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PubMed2003

Expression of cyclin D1, D3, E, and p27 in human renal cell carcinoma analysed by tissue microarray.

Aberrations in the G1/S transition of the cell cycle have been observed in many malignancies and seem to be critical in the transformation process. Few studies have delineated the presence of G1/S regulatory defects and their clinical relevance in renal cell carcinoma (RCC). Therefore, we have examined the protein contents of cyclin D1, D3, E, and p27 in 218 RCCs, using tissue microarray and immunohistochemistry. The results from a subset of tumours were confirmed by Western blotting and immunohistochemical staining of regular tissue sections. Interestingly, low protein contents of cyclin D1 and p27 were associated with high nuclear grade, large tumour size, and poor prognosis for patients with conventional tumours. We further observed substantial differences in the pattern of G1/S regulatory defects between the different RCC subtypes. The majority of both conventional and papillary cases expressed p27; however, chromophobe tumours generally lacked p27 staining. In addition, conventional RCCs often expressed high cyclin D1 protein levels, while papillary RCCs exhibited high cyclin E. In summary, we have shown that G1/S regulatory defects are present in RCC and are associated with clinico-pathological parameters. The pattern of cell cycle regulatory defects also differed between RCC subtypes.

Actuarial Analysis↗

PubMed1992

Prognostic significance of histopathologic subtype and stage in small cell lung cancer.

A study of 149 light microscopic tissue slides from 147 patients with recorded initial diagnoses of small cell lung cancer (SCLC) (114 cases) and undifferentiated carcinoma (35 cases) was undertaken to test the reproducibility and prognostic impact of a new histopathologic subclassification of SCLC proposed by the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). This study was further designed to test the impact of clinical stage, age, sex, and race on survival. The tissue slides were blindly reclassified as SCLC or non-SCLC by a panel of five pathologists with no knowledge of the initial diagnosis. The SCLCs were divided into the three subtypes outlined by the IASLC pathology panel: small (classic or pure), mixed (small cell/large cell), and combined (small cell/squamous carcinoma or small cell/adenocarcinoma). Small cell lung cancer was clinically staged as local, regional, or distant. Consensus diagnosis (defined as agreement by at least three of the five pathologists) was achieved in 144 (96.6%) of the 149 cases. Of these 144 cases, 124 were reclassified as SCLC (115 [92.8%] small, five [4.0%] mixed, and four [3.2%] combined) and 20 were classified as non-SCLC. The median lengths of survival for the small, mixed, and combined subtypes were 225, 1,110, and 203 days, respectively (P = .025). Adequate staging data were available in 123 of the 124 SCLC cases. Of the 123 SCLC cases, 27 (21.9%) were local, 22 (17.9%) were regional, and 74 (60.2%) were distant stage. The median lengths of survival for the local, regional, and distant stages were 428, 251, and 111 days, respectively. This association was highly significant (P = .0001). We conclude that stage is the major determinant of survival in SCLC. Mixed subtypes had significantly longer survival times than the small or combined subtypes (P = .025). Survival times were longer for women than for men, and the survival time difference between men and women was significant (P = .0028). We found no significant differences in survival according to age or race.

Carcinoma, Small Cell↗

PubMed1988

Histopathologic classification of small cell lung cancer. Changing concepts and terminology.

Considerable attention has been devoted to the diagnosis of small cell lung carcinoma (SCLC) and its subtypes. In the literature contradictory opinions have been published concerning the clinical implications of subtyping, largely because of the different criteria used by different pathologists. This article is a consensus report by the Pathology Committee of the International Association for the Study of Lung Cancer. The following classification of SCLC is recommended: (1) Small cell carcinoma. This subtype includes most of the tumors previously included in the oat cell and intermediate subtypes. More than 90% of untreated SCLC fall into this category. (2) Mixed small cell/large cell carcinoma. This subtype, which may be associated with a poor prognosis and response to therapy, contains a spectrum of cell types ranging from typical SCLC to larger cells having prominent nucleoli and resembling large cell carcinoma. (3) Combined small cell carcinomas. Typical SCLC elements are intimately admixed with areas of differentiated squamous cell or adenocarcinoma. This simplified classification of SCLC will facilitate uniformity in the diagnosis and further our understanding of the clinical significance of the rarer SCLC with variant morphologies.

