RESUMO
Pheochromocytomas, like several other tumors, may be either sporadic or the manifestation of a familial cancer syndrome. Recently, major advances have occurred in both the understanding of diverse molecular mechanisms leading to pheochromocytoma and the diagnostic modalities available for detection of the disease. Familial pheochromocytoma may be a manifestation of multiple endocrine neoplasia type 2 (MEN-2), von Hippel-Lindau (VHL), or neurofibromatosis-1 (NF 1) disease. Tumor-suppressor genes responsible for the familial occurrence of extra-adrenal pheochromocytoma, called paraganglioma, have been identified. This wealth of genetic information, coupled with the availability of sensitive and specific biochemical tests as well as imaging studies, allows for genetic screening and early diagnosis of pheochromocytoma. In addition, genetic screening of relatives at risk is now feasible. In this article, we review recent clinical and molecular advances in our understanding of pheochromocytoma.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Feocromocitoma/genética , Doença de von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Imageamento por Ressonância Magnética , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Paraganglioma/genética , Feocromocitoma/diagnóstico , Doença de von Hippel-Lindau/complicaçõesRESUMO
CONTEXT: Germline mutations of the genes encoding succinate dehydrogenase subunits B (SDHB) and D (SDHD) predispose to paraganglioma syndromes type 4 (PGL-4) and type 1 (PGL-1), respectively. In both syndromes, pheochromocytomas as well as head and neck paragangliomas occur; however, details for individual risks and other clinical characteristics are unknown. OBJECTIVE: To determine the differences in clinical features in carriers of SDHB mutations and SDHD mutations. DESIGN, SETTING, AND PATIENTS: Population-based genetic screening for SDHB and SDHD germline mutations in 417 unrelated patients with adrenal or extra-adrenal abdominal or thoracic pheochromocytomas (n = 334) or head and neck paragangliomas (n = 83), but without syndromic features, from 2 registries based in Germany and central Poland, conducted from April 1, 2000, until May 15, 2004. MAIN OUTCOME MEASURES: Demographic and clinical findings with respect to gene mutation in SDHB vs SDHD compared with nonmutation carriers. RESULTS: A total of 49 (12%) of 417 registrants carried SDHB or SDHD mutations. In addition, 28 SDHB and 23 SDHD mutation carriers were newly detected among relatives of these carriers. Comparison of 53 SDHB and 47 SDHD total mutation carriers showed similar ages at diagnosis but differences in penetrance and of tumor manifestations. Head and neck paragangliomas (10/32 vs 27/34, respectively, P<.001) and multifocal (9/32 vs 25/34, respectively, P<.001) tumors were more frequent in carriers of SDHD mutations. In contrast, SDHB mutation carriers have an increased frequency of malignant disease (11/32 vs 0/34, P<.001). Renal cell cancer was observed in 2 SDHB mutation carriers and papillary thyroid cancer in 1 SDHB mutation carrier and 1 SDHD mutation carrier. CONCLUSIONS: In contrast with SDHD mutation carriers (PGL-1) who have more frequent multifocal paragangliomas, SDHB mutation carriers (PGL-4) are more likely to develop malignant disease and possibly extraparaganglial neoplasias, including renal cell and thyroid carcinomas. Appropriate and timely clinical screening is recommended in all patients with PGL-1 and PGL-4.
Assuntos
Mutação em Linhagem Germinativa , Proteínas de Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Subunidades Proteicas/genética , Succinato Desidrogenase/genética , Neoplasias Abdominais/genética , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Feminino , Alemanha , Neoplasias de Cabeça e Pescoço/genética , Heterozigoto , Humanos , Proteínas Ferro-Enxofre , Masculino , Pessoa de Meia-Idade , Polônia , Sistema de Registros , Síndrome , Neoplasias Torácicas/genética , Neoplasias da Glândula Tireoide/genéticaAssuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Fluordesoxiglucose F18 , Linfoma Folicular/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/metabolismo , Feminino , Febre de Causa Desconhecida/etiologia , Fluordesoxiglucose F18/farmacocinética , Seguimentos , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cintilografia , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
It has been shown that after allogeneic peripheral blood stem cell transplantation (PBSCT), donor T cells can induce potent graft-versus-tumor (GVT) effects in hematologic malignancies and possibly solid tumors such as renal cell carcinoma. Two patients (27 and 30 years old) with metastatic melanoma received allogeneic PBSCT from an HLA-identical sibling donor after reduced conditioning with fludarabine, carmustine and melphalan. One patient showed a delayed mixed response with complete regression of lymph node metastases but persistent liver metastasis at day +60 and +120, consistent with a GVT response. In order to generate donor-derived tumor-reactive cytotoxic T lymphocytes (CTLs), peripheral blood mononuclear cells were stimulated with donor dendritic cells (DCs) loaded with host tumor lysate. Using these culture conditions, a marked increase in CD8(+) CTLs was observed in both donors exhibiting a strong MHC class I-restricted cytotoxic activity against the host tumor without cross-reactivity against nonmalignant host cells. CDR3 spectratyping was used to analyze the complexity of T-cell subpopulations in both CTL lines. Results demonstrate that oligoclonal T cells are expanded in vitro, exhibiting a marked overexpression of TCRVbeta3 (donor 1) and TCRVbeta4/Vbeta11 (donor 2) subfamilies. Functional (ELISPOT assay) and phenotypic (CDR3 spectratyping, sequencing Vbeta transcripts) analysis of patients' T cells at different time points after transplantation demonstrated an expansion of alloreactive T cells with a limited TCR Vbeta pattern. The Vbeta3 cDNA clone, being predominant in the CTL line from donor 1, could not be identified in patient 1 peripheral blood lymphocytes after transplant. Altogether, our results provide the first evidence that GVT effects against melanoma can induce tumor regression and that oligoclonal donor-derived CTLs specific against host tumor cells can be generated in vitro that may be used for adoptive T-cell transfer after allogeneic transplantation.
