 10 cases with focal mesenteric vein myointimal hyperplasia. Significantly more cases with focal myointimal hyperplasia of mesenteric veins (MHMV) were associated with pre-resection trauma to the involved bowel segment (5/11 vs. 5/57; p=0.0016). A significant association of MHMV with pre-resection trauma supports the hypothesis that idiopathic myointimal hyperplasia of the mesenteric veins may be the result of trauma through torsion/stretching of the sigmoid colon and, subsequently, increased mesenteric venous pressure through arterialization.

Adult↗

PubMed2006

Elevated microsatellite instability at selected tetranucleotide repeats does not correlate with clinicopathologic features of bladder cancer.

INTRODUCTION: The aim of the present study was to evaluate whether elevated microsatellite instability (MSI) at selected tetranucleotide repeats (EMAST) is associated with clinicopathologic and molecular parameters in urinary bladder cancer (BC). METHODS: A consecutive series of 117 nonselected urothelial BCs was studied. Microsatellite analysis and detection of loss of heterozygosity (LOH) was performed after microdissection by using 12 markers selected for sensitive detection of EMAST. Furthermore, five markers (BAT25, BAT26, D2S123, APC, and D17S250) of the Bethesda consensus panel for detection of colorectal cancer within the hereditary non-polyposis colon cancer syndrome (HNPCC) were analyzed. Expression of TP53 and mismatch repair (MMR) proteins hMSH2, hMLH1, and hMSH6 was investigated by immunohistochemistry. RESULTS: EMAST was detected in 10 of 117 patients (8.5%), whereas MSI in the HNPCC panel was found in one of 114 cases (0.9%). LOH in EMAST markers was seen in six of 114 (5.3%) cases. All tumours showed normal expression of hMSH2 and hMLH1. Overexpression of TP53 was observed in nine of 117 evaluated cases (7.7%). No association of EMAST and TP53 expression could be demonstrated. None of the clinicopathologic or molecular parameters were associated with EMAST. CONCLUSIONS: EMAST is another distinct form of MSI in urothelial BC. However, EMAST seems to be a rare event in non-selected urothelial BC and does not seem to be associated with commonly used clinicopathologic and clinical features in patients with BC.

Humans↗

PubMed2006

Nuclear Maspin expression is associated with response to adjuvant 5-fluorouracil based chemotherapy in patients with stage III colon cancer.

Maspin, a member of the Serpin protease inhibitor family, is overexpressed in poorly differentiated colorectal tumors and more frequently found in tumors with microsatellite instability. Immunohistochemical nuclear Maspin staining is predominantly seen in tumor cells at the invasion front of such cancers, suggesting that this molecule is associated with local tumor cell infiltration and aggressiveness. In a retrospective study, we studied nuclear Maspin expression as a potential prognostic tool in a total of 172 primary stage III colon cancers by immunohistochemistry. Of those 172 patients, 76 were treated by surgery only, and 96 patients received additional adjuvant 5-fluorouracil (5-FU) based chemotherapy. Nuclear Maspin expression was an independent adverse prognostic factor for overall survival in our patient cohort (hazard ratio 2.08; 95% CI, 1.13-3.81; p = 0.018). However, patients with primary tumors expressing Maspin in the nucleus showed a significant treatment benefit from 5-FU chemotherapy (hazard ratio 0.384; 95% CI, 0.188-0.784; p = 0.009) compared to adjuvantly treated patients whose tumors did not express this molecule. Nuclear Maspin expression is highly predictive of 5-FU chemotherapy response in patients with advanced stage colon cancer. Patients with negative immunohistochemical Maspin expression do not benefit from 5-FU treatment and may be candidates for an alternative (non-5-FU based) adjuvant therapy regime.

Aged↗

PubMed2006

Expression of Wnt-signaling pathway proteins in intraductal papillary mucinous neoplasms of the pancreas: a tissue microarray analysis.