Carcinoma, Small Cell↗

PubMed2005

A Japanese family with Alport syndrome associated with esophageal leiomyomatosis: genetic analysis of COL4A5 to COL4A6 and immunostaining for type IV collagen subtypes.

BACKGROUND: In some families, X-linked Alport syndrome (AS) is associated with diffuse leiomyomatosis. We describe clinical, pathologic and molecular-genetic findings in a Japanese family with this inheritance mode of AS in association with leiomyomatosis. PATIENT: AS was diagnosed in a one-year-old boy with recurrent aspiration pneumonia caused by esophageal stenosis from leiomyomatosis. Diagnosis was confirmed by electron microscopy coupled with type IV collagen chain subtype staining in a renal biopsy specimen. His mother, who exhibited esophageal leiomyomatosis and is heterozygous for AS, showed a discontinuous staining pattern for collagen alpha5(IV) chain along the epidermal basement membrane in a skin biopsy specimen. Genetic analysis in the boy revealed the deletion of the first two exons of COL4A6 together with deletion of the 5' end of COL4A5. Despite administration of cyclosporin A, massive proteinuria has persisted in the boy, although renal function otherwise remains normal. CONCLUSION: Identification of an AS patient during infancy is extremely rare. Clinical manifestations, including macroscopic hematuria, cataracts and leiomyomatosis caused by the large deletion involving COL4A5 to COL4A6, led to early presentation with AS.

Collagen Type IV↗

PubMed2003

Solid renal tumors: an analysis of pathological features related to tumor size.

PURPOSE: We examined the relationship between tumor size and malignancy among solid renal tumors, and the relationship between tumor size and RCC subtype within tumors with renal cell carcinoma (RCC). MATERIALS AND METHODS: We identified 2,770 adult patients who underwent radical nephrectomy or nephron sparing surgery for sporadic unilateral nonmetastatic solid renal tumors between 1970 and 2000. All pathology specimens were reviewed by a urological pathologist for diagnosis, and in RCC tumors, for histological subtype and nuclear grade. RESULTS: There were 376 benign (12.8%) and 2,559 (87.2%) malignant tumors. The percentage of benign tumors decreased from 46.3% for those less than 1 cm to 6.3% for those 7 cm or greater. Among RCC tumors the percentage that were clear cell increased from 25.6% for those less than 1 cm to 83.0% for tumors 7 cm or greater, while the percentage that were papillary decreased from 74.4% for those less than 1 cm to 10.0% for tumors 7 cm or greater. No RCC tumors less than 1 cm were chromophobe compared to 7.0% of tumors 7 cm or greater. The percentage of malignant tumors that were high grade RCC increased from 2.3% for those less than 1 cm to 57.7% for RCC tumors 7 cm or greater. Only 1% of all tumors less than 1 cm and 9.2% of all tumors less than 2 cm were high grade malignancies. CONCLUSIONS: As tumor size increased there was a significant increase in the odds of having a malignant compared to a benign tumor, clear cell compared to papillary RCC and high grade compared to low grade malignancy.

Carcinoma, Renal Cell↗

PubMed2002

Changes in breast cancer therapy because of pathology second opinions.

