RESUMO
In the current setting, we attempted to verify and validate miRNA candidates relevant to pediatric primary brain tumor progression and outcome, in order to provide data regarding the identification of novel prognostic biomarkers. Overall, 26 resected brain tumors were studied from children diagnosed with pilocytic astrocytomas (PAs) (n = 19) and ependymomas (EPs) (n = 7). As controls, deceased children who underwent autopsy and were not present with any brain malignancy were used. The experimental approach included microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression profiles of miR-15a and miR-24-1. The multiparameter analyses were performed with MATLAB. Matching differentially expressed miRNAs were detected in both PAs and EPs, following distinct comparisons with the control cohort; however, in several cases, they exhibited tissue-specific expression profiles. On correlations between miRNA expression and EP progression or outcome, miR-15a and miR-24-1 were found upregulated in EP relapsed and EP deceased cases when compared to EP clinical remission cases and EP survivors, respectively. Taken together, following several distinct associations between miRNA expression and diverse clinical parameters, the current study repeatedly highlighted miR-15a and miR-24-1 as candidate oncogenic molecules associated with inferior prognosis in children diagnosed with ependymoma.
Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Ependimoma/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Adolescente , Astrocitoma/patologia , Estudos de Casos e Controles , Criança , Progressão da Doença , Ependimoma/patologia , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Atypical Spitzoid neoplasms represent a controversial and incompletely defined diagnostic category for lesions with intermediate architecture and cytomorphology between Spitz nevus and melanoma. The vast majority of these neoplasms have a good overall prognosis. Only a small proportion of patients will end up developing distant metastases and death. The distinction between Spitz tumours with atypical features and Spitzoid melanoma remains difficult on clinical and histological grounds and the prediction of the biological behaviour of those tumours even with sentinel lymph node biopsy is impossible. Tools such as immunohistochemistry, genetic analysis, mutation analysis and mass spectometry have contributed to the better understanding of those tumours and may be useful in the differential diagnosis of Spitzoid tumours.
Assuntos
Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adolescente , Criança , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Melanoma/patologia , Neoplasias Cutâneas/patologiaRESUMO
Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.
Assuntos
Doenças do Sistema Endócrino , Hipofisite , Sistema Endócrino , Doenças do Sistema Endócrino/induzido quimicamente , Humanos , Hipofisite/induzido quimicamente , Inibidores de Checkpoint Imunológico , Imunoterapia/efeitos adversosRESUMO
Pleomorphic xanthoastrocytoma (PXA) is a recently recognized rare cerebral neoplasm that predominantly affects young patients. We report on the case of a 3-year-old boy who presented with a 2-week history of headaches and seizures. Radiological investigation revealed a lesion in the right parietal-occipital lobe. The lesion was excised and histology disclosed the presence of a PXA with anaplastic features. 1 year later follow-up magnetic resonance imaging (MRI) revealed tumor relapse. An MRI of the spine was also performed and demonstrated leptomeningeal dissemination. The patient underwent a second operation. Histology revealed that the presence of a malignant PXA with anaplastic features. The patient received radiotherapy and 9 months later on follow-up MRI a new tumor recurrence was noted. A third craniotomy was performed and the tumor removed. Histological examination revealed dedifferentiation to glioblastoma multiforme. The patient was referred to the oncology department and received chemotherapy with temozolamide. 8 months later the patient was stable without tumor recurrence. PXAs require close follow-up because of their unpredictable biological behaviour.