Abrogation of the Wnt-signaling pathway is implicated in the carcinogenesis of several malignancies, especially colorectal cancer where up to 90% of cases are thought to have impaired Wnt signaling. It is less frequently involved in conventional ductal pancreatic adenocarcinoma. This pathway has not been explored in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas previously and formed the basis of this study. A tissue microarray of 18 cases of IPMN was stained for proteins involved in the Wnt pathway: adenomatous polyposis coli (APC), pan-beta-catenin, axin 2, glycogen synthase 3alphabeta and 3beta, c-myc, E-cadherin, and cyclin D1. The IPMNs were classified as 8 adenomas, 3 borderline, and 7 cases with carcinoma in situ and/or invasive carcinoma, occurring in 13 females, and the overall age range was 45 to 73 years. Immunohistochemical analysis showed nuclear beta-catenin staining in 7 (39%) of the 18 cases. The cases with nuclear beta-catenin localization included 1 adenoma, 2 borderline IPMN, and 4 carcinomas in situ and/or invasive carcinomas. Seven cases showed absence of APC immunostaining and these included 4 cases with nuclear beta-catenin localization. Fourteen cases displayed marked diffuse up-regulation of c-myc protein, and 12 cases also showed diffuse cyclin D1 protein overexpression. E-cadherin expression was intense and membrane in location (comparable to normal tissue) in 6 of 8 adenomas (no tissue was available in 1 case). Decreased E-cadherin staining was noted in 8 cases where tissue was available for assessment. There was progressive decrease in membrane staining of E-cadherin in 2 of 3 borderline lesions, 1 of 2 carcinomas in situ, and 4 of 5 invasive carcinomas. All other immunostains were either normal in distribution or did not show any correlation with beta-catenin or clinicopathologic parameters. In conclusion, 7 (39%) of 18 cases of IPMN in this study demonstrated abnormal localization of beta-catenin, 4 of which also lacked APC expression. Of 5 carcinomas arising in IPMN, 4 displayed a decrease in E-cadherin expression. There was also a trend for the higher grades of IPMN to show nuclear localization of beta-catenin. These findings suggest that a proportion of cases of IPMN may show abnormalities in the Wnt-signaling pathway with consequent altered expression of downstream related proteins.

Adenoma↗

PubMed2006

Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi.

Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acanthosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepidermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicism of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi.

Adolescent↗

PubMed2006

MIB-1 and MCM-2 immunohistochemical analysis does not aid in identification of serrated colorectal polyps with abnormal proliferation.

We investigated the staining characteristics of serrated polyps with abnormal proliferation (SPAP) using MIB-1 and MCM-2 to determine if they could provide assistance in delineating SPAPs from traditional hyperplastic polyps (HPs). Using published morphologic criteria we reviewed H&E slides of 107 polyps from 80 patients. Thirty-nine (36.4%) polyps met the criteria for SPAP Within a given region, polyps in the transverse colon had the largest percentage of SPAPs (50.0%) followed by the right colon (40.9%). The majority of SPAPs (82.1%) and HPs (72.1%) showed MIB-1 staining confined to the basal third of the crypts. The majority of SPAPs (59.0%) and HPs (52.9%) showed MCM-2 staining extending into the apical third of the crypts. We do not recommend MIB-1 or MCM-2 staining to differentiate SPAPs from conventional HPs, since staining characteristics are not significantly different between the 2 groups, and frequent variable crypt staining within a given polyp is difficult to interpret.

Biomarkers, Tumor↗

PubMed2005

Molecular evidence for progression of nephrogenic metaplasia of the urinary bladder to clear cell adenocarcinoma.

Nephrogenic metaplasia or nephrogenic adenoma of the urinary tract may present a diagnostic challenge in surgical pathology practice. Previous case reports suggest the possibility of nephrogenic metaplasia progressing to clear cell adenocarcinoma, but a malignant potential of nephrogenic metaplasia is generally not acknowledged. A case of a 70-year-old female patient with multiple recurrences of nephrogenic metaplasia of the urinary bladder and subsequent development of clear cell adenocarcinoma is described. Immunohistochemical studies help to differentiate the 2 entities. Results of molecular studies, particularly comparative genomic hybridization analysis, suggest clonal evolution of nephrogenic metaplasia to clear cell adenocarcinoma in this case.

Adenocarcinoma, Clear Cell↗

PubMed2005

Elevated nuclear maspin expression is associated with microsatellite instability and high tumour grade in colorectal cancer.

Maspin, a member of the serpin family, has been reported to suppress metastasis and angiogenesis in breast and prostate cancers. Overexpression of maspin was associated with adverse prognostic features in several other tumours. In this study, expression of maspin was analysed in 41 colorectal carcinomas with high-frequency microsatellite instability (MSI-H) and 159 microsatellite stable colorectal cancers (MSS/MSI-L) by immunohistochemistry (IHC) and partly by relative quantitative real-time RT-PCR and western blot analyses. Significant upregulation of maspin expression was found in MSI-H tumours compared to both MSS/MSI-L tumours and matched benign colonic mucosa. Increased maspin expression was also found in three MSI-H colon cancer cell lines, but not in three MSS colon cancer cell lines by RT-PCR and western blot analyses. Regulation of maspin expression depended on promoter methylation as tissue specimens and cell lines expressing maspin showed unmethylated maspin promoters, whereas promoter hypermethylation was found in specimens with loss of maspin expression. Intense nuclear maspin immunostaining was seen specifically in MSI-H tumours (p = 0.013), de-differentiated tumours (p = 0.006), and at the invasion front. These findings provide new insights into the role of maspin in colorectal cancer progression and may be useful for diagnosis and treatment strategies.