BACKGROUND: Examination of pathology slides is a routine part of a breast cancer second opinion. The purpose of this study was to determine how often the pathologic second opinion (1) altered the diagnosis and (2) resulted in a change in the surgical procedure. METHODS: Patients presenting between 1997 and 2001 for a second opinion after a biopsy diagnosis of breast cancer (invasive or noninvasive) were included in this study. RESULTS: There were 340 patients presenting for second opinions regarding 346 breast cancers. Sixty-eight pathologic second opinions (20%) did not result in any change in pathology or prognostic factors, whereas in the remaining 80%, some change occurred. Major changes that altered surgical therapy occurred in 7.8% of cases, and pathology review provided additional prognostic information in 40%. Changes were more common in in situ carcinoma than invasive carcinoma (P =.004), but biopsy type (core vs. excisional biopsy) was not a significant predictor of change in pathologic information. CONCLUSIONS: This study confirms the benefit of a pathology second opinion to improve preoperative estimates of prognosis and to determine the appropriate surgical procedure. Missing information on grade and histological subtype was responsible for a large number of cases, suggesting a need for widespread application of standardization and quality improvement in pathology reporting.

Biopsy↗

PubMed2002

Lentigo maligna and superficial spreading melanoma are different in their in situ phase: an immunohistochemical study.

Clinical and pathologic observations have prompted the categorization of malignant melanoma into 4 subtypes. Although some authorities challenge the value of this classification, nevertheless it is generally accepted that lentigo maligna (LM), or melanoma on sun-damaged skin, has a different biological behavior than so-called superficial spreading melanoma (SSM), at least in the early stage of its evolution. To characterize some aspects of this different behavior, the in situ phase of SSM and LM was studied using immunohistochemical methods. Seventeen cases of SSM in situ and 13 cases of LM were chosen for the study. All cases qualified with strict histologic criteria. Sections from these lesions were stained with antibodies against HMB-45 antigen, basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), and factor VIII. Semiquantitative analysis was performed. Cases classified as either LM or SSM corresponded well to the epidemiologic and clinical characteristics as described in the literature; that is, LM appeared in older patients and occurred mostly on the face, whereas SSM occurred mostly on the trunk and lower limbs. Although no difference in HMB-45 stain was observed, melanoctyes of SSM showed greater proliferative activity, as reflected by PCNA stain (P < 0.02) and higher levels of bFGF (P < 0.001), than melanocytes of LM. More blood vessels were counted under SSM than under LM (P < 0.05). These results are in accordance with the biological behavior of SSM and LM, that is, the longer in situ phase of the latter. bFGF is both a growth factor for melanocytes and an angiogentic factor. The differences in PCNA, a proliferation marker, and blood vessel count may be related to the bFGF effect. Thus this study reveals some of the biological differences between LM and SSM. Location and sun exposure habits may contribute to these differences, which already exist in the in situ phase.

Aged↗

PubMed2000

Platelet-derived growth factor rapidly increases activity and cell surface expression of the EAAC1 subtype of glutamate transporter through activation of phosphatidylinositol 3-kinase.

Na(+)-dependent glutamate transporters are the primary mechanism for removal of excitatory amino acids (EAAs) from the extracellular space of the central nervous system and influence both physiologic and pathologic effects of these compounds. Recent evidence suggests that the activity and cell surface expression of a neuronal subtype of glutamate transporter, EAAC1, are rapidly increased by direct activation of protein kinase C and are decreased by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K). We hypothesized that this regulation could be analogous to insulin-induced stimulation of the GLUT4 subtype of glucose transporter, which is dependent upon activation of PI3-K. Using C6 glioma, a cell line that endogenously and selectively expresses EAAC1, we report that platelet-derived growth factor (PDGF) increased Na(+)-dependent L-[(3)H]-glutamate transport activity within 30 min. This effect of PDGF was not due to a change in total cellular EAAC1 immunoreactivity but was instead correlated with an increase cell surface expression of EAAC1, as measured using a membrane impermeant biotinylation reagent combined with Western blotting. A decrease in nonbiotinylated intracellular EAAC1 was also observed. These studies suggest that PDGF causes a redistribution of EAAC1 from an intracellular compartment to the cell surface. These effects of PDGF were accompanied by a 35-fold increase in PI3-K activity and were blocked by the PI3-K inhibitors, wortmannin and LY 294002, but not by an inhibitor of protein kinase C. Other growth factors, including insulin, nerve growth factor, and epidermal growth factor had no effect on glutamate transport nor did they increase PI3-K activity. These studies suggest that, as is observed for insulin-mediated translocation of GLUT4, EAAC1 cell surface expression can be rapidly increased by PDGF through activation of PI3-K. It is possible that this PDGF-mediated increase in EAAC1 activity may contribute to the previously demonstrated neuroprotective effects of PDGF.

