Regulation of stress-inducible phosphoprotein 1 nuclear retention by protein inhibitor of activated STAT PIAS1.

Stress-inducible phosphoprotein 1 (STI1), a cochaperone for Hsp90, has been shown to regulate multiple pathways in astrocytes, but its contributions to cellular stress responses are not fully understood. We show that in response to irradiation-mediated DNA damage stress STI1 accumulates in the nucleus of astrocytes. Also, STI1 haploinsufficiency decreases astrocyte survival after irradiation. Using yeast two-hybrid screenings we identified several nuclear proteins as STI1 interactors. Overexpression of one of these interactors, PIAS1, seems to be specifically involved in STI1 nuclear retention and in directing STI1 and Hsp90 to specific sub-nuclear regions. PIAS1 and STI1 co-immunoprecipitate and PIAS1 can function as an E3 SUMO ligase for STI. Using mass spectrometry we identified five SUMOylation sites in STI1. A STI1 mutant lacking these five sites is not SUMOylated, but still accumulates in the nucleus in response to increased expression of PIAS1, suggesting the possibility that a direct interaction with PIAS1 could be responsible for STI1 nuclear retention. To test this possibility, we mapped the interaction sites between PIAS1 and STI1 using yeast-two hybrid assays and surface plasmon resonance and found that a large domain in the N-terminal region of STI1 interacts with high affinity with amino acids 450-480 of PIAS1. Knockdown of PIAS1 in astrocytes impairs the accumulation of nuclear STI1 in response to irradiation. Moreover, a PIAS1 mutant lacking the STI1 binding site is unable to increase STI1 nuclear retention. Interestingly, in human glioblastoma multiforme PIAS1 expression is increased and we found a significant correlation between increased PIAS1 expression and STI1 nuclear localization. These experiments provide evidence that direct interaction between STI1 and PIAS1 is involved in the accumulation of nuclear STI1. This retention mechanism could facilitate nuclear chaperone activity.

33 year-old woman with a large sellar tumor.

The authors describe a case of paraganglioma of the sellar region in a young female patient with loss of vision and headache. She presented with amaurosis, depression, anxiety and amenorrhea. Clinical and radiological impression was that it was a meningioma or pituitary adenoma. She received bromocriptine with no reduction of the lesion. She developed panhypopituitarism, but with normal levels of prolactin. It was resected and histological examination revealed nests of large cells with moderate nuclear pleomorphism, vesicular nuclei with occasional nucleoli. There were rare mitotic figures, but no necrosis. Immunohistochemistry was positive for synaptophysin, chromogranin A, and neuron-specific enolase with a few sustentacular cells positive for S100. The Ki67 proliferation was 1-2%. All pituitary hormonal antibodies were negative as well as GFAP, AE1/AE3, p53 and EMA. Paragangliomas affecting the sellar region are extremely rare and might be due to the presence of remnants of paraganglionic tissue or abnormal migration. The patient's post-operative diabetes insipidus remains under medical control.

Large and round tumor nuclei in osteosarcoma: good clinical outcome.

Osteosarcoma is the most frequent primary malignant bone tumor. Distinct histological features are distinguishable based on the morphology of the tumor. Differences in nuclei size and shape are often observed in osteosarcoma reflecting its broad histopathological heterogeneity. This study explores the relevance of two nuclear parameters in osteosarcoma: large area and round shape. Computerized nuclear morphometry was performed in 56 conventional osteosarcoma preoperative biopsies. The mean patient follow-up time was 35.1 months. Based on the nuclear area, no significant difference (P = 0.09) in overall survival between patients with large (> 42.5 µm(2)) and small (< 42.5 µm(2)) tumor nuclei was found. However, when cases with large and round nuclei were analyzed jointly (> 42.5 µm(2) and coefficient of nuclear roundness > 0.7), these two parameters together were likely to be a predictive factor (P = 0.05). Osteosarcoma patients with large and round tumor nuclei had a better outcome than patients with small and polymorphic (ovoid or spindle-shaped) nuclei. In this study, nuclear morphometry proved to be a useful tool to shed light on the biology of osteosarcoma showing that some morphometric parameters can be easily applied to help identifying patients with a good prognosis.

