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1.
Mod Pathol ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375771

RESUMO

Uterine yolk sac tumors have gained increased recognition in recent years. The current study is a multi-faceted examination of yolk sac tumor-like phenotypes in endometrial tumors, based on an analysis of 3 groups of uterine tumors: Group 1: 9 endometrial tumors that had been classified as yolk sac tumor, or as having a yolk sac tumor component, were assessed with a 35-marker immunohistochemical panel, with the goal of defining their immunophenotypic spectrum; Group 2, comprised of 70 endometrial carcinomas of various histotypes, were analyzed for their expression of SALL4, Glypican-3, and AFP, to assess the specificity of these markers for yolk sac tumors relative to endometrial carcinomas; Group 3, comprised of 626 archived cases of endometrial carcinoma/carcinosarcoma, reviewed to define the frequency of yolk sac tumor-like morphology therein. Yolk sac tumor areas in the Group 1 cases were consistently immunoreactive for SALL4 and Glypican-3; variably positive for AFP (89%), Villin (89%), PLAP (78%), 34ßE12 (67%), CAM 5.2 (62.5%), EMA (56%), CD117 (50%), p16 (50%), CDX2 (44%), p53 (44% aberrant), MOC31 (37.5%), CK7 (33%), GATA3 (33%), CK5 (25%), and PAX8 (11%); and were negative for CD30, Napsin A, OCT4, estrogen, androgen, and progesterone receptors. 29 (41%) of the 70 group-2 cases expressed at least one of the 3 markers, and 96% of the positive cases was a high-grade histotype. Glypican-3, SALL4, and AFP were positive in 30, 20, and 2.8% of group-2 cases respectively; however, co-expression of any 2, or all 3 markers was uncommon (<9 and 1.4% of cases respectively). Potential yolk sac tumor-like morphology was identified in 5 (0.8%) of 626 group-3 cases, and three were ultimately deemed to be true yolk sac tumor phenotypes based on their morphologic and immunophenotypic similarity to the group 1 cases. These findings highlight the broad immunophenotypic spectrum of uterine yolk sac tumors, the potential pitfalls associated with using immunophenotypes alone to define yolk sac tumor differentiation in endometrial carcinoma, and the utility and limitations of morphologic assessment to identify yolk sac tumors at this site.

2.
Mod Pathol ; 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31190001

RESUMO

A rare subset of aggressive SMARCA4-deficient uterine sarcomas has been recently proposed, with only a limited number of cases having been previously described. Here, we identify 16 additional cases of SMARCA4-deficient uterine sarcoma from the database of a large, CLIA-certified and CAP-accredited, reference molecular laboratory, and we expand on their clinicopathological and genomic features. Median patient's age was 49 years (range 32-70). Most tumors were aggressive with distant metastasis. SMARCA4-deficient uterine sarcoma demonstrated predominantly rhabdoid or large epithelioid cells with abundant cytoplasm, but also had varying degrees of small cell and spindle cell morphology. Tumors were microsatellite stable and exhibited no other or only few co-occurring genomic alterations by comprehensive genomic profiling. We discovered one patient, who developed SMARCA4-deficient uterine sarcoma at the age of 55, had a germline SMARCA4 mutation, whose daughter had previously died of small cell carcinoma of the ovary, hypercalcemic type, at the age of 32. Our data support the notion that SMARCA4 inactivation is the driver oncogenic event of a morphologically and molecularly distinct form of uterine sarcoma. Identification of SMARCA4-deficient uterine sarcomas may be clinically important due to their aggressive behavior, germline association, and emerging targeted therapies.

3.
JBJS Case Connect ; 9(1): e3, 2019 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628921

RESUMO

CASE: A 31-year-old woman developed worsening pain and paresthesia in the neck, shoulder, and arm over a period of 6 years. Magnetic resonance imaging revealed a soft-tissue mass in the subscapular region, with likely involvement of the scapula and the subscapularis muscle. The mass was resected, and the final histologic diagnosis was desmoid-type fibromatosis. CONCLUSION: Desmoid tumors with subscapularis muscle involvement are exceedingly rare. Although limited range of motion is the more common presentation for these tumors, this case demonstrates that desmoid tumors may present with primarily neurologic symptoms.

