Biomedical subjects

I Leivo

Publications and source records attributed to I Leivo.

At least 19 recordsLinked to original sources

PubMed2006

Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses.

Molecular mechanisms contributing to initiation and progression of head and neck squamous cell carcinoma are still poorly known. Numerous genetic alterations have been described, but molecular consequences of such alterations in most cases remain unclear. Here, we performed an integrated high-resolution microarray analysis of gene copy number and expression in 20 laryngeal cancer cell lines and primary tumors. Our aim was to identify genetic alterations that play a key role in disease pathogenesis and pinpoint genes whose expression is directly impacted by these events. Integration of DNA level data from array-based comparative genomic hybridization with RNA level information from oligonucleotide microarrays was achieved with custom-developed bioinformatic methods. High-level amplifications had a clear impact on gene expression. Across the genome, overexpression of 739 genes could be attributed to gene amplification events in cell lines, with 325 genes showing the same phenomenon in primary tumors including FADD and PPFIA1 at 11q13. The analysis of gene ontology and pathway distributions further pinpointed genes that may identify potential targets of therapeutic intervention. Our data highlight genes that may be critically important to laryngeal cancer progression and offer potential therapeutic targets.

Carcinoma, Squamous Cell↗

PubMed2005

Non-invasive (intracapsular) carcinoma ex pleomorphic adenoma: recognition of focal carcinoma by HER-2/neu and MIB1 immunohistochemistry.

AIMS: Non-invasive carcinoma ex pleomorphic adenoma is defined as a carcinoma arising within the boundaries of a pleomorphic adenoma (PA), but which fails to display invasion beyond the capsule of host PA. Alternative names are intracapsular, in situ, or focal carcinoma. The true nature of non-invasive carcinoma ex-PA is still controversial; for example, it is not clear whether it represents early but genuine carcinomatous changes with the genetic make-up of malignant cells, or simply cytological, possibly metaplastic or 'bizarre' changes in PA. Strong overexpression and amplification of HER-2/neu protein has recently been demonstrated in invasive carcinoma ex-PA. In addition, data from breast cancer studies suggest that amplification of HER-2/neu and overexpression of its gene product is mainly involved in the initiation of breast oncogenesis. We sought to establish whether this method could help to demonstrate that what is described as non-invasive carcinoma ex-PA is really a genuine malignancy, albeit in an early phase. METHODS AND RESULTS: Eleven cases of non-invasive carcinoma (in situ) ex-PA were studied for HER-2/neu status using immunohistochemistry and fluorescent in-situ hybridization (FISH). Cells of focal non-invasive carcinoma ex-PA were strongly positive for HER-2/neu protein, while the cells of the maternal PA were always negative. Two cases of low-grade non-invasive myoepithelial carcinoma ex-PA were negative. In four cases out of a total of six tumours studied by FISH, we detected amplification of HER-2/neu gene signals in tumour cells of focal, non-invasive, carcinoma. CONCLUSIONS: The current data suggest that non-invasive carcinoma ex PA is a genuine carcinoma within a PA. However, the presence of cyto-nuclear atypia is not sufficient to make a definite diagnosis of malignant change, which requires a combination of morphology and immunohistochemistry.

Adenoma, Pleomorphic↗

PubMed2005

The MDM2 promoter polymorphism SNP309T-->G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck.

BACKGROUND: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans. METHODS: We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309. RESULTS: Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials. CONCLUSION: SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.

Adult↗

PubMed2004

Sentinel lymph node biopsy in oral cavity squamous cell carcinoma without clinically evident metastasis.

BACKGROUND: The clinically N0 neck in patients with oral SCC is commonly treated by neck dissection because the existence of metastases cannot be excluded. To determine whether unnecessary treatment could be avoided, we evaluated the feasibility of sentinel lymph node (SLN) biopsy. METHODS: Fifteen previously untreated patients with T1 or T2 oral SCC without clinically or radiologically detectable metastasis were included. A blue dye and gamma probe were used to identify SLNs. SLNs were stained with cytokeratins. All nodes in neck dissection specimens were stained using H and E. RESULTS: SLNs were identified in 14 patients by lymphoscintigraphy and in all patients when probe and dye were combined. Four neck dissection specimens contained four metastatic lymph nodes. Three of the four lymph nodes were SLN. One SLN was found to be metastatic after immunostaining. However, although there was one blue sentinel node in one neck, a metastatic non-SLN was present. CONCLUSIONS: Our results show that SLN biopsy is a promising tool for use in patients with oral SCC. However, further studies are necessary.