Comparative study of abnormalities of central nervous system in children and adults autopsied after bone marrow transplantation / Estudo comparativo das alterações no sistema nervoso central de crianças e adultos autopsiados após transplante de medula óssea

BACKGROUND: We compare neuropathological abnormalities in children and adults after bone marrow transplantation (BMT) by means of autopsy in the Department of Medical Pathology, Universidade Federal do Paraná (UFPR), Brazil. METHODS: Autopsy reports of 180 patients were reviewed. They were divided in two groups: patients under 15 years old and those 15 or older. Age, gender, clinical diagnosis at time of BMT, survival time, neuropathological abnormalities and cause of death were analyzed. RESULTS: In children (26.6 percent of total) and in the adult group (73.4 percent of total), the main clinical diagnoses prior to BMT were, respectively, severe aplastic anemia (31.2 percent) and chronic myeloid leukemia (36.3 percent). The mean survival time for children was 102.6 days and for adults, 185.9 days after BMT. Brain lesions were considered cause of death in 20.8 percent of pediatric cases and 11.3 percent of the adult group. Neuropathological abnormalities were morphologically similar in children and adults, with the following respectively prevalence: cerebrovascular diseases in 58.3 and 56 percent (p = 0.8655), neurotoxoplasmosis in 6.2 percent and 3 percent (p = 0.3856) and infections in 27 and 25.7 percent (p = 0.8489). CONCLUSIONS: The pediatric patients had shorter survival than adults, with increasing prevalence of neurotoxoplasmosis, and brain lesions were considered cause of death in twice as many as compared to adult patients.

INTRODUÇÃO: Foram comparadas as anormalidades encontradas no sistema nervoso central de adultos e crianças submetidos à autópsia após transplante de medula óssea (TMO) no Departamento de Patologia Médica da Universidade Federal do Paraná (UFPR). MÉTODOS: Relatórios das autópsias de 180 pacientes foram revistos. Foram considerados crianças os pacientes abaixo de 15 anos; adultos, aqueles com 15 ou mais. A idade, o sexo, o diagnóstico clínico na época do TMO, o tempo de sobrevivência, as anormalidades neuropatológicas e a causa da morte foram analisados. RESULTADOS: Nas crianças (26,6 por cento do total) e nos adultos (73,4 por cento do total) o principal diagnóstico clínico prévio ao TMO foi, respectivamente, anemia aplásica severa (31,2 por cento) e leucemia mielóide crônica (36,3 por cento). O tempo médio de sobrevivência pós-TMO para crianças foi de 102,6 dias; para os adultos, 185,9. Lesões cerebrais foram consideradas causa de morte em 20,8 por cento dos casos pediátricos e 11,3 por cento do grupo adulto. As anormalidades neuropatológicas foram morfologicamente similares nas crianças e nos adultos e apresentaram, respectivamente, as seguintes prevalências: doenças cerebrovasculares em 58,3 por cento e 56 por cento (p = 0,8655), neurotoxoplasmose em 6,2 por cento e 3 por cento (p = 0,3856) e infecções em 27 e em 25,7 por cento (p = 0,8489). CONCLUSÕES: As crianças tiveram sobrevida menor, maior número de casos de neurotoxoplasmose e duas vezes mais lesões graves do sistema nervoso central que o grupo adulto.

Quality assurance in cervical screening of a high risk population: a study of 65,753 reviewed cases in Parana Screening Program, Brazil.

