Fibrose hepática congênita e venopatia portal obliterativa sem hipertensão portal - revisão da literatura com base em um caso assintomático / Congenital hepatic fibrosis and obliterative portal venopathy without portal hypertension - a review of literature based on an asymptomatic case

ABSTRACT The disease and the case reported here are relevant especially because of their varied clinical presentation, possibility of being associated with other disorders affecting several organs and possible differential diagnoses. Congenital Hepatic Fibrosis is an autosomal recessive disease due to mutation in the PKHD1 gene, which encodes the fibrocystin/polyductine protein. It is a cholangiopathy, characterized by varying degrees of periportal fibrosis and irregular proliferation of bile ducts. Affected patients are typically diagnosed in childhood, but in some cases the disease may remain asymptomatic for many years. The exact prevalence and incidence of the disease are not known, but it is consider a rare disease, with a few hundred cases described worldwide. It can affect all ethnic groups and occur associated with various hereditary and non-hereditary disorders. The clinical presentation is quite variable, with melena and hematemesis being initial symptoms in 30%-70% of the cases. More rarely, they may present episodes of cholangitis. The disease has been classified into four types: portal hypertension, cholestasis / cholangitis, mixed and latent. Diagnosis begins with imaging tests, but the definition is made by the histopathological sample. So far, there is no specific therapy that can stop or reverse the pathological process. Currently, the therapeutic strategy is to treat the complications of the disease.

RESUMO A patologia e o caso aqui reportados são relevantes especialmente devido sua variada apresentação clínica, possibilidade de estar associada com outras desordens acometendo diversos órgãos e pelos possíveis diagnósticos diferenciais. A fibrose hepática congênita é uma doença autossômica recessiva, devido mutação no gene PKHD1, que codifica a proteína fibrocistina/poliductina. É uma colangiopatia, caracterizada por variados graus de fibrose periportal e proliferação irregular de ductos biliares. Os pacientes acometidos são tipicamente diagnosticados na infância, mas em alguns casos a doença pode permanecer assintomática por muitos anos. Exatas prevalência e incidência da doença não são conhecidas, mas sabe-se que é uma doença bastante rara, com algumas centenas de casos descritos no mundo. Pode afetar todos grupos étnicos e ocorrer associada com diversas desordens hereditárias e não-hereditárias. A apresentação clínica é bastante variável, com melena e hematêmese sendo sintomas iniciais em 30%-70% dos casos. Mais raramente, podem apresentar episódios de colangite. A doença tem sido classificada em quatro tipos: hipertensão portal, colestática/colangite, mista e latente. O diagnóstico inicia com exames de imagem, mas a definição é feita pela amostra histopatológica. Até o momento, não há terapia específica que possa parar ou reverter o processo patológico e a estratégia terapêutica atual é tratar as complicações da doença.

Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone.

CONGENITAL HEPATIC FIBROSIS AND OBLITERATIVE PORTAL VENOPATHY WITHOUT PORTAL HYPERTENSION - A REVIEW OF LITERATURE BASED ON AN ASYMPTOMATIC CASE.

The disease and the case reported here are relevant especially because of their varied clinical presentation, possibility of being associated with other disorders affecting several organs and possible differential diagnoses. Congenital Hepatic Fibrosis is an autosomal recessive disease due to mutation in the PKHD1 gene, which encodes the fibrocystin/polyductine protein. It is a cholangiopathy, characterized by varying degrees of periportal fibrosis and irregular proliferation of bile ducts. Affected patients are typically diagnosed in childhood, but in some cases the disease may remain asymptomatic for many years. The exact prevalence and incidence of the disease are not known, but it is consider a rare disease, with a few hundred cases described worldwide. It can affect all ethnic groups and occur associated with various hereditary and non-hereditary disorders. The clinical presentation is quite variable, with melena and hematemesis being initial symptoms in 30%-70% of the cases. More rarely, they may present episodes of cholangitis. The disease has been classified into four types: portal hypertension, cholestasis / cholangitis, mixed and latent. Diagnosis begins with imaging tests, but the definition is made by the histopathological sample. So far, there is no specific therapy that can stop or reverse the pathological process. Currently, the therapeutic strategy is to treat the complications of the disease.

Hepatocellular Carcinoma Management in Nonalcoholic Fatty Liver Disease Patients: Applicability of the BCLC Staging System.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) has emerged as an important cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) system is the preferred staging system to evaluate patients with HCC and links prognosis assessment with treatment recommendation. The aim of this retrospective study was to evaluate whether the BCLC staging system and its treatment algorithm are suitable for patients with HCC arising from NAFLD. METHODS: Forty-two patients with HCC related to either to NAFLD or cryptogenic cirrhosis were retrieved retrospectively from 2 centers in Brazil. Patients were classified according to BCLC staging system. If the proposed HCC therapy could not be applied, the case was considered to represent deviations from the recommended BCLC guideline. Causes of treatment deviations were investigated. RESULTS: There were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the very early (0), early (A), intermediate (B), advanced (C), and terminal (D) BCLC stages, respectively. Thirty-five patients (83%) were treated according to BCLC recommendations. There were 3 cases (of 5) of protocol deviation in BCLC C patients. The 1- and 2-year overall survival rates were 81% and 66%, respectively. CONCLUSIONS: The BCLC system is applied in most cases of NAFLD-related HCC cases. Deviation of BCLC is found more frequently in BCLC C stage patients.

Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling.

BACKGROUND: We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines. METHODS: DCD expression was evaluated by qRT-PCR, immunohistochemical and immunoblot assays in normal and neoplastic tissues and cell lines. To investigate the role of DCD in breast tumorigenesis, we analyzed the consequences of its downregulation in human breast cancer cell lines using three specific shRNA lentiviral vectors. Genes up- and down-regulated by DCD were identified using Affymetrix microarray and analyzed by MetaCore Platform. RESULTS: We identified DCD splice variant (DCD-SV) that is co-expressed with DCD in primary invasive breast carcinomas and in other tissue types and cell lines. DCD expression in breast tumors from patients with clinical follow up data correlated with high histological grade, HER2 amplification and luminal subtype. We found that loss of DCD expression led to reduced cell proliferation, resistance to apoptosis, and suppressed tumorigenesis in immunodeficient mice. Network analysis of gene expression data revealed perturbed ERBB signaling following DCD shRNA expression including changes in the expression of ERBB receptors and their ligands. CONCLUSIONS: These findings imply that DCD promotes breast tumorigenesis via modulation of ERBB signaling pathways. As ERBB signaling is also important for neural survival, HER2+ breast tumors may highjack DCD's neural survival-promoting functions to promote tumorigenesis.

Clinical and pathological evaluation of fibrolamellar hepatocellular carcinoma: a single center study of 21 cases

OBJECTIVES: Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver tumor that differs from conventional hepatocellular carcinoma in several aspects. The aim of this study was to describe the clinical, surgical and histopathological features of fibrolamellar hepatocellular carcinoma and to analyze the factors associated with survival. METHODS: We identified 21 patients with histopathologically diagnosed fibrolamellar hepatocellular carcinoma over a 22-year period. Clinical information was collected from medical records and biopsies, and surgical specimens were reviewed. RESULTS: The median age at diagnosis was 20 years. Most patients were female (67%) and did not have associated chronic liver disease. Most patients had a single nodule, and the median tumor size was 120 mm. Vascular invasion was present in 31% of patients, and extra-hepatic metastases were present in 53%. Fourteen patients underwent surgery as the first-line therapy, three received chemotherapy, and four received palliative care. Eighteen patients had “pure fibrolamellar hepatocellular carcinoma,” whereas three had a distinct area of conventional hepatocellular carcinoma and were classified as having “mixed fibrolamellar hepatocellular carcinoma.” The median overall survival was 36 months. The presence of “mixed fibrolamellar hepatocellular carcinoma” and macrovascular invasion were predictors of poor survival. Vascular invasion was associated with an increased risk of recurrence in patients who underwent surgery. CONCLUSION: Fibrolamellar hepatocellular carcinoma was more common in young female patients without chronic liver disease. Surgery was the first therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was a risk factor for tumor recurrence. The presence of macrovascular invasion and areas of conventional hepatocellular carcinoma were directly related to poor survival. .

Percutaneous radiofrequency ablation for early hepatocellular carcinoma: risk factors for survival.

AIM: To evaluate outcomes of radiofrequency ablation (RFA) therapy for early hepatocellular carcinoma (HCC) and identify survival- and recurrence-related factors. METHODS: Consecutive patients diagnosed with early HCC by computed tomography (CT) or magnetic resonance imaging (MRI) (single nodule of ≤ 5 cm, or multi- (up to 3) nodules of ≤ 3 cm each) and who underwent RFA treatment with curative intent between January 2010 and August 2011 at the Instituto do Câncer do Estado de São Paulo, Brazil were enrolled in the study. RFA of the liver tumors (with 1.0 cm ablative margin) was carried out under CT-fluoro scan and ultrasonic image guidance of the percutaneous ablation probes. Procedure-related complications were recorded. At 1-mo post-RFA and 3-mo intervals thereafter, CT and MRI were performed to assess outcomes of complete response (absence of enhancing tissue at the tumor site) or incomplete response (enhancing tissue remaining at the tumor site). Overall survival and disease-free survival rates were estimated by the Kaplan-Meier method and compared by the log rank test or simple Cox regression. The effect of risk factors on survival was assessed by the Cox proportional hazard model. RESULTS: A total of 38 RFA sessions were performed during the study period on 34 patients (age in years: mean, 63 and range, 49-84). The mean follow-up time was 22 mo (range, 1-33). The study population showed predominance of male sex (76%), less severe liver disease (Child-Pugh A, n = 26; Child-Pugh B, n = 8), and single tumor (65%). The maximum tumor diameters ranged from 10 to 50 mm (median, 26 mm). The initial (immediately post-procedure) rate of RFA-induced complete tumor necrosis was 90%. The probability of achieving complete response was significantly greater in patients with a single nodule (vs patients with multi-nodules, P = 0.04). Two patients experienced major complications, including acute pulmonary edema (resolved with intervention) and intestinal perforation (led to death). The 1- and 2-year overall survival rates were 82% and 71%, respectively. Sex, tumor size, initial response, and recurrence status influenced survival, but did not reach the threshold of statistical significance. Child-Pugh class and the model for end-stage liver disease score were identified as predictors of survival by simple Cox regression, but only Child-Pugh class showed a statistically significant association to survival in multiple Cox regression analysis (HR = 15; 95%CI: 3-76 mo; P = 0.001). The 1- and 2-year cumulative disease-free survival rates were 65% and 36%, respectively. CONCLUSION: RFA is an effective therapy for local tumor control of early HCC, and patients with preserved liver function are the best candidates.

