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PubMed2005

Genotypically defined lissencephalies show distinct pathologies.

Lissencephaly is traditionally divided into 2 distinct pathologic forms: classic (type I) and cobblestone (type II). To date, mutations in 4 genes, LIS1, DCX, RELN, and ARX, have been associated with distinct type I lissencephaly syndromes. Each of these genes has been shown to play a role in normal cell migration, consistent with the presumed pathogenesis of type I lissencephaly. Based on these data, we hypothesized that all forms of radiographically defined type I lissencephaly independent of genotype would be pathologically similar. To test this hypothesis, we examined brains from 16 patients, including 15 lissencephalic patients and one patient with subcortical band heterotopia. Of these 16 patients, 6 had LIS1 deletions, 2 had DCX mutations, and 2 had ARX mutations. In addition, 6 patients had no defined genetic defect, although the patient with subcortical band heterotopia exhibited the same pattern of malformation expected with an XLIS mutation. In all cases, the cortex was thickened; however, the topographic distribution of the cortical pathology varied, ranging from frontal- to occipital-biased pathology to diffuse involvement of the neocortex. Although brains with LIS1 deletions exhibited the classic 4-layer lissencephalic architecture, patients with DCX and ARX mutations each had unique cytoarchitectural findings distinct from LIS1. Furthermore, 2 of the 5 patients with no known genetic defect showed a fourth type of histopathology characterized by a 2-layered cortex. Interestingly, the 2 brains with the fourth type of lissencephaly showed profound brainstem and cerebellar abnormalities. In summary, we identified at least 4 distinct histopathologic subtypes of lissencephaly that stratify with the underlying genetic defect. Based on these data, a new classification for lissencephaly is proposed that incorporates both pathologic and genetic findings.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2006

Frontotemporal dementia.

PURPOSE OF REVIEW: The syndromes of frontotemporal lobar degeneration are increasingly recognized as an important cause of early-onset dementia. Diagnostic consensus criteria have now been established for almost a decade, and form the framework for its clinical classification. While these criteria remain useful, a growing body of evidence suggests that revisions may be necessary to improve their validity and applicability. RECENT FINDINGS: In each individual syndrome, the core features are not uniformly present, and criteria that are currently used to exclude a condition, such as impaired episodic memory, are often present. Imaging, however, may warrant increased diagnostic prominence, particularly for diagnosis in semantic dementia and prognosis in behavioural syndromes. There is clinical and pathological overlap between the syndromes, but the clinical distinction between progressive nonfluent aphasia and semantic dementia is strengthening. Several series have refined our understanding of the correspondence between clinical syndromes and histopathological subtype: strong for tau-negative, ubiquitin-positive forms and more variable for tau-positive forms, yet prospective studies are still rare. The influence of genetic factors varies substantially across the syndromes. SUMMARY: Further research should aim to integrate detailed clinical, radiological, pathological and genetic information.

Aphasia, Primary Progressive↗

PubMed2001

Pathology of low- and intermediate-grade gliomas.

Under the current World Health Organization (WHO) classification, gliomas can be divided into diffuse variants such as astrocytoma, oligodendroglioma, and mixed oligo-astrocytoma versus more discrete subtypes such as pilocytic astrocytoma and other less common entities. These tumors have been assigned histologic grades ranging from I to IV to reflect expected biological behavior. The ever-growing body of literature on genetic alterations of glial neoplasms promises to augment therapeutic and prognostic information in the future. An important example is the 1p and 19q deletions in oligodendrogliomas that recently have been associated with chemosensitivity and prolonged patient survival. This article reviews the pathology of low- and intermediate-grade gliomas, highlighting practical diagnostic and prognostic issues.

Astrocytoma↗

PubMed1996

Early age onset of hairy cell leukemia presenting with leukocytosis.

Hairy cell leukemia (HCL) is an uncommon type of chronic B cell leukemia mainly affecting middle-aged adults. HCL presenting with pancytopenia is rare in Japan and a distinct subtype of HCL termed HCL-Japanese variant is predominantly seen. We describe a HCL patient with unusual presentation. The patient was a 26-year-old male, such early onset of HCL being quite rare. The patient showed leukocytosis with many circulating hairy cells and cellular bone marrow. These findings were preferentially seen in HCL-Japanese variant, but, cytomorphologic, cytochemical and immunophenotypical studies on the pathologic cells were consistent with those of typical HCL seen in Western countries. Interferon-alpha therapy was very effective in this case. Differentiation of the subtype of HCL appears to be important for the choice of the treatment. The cytological findings were useful for the differential diagnosis of HCL presenting with leukocytosis.