Amino Acid Transport System X-AG↗

PubMed2006

Reduced platelet [3H]paroxetine binding in anorexia nervosa: relationship to eating symptoms and personality pathology.

Alterations in serotonin function have been implicated in both anorexia and bulimia nervosa, and previous studies suggest associations between serotonin function and variations in pathological personality traits. Women meeting DSM-IV criteria for anorexia nervosa (AN, 16 with the restricting subtype and 14 with the binge-purge subtype) and 49 healthy control women (CW) provided blood samples for analyses of platelet [(3)H]paroxetine binding. Participants also filled out questionnaires tapping eating disorder symptoms, depression, and personality pathology. Compared with CW, women with restricting and binge-purge AN had significantly lower levels of paroxetine binding (respectively: 1012 + 487 vs. 560 + 253 vs. 618 + 217 fmol/mg protein). Simple correlation analyses showed that, within AN but not within controls, paroxetine binding was inversely related to dieting preoccupations, affective instability, anxiousness, compulsivity, restricted expression and social avoidance but independent of age, body mass index, depression, and other eating symptoms. Findings suggest that reduced peripheral serotonin transporter density in AN relates to increased dieting preoccupations, affective instability and anxiousness-fearfulness.

Adolescent↗

PubMed1989

Mast cells and their mediators.

Mast cells (MC) are the most important cells in hypersensitivity reactions. Their functions in other pathological conditions are, however, not completely understood. At least two different MC subtypes have been isolated and it seems that due to environmental changes further differences in the morphology and functions of MC:s exist. The activation of MC:s can be both due to immunological and non-immunological factors and results in a release of different mediators and production of so called newly generated MC mediators. The functions following mediator release are complicated and several other inflammatory cells are involved in these reactions. Due to the more slowly effect of the newly generated mediators and the interaction of different cell types the effects of these reactions are often spread over a long time. It seems that MC:s may play an important part not only in hypersensitivity reactions but also in other pathological conditions as in inflammatory disorders.

Humans↗

PubMed2006

Microarray-MD: a system for exploratory analysis of microarray gene expression data.

In this paper, we present Microarray Medical Data explorer (Microarray-MD), a novel software system that is able to assist in the exploratory analysis of gene expression microarray data. It implements a combination scheme of multiple Support Vector Machines, which integrates a variety of gene selection criteria and allows for the discrimination of multiple diseases or subtypes of a disease. The system can be trained and automatically tune its parameters with the provision of pathologically characterized gene expression data to its input. Given a set of new, uncharacterized, patient's data as input, it outputs a decision on the type or the subtype of a disease. A graphical user interface provides easy access to the system operations and direct adjustment of its parameters. It has been tested on various publicly available datasets. The overall accuracy it achieves was estimated to exceed 90%.

Colonic Neoplasms↗

PubMed2002

Expression pattern of MUM1/IRF4 in the spectrum of pathology of Hodgkin's disease.