Epidemiological data from the Quality Assurance Unit (QAU) of the Cervical Cancer Screening Program of Paraná is discussed. Slides (65,753) reviewed by the QAU, from October 1997 to July 1999, were analyzed. Relations between agreement rate, diagnostic categories, and age groups were tested. The overall agreement rate was 97.04% (kappa +/- 95%, confidence interval = 0.888 +/- 0.003). Low-grade squamous intraepithelial lesion (LSIL) showed its peak prevalence in patients < or = 19 yr (8.3%). High-grade squamous intraepithelial lesion (HSIL) was more common in women between 40 and 49 yr (5.0%). Squamous-cell carcinoma (SCC) was almost exclusively seen in women > or = 40 yr. The lowest agreement rates were seen in adenocarcinoma (54.5%; kappa = 0.667) and LSIL cases (76.3%, kappa = 0.822), and in women < or = 19 yr (95.8%). It was concluded that constant monitoring to assess specific errors allows directed measures. The 10% rescreening model of quality assurance proved to be effective in a low resources setting with a positive overall financial impact.

Granular cell tumor of the neurohypophysis: report of a case with unusual age presentation.

Granular cell tumor (GCT) usually occurs as a solitary, small, nodular tumor and rarely grows to a sufficient size to present symptoms. The tumor is more prevalent in female adults. The authors report a case of an 8-year-old boy with GCT of the neurohypophysis presenting with central precocious puberty. Few cases of symptomatic GCT have been reported in the literature, none of them in a patient in the first decade of life. Clinical picture, histopathological features, and histogenesis of GCT of neurohypophysis are discussed.

Influence of specimen adequacy on the diagnosis of ASCUS.

The impact of specimen adequacy on the diagnosis of cervical cytology is not fully understood. Virtually, the greatest impact of smear quality limitation factors is on the diagnosis of atypical squamous cells of undetermined significance (ASCUS) because this category is more susceptible to interpretation mistake due to its criteria subjectivity. This study aims to evaluate the impact of smear quality impairing factors on the diagnosis of ASCUS. The 1,507 cases of ASCUS studied were obtained from the Cervical Cancer Screening Program of Paraná (CCSPP). The cases were reviewed by expert cytopathologists and the results were correlated to the specimen adequacy. The results showed that the presence of obscuring blood impairs the correct diagnosis and leads the pathologist to overdiagnose negative smears as ASCUS. The presence of adequate endocervical sampling contributes to a higher rate of correct ASCUS diagnoses but did not influence the pathologist to over- or underestimate the cytological findings.

Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors.

The accumulation of genetic and epigenetic changes plays a pivotal role in tumor development and progression. In this study, we investigated these changes using comparative genomic hybridization and bisulfite polymerase chain reaction analysis for CpG island hypermethylation of the following genes: TP16, THBS2, E-Cadherin (ECAD), RARbeta2, MINT1, MINT2, and MINT31 in six paired primary breast tumors and their matched sentinel lymph nodes (SLN). The most frequent chromosomal alterations observed were the following: losses of 6q13 approximately q23 and 13q13 approximately q32 and gains of 9q31 approximately qter, 11p15 approximately q21, 12q23 approximately qter, and 20q12 approximately qter. Gain of 6p21 approximately pter was observed in the SLN but in none of the primary tumors. Overall, 71% (30/42) of the methylation measurements were identical between the primary tumors and the SLN. Of the six cases, two showed no differences between the primary tumors and SLN, one tumor with 4 of 7 genes hypermethylated in the primary tumor showed loss of all four hypermethylation events in the SLN, and the remaining three tumors showed loss of one methylation event and simultaneous gain of one to two methylation changes in the SLN. This is the first study reporting genetic and epigenetic alterations in breast sentinel lymph nodes compared to their corresponding primary tumors. Characterization of such alterations may lead to identification of initial events associated with the metastatic dissemination process.

Cervical cancer screening program of Paraná: cost-effective model in a developing country.