Acid Phosphatase↗

PubMed2007

Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM.

Activation of c-fos in brain is related to coupling of neuronal activity to gene expression, but also to pathological conditions such as seizures or excitotoxicity-induced cell death. Glutamate activates c-fos in neurons through the calcium-dependent phosphorylation of CREB by ERK and/or CaMKIV kinase pathways downstream NMDA-receptors. In glial cells, however, the activation of c-fos by glutamate is poorly understood. Because glial cells actively modulate neuronal excitability and the brain's response to injury, we studied the mechanisms by which glutamate activates c-fos in rat cortical glial cells. Glutamate potently induced c-fos mRNA in a calcium-dependent manner, as demonstrated by using the calcium chelator BAPTA-AM. Glutamate-induced c-fos mRNA expression was not sensitive to inhibitors of ERK, p38(MAPK), or CaMK pathways, indicating that glial c-fos is activated by a distinct mechanism. Thapsigargin abolished the glutamate effect on c-fos mRNA, indicating ER calcium mobilization. Additionally, glutamate induction of c-fos mRNA was sensitive to the mGluR5 antagonist MPEP but not the NMDA-R antagonist MK-801. In luciferase reporter assays, DRE, which actively represses c-fos by binding the calcium-binding transcriptional repressor DREAM, was activated by glutamate, whereas SRE and CRE were not. Finally, glutamate caused the nuclear export of DREAM in astrocytes, and transfection of astrocytes with a mutant variant of DREAM that constitutively binds DNA inhibited glutamate-induced c-Fos expression. These findings are in sharp contrast to the mechanism described in neurons and suggest a novel pathway activated by glutamate in glial cells that employs mGluR5, ER calcium, and the derepression of c-fos at the DRE.

Animals↗

PubMed1982

Alpha-1-antitrypsin (alpha 1AT) phenotypes and PiM subtypes in Italy. Evidence of considerable geographic variability.

Genetic typing of alpha 1AT was performed in 3751 individuals from Italian towns. The following was observed: (a) The pathologic phenotypes (SZ, MZ, ZZ) appeared to decrease progressively from northern to southern Italy; (b) the distribution of the PiM suballeles showed considerable geographic variability, but the suballele M2 was more frequently encountered in southern Italy; and (c) in the large cities of southern Italy, the frequency of the deficiency more closely resembled that found in northern Italy than that of the remaining populations of the south.

Electrophoresis, Polyacrylamide Gel↗

PubMed1998

Analysis of K-ras gene mutations in lung carcinomas: correlation with gender, histological subtypes, and clinical outcome.

PURPOSE: Lung cancer is respectively the leading and second-leading cause of cancer deaths among women and men in Taiwan. The commonest pathological type of lung carcinoma found in Taiwan is adenocarcinoma. and it has been documented that K-ras oncogene mutation occurs in a subset of lung adenocarcinoma. We therefore investigated the mutation spectrum and clinicopathological significance of K-ras oncogene mutations in lung cancer patients in Taiwan. METHODS: The lung tumors were surgically resected from 84 lung cancer patients. DNA was isolated and the mutation spectrum was examined by direct sequencing. These data were also correlated with the clinicopathological characteristics of patients. RESULTS: K-ras gene mutations were detected in 5 cases among the 84 patients investigated (6.0%). The majority of mutations occurred in exon 1 (80%, 4 of 5) and were located mainly in codons 12 and 13. Two patients had G x C --> T x A transversions and 2 patients had G x C --> A x T transitions. Notably, 1 patient had a G x C base-pair deletion from the contiguous G x C base pairs located between codons 68 and 69. All mutations occurred in male patients who were smokers. The incidences of K-ras gene mutation among male and female patients with adenocarcinoma were 13% and 0% respectively. Patients with K-ras gene mutation survived for shorter periods than those without mutations (P = 0.08, by the log-rank test). CONCLUSIONS: The incidence of K-ras gene mutations for male and female patients with adenocarcinoma was 13% and 0% respectively. Thus, the role of K-ras in the development of lung adenocarcinoma among Chinese men who are predominantly smokers is not significantly different from that in other populations worldwide. However, K-ras mutations may not be associated with adenocarcinoma among women in Taiwan, who are virtually all nonsmokers.