Adult↗

PubMed2003

Sinonasal tubulopapillary low-grade adenocarcinoma. Histopathological, immunohistochemical and ultrastructural features of poorly recognised entity.

We present the clinicopathological, histological and immunohistochemical findings of six cases of primary tubulopapillary low-grade adenocarcinoma of the sinonasal tract with ultrastructural examination in one case. Due to its unique features, we believe that primary tubulopapillary low-grade adenocarcinoma of the sinonasal tract represents a tumour entity different from any tumours generally recognised in the sinonasal region. Our cases had an equal sex incidence, with an age range of 44-76 years. The tumour has a tendency to recur, but none of our six patients developed metastases. We feel that it is important to separate this tumour entity from other types of sinonasal adenocarcinomas that exhibit a papillary growth pattern, as they frequently pursue a much more aggressive clinical course than the tumours in this study.

Adenocarcinoma↗

PubMed2003

Expression of HER-2/neu gene and protein in salivary duct carcinomas of parotid gland as revealed by fluorescence in-situ hybridization and immunohistochemistry.

AIMS: Salivary duct carcinoma is a highly malignant salivary gland tumour with aggressive clinical behaviour, characterized by histological resemblance to invasive ductal carcinoma of the breast. Amplification of HER-2/neu oncogene and over-expression of its gene product have both prognostic and therapeutic implications in breast cancer. Recent report on salivary duct carcinomas for HER-2/neu using immunohistochemistry (IHC) has shown over-expression in most cases. However, correlation between IHC and molecular genetic analysis of HER-2/neu in salivary duct carcinoma has not yet been performed. METHODS AND RESULTS: We have now evaluated 11 cases of salivary duct carcinomas for HER-2/neu status using IHC and fluorescent in-situ hybridization (FISH). To our knowledge, this is the first molecular genetic analysis of HER-2/neu in salivary duct carcinoma. CONCLUSIONS: In immunohistochemistry, over-expression of HER-2/neu protein was identified as distinct membrane staining in most carcinoma cells in all our salivary duct carcinoma cases, while only four cases revealed an amplification of HER-2/neu gene by means of FISH analysis. Both amplified and non-amplified salivary duct carcinomas with strong immunohistochemical staining for HER-2/neu protein were associated with poor clinical outcome for the patients. Apparently, HER-2/neu protein over-expression could also be controlled by mechanisms other than gene amplification. In the group of salivary gland tumours other than salivary duct carcinoma, strong over-expression was detected only in three cases of carcinoma ex pleomorphic adenoma. Thus, over-expression of HER-2/neu protein is also a useful marker of malignant transformation in pleomorphic adenomas.

Adult↗

PubMed2002

Gene expression profiling of ameloblastoma and human tooth germ by means of a cDNA microarray.

The molecular and genetic characteristics of ameloblastoma are still poorly understood. We analyzed gene expression in fresh-frozen ameloblastomas and human fetal tooth germs, using a cDNA microarray. Thirty-four genes exhibited significant changes in expression levels in the ameloblastoma. Eleven genes were overexpressed more than three-fold, and 23 genes were underexpressed to below 0.4 of the control level. The oncogene FOS was the most overexpressed gene (from eight- to 14-fold), followed by tumor-necrosis-factor-receptor 1 (TNFRSF1A). Genes for sonic hedgehog (SHH), TNF-receptor-associated-factor 3 (TRAF3), rhoGTP-ase-activating protein 4 (ARHGAP4), deleted in colorectal carcinoma (DCC), cadherins 12 and 13 (CDH12 and 13), teratocarcinoma-derived growth-factor-1 (TDGF1), and transforming growth-factor-beta1 (TGFB1) were underexpressed in all tumors. In selected genes, a comparison between cDNA microarray and real-time RT-PCR confirmed similar relative gene expression changes. The gene expression profile identifies candidate genes that may be involved in the origination of ameloblastoma and several genes previously unidentified in relation to human tooth development.

Adolescent↗

PubMed2001

Relative levels of SCCA2 and SCCA1 mRNA in primary tumors predicts recurrent disease in squamous cell cancer of the head and neck.