The purpose of this study is to report the organization of a cost-effective screening program for cervical cancer in a developing country such as Brazil. The Cervical Cancer Screening Program of Paraná (CCSPP) was launched in October 1997 and was the result of a joint collaboration between the government of Paraná (Secretary of Health of the State of Paraná), scientific societies (pathologists, gynecologists, and nurses), and a non governmental organization called the Women's Popular Forum of Paraná. The main goal of the program was to enhance the Papanicolaou (Pap) smear screening to coverage up to 85% of female adult population with a 3-yr interval between examinations, as well as to reduce the incidence and mortality from cervical cancer in the state of Paraná, a Southern state of Brazil. The cytological findings in all Pap smears recorded in a central computer-based register during 5 yr of the program (October 1997-October 2002) are discussed. During that period, 2,244,158 Pap smears were performed in women included in the program from the 398 cities of the state of Paraná. The cytological smears were analyzed according to the Bethesda System. The previous year, before the program was launched, a Pap smear was taken from 43% of women of Paraná. At the end of 5 yr, coverage was increased to around 86%. The great majority of examinations had a negative result (98%). Only 2% of examinations had cytological abnormalities (n = 44,621). Low-grade lesions predominated in women aged 15-30 yr, and the high-grade lesions were more common in women aged 25-45 yr. Patients older than 40 yr had the greatest incidence of invasive cancer. Although the program is only 5 yr old, a decrease in the mortality from cervical cancer in women from Paraná is clearly apparent: in 1998, 297 women died of cervical cancer, as compared with 188 as of September 2002.

Influence of the greater saphenous vein graft quality in the early patency of infrainguinal revascularizations

Objectives: The authors evaluate the quality of the greater saphenous veins used in lower limb revascularization at the moment of their implantation, using a semiquantitative histopathological method, relating the vein quality with patient's sex and age, as well as the influence on early patenct rates. Method: A total of 144 veins of 144 patients were studied, 88 male and 56 female, with a mean age of 65,7 years. The vein was stained with hematoxylin-eosin. The degree of intimal hyperplasia and hypertrophy of the longitudinal and circular muscular layers of the media were analyzed. The quality of the vein was classified, by adding the grades of each layer, into good, regular and questionable quality. Results: As to quality, 82 veins (57 por cento) were classified as good, 49 (34 por cento) as regular and 13 (9 por cento) as questionable. In six months, the primary patency of good quality veinsas 80,5 por cento, that of regularuality veins was 79,6 por cento and the patency of questionable quality veins was 84,6 por cento. Conclusion: No differences were seen in vein quality, either in the individual evaluation of each layer or in the global evaluation of the three layers, regarding the patient's sex and age. No differences was observed regarding the patency of the grafts...

Meningioma with extensive noncalcifying collagenous whorls and glial fibrillary acidic protein expression: new variant of meningioma diagnosed by smear preparation.

The purpose of this report is to describe the unique cytological findings of a new recently characterized type of meningioma that has extensive noncalcifying collagenous whorls and glial fibrillary acid protein (GFAP) expression. This new entity, described by Haberler and colleagues, was named whorling sclerosing variant of meningioma. The patient was a 34-yr-old white man with a large tumor in the brainstem. Intraoperative smear preparations showed a tumor with a large number of solid hyaline masses in a loose background and in focal areas tumor cells formed cohesive nests with a somewhat whorling appearance. The histological sections showed a neoplasia composed of innumerable eosinophilic, collagenous, noncalcified round deposits, cuffed by scattered meningothelial tumor cells. The neoplastic cells showed diffuse cytoplasmic reactivity for EMA and vimentin, as well as positivity to GFAP. This is the first cytological description of this new entity in the literature.

Comprehensive cytogenetic evaluation of a mature ovarian teratoma case.