Adenocarcinoma↗

PubMed1998

Consistency achieved by 23 European pathologists in categorizing ductal carcinoma in situ of the breast using five classifications. European Commission Working Group on Breast Screening Pathology.

The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening, the greater use of breast-conserving surgery, and the recognition that certain histological subtypes are associated with a greater risk of local recurrence has led to the formulation of several new classifications of DCIS in recent years. There are, however, no data concerning the degree of consistency with which these schemes can be applied by reasonable numbers of pathologists. Thirty-three cases of DCIS were thus examined by a working group of 23 European pathologists who categorized them using five recently published classifications: (1) that of the European Pathologists' Working Group based on differentiation (a combination of nuclear grade and cell polarization) with categories of poorly, intermediately, and well differentiated; (2) one based entirely on nuclear grade with categories of high, intermediate, and low, currently in use in the UK national and EC-funded breast screening programs; (3) the same classification in which only two categories, high nuclear grade and other, were used; (4) the Van Nuys system in which lesions are divided into high grade, non-high grade with necrosis and non-high grade without necrosis; and (5) a two-category classification based entirely on the presence or absence of comedo necrosis. Of the three systems with three categories, Van Nuys gave the highest overall kappa statistic of 0.42. Others gave similar values of 0.37 and 0.35 showing that assessing cell polarization in addition to nuclear grade neither improves nor worsens consistency. In all three systems, the middle category was associated with the lowest value for kappa. Of the two systems with two categories, that based on nuclear grade gave the highest overall kappa of 0.46 and that based on comedo necrosis the lowest of 0.34. The most robust histological features were thus high- and low-grade nuclei and necrosis as long as the latter did not involve the recognition of a comedo growth pattern. These values probably represent the maximum achievable, at least by reasonable numbers of pathologists in everyday practice. They are better than those previously reported for classification based entirely on architecture, but further improvement is needed.

Breast Neoplasms↗

PubMed2005

Subtypes of binge eating disorder based on psychiatric history.

OBJECTIVE: This investigation sought to identify subtypes of binge eating disorder (BED) based on history of mood disorder (MOOD) and substance use disorder (SUD). METHOD: Eighty-four women who met criteria for BED were administered semistructured interviews and completed self-report questionnaires assessing eating pathology, depressive symptoms, self-esteem, body dissatisfaction, and personality traits. RESULTS: Thirty-nine participants (46.4%) had a lifetime history of a SUD and 60 (71.4%) had a lifetime history of a MOOD. The SUD subtype was associated with a greater impulsivity and frequency of binge eating episodes compared with the no SUD subtype. The MOOD subtype participants reported greater distress, more psychopathology, less dietary restraint, lower self-esteem, more frequent binge eating, higher levels of negative affect, and more frequent trauma and abuse history than the no MOOD subtype. DISCUSSION: The results of this study indicate that subtypes of BED on the basis of MOOD and SUD may be associated with a more severe variant of the disorder.

Adult↗

PubMed1984

T-lymphocyte subsets in liver tissues of patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis (PSC), and normal controls.

T lymphocytes infiltrating hepatic tissues were typed and enumerated in liver biopsies of patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis (PSC), and normal controls using monoclonal antibodies and the avidin-biotin-immunoperoxidase technique. The peripheral blood mononuclear cells were studied also by flow cytometry. In PBC, T lymphocytes were decreased (P less than 0.001) in the blood [absolute number was 426 +/- 200 (SE) vs 1351 +/- 416 in 15 controls], as was the helper/suppressor (T4/T8) ratio (1.0 +/- 0.1 vs normal 2.3 +/- 0.3). T lymphocytes were the most numerous mononuclear cells infiltrating portal areas of PBC livers: 749 +/- 93/5 high-power fields (HPF) in PBC vs 98 +/- 15/5 HPF (P less than 0.01) in controls. The T4/T8 ratios varied from 0.9 to 2.3 (mean, 1.8 +/- 0.1) in the portal triads (normal mean, 1.6 +/- 0.1), with the T4+ cells accounting for more than 75% of infiltrating T cells. In contrast, the mean T4/T8 ratio in portal triads of PSC was reduced (1.0 +/- 0.3) due to a significant increase (P less than 0.001) in the number of T8+ cells. The T cells around and in the walls of bile ducts in PBC were mostly T8+, and the T4/T8 ratio was 0.8 +/- 0.2. No T8+ cells were seen in this location in PSC and normal livers. Few mononuclear cells were present in hepatic lobules. Subtyping of T lymphocytes in liver tissues of patients with PBC and PSC may be helpful in the differential pathologic diagnosis. In patients with advanced PBC, a decrease in T4+ cells in the blood appeared to be accompanied by their accumulation in the portal triads. In contrast, T8+ cells accumulated preferentially around bile ducts.