Squamous cell carcinoma antigen (SCCA) is widely used as a serum marker in cancers of the uterine cervix, the head and neck, lung and esophagus. Two isoforms of SCCA, deriving from 2 highly homologous serine proteinase inhibitor genes, are co-expressed in normal and malignant squamous epithelium, but it is mainly the acidic isoform SCCA2 that is present in the circulation of cancer patients. We studied the relative levels of SCCA2 and SCCA1 mRNA in frozen sections of squamous cell carcinomas of the head and neck (SCCHN) in relation to disease recurrence, using a new reverse transcription-polymerase chain reaction-based technique for accurate quantitation of relative mRNA levels. Primary tumors from 30 SCCHN patients, recurrent tumors from 11 patients and normal epithelium from 16 controls were examined. In patients responding to initial therapy (n = 26), an elevated SCCA2/SCCA1 mRNA ratio in the primary tumor predicted recurrence independent of clinical stage (p = 0.011). The relative risk of developing a recurrence was 7.2 (CI 1.2-13.3) in patients with elevated vs. normal SCCA2/SCCA1 mRNA ratios. We demonstrate that subtle differences in expression levels of the SCCA genes are reflected in the course of the SCCHN disease and may provide a target for molecular grading of SCCHN tumors. If this finding can be confirmed in a larger study the SCCA2/SCCA1 mRNA ratio in primary tumors could be useful for individual selection of treatment strategy for patients with head and neck cancer.

Adult↗

PubMed2001

Cartilage invasion of laryngeal cancer detected by magnetic resonance imaging.

Cartilage invasion of laryngeal cancer has a significant impact on the choice of treatment modality and on the outcome for the patients. Cartilage invasion was evaluated radiologically and histopathologically in 18 patients who underwent total laryngectomy. The histopathological examination showed intracartilaginous tumor spread in nine specimens, whereas in the other nine no cartilage invasion was found. Magnetic resonance imaging (MRI) detected the cartilage invasion in six patients and excluded it in six. There were three false negative and three false positive findings from the MRI examination. The relatively common false findings of MRI should be kept in mind in the choice of treatment.

Aged↗

PubMed2001

Basaloid squamous carcinoma with collagenous spherules and crystalloids.

A case of basaloid squamous carcinoma with unusual spheruloid and crystalloid structures occurring in the left submandibular region of 45-year-old woman is described. The tumor displayed features typical of basaloid squamous carcinoma. In addition, there were numerous eosinophilic deposits of extracellular matrix, which reacted positively on periodic acid-Schiff staining. These deposits were arranged in lamellar concentric and radial patterns. Ultrastructurally, they were composed of extracellular matrix components rich in basement membrane substances. A few banded collagen fibers were found in some deposits. Basaloid squamous carcinoma is an aggressive variant of squamous cell carcinoma, with a predilection to the head and neck region, that needs to be distinguished from other tumors that may contain abundant deposits of basement membrane rich material, especially from adenoid cystic carcinoma.

Carcinoma, Basosquamous↗

PubMed2001

Histology of injected autologous fascia in the paralyzed canine vocal fold.

OBJECTIVE: To evaluate the histology of minced and injected autologous fascia graft in the augmentation of unilateral vocal fold paralysis. STUDY DESIGN: Prospective study using a canine model. METHODS: Nine dogs were operated. At first, a piece of fascia was harvested from fascia lata and minced into tiny chips with a scalpel. Cutting off a section of the recurrent nerve paralyzed the right vocal fold. The minced fascia-paste (0.1 mL) was injected using a pressure syringe into the paralyzed thyroarytenoid muscle under direct laryngoscopy. Two animals were killed at 3 days, one at 10 days, three at 6 months, and three at 12 months postinjection. Each dog underwent laryngectomy and serial coronal sections of paraffin blocks from the posterior part of the vocal folds were made. RESULTS: The dogs experienced no complications perioperatively or during follow-up. Under microscopy, muscle of the paralyzed vocal fold was atrophied in comparison to the contralateral control. There was an acute inflammatory reaction induced by the graft. This did not exist in the specimens taken at 6 and 12 months. No extensive edema, areas of necrosis, or formation of granulomas was seen at any time. Maturation of the graft was characterized by active collagen remodeling up to 12 months. At that time the graft consisted of firm, condensed fibrous tissue. Scar formation around the graft was moderate, and the subepithelial layer of the vocal fold remained undisturbed. Each graft consisted of singular foreign bodies from the polyamide mincing plate. We cannot exclude that their presence would have had an impact on the final architecture of the graft. CONCLUSION: In a canine vocal fold, the free fascia graft is well tolerated and after 12 months a well-organized, collagen rich tissue is seen on histological sections. The findings are in accordance with clinical studies applying free fascia grafts.