4.
Am J Surg Pathol ; 43(4): 531-537, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30585826

RESUMO

Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

5.
Int J Gynecol Pathol ; 38 Suppl 1: S9-S24, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30550481

RESUMO

Endometrial cancer is the most common gynecologic neoplasm in developed countries; however, updated universal guidelines are currently not available to handle specimens obtained during the surgical treatment of patients affected by this disease. This article presents recommendations on how to gross and submit sections for microscopic examination of hysterectomy specimens and other tissues removed during the surgical management of endometrial cancer such as salpingo-oophorectomy, omentectomy, and lymph node dissection-including sentinel lymph nodes. In addition, the intraoperative assessment of some of these specimens is addressed. These recommendations are based on a review of the literature, grossing manuals from various institutions, and a collaborative effort by a subgroup of the Endometrial Cancer Task Force of the International Society of Gynecological Pathologists. The aim of these recommendations is to standardize the processing of endometrial cancer specimens which is vital for adequate pathological reporting and will ultimately improve our understanding of this disease.


Assuntos
Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/cirurgia , Feminino , Ginecologia , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Estadiamento de Neoplasias , Patologistas , Guias de Prática Clínica como Assunto , Linfonodo Sentinela/patologia , Sociedades Médicas
6.
Int J Gynecol Pathol ; 38 Suppl 1: S93-S113, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30550486

RESUMO

Although endometrial carcinoma (EC) is generally considered to have a good prognosis, over 20% of women with EC die of their disease, with a projected increase in both incidence and mortality over the next few decades. The aim of accurate prognostication is to ensure that patients receive optimal treatment and are neither overtreated nor undertreated, thereby improving patient outcomes overall. Patients with EC can be categorized into prognostic risk groups based on clinicopathologic findings. Other than tumor type and grade, groupings and recommended management algorithms may take into account age, body mass index, stage, and presence of lymphovascular space invasion. The molecular classification of EC that has emerged from the Cancer Genome Atlas (TCGA) study provides additional, potentially superior, prognostic information to traditional histologic typing and grading. This classifier does not, however, replace clinicopathologic risk assessment based on parameters other than histotype and grade. It is envisaged that molecular and clinicopathologic prognostic grouping systems will work better together than either alone. Thus, while tumor typing and grading may be superseded by a classification based on underlying genomic abnormalities, accurate assessment of other pathologic parameters will continue to be key to patient management. These include those factors related to staging, such as depth of myometrial invasion, cervical, vaginal, serosal surface, adnexal and parametrial invasion, and those independent of stage such as lymphovascular space invasion. Other prognostic parameters will also be discussed. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.


Assuntos
Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Prognóstico , Sociedades Médicas
7.
Cancer Epidemiol Biomarkers Prev ; 27(12): 1509-1517, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30377203

RESUMO

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use may affect ovarian cancer risk via prostaglandin synthesis and tumor-associated macrophage (TAM) infiltration. We evaluated if associations between aspirin or non-aspirin NSAID use and ovarian cancer risk differed by tumor expression of prostaglandin-related (COX1, COX2) and TAM-related (CD68, CD163) markers. METHODS: We evaluated cases and matched controls from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (NECC). Cases with IHC data on COX1 and COX2 (n = 532) or CD68 and CD163 (n = 530) were included. We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate OR for NSAID use and ovarian cancer risk by marker level. RESULTS: Recent aspirin use had a nonsignificant inverse association and recent non-aspirin NSAID use had no association with ovarian cancer risk. NSAID use was not differentially associated with ovarian cancer by COX1 or COX2 expression. However, recent aspirin use was associated with lower ovarian cancer risk for high [OR 0.54; 95% confidence interval (CI), 0.37-0.78], but not low (OR 1.50; 95% CI, 0.97-2.31), CD163 density (P heterogeneity < 0.001). Similar results were observed for aspirin duration and tablets and for recent non-aspirin NSAID use. Results were not clearly different by macrophage density defined by the less specific macrophage marker, CD68. CONCLUSIONS: NSAID use was inversely associated with risk of ovarian cancer with high density CD163, a marker for M2-type, immunosuppressive macrophages. However, the relationship did not differ by prostaglandin synthesis markers. IMPACT: Future research should explore prostaglandin-independent mechanisms for the association between NSAID use and ovarian cancer risk, including immune mechanisms.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30411435