Biomarkers, Tumor↗

PubMed2005

The effect of tissue fixation and processing on breast cancer size.

Precise measurement of an invasive breast cancer is crucial for pathological staging and subsequent patient management. Formalin fixation and histological processing may change tissue size, but there is no agreement on which state of the specimen, fresh or fixed, should be used for final tumor measurement. To determine the influence of fixation and processing on breast tumor size, a specific 1-dimensional measurement from 50 invasive breast tumors was recorded in fresh, fixed, and processed/mounted states. Tumors varied in maximum measured dimension from 4 to 20 mm and contained 10% to 90% estimated fibrous tissue (mean, 52.8%). In 96% of cases, there was no difference in measured size between fresh and fixed states. After final processing and mounting, a decrease in size from initial fresh measurement was noted in 40% of cases (mean difference, 2.4 mm; maximum difference, 7 mm). In 9 cases (18%), the measured size increased by a maximum of 3 mm (mean, 1.7 mm) after processing/mounting. Twenty-one cases (42%) showed no change in measurement during the entire fixation and processing protocol. Increases in measured size were attributed largely to tissue expansion during histological sectioning/mounting. One can arguably measure the size of an invasive breast cancer from either the fresh or fixed state without affecting accuracy, but caution should be exercised in relying solely on the microscopic measurements.

Adenocarcinoma↗

PubMed2005

Microsatellite analysis of pleural supernatants could increase sensitivity of pleural fluid cytology.

Pleural effusions may result from various inflammatory, hemodynamic, or neoplastic conditions. A common diagnostic problem lies in distinguishing malignant from benign pleural effusions using routine cytological evaluation. We studied pleural fluid samples obtained from 14 patients with histologically confirmed malignancy and from 6 patients with benign pleural effusions using 12 microsatellite markers from 8 different chromosomal regions. Supernatants and cellular sediments of all 20 pleural fluid samples were analyzed. Routine cytological examination was 100% specific for malignancy but was only 57% sensitive. Microsatellite analyses of pleural fluid supernatants showed genetic alterations in tumor patients only. However, 50% of pleural effusions that were considered negative for malignancy by routine cytological analysis showed either loss of heterozygosity or microsatellite instability. The sensitivity of pleural fluid examination rose to 79% when routine cytological assessment was supplemented by molecular studies. Our data suggest that microsatellite analysis increases the sensitivity of cytological pleural fluid examination in assessing potential malignancy and that combining cytological and molecular methods may improve yield and certainty in diagnostically challenging cases.

Aged↗

PubMed2005

Idiopathic myointimal hyperplasia of mesenteric veins: a rare mimic of idiopathic inflammatory bowel disease.

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare and poorly understood disease that occurs in the rectosigmoid colon of predominantly young, previously healthy male patients. IMHMV typically requires segmental resection due to complications after a relatively protracted clinical course. This disease presents a challenging diagnostic dilemma for the clinician because it is initially often confused with chronic idiopathic inflammatory bowel disease. We report a case of IMHMV, illustrate endoscopic and histopathologic features, and review key characteristics of this rare entity.

Adult↗

PubMed2005

Esophageal squamous papillomatosis.

Esophageal squamous papillomatosis is rare and has been associated with gastroesophageal reflux and recurrent respiratory papillomatosis. We report a case of extensive esophageal papillomatosis, no airway involvement and a slowly progressive clinical course with progressive strictures and ultimately fatal squamous cell carcinoma. In-situ hybridization performed on biopsy specimens was negative for high-risk human papilloma virus types. Due to the paucity of reported cases, little is conclusively known about the etiology, natural course and best clinical management of this disease. Human papilloma virus has been linked to some, but not all, cases, and the clinical course has been reported to vary from spontaneous regression to malignant transformation. Surveillance for malignancy by conventional endoscopic biopsies or computed tomography scan appears to have low sensitivity. This case illustrates the difficulties in clinical management and establishing a definite etiology in esophageal squamous papillomatosis.

Aged↗