Assuntos
Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatologia , Glioblastoma/diagnóstico , Astrocitoma/complicações , Pré-Escolar , Progressão da Doença , Gadolínio , Glioblastoma/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Most true hermaphrodite patients--characterized by the presence of both ovarian and testicular tissue--demonstrate ambiguous genitalia and are diagnosed at birth, most commonly bearing a 46,XX karyotype. PATIENT AND METHODS: We report on a 13-year-old boy presenting with left scrotal hemorrhage. He had a left inguinal hernia, a palpable testis in the right, normal male external genitalia and significant gynecomastia. During operation, the left gonad and adjacent tissue were removed for histological examination, which revealed the presence of a normal ovary, rich in follicles and a ruptured corpus luteum, suggestive of spontaneous ovulation, with a normal ipsilateral adnexa and semi-uterus. Biopsy of the right gonad revealed a dysgenetic testicle. Endocrinological assessment postoperatively depicted high FSH, pubertal testosterone and low estradiol levels. Cytogenetic analysis in peripheral blood lymphocytes and FISH of the right gonad revealed a 46,XX (70-60%)/47,XXY (30-40%) karyotype, respectively, while molecular analysis verified the presence of SRY and azoospermia factor genes. CONCLUSION: The importance of full histological, cytogenetic and molecular investigation and of interdisciplinary approach in every single patient with sex differentiation disorders is highlighted by this rare case of spontaneous ovulation in a true hermaphrodite with normal male external genitalia and Klinefelter mosaicism.
Assuntos
Síndrome de Klinefelter/fisiopatologia , Mosaicismo , Transtornos Ovotesticulares do Desenvolvimento Sexual/fisiopatologia , Ovulação , Feminino , Humanos , Síndrome de Klinefelter/patologia , Masculino , Ovário/patologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologiaRESUMO
Gastrointestinal lipomas are uncommon benign tumors usually occurring in the colon and rarely in the stomach. We report a case of a 10-year-old boy who presented with a two-week history of epigastric abdominal pain and several episodes of melena. Gastroscopy revealed a soft, elevated, broad based, polypoid lesion on the posterior wall, without superficial erosion or ulceration. One week later the patient was readmitted with melena and hematemesis, followed by a significant drop of hematocrit levels. A laparotomy was carried out and the mass was excised. Histological findings were consistent with a submucosal gastric fibrolipoma resected IN TOTO. The clinical presentation, diagnosis and management of this condition are discussed.
Assuntos
Gastrectomia/métodos , Hemorragia Gastrointestinal/etiologia , Lipoma/complicações , Neoplasias Gástricas/complicações , Biópsia , Criança , Seguimentos , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/cirurgia , Gastroscopia , Humanos , Lipoma/diagnóstico , Lipoma/cirurgia , Masculino , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgiaRESUMO
Subcutaneous fat necrosis (SFN) of the newborn is an uncommon disorder of the adipose tissue, mostly affecting full-term or post-term newborns who experience perinatal distress. The lesions of SFN typically occur during the first six weeks of life; they are usually self-limited and no specific therapy is required. The disorder may be rarely complicated with hypercalcaemia. We present the case of a neonate with perinatal asphyxia who manifested SFN followed by hypocalcaemia instead of hypercalcaemia and a biochemical profile of pseudohypoparathyroidism four weeks after the eruption of skin lesions. The infant was treated with alfacalcidiol. Blood biochemistry was normalized within one week and serum parathyroid hormone levels declined to normal over the next two months. It is suggested that perinatal asphyxia was the common etiopathogenetic factor for the development of both SFN and pseudohypoparathyroidism.