RESUMO

AIM: Fetal membranes are composed of the amnion and chorion, which fuse during the early second trimester. Persistent separation confers increased risk of adverse perinatal outcomes. This study characterizes sonographic and placental findings associated with persistent amnion-chorion (AC) membrane separation. METHODS: This is a case series of 23 patients carrying singleton pregnancies with persistent AC membrane separation after 16 weeks' gestation diagnosed by ultrasound from 2010 to 2016 at our institution. Twenty placentas were available for analysis. RESULTS: Obstetrical complications occurred in 13 (56.5%) cases; two (8.7%) cases resulted in intrauterine fetal demise. Fetal malformations were reported in eight (34.8%) cases. Four (17.4%) neonates were small-for-gestational age (SGA; <10th percentile). Placental size measured ≤10th percentile for gestational age in eight (40%) cases. Placental cord insertion was marginal or velamentous in eight (34.8%) cases. Maternal and/or fetal placental perfusion abnormalities occurred in 11 (55%) cases. CONCLUSION: AC membrane separation is associated with adverse obstetrical outcomes, placental abnormalities, including marginal and velamentous cord insertion, placental growth restriction and placental perfusion defects. This membrane complication is associated with increased incidence of fetal malformations in the absence of identifiable genetic etiologies.

9.
Gynecol Oncol ; 151(3): 401-406, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30340772

RESUMO

OBJECTIVE: A subset of endometrial cancer is characterized by deficiencies in the mismatch repair (MMR) pathway. MMR testing is a well-established tool to screen for Lynch syndrome, but has also become a companion diagnostic test for immunotherapy. We compared the MMR status of primary and paired metastatic endometrial cancer to determine whether MMR deficiency can occur specifically in advanced endometrial cancer compared to primary tumor. METHODS: Matched primary uterine and metastatic endometrioid adenocarcinoma from 2009 to 2018 at our institution were identified. PMS2 and MSH6 protein expression in metastatic and matched primary tumor was assessed using clinically validated immunohistochemistry methods for Lynch syndrome screening. MLH1 promoter hypermethylation and microsatellite instability (MSI) were performed in discordant cases. RESULTS: 29 patients were identified with paired primary endometrial endometrioid adenocarcinoma and metastasis or recurrence after the original hysterectomy. Fourteen of 29 cases (48.2%, 14/29) were found to be MMR deficient at the metastatic or recurrent site. Two patients (6.9%, 2/29) showed discordant MMR status with PMS2 protein loss at the metastatic sites and intact expression in the primary uterine tumors. Both discordant cases exhibited abnormal subclonal loss at primary site and MLH1 promoter hypermethylation. High levels of microsatellite instability (MSI-H) was confirmed in one discordant metastatic site. CONCLUSION: Advanced endometrial cancer can rarely (~7%) show somatic loss of MMR protein expression in recurrent or metastatic sites compared to matched paired primary tumor. MMR testing of recurrent or metastasis should be considered for guiding immunotherapy if primary uterine tumor exhibits abnormal subclonal MMR loss.

10.
Neuron ; 99(5): 905-913.e7, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30146301

RESUMO

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.