Biological and clinical studies have shown that Hodgkin's disease (HD) can be divided into two major categories, termed nodular lymphocyte predominance HD (NLP HD) and classic HD (CHD). Within CHD four subtypes have been distinguished: nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depletion. To refine the histogenesis of the pathological spectrum of HD, 75 CHD and 13 NLP HD were analysed for the expression pattern of MUM1/IRF4 (Multiple Myeloma-1/Interferon Regulatory Factor-4), a lymphocyte-specific member of the IRF family, that is expressed by late centrocytes and post-germinal centre (GC) B cells. MUM1 reacted with Hodgkin's and Reed-Sternberg (HRS) cells of all CHD cases (75/75 cases), with a moderate to strong staining intensity. Conversely, lymphocyte and histiocyte (L & H) cells, the putative tumour cells of NLP HD, were negative for MUM-1 expression (9/13 cases) or displayed a weak reactivity for the antigen in < 10% neoplastic cells (4/13 cases). With respect to HD microenvironment, NLP HD displayed numerous MUM1-positive T lymphocytes located in close proximity to L & H cells whereas, in CHD, MUM1-positive T lymphocytes appeared to be distributed randomly with no specific relationship with HRS cells. Overall, this study shows that MUM1 expression differs in L & H cells versus HRS cells, corroborating the notion that NLP HD and CHD represent different stages of B-cell differentiation. As MUM1-positive T lymphocytes form rosettes around tumour cells of NLP HD, but not of CHD, these data point also to differences in the microenvironment of NLP HD and CHD, and postulate an interactive role of MUM1-positive T lymphocytes with L & H cells.

CD4-Positive T-Lymphocytes↗

PubMed2005

Systemic therapy of advanced bronchioloalveolar cell carcinoma: challenges and opportunities.

Bronchioloalveolar cell carcinoma (BAC) has fascinated physicians with its unique epidemiology, pathology, clinical manifestations, and natural history when compared with other non-small-cell lung cancer (NSCLC) subtypes. However, the relative rarity of pure BAC as defined by the WHO, and the inconsistent definitions used in various series, has limited systematic study of this entity. Retrospective and prospective studies suggest that patients with BAC treated with cytotoxic chemotherapy have a longer median survival than those with other subtypes of NSCLC. However, the widely accepted view that BAC is less chemosensitive than other NSCLCs is not clearly supported by the small body of available literature. Antitumor activity of cytotoxic agents and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors has been documented in phase II trials but no phase III trials have been conducted in this disease. The observation that profound responses to gefitinib and erlotinib often occurred in NSCLC patients with BAC, and that EGFR tyrosine kinase domain mutations were identified in large part by careful study of such patients, serves as a paradigm for translational research in this disease. The recognition that pure BAC and adenocarcinoma with BAC features behave similarly and as such represent a relatively common entity will facilitate accrual to BAC specific studies. Alternatively, stratification of these histologic subtypes in broader clinical trials in NSCLC is warranted. However, for either strategy to succeed in advancing our understanding of the molecular biology of BAC, it must be accompanied by central pathologic review with detailed classification of such, and of adequate tissue for measurement of known or putative targets of action of the agent under study.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1987

Vacuolar change in Alzheimer's disease.

A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.

Aged↗

PubMed2002

Prostate carcinoma with testicular or penile metastases. Clinical, pathologic, and immunohistochemical features.

BACKGROUND: Despite the proximity, prostate carcinoma seldom metastasizes to the penis or testis. METHODS: In the current study, the authors retrospectively examined the clinical history of 12 patients with prostate carcinoma and testicular or penile metastases. Pathologic review and immunohistochemical staining were performed on tumors from eight of these patients. RESULTS: Patients with prostate carcinoma and testicular or penile metastasis responded to androgen ablative therapy (median duration, 33 months). They were predisposed to developing persistent or recurrent urinary symptoms and visceral metastases. Six of 9 evaluable patients had elevated serum carcinoembryonic antigen levels (> 6 ng/mL), whereas 2 of 10 patients had low or undetectable serum prostate specific antigen levels (< 4 ng/mL). In seven of the eight patients for whom specimens were available, the tumors were found to contain histologic features that were compatible with a diagnosis of ductal or endometrioid adenocarcinoma of the prostate. CONCLUSIONS: Patients with prostate carcinoma and testicular or penile metastases have unique clinical and pathologic characteristics. Many of these patients' tumors are compatible with a subtype of prostate carcinoma known as ductal adenocarcinoma. Further studies need to be performed to elucidate the biologic basis of the various histologic subtypes of prostate carcinoma.

Aged↗

PubMed1988

Chordoma: natural history and treatment results in 33 cases.