Assuntos
Asfixia Neonatal/complicações , Necrose Gordurosa/etiologia , Hipocalcemia/etiologia , Pseudo-Hipoparatireoidismo/etiologia , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Necrose Gordurosa/diagnóstico , Necrose Gordurosa/tratamento farmacológico , Feminino , Humanos , Hidroxicolecalciferóis/administração & dosagem , Hidroxicolecalciferóis/uso terapêutico , Recém-Nascido , Hormônio Paratireóideo/sangue , Pseudo-Hipoparatireoidismo/tratamento farmacológico , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Intraabdominal desmoplastic small round cell tumors (IDSRCT) are rare in children and predominantly affect male adolescents and young adults. We present our experience in the management of five children with diffuse IDSRCT, managed with aggressive chemotherapy, surgery, radiotherapy and peripheral blood stem cell transplantation. MATERIAL AND METHODS: During the last decade five patients, four males and one female (mean age 9.6 years), with diffuse IDSRCT were managed in our department. The main symptoms were abdominal distention, vague abdominal pain, and vomiting. Three patients with inoperable tumor on admission were submitted initially to open biopsy followed by aggressive chemotherapy. Regression of the tumor was followed by a second laparotomy and radical excision of any macroscopically distinguishable masses, followed by chemotherapy. In the remaining two patients a debulking procedure was done initially, followed by chemotherapy. The accurate diagnosis of the disease was established by immunohistochemistry, additionally confirmed in the last two patients by molecular analysis. RESULTS: Three patients who had radical excision of the tumor and adjuvant chemotherapy had recurrence after two to six months. In the remaining two patients, recurrence was evident after two and eighteen months, respectively, following debulking. In addition, one patient with recurrence received radiotherapy and two others underwent peripheral blood stem cell transplantation. All but one patient died within three years from diagnosis. The last patient, who was submitted to a debulking procedure, is still alive eight months after the operation. CONCLUSIONS: Intrabdominal desmoplastic small round cell tumor is a highly aggressive malignancy with a very poor prognosis. Multiagent chemotherapy usually leads initially to a temporary regression of the tumor, but recurrence is the rule. Radical surgical excision, radiotherapy and peripheral blood stem cell transplantation does not seem to improve prognosis significantly. Despite all therapeutic modalities the outcome is dismal and surgical efforts can be considered only as palliative.
Assuntos
Neoplasias Abdominais/tratamento farmacológico , Neoplasias Abdominais/cirurgia , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/cirurgia , Neoplasias Abdominais/diagnóstico , Adolescente , Antineoplásicos/uso terapêutico , Carcinoma de Células Pequenas/diagnóstico , Criança , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , MasculinoRESUMO
Among noncoding RNAs, microRNAs (miRNAs) have been most extensively studied, and their biology has repeatedly been proven critical for central nervous system pathological conditions. The diagnostic value of several miRNAs was appraised in pediatric dysembryoplastic neuroepithelial tumors (DNETs) using miRNA microarrays and receiving operating characteristic curves analyses. Overall, five pediatric DNETs were studied. As controls, 17 samples were used: the FirstChoice Human Brain Reference RNA and 16 samples from deceased children who underwent autopsy and were not present with any brain malignancy. The miRNA extraction was carried out using the mirVANA miRNA Isolation Kit, while the experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction was performed to validate the expression profiles of miR-1909* and miR-3138 in all samples initially screened with miRNA microarrays. Our findings indicated that miR-3138 might act as a tumor suppressor gene when down-regulated and miR-1909* as a putative oncogenic molecule when up-regulated in pediatric DNETs compared to the control cohort. Subsequently, both miRNA signatures might serve as putative diagnostic biomarkers for pediatric DNETs.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , MicroRNAs/biossíntese , Neoplasias Neuroepiteliomatosas/genética , Área Sob a Curva , Biomarcadores Tumorais/análise , Criança , Pré-Escolar , Feminino , Humanos , Masculino , MicroRNAs/análise , Análise de Sequência com Séries de Oligonucleotídeos , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , TranscriptomaRESUMO
Granulocytic sarcoma (GS) is a form of extramedullary leukaemia (EML). The presence of the neural cell adhesion molecule (NCAM) on the surface of the blasts, which is recognized by the CD56 monoclonal antibody, enhances their propensity for tissue penetration. GS within the central nervous system (CNS), in particular within the cerebellum, is extremely uncommon. We review the literature and describe an infant with isolated cerebellar GS relapse, which antedated a CD56+ acute monoblastic leukaemia bone marrow (BM) relapse.