Mature ovarian teratomas are benign ovarian germ cell tumors that usually present with a normal karyotype. There are very few reports describing chromosomal abnormalities in these tumors, none of which are recurrent. In this study we report on a mature teratoma case with clonal chromosomal alterations which include monosomies of chromosomes 6, 14, 16, and 21; trisomies of chromosomes 14 and 21; and deletions of Xq, 5p, 16p, and 17p. Comparative genomic hybridization evaluation of the sample revealed a normal profile. These findings are discussed together with the cytogenetic reports on other cases of ovarian teratomas described in the literature.

Dysembrioplastic neuroepithelial tumor: cytological diagnosis by intraoperative smear preparation.

The dysembrioplastic neuroepithelial tumor (DNT) is a benign and slow-growing temporal lobe cortical lesion that presents with clinically unresponsive partial and complex seizures, with onset before age 20 yr. DNT shows a multinodular architecture and the presence of mixed glioneural elements. The authors report on a case of DNT diagnosed by the intraoperative smear cytological technique. We describe the cytological characteristics of smear preparations of DNT, with emphasis on the differential diagnosis. The authors present a 5-yr-old male with partial seizures for the preceding 3 yr. The patient showed no other neurological deficits. Magnetic resonance identified a lesion in the cortical area of the right temporal lobe. The smear cytology showed small, round, oligodendroglial-like cells arranged in lobules, with microcystic spaces containing ganglion cells floating in a fine fibrillary background. Histology confirmed the diagnosis of DNT. This report shows that the smear preparation can be trustworthy for the intraoperative diagnosis of DNTs, helping to determine the appropriate neurosurgical procedure and thus avoiding extensive and unnecessary resections.

Unusual presentation of Rosai-Dorfman Disease in a 82 years-old patient / Apresentaçäo incomum da doença de Rosai-Dorfman em uma paciente de 82 anos

A doença de Rosai- Dorfman (DRD) é uma doença histioproliferativa idiopática rara, caracterizada, principalmente, por linfadenomegalia. E uma doença predominantemente da infância e da adolescência. A DRD é geralmente caracterizada por linfonodopatia cervical bilateral, associada a febre e leucocitose. Histologicamente, ela é caracterizada por aumento dos seios linfáticos, devido à proliferaçäo de histiócitos positivos para proteinas S-100, e linfofagocitose. Os autores apresentam um caso de DRD em uma paciente de 82 anos, que representa o paciente mais idoso da literatura afetado por esta entidade

Desenvolvimento embriológico da pele humana: análise histológica e revisäo da literatura / Skin embriology: histological analysis and review of literature

A histopatologia representa um recurso diagnóstico fundamental na dermatologia. Entretanto, a grande variedade de entidades nosológicas que acometem a pele, principalmente na faixa etária pediátrica, torna complexa a formaçäo de um profissional treinado para o diagnóstico anatomopatológico em pele, o dermatopatologista, exigindo o conhecimento dos métodos diagnósticos de ponta e de diversas disciplinas básicas, como embriologia e histologia. O objetivo do presente trabalho foi estudar a embriologia do tegumento por meio da avaliaçäo histógica de amostras da pele da regiäo interna da coxa direita, coletadas de fetos e natinortos submetidos a autópsia no Hospital de Clínicas de Curitiba da Universidade Federal do Paraná (UFPR). Os resultados foram descritos por meio de fotomicrografias e comparados com dados de literatura

Carcinoma de plexo coróide: relato de quinze casos / Choroid plexus carcinoma: report of 15 cases

O carcinoma de plexo coróide (CPC) é um raro tumor do sistema nervoso central (SNC), derivado do epitélio de revestimento dos plexos coróides, que acomete pacientes abaixo dos 3 anos de idade. Apresentamos um estudo clínico, epidemiológico e histopatológico de 15 casos de CPC. Destes, 10 eram do gênero masculino. As idades variaram de 4 meses a 21 anos. Quanto a localização, acometeram predominante o ventrículo lateral (73,3 por cento). Os sinais e sintomas predominantes foram hidrocefalia (62,5 por cento), hipertensão intracrania (25 por cento) e crise convulsiva (12, por cento). Os pacientes foram submetidos a tratamento cirúrgico com ressecção parcial em 75 por cento dos casos e completa em 25 por ento. Houve um óbito per-operatório. Em 85,7 por cento dos pacientes houve recidiva tumoral, com evolução a óbito em média 13,6 meses após o diagnóstico. Apenas um paciente encontra-se vivo num seguimento de 5 anos. Esses dados suportam o prognóstico sombrio e a alta mortalidade do CPC.