Adult↗

PubMed1990

DBI (diazepam binding inhibitor): the precursor of a family of endogenous modulators of GABAA receptor function. History, perspectives, and clinical implications.

Biochemical, electrophysiological, and lately, molecular biological techniques have shown that GABAA receptors are heterogeneous supramolecular complexes and can be divided into at least three major subgroups: GABAA1, GABAA2, and GABAA3. They differ mainly in the structural and functional properties of the allosteric modulatory center associated with each one of them. This paper will review the present state of research based on the evidence that DBI (diazepam binding inhibitor) and its natural processing products can selectively modulate GABAergic transmission at different GABAA receptor subtypes. Furthermore, the possibility that the DBI family of peptides represents a novel and meaningful neurochemical correlate for neuropsychiatric pathology, sustained by an alteration of GABAergic transmission, will be discussed.

Animals↗

PubMed1997

Pathogenesis of myasthenia gravis.

Various studies over the last 25 years in Man and animal models have revealed many steps in the pathogenesis of myasthenia gravis (MG) which is now considered the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. Though not a disease entity, MG is associated with pathological alterations of the thymus in about 80% of cases. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis, intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and probably involves AChR on myoid cells as the triggering (myasthenogenic) antigen. Genetic factors contribute essentially to the pathogenesis of this form of MG. In thymoma-associated MG genetic factors are probably of marginal significance. Neither intratumour autoantibody production nor T cell activation seem to occur and the AChR is not the myasthenogenic antigen. Instead, abnormal neurofilaments that share epitopes with the AChR and other auto-antigen targets in paraneoplastic MG are expressed in thymomas and may trigger autoantigen-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of most MG cases take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. Where these initial steps occur in MG cases without thymic pathology is not known. Likewise, the factors involved in the initial triggering of MG remain enigmatic in all MG subtypes.

Adolescent↗

PubMed2006

Emerging approaches to advanced bronchioloalveolar carcinoma.

Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung adenocarcinoma that has distinct epidemiologic, histologic, radiographic, and clinical features. The strict pathologic definition requires an absence of any invasion through the basement membrane into pulmonary parenchyma, but there is a growing consensus based on recent clinical studies that this diagnosis should be considered to be based on the clinical features of diffuse ground-glass opacities with minimal or no extra-thoracic spread and histology demonstrating adenocarcinoma with a lepidic growth pattern characteristic of BAC, even if there is a component of invasive adenocarcinoma. Although unifocal or even potentially oligometastatic disease is appropriately treated with resection, advanced BAC is generally treated with systemic therapy. However, multifocal BAC may be indolent enough to follow asymptomatic patients without any systemic therapy if patients are comfortable with this approach, because the rate of disease progression may be slow enough to warrant no therapy for many months or even years. For patients who have symptoms and/or clear evidence of progression over a short interval, standard chemotherapy is appropriate, but I would consider treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to be the most appropriate initial therapy. This is based on the well-documented activity of the EGFR TKIs erlotinib and gefitinib, the latter no longer commercially available in advanced BAC. Advanced BAC is now emerging as an area of significant research, and clinical trials are particularly appealing considerations for such patients.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2003

Loss of heterozygosity of the VHL gene identifies malignancy and predicts death in follicular thyroid tumors.