Expression of human protein S100A7 (psoriasin), preparation of antibody and application to human larynx squamous cell carcinoma.

BACKGROUND: Up-regulation of S100A7 (Psoriasin), a small calcium-binding protein, is associated with the development of several types of carcinomas, but its function and possibility to serve as a diagnostic or prognostic marker have not been fully defined. In order to prepare antibodies to the protein for immunohistochemical studies we produced the recombinant S100A7 protein in E. coli. mRNA extracted from human tracheal tumor tissue which was amplified by RT-PCR to provide the region coding for the S100A7 gene. The amplified fragment was cloned in the vector pCR2.1-TOPO and sub-cloned in the expression vector pAE. The protein rS100A7 (His-tag) was expressed in E. coli BL21::DE3, purified by affinity chromatography on an Ni-NTA column, recovered in the 2.0 to 3.5 mg/mL range in culture medium, and used to produce a rabbit polyclonal antibody anti-rS100A7 protein. The profile of this polyclonal antibody was evaluated in a tissue microarray. RESULTS: The rS100A7 (His-tag) protein was homogeneous by SDS-PAGE and mass spectrometry and was used to produce an anti-recombinant S100A7 (His-tag) rabbit serum (polyclonal antibody anti-rS100A7). The molecular weight of rS100A7 (His-tag) protein determined by linear MALDI-TOF-MS was 12,655.91 Da. The theoretical mass calculated for the nonapeptide attached to the amino terminus is 12,653.26 Da (delta 2.65 Da). Immunostaining with the polyclonal anti-rS100A7 protein generated showed reactivity with little or no background staining in head and neck squamous cell carcinoma cells, detecting S100A7 both in nucleus and cytoplasm. Lower levels of S100A7 were detected in non-neoplastic tissue. CONCLUSIONS: The polyclonal anti-rS100A7 antibody generated here yielded a good signal-to-noise contrast and should be useful for immunohistochemical detection of S100A7 protein. Its potential use for other epithelial lesions besides human larynx squamous cell carcinoma and non-neoplastic larynx should be explored in future.

Estudo comparativo entre vitiligo, nevo halo e lúpus eritematoso vitiligóide por meio de métodos imunológicos, histológicos e imuno-histoquímicos / Comparative study of vitiligo, halo nevus andd vitiligoid variant of lupus erythematosus by immunological, histological, and immunohistochemical methods

Fundamentos: O estudo compara o vitiligo, o nevo halo (NH) e lúpus eritematoso vitiligóide (LEV) do ponto de vista imunológico, histológico e histoquímico.Objetivos: Avaliar diferenças imuno-histoquímicas entre essas doenças e investigar se a despigmentação do LEV deve-se à destruição pós-inflamatória ou à agressão imunológica aos melanócitos. Métodos: Foram avaliados 20 pacientes com vitiligo, 17 com vitiligo e NH, cinco com NH isolado e 15 com LEV. Detecção de anticorpos: IF direta e indireta com células névicas e de melanoma. Citotoxicidade: atividade NK contra células de melanoma. Estudo anátomo-histoquímico: exame histológico com hematoxilina e eosina, Fontana-Masson, Dopa e Dopa mais prata (D+P) e exame histoquímico com proteína S-100. Resultados: Doentes com vitiligo, NH e LEV apresentaram anticorpos antimelanócitos. Tanto no vitiligo e NH, como no LEV, demonstrou-se a presença de fatores de risco favorecedores da citotoxicidade celular. A coloração com D+P foi superior às colorações tradicionais e à proteína S-100 na detecção de melanócitos e melanina nas lesões de vitiligo, NH e LEV.Conclusões: Demonstrou-se a existência de anticorpos antimelanócitos no vitiligo e NH. É possível que a despigmentação no LEV se deva a fenômenos imunológicos semelhantes aos do vitiligo e NH. A detecção de melanócitos nas lesões de vitiligo sugere mais inibição funcional do que destruição dessas células