Doença de Krabbe - relato de caso / Krabbe's disease - case report

Objetivo: relatar um caso de doença de Krabbe com estuto de necropsia. Métodos: Revisão de prontuários e laudos de necrópsia. Resultados: Paciente masculino, 8 meses, apresentou tremores de extremidades, dificuldade para de deglutição e salivação excessiva há 4 meses, evoluindo com vômitos e picos febris noturnos. O exame físico demonstrou microcefalia e dispersão pigmentar difusa da retina. Ao exame neurológico, evidenciou-se flexão e hipertonia espástica dos membros superiores, com abdução dos polegares, hiperreflexiaa simétrica generalizada com sinal de Babinski bilateral, nistagmo relatório, bem como espasmos espontâneos. O exame eletroencefalográfico demonstrou atividade irritativa multifocal. Houve ainda proteinorraquia com aumento da gamaglobuna. O paciente evoluiu com hipertermia transitória, vômitos e pneumopatia, indo a óbito no 23§ dia de internação. A necrópsia demonstrou microcefalia com encéfalo apresentando giros alargados. Microscopicamente evidenciaram-se numerosas células globóides na porção profunda da substância branca, gliose nacianal e desmielinização. Conclusões: Estes achados foram semelhantes aos da literatura mundial, indicando um prognóstico sombrio devido a lesões cerebrais substanciais

Apresentaçao histologica incomum de fibroadenoma com concomitância de tumor phyllodes e carcinona lobular "in situ": relato de um caso / Unusual histological presentation of a fibroadenoma with a concomitant phyllodes tumor and lobular carcinoma: a case report

Alteraçoes malignas nos tumores phyllodes sao incomuns e geralmente comprometem apenas o componente estromal. A ocorrência de carcinomas em tumores phyllodes é rara porém, quando ocorrem, os carcinomas loburares in situ correspondem a 81 por cento dos casos. Os autores relatam um caso de paciente feminina apresentando ao exame histopatológico um fibroadenoma gigante exibindo área de tumor phyllodes benigno com metaplasia e carcinoma lobular in situ. Há escassos relatos na literatura estrangeira da coexistência deste tipo de carcinoma com os tumores phyllodes e fibroadenomas, sendo que até o presente momento este é o primeiro relato na literatura latino-americana indexada no Index Medicus e no Latino Americano (LILACS)

Von Hippel-Lindau's disease

Os autores relatam os achados de autópsia de pacientes de uma mesma família e o diagnóstico por biópsia de hemangioblastoma de um terceiro membro desta mesma família. O primeiro paciente tinha 34 anos por ocasiao do óbito e os achados de necrópsia mostraram hemangioblastoma de retina, cerebelo, bulbo e medula espinhal, além de carcinoma renal, feocromocitoma, lesoes císticas de rim e pâncreas, hidromielia e meningiomas atípicos. Seu irmao morreu com 30 anos de idade e a autópsia revelou hemangioblastomas de cerebelo, carcinoma renal e cistoadenoma de células de células claras de epidídimo. A terceira paciente era filha do primeiro paciente e apresentou cefaléia e ataxia. A tomografia computadorizada mostrou lesao cerebelar cística e a biópsia confirmou tratar-se de hemangioblastoma. Sao feitas consideraçoes epidemiológicas sobre lesoes viscerais e do sistema nervoso mais comumente encontradas, além de discutir critérios diagnósticos.