BACKGROUND: Follicular thyroid tumors (FTT) usually require resection to distinguish adenoma from carcinoma. Better markers that predict histologic subtype and prognosis are needed for FTT. METHODS: Seventeen benign and malignant FTT with follow-up were selected. Pathologic diagnosis was confirmed, tumor and normal tissue were microdissected, and DNA was extracted. Polymerase chain reaction (PCR) products for a microsatellite marker at the von Hippel Lindau gene (VHL) gene locus (3p26) were analyzed with semiquantitative capillary gel electrophoresis to detect loss of heterozygosity (LOH). Data were assessed for statistical significance with chi(2). RESULTS: Mean follow-up was 77 months (range 29 to 120 months). Four cases were uninformative (homozygous microsatellite). Among 13 evaluable patients (6 adenomas, 7 follicular cancers) LOH of VHL was present only in carcinomas (P=.013). LOH was present in 4/4 patients with recurrence and 0/3 patients without recurrence (P=.017). Death from disease has occurred in 3 patients. LOH of VHL was strongly associated with death from disease (P=.034). CONCLUSIONS: FTT can be analyzed for LOH at the VHL gene locus. In this initial study, LOH of VHL was highly specific for malignancy and predicted death from disease. The analysis of VHL may provide for preoperative detection in cytologic samples with potential impact on clinical management of FTT.

Adenocarcinoma, Follicular↗

PubMed2004

Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer.

Improvement of ovarian cancer patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. Xenograft models are frequently used, but with little discussion of disease histology. The objectives of this study were to inject 11 ovarian cancer cell lines intraperitoneally (ip), and a subset intrabursally (ib; orthotopic), into nude mice and to analyze the resulting pathologies. Eight of 11 lines injected ip formed tumors within 3 months at variable rates with the following histological subtype distribution: one endometrioid, one serous, one clear cell, and five undifferentiated. Only mice injected with A2780-cp cells presented with ovarian-specific metastases (11 of 88), and the survival time of these animals was significantly shorter, which may be attributed to the higher proliferation rate as determined by Ki67 positivity. Additional analysis of the influence of the ovarian microenvironment on cell characteristics was conducted with ib injection of two cell lines (OVCA 429 and ES-2). The site of injection did not affect the tumor histology, the effect on proliferation was cell-type dependent, and the tumor take rate (cell survival) was negatively affected for OVCA 429 cells. The animal models described herein represent histologically distinct models of both early and late stage ovarian cancer useful for evaluation of therapeutics.

Animals↗

PubMedDate not supplied

Primary combined small cell carcinoma of the larynx.

The clinical and pathologic findings of six cases of combined small cell carcinoma of the larynx are described. This tumor is a subtype of small cell carcinoma in which there is a definite component of oat cell carcinoma (or intermediate cell type carcinoma) together with squamous cell carcinoma or adenocarcinoma or both. The neoplasm seems to derive from a common cell with subsequent divergent differentiation into the Kulchitsky cells, squamous cells, and/or glandular cells. After histologic diagnosis, adequate evaluation for tumor staging is mandatory. Like pulmonary combined small cell carcinoma, this neoplasm may be best treated with systemic chemotherapy and radiotherapy. The prognosis is similar to that of other subtypes of small cell carcinoma of the larynx.

Carcinoma, Small Cell↗

PubMed2003

The role of voltage-gated sodium channels in neuropathic pain.

Use-dependent inhibitors of voltage-gated sodium channels (VGSC) are important therapeutic tools for chronic pain management, but are limited by possible severe side effects. Recent studies have provided much new information on the function of several voltage-gated sodium channels that are predominantly expressed in peripheral sensory neurons, and on their possible link to pathological pain states arising from injuries to the sensory nerve. The use of antisense oligonucleotides to target specific channel subtypes shows that the functional localization of the channel subtype Na(V)1.8 after nerve injury is essential for persistent pain states. The putative roles of Na(V)1.3 and Na(V)1.9 in neuropathic pain are also discussed. These studies may form a basis for developing inhibitors to target specific channel subtype(s) for use in chronic pain treatment.

Animals↗

PubMed1999

Management of the clinically negative cervical lymph nodes in patients with non-conventional squamous carcinoma of the larynx.

This paper discusses the indications for neck dissection in those patients with laryngeal tumours which prove to be, on pathologic examination, not conventional squamous carcinomas but rather fall into the category either of one of the uncommon histological subtypes of carcinoma, or another type of unusual histological variant of laryngeal malignancy, a mesenchymal tumour. It appears as though these unusual laryngeal malignancies may manifest both biological behaviours and propensities to metastasize to regional lymph nodes that differ from those of the more commonly encountered conventional squamous carcinomas of the larynx. This heterogeneous group of tumours accounts for about 10 per cent of all malignant tumours of the larynx.

Carcinoma↗