Assuntos
Antígeno CD56/análise , Neoplasias Cerebelares/etiologia , Leucemia Monocítica Aguda/complicações , Leucemia Monocítica Aguda/imunologia , Sarcoma Mieloide/etiologia , Neoplasias Cerebelares/patologia , Evolução Fatal , Humanos , Imunofenotipagem , Lactente , Leucemia Monocítica Aguda/diagnóstico , Infiltração Leucêmica , Imageamento por Ressonância Magnética , Masculino , Sarcoma Mieloide/patologiaRESUMO
The aim of this study was to evaluate the immunohistochemical expression of epidermal growth factor (EGFR) and c-erb-B-2 oncoprotein in a series of 71 hepatocellular carcinomas as well as in the adjacent hepatic tissue and to assess any correlation with HBsAg expression. The total of the 71 hepatocellular carcinomas (HCCs) was classified into 17 low grade and 54 high grade cases with adjacent non-neoplastic liver parenchyma, observed in 14 and 28 cases respectively. Coexisting cirrhosis or fibrosis was noticed in the adjacent non-neoplastic parenchyma in 12 cases of low grade and 22 cases of high grade HCC. The immunohistochemical avidin-biotin-peroxidase complex (ABC) method was performed on formalin-fixed paraffin sections for the detection of EGFR, c-erb-B-2 oncoprotein and HBsAg using monoclonal antibodies. The expression of c-erb-B-2 was observed in 29.5% (21/71) of the HCCs showing no statistically significant correlation with histological grade. The c-erb-B-2 was also detected in the adjacent non-neoplastic parenchyma in 7/14 low grade HCCs, and in 9/28 high grade HCCs. No statistically significant differences in c-erb-B-2 oncoprotein expression were observed between the HCCs and the adjacent non-neoplastic parenchyma. In addition, HBsAg was detected in 10/42 examined cases of HCC with adjacent non-neoplastic parenchyma, while only 4 cases of HCCs were simultaneously positive for c-erb-B-2 and HBsAg. EGFR was detected in only 3/71 cases of HCC, while the antigen was not detected at all in the adjacent non neoplastic parenchyma. HBsAg expression was not observed in any of the EGFR-positive HCCs. Our results suggest that both c-erb-B-2-oncoprotein and EGFR do not seem to be predominantly involved in the transformation of hepatocytes to the malignant phenotype.
Assuntos
Carcinoma Hepatocelular/metabolismo , Receptores ErbB/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor ErbB-2/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Feminino , Antígenos de Superfície da Hepatite B/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
The patterns of Hepatitis B surface antigen (HBsAg) and Hepatitis B core antigen (HBcAg) expression were studied in liver biopsies taken from 41 patients with chronic HBV disease. Immunohistochemical methods were used on deparaffinized sections for the identification of HBsAg and HBcAg in liver tissue. Twenty-one of the 41 cases (51.2%) were classified as inactive liver disease and 20 (48.8%) as active liver disease. In liver biopsies with inactive disease, HBsAg demonstrated varying types of cytoplasmic expression in a rather high number of hepatocytes distributed mainly in clusters, while HBcAg was rarely expressed in liver nuclei. On the other hand, in liver biopsies with active disease HBsAg was characterized by a diffuse cytoplasmic expression in a few discrete hepatocytes, while HBcAg was expressed in the nuclei of the hepatocytes in 70% of the cases and in half of the positive cases it was also detected in the cytoplasm. In conclusion, HBsAg expression in a few scattered hepatocytes correlates with active liver disease and positive HBcAg, while varying HBsAg cytoplasmic expression in a rather high number of clustered hepatocytes is related to chronic inactive liver disease and negative expression of HBcAg.