11.
Epigenetics ; 13(7): 742-750, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30045669

RESUMO

Infants born preterm are at increased risk of multiple morbidities and mortality. Why some women deliver preterm remains poorly understood. Prior studies have shown that cervical microRNA expression and DNA methylation are associated with the length of gestation. However, no study has examined the role of long noncoding RNAs (lncRNAs) in the cervix during pregnancy. To determine whether expression of lncRNAs is associated with length of gestation at delivery, we analyzed RNA from cervical swabs obtained from 78 women during pregnancy (mean 15.5, SD 5.0, weeks of gestation) who were participating in the Spontaneous Prematurity and Epigenetics of the Cervix (SPEC) Study in Boston, MA, USA. We used a PCR-based platform and found that 9 lncRNAs were expressed in at least 50% of the participants. Of these, a doubling of the expression of TUG1, TINCR, and FALEC was associated with shorter lengths of gestation at delivery [2.8 (95% CI: 0.31, 5.2); 3.3 (0.22, 6.3); and 4.5 (7.3, 1.6) days shorter respectively]. Of the lncRNAs analyzed, none was statistically associated with preterm birth, but expression of FALEC was 2.6-fold higher in women who delivered preterm vs. term (P = 0.051). These findings demonstrate that lncRNAs can be measured in cervical samples obtained during pregnancy and are associated with subsequent length of gestation at delivery. Further, this study supports future work to replicate these findings in other cohorts and perform mechanistic studies to determine the role of lncRNAs in the cervix during pregnancy.

12.
Gynecol Oncol ; 150(3): 521-526, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30001835

RESUMO

BACKGROUND: Grade and histotype of ovarian carcinomas are often used as surrogates of molecular subtypes. We examined factors affecting pathologists' reproducibility in two prospective studies. METHODS: Two pathologists independently reviewed slides from 459 incident ovarian cancers in the Nurses' Health Study (NHS) and NHSII. We described agreement on tumor characteristics using percent agreement and Cohen's standard kappa (κ) coefficients. We used logistic regression, with disagreement as the outcome, to evaluate the contribution of case and tumor characteristics to agreement. RESULTS: Inter-rater agreement was 95% (κ = 0.81) for carcinoma versus borderline, 89% (κ = 0.58) for grade and 85% (κ = 0.71) for histotype. Inter-rater grading disagreement was higher for non-serous histotypes (OR = 4.66, 95% CI 2.09-10.36) and lower for cancers with bizarre atypia (OR = 0.13, 95% CI 0.04-0.38). Agreement with original pathology reports was 94% (κ = 0.73) for carcinoma versus borderline, 78% (κ = 0.60) for histotype, and 79% (κ = 0.24) for grade. Grading disagreement was significantly lower for tumors with 'solid, pseudoendometrioid or transitional' (SET) architecture (OR = 0.08, 95%CI 0.01-0.84). Date of original diagnosis, hospital type, number of slides available for review, tumor stage, and slide quality were not related to agreement. CONCLUSION: Overall, inter-rater agreement for tumor type and grade for archival tissue specimens was good. Agreement between the consensus review and original pathology reports was lower. Factors contributing to grading disagreement included non-serous histotype, absence of bizarre atypia, and absence of SET architecture.


Assuntos
Carcinoma/patologia , Neoplasias Ovarianas/patologia , Feminino , Humanos , Gradação de Tumores , Invasividade Neoplásica , Variações Dependentes do Observador , Reprodutibilidade dos Testes
13.
Int J Gynecol Pathol ; 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29750700

RESUMO

A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS system. We retrospectively identified advanced stage HGSC patients who received neoadjuvant chemotherapy and underwent interval debulking. If available, a hemotoxylin and eosin slide from the omentum and the adnexa was selected for the study. Slides were independently scored by 13 pathologists using the 3-tiered CRS system. Reviewers then received web-based training and rescored the slides. Overall survival and progression-free survival were estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 68 patients with omental (n=65) and/or adnexal (n=59) slides were included in the study. Interobserver reproducibility was moderate for omentum (κ, 0.48) and poor for adnexa (κ, 0.40), which improved for omentum (κ, 0.62) but not for adnexa (κ, 0.38) after online training. For omental slides, a consensus CRS of 1/2 was associated with a shorter median progression-free survival (10.9 mo; 95% confidence interval, 9-14) than a CRS of 3 (18.9 mo; 95% CI, 18-24; P=0.020). In summary, a 3-tiered CRS system of hemotoxylin and eosin-stained omental deposits can yield prognostic information for HGSC patients receiving neoadjuvant chemotherapy, and web-based training improved reproducibility but did not alter determination of clinical outcomes. The CRS system may allow oncologists to identify potential nonresponders and triage HGSC patients for heightened observation and/or clinical trials.