Animals↗

PubMed2000

Oncocytic cystadenoma of the parotid gland with tyrosine-rich crystals.

A case of benign oncocytic cystadenoma with abundant intraluminal tyrosine-rich crystals involving the parotid gland is described.

Adenoma, Oxyphilic↗

PubMed2000

Muscle membrane-skeleton protein changes and histopathological characterization of muscle-eye-brain disease.

Muscle-eye-brain disease belongs to congenital muscular dystrophies with central nervous system abnormalities. The etiology of MEB is still unknown, but abnormal immunoreactivity for laminin-2 has been reported. To evaluate disease progression in muscle tissue, 32 biopsy specimens from 17 muscle-eye-brain patients were analysed. The samples of four patients were studied by immunohistochemical techniques and by quantitative Western blotting. The samples showed a great variation in the muscle pathology. Regenerative fibers and mild fiber size variation were present in over 60%. At infancy, necrotic and regenerative fibers were common, while fat infiltration was the most prominent finding in the age group over five years. In quantitative studies, the amount of laminin alpha 2 chain was clearly reduced to 10-20% of normal. In contrast, laminin beta 2 chain was overexpressed in the Western blotting studies. These findings may reflect a yet unidentified primary disturbance in the basement membrane composition and function.

Adolescent↗

PubMed2000

Basement membrane laminin-5 is deposited in colorectal adenomas and carcinomas and serves as a ligand for alpha3beta1 integrin.

Interplay between laminin-5 (Ln-5) and its integrin (Int) receptors alpha2beta1, alpha3beta1 and alpha6beta4 has been implicated in the progression and invasion of carcinomas. In this study we found abundant immunoreactivity for chains of Ln-5 (alpha3-beta3-gamma2) and Ln-10 (alpha5-beta1-gamma1), as well as for type VII collagen, in basement membranes (BM) of colorectal adenomas. In carcinomas of all differentiation grades, Lns were seen in tumor BMs, whereas type VII collagen was almost absent. Ln-5 appeared to accumulate along the invading edges of carcinomas, while Ln-10 was mostly absent. Immunoreactivity for Ln al chain, a component of Lns-1 and -3, was not seen in adenomas or carcinomas. Immunoreactivity for alpha2, alpha6, beta1 and beta4 Ints was found in all tumors and that for alpha3 Int in all adenomas and most of the carcinomas, often in colocalization with Ln-5. Immunoblotting of carcinoma tissues showed that the gamma2 chain of Ln-5 was present as typical Mr 105000 and 155000 isoforms. Immunoprecipitation experiments showed production of Ln-5 by cultured colon carcinoma cells. In quantitative cell adhesion experiments, function-blocking MAbs to alpha3 and beta1 Int subunits, but not those to Int alpha2 or alpha6 subunits, significantly inhibited the adhesion of cells to Ln-5. Our results suggest that BM composition in colorectal adenomas reflects the properties of surface epithelial BM of colorectal mucosa. In invading carcinomas, trimeric Ln-5, produced by carcinoma cells, is a major BM component and the cells use the alpha3beta1 Int complex for adhesion to Ln-5.

Adenoma↗

PubMed1999

Oncocytic myoepithelioma and pleomorphic adenoma of the salivary glands.

Twenty oncocytic myoepitheliomas (MEs) and pleomorphic adenomas (PAs) were composed of interlacing fascicles of swollen spindle-shaped or/and epithelioid oncocytic myoepithelial cells showing intense finely granular immunoreactivity with anti-mitochondrial antibody. Focal vacuolation of the cytoplasm of oncocytic myoepithelial cells and their gradual transition into sebaceous metaplasia were observed in 3 cases. Another unusual feature found in 5 cases was the presence of slit-like adenomatoid spaces lined with double-layered oncocytic myoepithelium closely resembling Warthin's tumour. The nuclei of oncocytic cells were characterized by enlargement, hyperchromasia and polymorphism, which should not be confused with malignancy. Oncocytic change in myoepithelial cells in MEs and PAs can cause pitfalls in the differential diagnosis of salivary gland tumours. We describe some unusual histological features associated with onococytic metaplasia in benign myoepithelial cell-derived salivary gland tumours, hoping to help to avoid the overdiagnosis of malignancy.