Assuntos
Antígenos do Núcleo do Vírus da Hepatite B/metabolismo , Antígenos de Superfície da Hepatite B/metabolismo , Hepatite B/imunologia , Hepatite Crônica/imunologia , Adulto , Idoso , Núcleo Celular/imunologia , Citoplasma/imunologia , Hepatite B/classificação , Hepatite B/patologia , Hepatite Crônica/patologia , Humanos , Imuno-Histoquímica , Fígado/imunologia , Fígado/patologia , Pessoa de Meia-IdadeRESUMO
UNLABELLED: In this study a morphological subdivision of grade (g)II superficial bladder cancer is proposed and correlated with recurrence and progression rate. Forty patients, 33 males and 7 females, of 70 years mean age, with initial gII superficial transitional bladder cancer were treated with transurethral resection between January and December 1987 with follow-up for a mean period of 4 years. Recurrences were observed in 24 patients. All histological specimens were reviewed and reclassified to gIIa and gIIb mainly according to the variation in nuclear size, the degree of nuclear atypia and the number of mitoses. 42.1% (8/19) of the gIIa and 76.2% (16/21) of the gIIb tumors recurred. The observed difference in recurrence rate was statistically significant (s.s)-p < 0.05. The disease-free interval after the initial presentation was over two years in 50% (4/8) of gIIa and in 6.25% (1/16) of gIIb patients (s.s. difference-p < 0.05). None of the patients with gIIa, but 37.5% (6/16) with gIIb urothelial cancer had more than two recurrences (s.s. difference-p < 0.05). All gIIa recurred as gIIa superficial cancers, 62.5% (10/16) of gIIb as gIIb (5 superficial and 5 invasive) and the remainder 37.5% (6/16) as invasive gIII tumors. Only one patient with repeated recurrences died two years after the initial presentation. 3 patients died from other causes. IN CONCLUSION: 1. The morphological subdivision of gII urothelial cancer into gIIa and gIIb has a prognostic significance, as it is related to the recurrence rate, the disease-free interval after the initial resection, the number of recurrences and the progression rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Carcinoma de Células de Transição/classificação , Recidiva Local de Neoplasia/classificação , Neoplasias da Bexiga Urinária/classificação , Idoso , Carcinoma de Células de Transição/patologia , Núcleo Celular/ultraestrutura , Feminino , Seguimentos , Humanos , Masculino , Índice Mitótico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologiaRESUMO
Laminin (LAM) and fibronectin (FI) are regarded as major components of the glomerular extracellular matrix. The aim of this study was to define the distribution of LAM and FI in primary glomerulonephritis (GN) and GN of systemic lupus erythematosus (SLE) and to correlate the type of glomerular disorders with possible changes in the expression of these components. Normal portions of kidney tissue from 10 patients with renal tumors and sixty-six renal biopsies obtained from patients with GN were studied by the immunoperoxidase-antiperoxidase (PAP) method for the detection of LAM and FI. Twelve patients had membranous GN (MGN), 8 mesangiocapillary GN (MCGN), 21 mesangioproliferative GN (MPGN), including 11 cases of IgA nephropathy, 11 focal segmental glomerulosclerosis (FSGS) and 14 had SLE. In MGN, LAM was detected more intensely than FI along the glomerular basement membranes (GBM), in subepithelial GBM protrusions and in the newly-formed GBM. On the contrary, FI was intensely expressed in the mesangium. LAM and FI expression was pronounced in stages II and III of MGN. In MCGN, LAM and FI were diffusely expressed along the GBM and in the mesangium. The distribution of the two antigens in MPGN and FSGS was similar to that seen in normal glomeruli. However, the FI staining reaction was more intense in severe mesangioproliferative lesions, mainly observed in the cases of IgA-nephropathy. There were no differences in the distribution of LAM and FI between primary and SLE GN. The antigen staining pattern was pronounced in the membranous and mesangiocapillary lesions of SLE GN.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Fibronectinas/metabolismo , Glomerulonefrite/metabolismo , Laminina/metabolismo , Membrana Basal/ultraestrutura , Matriz Extracelular/metabolismo , Fibronectinas/imunologia , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite/patologia , Humanos , Técnicas Imunoenzimáticas , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Laminina/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Inclusão em Parafina , Coloração e RotulagemRESUMO