14.
Cell ; 173(5): 1111-1122.e10, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29606355

RESUMO

The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.

15.
Ann Thorac Surg ; 105(2): e71-e73, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29362196

RESUMO

The Amplatzer family of vascular devices has been used off-label for the treatment of complex gastrointestinal and airway fistulas. We report a case in which closure of a benign gastrobronchial fistula with the use of an Amplatzer device resulted in massive hemoptysis and death.


Assuntos
Fístula Brônquica/cirurgia , Broncoscopia/efeitos adversos , Fístula Gástrica/cirurgia , Gastroscopia/efeitos adversos , Hemoptise/etiologia , Hemorragia Pós-Operatória/etiologia , Dispositivo para Oclusão Septal/efeitos adversos , Idoso , Fístula Brônquica/diagnóstico , Evolução Fatal , Fístula Gástrica/diagnóstico , Hemoptise/diagnóstico , Humanos , Masculino , Hemorragia Pós-Operatória/diagnóstico
17.
Int J Gynecol Pathol ; 37(6): 525-535, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29140878

RESUMO

Clear cell renal cell carcinomas (CCRCC) rarely metastasizes to the gynecologic tract. In this study, we analyzed a multi-institutional data set to provide insights into the clinical, morphologic, and immunophenotypic features of this phenomenon. Seventeen metastatic CCRCC involving the gynecologic tract [ovary/fallopian tube (n=9), vulva (n=2), uterine corpus (n=3), cervix (n=2), uterine serosa (n=1)] were analyzed. Mean patient age was 62 yr (range: 45-79 yr). Most cases (15/17) presented as a recurrence 6 to 72 mo postnephrectomy, 1 case was concurrently diagnosed, and 1 case (a cervical metastasis) was diagnosed prenephrectomy. In 10 cases, metastases to other locations were identified within 6 wk of the gynecologic tract lesion. The adnexa were the most common site of metastases and the mean tumor size of adnexal metastases was 3.7 cm; in only 2 of 9 cases were metastases bilateral and only 1 had external surface nodules. The morphologic and immunohistochemical features of metastatic CCRCC were compared with those of 102 müllerian clear cell carcinomas (müllerian CCC: 49 endometrial, 53 ovarian). Although CCRCC and müllerian CCC displayed extensive morphologic overlap, a higher mitotic index and a higher frequency of an alveolar pattern were seen in CCRCC, whereas diffuse hobnail cells, hyaline globules, tubulocystic pattern, or any papillary pattern were more frequently seen in müllerian CCC. CA-IX, CD10, and renal cell carcinoma antigen were more frequently expressed in CCRCC than müllerian CCC, whereas Napsin-A, CK7, and p504S showed the reverse. PAX8 and HNF1ß did not significantly distinguish between the 2 groups. In summary, gynecologic tract metastases most often occur as a relapse of a previously resected CCRCC, and these relapses may occur many years postnephrectomy. Gynecologic tract metastases are often accompanied by concurrent metastases to other organs. The gross pathology of metastatic CCRCC in the ovary may potentially overlap with primary neoplasia. However, the expected morphology and immunophenotype of CCRCC are maintained in most gynecologic tract metastases. As such, although metastatic CCRCC and müllerian CCC may display significant overlap in pathologic features, several morphologic and immunophenotypic features are useful in their distinction.