Adenoma, Pleomorphic↗

PubMed1999

Malignancy-simulating change in parotid gland oncocytoma following fine needle aspiration. Report of 3 cases.

We report here there cases of benign parotid gland oncocytoma with pseudomalignant change that mimic acinic cell carcinoma. All patients underwent fine-needle aspiration biopsy of the tumor 62, 725 and 33 days before surgical excision. In histologic sections, there were clusters of pigmented cells with PAS-positive foamy to finely granular cytoplasm similar to those seen in salivary gland acinic cell carcinomas. This report provides another, previously undescribed, example of a diagnostic pitfall that may be observed in histologic tissue specimens removed after FNA of oncocytic tumors.

Adenoma, Oxyphilic↗

PubMed1999

Hemidesmosomal molecular changes in dermatitis herpetiformis; decreased expression of BP230 and plectin/HD1 in uninvolved skin.

Recent BP230-knockout experiments with subsequent blistering and recently identified plectin/HD1 mutations in epidermolysis bullosa simplex patients suggest that defective expression of BP230 and plectin/HD1 may predispose to blister formation in human skin. We have studied the expression of the epithelial adhesion complex as well as the basement membrane and anchoring fibril antigens in uninvolved dermatitis herpetiformis skin to find out if alterations can be detected in these structures predisposing to the blister formation typical of the disease. Ten uninvolved dermatitis herpetiformis skin specimens, which all showed clear granular deposits of IgA under the basement membrane in direct immunofluorescence and five normal skin specimens, were studied by indirect immunofluorescence technique. Six uninvolved dermatitis herpetiformis skin specimens showed distinctly decreased immunoreaction for BP230 and four uninvolved dermatitis herpetiformis skin specimens showed distinctly decreased immunoreaction for plectin/HD1. All five skin controls showed strong immunoreactions for BP230 and plectin/HD1. Other hemidesmosomal proteins including BP180 and integrin alpha6beta4, as well as basement membrane proteins laminin-5, laminin-1, nidogen and type IV collagen, and the anchoring fibril protein type VII collagen showed a normal strong expression. Our results suggest that alterations in BP230 and plectin/HD1 may contribute or predispose to blister formation in dermatitis herpetiformis skin.

Autoantigens↗

PubMed1999

Cribriform adenocarcinoma of the tongue: a hitherto unrecognized type of adenocarcinoma characteristically occurring in the tongue.

AIMS: We report a review of our institutional and consultation files in order to select cases of hitherto unrecognized type of adenocarcinoma occurring in the tongue. MATERIALS AND RESULTS: Eight cases of a characteristic adenocarcinoma of the tongue resembled solid and follicular variants of the papillary carcinoma of the thyroid. All the tumours were unencapsulated and were divided by fibrous septa into lobules. Major parts of the lesions were composed of areas with solid and microcystic growth patterns. The most striking cytological feature was that the tumour nuclei were pale-staining with a 'ground glass' quality, and they often appeared to overlap. Immunohistochemically, the tumours expressed cytokeratin and S100 protein and, focally, actin; thyroglobulin was negative. Ultrastructurally the cells had clefted nuclei, and the cytoplasm contained a few mitochondria, lysosomes and Golgi apparatus. Many tumour cells had combined features of both myoepithelial and secretory differentiation-well formed microvilli on their apical borders and bundles of microfilaments. At first presentation, all eight patients had metastases in the regional neck lymph nodes, but all are alive 2-6 years after the initial excision and irradiation. CONCLUSION: We describe a distinctive type of adenocarcinoma of the tongue, for which we propose the name cribriform adenocarcinoma of the tongue (CAT). CAT usually presents with metastases in the neck lymph nodes at the time of presentation. We hypothesize that the tumour might arise from the thyroglossal duct anlage.

Adenocarcinoma, Papillary↗