Proliferating cell nuclear antigen (PCNA)/cyclin is an acidic nuclear protein increasing from the late G1 to S phases of the cell cycle and whose detection parallels other standard methods for assessing cell proliferation. The aim of this study was to investigate PCNA expression in normal and diseased human kidneys, in order to clarify cell proliferation in renal tissue and to define a possible correlation of its expression with various types of glomerulonephritis (GN). The immunohistochemical avidin-biotin complex (ABC) method was used for the demonstration of PCNA applying the monoclonal antibody PC-10 to paraffin sections from: 10 normal kidneys, 55 renal biopsies with various types of proliferative GN (PGN), 44 renal biopsies with various types of non proliferative GN (NPGN). In PCNA-positive renal biopsies with GN the antigen showed a heterogenous nuclear expression in occasional or few mesangial and glomerular epithelial cells as well as in a greater number of tubular epithelial cells. PCNA was expressed in 20% of normal kidneys and in 38% of renal biopsies with GN. The frequency of PCNA expression was significantly increased in the cases of PGN (47%) compared to that observed in the cases of NPGN (27%) (p = 0.03). PCNA was detected in 10/24 cases of IgA nephropathy, in 3/4 cases of IgM nephropathy, in 5/14 of other types of primary PGN and in 8/13 of secondary PGN. PCNA expression was not correlated with the degree of mesangial cellularity in PGN. Moreover, there was no significant difference in PCNA expression between primary and secondary PGN. PCNA demonstrated an intense expression in the majority of epithelial cells forming cellular crescents in 8/11 cases of PGN. In conclusion, PCNA was observed more frequently in diseased than in normal kidneys. The significant increase in the frequency of PCNA intraglomerular expression in PGN suggests that PCNA has a certain value in the assessment of mesangial proliferation. Moreover, the increased PCNA expression in tubular epithelial cells especially in PGN, indicates their proliferative state and may be correlated with their proposed activation and role in the progression of renal injury.
Assuntos
Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Biópsia , Divisão Celular , Núcleo Celular/metabolismo , Glomerulonefrite/patologia , Humanos , Imuno-Histoquímica , Glomérulos Renais/ultraestruturaRESUMO
The aim was to investigate the combined immunoexpression of p53, p21, bcl-2, bax, Rb and Ki67 proteins in Hodgkin's lymphomas (HL) and correlate expression patterns with the histotype and the Epstein-Barr Virus (EBV) status. Paraffin-sections from 56 cases of HL (18 nodular sclerosis and 38 mixed cellularity) and from ten "reactive" lymph nodes were investigated. P53, p21, bcl-2, bax, Rb and Ki67 proteins were detected in Hodgkin and Reed-Sternberg (HRS) cells in 35/56, 56/56, 24/56, 23/56, 56/56 and 56/56 cases of HL, respectively. No correlation was found between the expression of each protein and the EBV status or the histotype of HL. Comparison between p53 and p21 staining revealed two patterns: a) p53+/p21+ (35 cases); and b) p53-/p21+ (21 cases). The pattern p53+/p21+ suggests wild type p53 protein able to induce the expression of p21 while the p53-/p21+ pattern suggests p53-independent p21 expression. These results are consistent with the interpretation that inactivating p53 gene mutations may be rare in HL. Comparison between bcl-2 and bax staining showed a statistically significant relationship (p<0.001) for coexpression (19 cases) or absence of expression of both proteins (28 cases) in HRS cells. In contrast, bax expression was observed in most lymphoid cells in all "reactive" lymph nodes. Since the proapoptotic bax protein may act as tumour suppressor it is possible that the absence of this protein in HRS cells in a substantial proportion of HL may confer growth advantage and play a role in their pathogenesis. This could suggest bax gene alterations in some HL since in other studies acute lymphoblastic leukaemia cell lines demonstrate bax gene mutations with loss of bax immunoexpression. Another possibility is that reduced bax expression may be due to post transcriptional regulation, as was described in lymphoma cell lines. Comparison between Rb and Ki67 staining disclosed two main deviations from the normal parallel relationship in reactive lymph nodes: a) 2 cases with low Rb and high Ki67 expression possibly reflecting loss of Rb expression due to chromosome loss or to other abnormalities in the structure or the expression of Rb gene; and b) 9 cases with high RB and low Ki67 possible reflecting an attempt of Rb protein in excess to induce cell cycle arrest. Taken together, our findings provide combined immunohistological evidence for deregulated expression of cell-cycle and apoptosis-related proteins, that may play a role in the pathogenesis of HL.