18.
Cancer Epidemiol Biomarkers Prev ; 27(1): 96-102, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133366

RESUMO

Background: One model of ovarian cancer development model divides tumors into two types. Type I tumors are characterized by KRAS and BRAF mutations, which can activate mitogen-activated protein kinase (MAPK). Type II tumors are characterized by tubal precursor lesions with p53 mutations. We evaluated the association between lifestyle and reproductive factors and risk of ovarian cancer defined by p53 and MAPK expression.Methods: Epithelial ovarian cancer cases (n = 274) and controls (n = 1,907) were identified from the Nurses' Health Study and Nurses' Health Study II prospective cohorts, and the population-based New England Case-Control study. Reproductive and lifestyle exposures were assessed by questionnaire/interview. We performed immunohistochemical assays for p53 and MAPK expression. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using polytomous logistic regression.Results: Parity was associated with a decreased risk of p53 wild-type tumors (OR = 0.31; 95% CI, 0.18-0.55), but not p53-mutant tumors (OR = 0.92; 95% CI, 0.54-1.59)(Pheterogeneity < 0.01). Family history of breast or ovarian cancer was associated with risk of MAPK-negative (OR = 2.06; 95% CI, 1.39-3.06), but not MAPK-positive tumors (OR = 0.74; 95% CI, 0.43-1.27; Pheterogeneity< 0.01). In cross-classified analyses, family history of breast or ovarian cancer was most strongly associated with p53-mutant/MAPK-negative tumors (OR = 2.33; 95% CI, 1.44-3.75). Differences by MAPK expression were also observed for estrogen plus progesterone hormone therapy use (Pheterogeneity = 0.03).Conclusions: These findings provide evidence that parity, family history, and estrogen plus progesterone hormone therapy use may be differentially associated with tumor subtypes defined by p53 and MAPK expression.Impact: In future studies, other immunohistochemical markers or gene expression profiles that more clearly define these subtypes should be considered. Cancer Epidemiol Biomarkers Prev; 27(1); 96-102. ©2017 AACR.

19.
Hypertens Pregnancy ; 36(3): 259-268, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28678644

RESUMO

OBJECTIVE: We describe the main lesions in the liver, brain, and kidney from autopsies of women who died of eclampsia and characterize the endothelial injury. METHODS: Cases were identified from a study involving 317 maternal deaths (2003-2006) conducted at the Maputo Central Hospital (Maputo, Mozambique) in association with ISGlobal (Barcelona, Spain). Histology slides along with stains for endothelial, histiocyte, and platelet markers (CD31, CD34, CD68, CD42B) were reviewed to identify the relevant lesions. Malondialdehyde stain was performed to demonstrate free radical generation. RESULTS: Brain lesions were characterized by perivascular "edema" (68.4%), hemorrhage (36.8%), hemosiderin (31.6%), small vessel thrombosis (10.5%), and parenchymal necrosis (15.8%). Liver sections showed periportal/portal necrosis and sinusoidal fibrin (72.2%) with associated hepatic arterial medial necrosis (44.4%). Kidneys showed glomerular endotheliosis. Endothelial, histiocytic, and platelet markers highlighted capillary injury in the otherwise intact brain parenchyma. Stains for free radical formation were positive predominantly in the areas of tissue injury, but intact glial/neuronal elements were focally positive as evidence of widespread oxidative stress. CONCLUSION: Pathological changes in cases of eclampsia include widespread endothelial/vascular injury in vulnerable organ beds.


Assuntos
Encéfalo/patologia , Eclampsia/patologia , Rim/patologia , Fígado/patologia , Útero/patologia , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Gravidez , Adulto Jovem
20.
Arch Gynecol Obstet ; 296(2): 257-262, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28631072

RESUMO

PURPOSE: To confirm reduced expression of soluble fms-like tyrosine kinase 1 (sFlt-1) in accreta/increta. METHODS: Formalin-fixed tissue sections from 11 peripartum hysterectomies with invasive placentation and 5 controls were stained for sFlt-1. Stain intensity was scored in selected 100× microscopic fields. We compared sFlt-1 expression in invasive areas among cases, non-invasive areas among cases and areas from control placentas. RESULTS: Chorionic villi displayed significantly decreased sFlt-1 expression in invasive areas of cases compared to control placentas (p = 0.003), as well as in non-invasive areas of cases compared to control placentas (p = 0.01). There was no difference in sFlt-1 expression between invasive and non-invasive areas among cases. CONCLUSIONS: Expression of sFlt-1 is diminished in villous trophoblasts from patients with placenta increta or percreta. Local depth of invasion was not associated with sFlt-1 expression, suggesting a more global abnormality across the implantation site rather than localized to areas of histologic invasion.


Assuntos
Regulação para Baixo , Placenta Acreta/genética , Placentação , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Placenta/metabolismo , Placenta/patologia , Placenta Acreta/metabolismo , Placenta Acreta/patologia , Pré-Eclâmpsia/metabolismo , Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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