Thirty-three chordomas were observed at the Istituto Nazionale Tumori of Milan from 1933 to 1983: 27 sacrococcygeal, 3 spheno-occipital, and 3 vertebral. The male:female ratio was 2.7, and the median age was 63 yr for patients with sacrococcygeal and 35.2 yr for those with nonsacral chordomas. After pathologic reassessment, distinct cytologic patterns were found: physaliphorous, syncytial, and mixed subtypes, with variable degrees of cytologic atypia. However, no evident difference in survival was documented in relation to these cytohistologic features. Four cases had a prior traumatic fracture, and the pathogenetic role of trauma is stressed. Eight cases were operated with adequate surgery and only three recurred, whereas of 11 inadequate operations, 10 developed local relapse. However, follow-up for recent adequate operations is short. Radiation therapy seemed to be effective with adjuvant or palliative aims. No chemotherapeutic regimen achieved any result; one case had a short complete remission after cis-dichlorodiammineplatinum + vinblastine + bleomycin (PVB). This analysis confirms the possibility of achieving radicality with high resection of the sacrum for lesions confined below the second sacral vertebra. Nonsacral chordomas were all unresectable. The best treatment for unresectable lesions seems to be palliative surgery plus radiotherapy.

Adolescent↗

PubMed1998

Alterations in potassium currents may trigger neurodegeneration in murine scrapie.

Conventional electrophysiological intracellular recording techniques were used to test the hypothesis that enhanced calcium entry via voltage-gated calcium channels or the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor-channel complex may be a primary pathological mechanism triggering neurodegeneration in scrapie and related diseases. This study was carried out at a time when cell loss is known to occur and when hippocampal pyramidal cells in area CA1 are rendered hyperexcitable following scrapie infection. There was no change to the NMDA receptor-mediated component of the Schäffer collateral evoked excitatory postsynaptic potential (EPSP) or the level of spontaneous firing activity of CA1 cells following addition of the specific NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV, 20 microM), to the perfusate in scrapie-infected mice, indicating that the NMDA receptor-channel complex is not compromised by scrapie. There was also no change seen in the non-NMDA mediated component of the EPSP. The calcium spike of CA1 pyramidal cells was not significantly altered by scrapie infection, indicating that high threshold voltage-gated Ca2+ channel function is not compromised by scrapie. By contrast, cells from scrapie-infected mice fired calcium spikes repetitively and the long, slow AHP, which in control cells inhibited repetitive firing, was absent. Cells from scrapie-infected mice showed more depolarized membrane potentials than controls but this difference in potential was no longer observed after exposure to TEA. These data indicate a loss of TEA-insensitive and TEA-sensitive potassium conductances. We suggest that altered potassium currents rather than increased calcium entry via voltage-sensitive calcium channels or the NMDA receptor complex may be the primary pathological mechanism triggering neurodegeneration in scrapie and related diseases.

2-Amino-5-phosphonovalerate↗

PubMed2002

[Etiologic and pathogenetic heterogeneity of Alzheimer disease].

The present review discusses whether the clinically and pathologically uniform phenotype of Alzheimer's disease (AD) consists of different subtypes with respect to etiopathogenesis. In a minority of patients with AD, the disease is determined by mutations of genes on chromosomes 1, 14, and 21. The amyloid cascade hypothesis provides a conclusive model for etiopathogenesis of these cases. The majority of patients, however, suffer from the sporadic subtype of AD, the etiopathogenesis of which is presently unknown. This subtype's pathogenesis is determined by a cascade of events, among which age, a disturbance of neuronal insulin receptor function leading to a deficit in acetylcholine and available energy, and membrane instability are the most important factors. The effects of these factors are modulated by the presence or absence of apolipoprotein E4. Thus, the development of this form of AD is characterized by dynamic cellular biological changes in the brain which are independent of the metabolism of the amyloid precursor protein and genetic factors. Therefore, the sporadic subtype of AD may be regarded as an age-associated metabolic disease of the brain.

Aged↗