Assuntos
Ciclinas/biossíntese , Doença de Hodgkin/metabolismo , Antígeno Ki-67/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteína do Retinoblastoma/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/genética , Herpesvirus Humano 4/metabolismo , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Antígeno Ki-67/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Viral/biossíntese , Proteína do Retinoblastoma/genética , Proteína Supressora de Tumor p53/genética , Proteínas da Matriz Viral/biossíntese , Proteína X Associada a bcl-2RESUMO
The immunohistochemical expression of p53, p21, Rb, p16, cyclin D1, Ki67, cyclin A, cyclin B1, p27, bcl2, bax, and bak proteins and the apoptotic index (Al) were investigated in 20 normal thymuses (8 adults, 3 adolescents, 5 infants and 4 newborns). The expressions of Rb, Ki67, cyclin A and cyclin B1 were overlapping, being high in the cortex with a tendency for decreased expression toward the medulla. Apoptotic cells were mainly detected in the cortex and the corticomedullary junction, rarely being present in Hassall's corpuscles. The mean values of Ki67, cyclin A, and cyclin B1 expression in thymuses were 77.2%, 32.2% and 21.4% (newborns), 62.4%, 33.7% and 18.5% (infants), 56.9%, 23.4% and 18.9% (adolescents) and 38.7%, 21.7% and 14.6% (adults), respectively. The mean values of AI in thymuses from newborns, infants, adolescents and adults were 1.4%, 2.9%, 2.7% and 3.8%, respectively. This decrease in proliferation and increase in apoptosis may account for the process of thymic involution. P16 expression was widespread with most of Hassall's corpuscles being p16-positive. P16-positive cells and Hassall's corpuscles increased with the increase in age, in keeping with the suggested role of p16 in cellular senescence. P27 expression was undetectable in subcapsular thymocytes with a tendency for increased expression toward the medulla. The expressions of Ki67, cyclin A and cyclin B1 were inversly related with that of p27, consistent with previous evidence that p27 concentration is reduced when the cell-cycle progresses. P21 and much less frequently p53 proteins were mainly detected in a part of the subcapsular cortical epithelial cells. These findings suggest that a) in thymocytes, the apoptotic pathway is mostly p53-independent and the function of p21 as a negative regulator of the cell cycle must be redundant to other negative regulators, such as p16 and p27 which were abundantly detected in thymocytes and b) in some thymic epithelial cells, the p21 expression may be induced by p53, but in most of them seems to be p53-independent. Most of Hassall's corpuscles were p21-positive, consistent with previous evidence that these structures represent end stages of maturation of thymic medullary epithelium and that p21 protein is involved in the process of terminal differentiation. Cyclin D1 positivity was found in some macrophages. Bcl2 expression was mainly seen in medullary thymocytes, reflecting the surviving thymocytes in this region. The expressions of Bax and bak were more widespread in both the medulla and cortex, suggesting that these proteins play a broader role than bcl2 in the regulation of thymic apoptosis.
Assuntos
Apoptose/fisiologia , Ciclina A/biossíntese , Ciclina B/biossíntese , Ciclina D1/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Ciclinas/biossíntese , Antígeno Ki-67/biossíntese , Proteínas de Membrana/biossíntese , Proteínas dos Microfilamentos/biossíntese , Proteínas Musculares , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteína do Retinoblastoma/biossíntese , Timo/citologia , Timo/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Adolescente , Adulto , Envelhecimento/fisiologia , Divisão Celular/fisiologia , Ciclina B1 , Inibidor de Quinase Dependente de Ciclina p21 , Células Epiteliais/fisiologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Lactente , Recém-Nascido , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína X Associada a bcl-2RESUMO
Fifty-seven cases of T-cell lymphomas (TCL) including 5 lymphoblastic (T-LBL) and 52 peripheral TCL (PTCL) were analyzed by immunohistochemistry for the expression of p53, mdm2, p21, Rb, cyclin D1, cyclin A, cyclin B1, and Ki67/MIB1 proteins and 39/52 PTCL were also analyzed for the expression of p16 protein and for the presence of apoptotic cells by the TUNEL method. The aim was to search for abnormal immunoprofiles of p53 and Rb growth control pathways and to determine the proliferative activity and the apoptotic index of TCL. Abnormal overexpression of p53, p21 and mdm2, in comparison to normal lymph nodes, was found in 12/57, 10/57 and 2/57 cases of TCL, respectively. Abnormal loss of Rb and p16 expression was found in 1/57 and 2/39 cases, respectively, whereas abnormal overexpression of cyclin D1 was not detected in any of the 57 cases. Our data revealed entity-related p53/p21/mdm2 phenotypes. Indeed, most nodal and cutaneous CD30+ anaplastic large cell lymphomas (ALCL) showed concomitant overexpression of p53 and p21 proteins (7/8 cases), and mdm2 was overexpressed in 2 p53-positive nodal ALCL. In contrast, overexpression of p53 was found in 3/17 cases of nodal peripheral TCL unspecified (PTCL-UC) and 2/7 non-ALCL cutaneous pleomorphic TCL. Overexpression of p21 protein was detected in 2/3 p53-positive PTCL-UC and in 1/2 p53-positive non-ALCL cutaneous pleomorphic TCL. Finally, all the remaining 25 cases of TCL did not show p53 and p21 overexpression. Overall, the p53+/p21+ phenotype in 10/57 TCL suggests wild-type p53 capable of inducing p21 expression. The highest apoptotic index (AI) was found in ALCL and a positive correlation between apoptotic index and Ki67 index (p<0.001) was detected. Ki67, cyclin A and cyclin B1 expression was found in all 57 TCL and on the basis of the combined use of these 3 variables, 3 groups of proliferative activity could be determined: a) high in ALCL and T-LBL, b) low in mycosis fungoides (MF) and gammadelta hepatosplenic TCL, and c) intermediate in the remaining TCL entities. The proliferative activity in the 12 p53 overexpressing cases was higher in comparison to the 45 p53-negative cases. Ki67 expresion in more than 25% of tumour cells showed significant correlation with p53 overexpression (p<0.001). Rb expression tended to be parallel to Ki67, cyclin A and cyclin B1 expression in all but one case of nodal PTCL-UC which displayed loss of RB expression. Interestingly, this case was p53-negative, whereas the p53-positive cases were Rb-positive. These findings suggest that different pathogenetic routes may function in some TCL, involving either the p53 or, less frequently, the Rb pathways.
Assuntos
Proteínas E1A de Adenovirus , Apoptose/imunologia , Proteínas de Transporte/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Ciclinas/análise , Antígeno Ki-67/análise , Linfoma de Células T Periférico/metabolismo , Proteínas Nucleares , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas/análise , Proteína Supressora de Tumor p53/análise , Proteínas de Ciclo Celular/análise , Ciclina A/análise , Ciclina B/análise , Ciclina B1 , Ciclina D1/análise , Inibidor de Quinase Dependente de Ciclina p21 , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Proteínas de Neoplasias/análise , Proteínas Proto-Oncogênicas c-mdm2 , Proteínas Repressoras , Estatística como AssuntoRESUMO
This report documents the occurrence of an extranodal cytotoxic peripheral T-cell lymphoma (PTCL) in a patient with X-linked agammaglobulinaemia (XLA). The diagnosis was based on the immunohistochemical detection of T-cell antigens and of the cytotoxic proteins TIA1 and Granzyme B in the tumour cells. This report provides further evidence that cytotoxic lymphomas are part of the differential diagnosis of neoplasia in patients with immunodeficiencies.