Assuntos
Efeito Enxerto vs Tumor/imunologia , Transplante de Células-Tronco Hematopoéticas , Melanoma/imunologia , Transplante Homólogo/imunologia , Adulto , Células Dendríticas/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Tomografia Computadorizada de Emissão , Células Tumorais CultivadasRESUMO
The diagnostic utility of fluorine-18 2-deoxy-D-glucose positron emission tomography (FDG PET) for the non-invasive differentiation of focal pancreatic lesions originating from cancer or chronic pancreatitis by combined visual image interpretation and semiquantitative uptake value analysis has been documented. However, in clinical routine some misdiagnosis is still observed. This is because there is potential overlap between the semiquantitative uptake values obtained for active inflammatory lesions and cancer. Therefore, this prospective study was undertaken to test the hypothesis that analysis of dynamic kinetics of focal pancreatic lesions based on FDG PET may more accurately determine the benign or malignant nature of such lesions. Thirty patients (56+/-17 years) were studied dynamically with FDG PET for a period of 60-90 min. Patients were assigned to one of four groups: control, acute pancreatitis, chronic pancreatitis or pancreatic cancer. Two observers, blinded to the clinical data, analysed the time-activity curves of FDG kinetics based on region of interest analysis. The diagnosis predicted by FDG PET was compared with the result of histological examination of the surgical specimen. Analysis of FDG kinetics revealed significant differences in the shape of the time-activity curve for controls, pancreatic cancer and inflammatory disease. Surprisingly, there was no significant difference in the time-activity curve shape for chronic pancreatitis and acute pancreatitis; this is, however, not a clinical issue. Furthermore, acquisition time (60 min vs 90 min) did not affect interpretation of the time-activity curve, so that scanning time may be regularly shortened to 60 min. Interobserver agreement was 1. Based on these findings, non-invasive differentiation between pancreatic cancer and chronic pancreatitis was correctly predicted in all cases, as confirmed by histology. In addition, the specificity was increased compared with that obtained from standardised uptake value analysis. Non-invasive differentiation between pancreatic cancer and chronic pancreatitis may best be achieved based on a dynamic FDG PET study including kinetic analysis. This approach yields results superior to those obtained from a semiquantitative analysis of pancreatic lesions.
Assuntos
Fluordesoxiglucose F18 , Neoplasias Pancreáticas/diagnóstico por imagem , Compostos Radiofarmacêuticos , Doença Aguda , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico por imagem , CintilografiaRESUMO
The purpose of this study was to evaluate (18)F-DOPA whole-body positron emission tomography ((18)F-DOPA PET) as a biochemical imaging approach for the detection of glomus tumours. (18)F-DOPA PET and magnetic resonance imaging (MRI) were performed in ten consecutive patients with proven mutations of the succinate dehydrogenase subunit D ( SDHD) gene predisposing to the development of glomus tumours and other paragangliomas. (18)F-DOPA PET and MRI were performed according to standard protocols. Both methods were assessed under blinded conditions by two experienced specialists in nuclear medicine (PET) and diagnostic radiology (MRI). Afterwards the results were compared. A total of 15 lesions (four solitary and four multifocal tumours, the latter including 11 lesions) were detected by (18)F-DOPA PET. Under blinded conditions, (18)F-DOPA PET and MRI revealed full agreement in seven patients, partial agreement in two and complete disagreement in one. Eleven of the 15 presumed tumours diagnosed by (18)F-DOPA PET were confirmed by MRI. The correlation of (18)F-DOPA PET and MRI confirmed three further lesions previously only detected by PET. All of them were smaller than 1 cm and had the signal characteristics of lymph nodes. For one small lesion diagnosed by PET, no morphological MRI correlate could be found even retrospectively. No tumour was detected by MRI that was negative on (18)F-DOPA PET. All tumours diagnosed by MRI showed a hyperintense signal on T2-weighted images and a distinct enhancement of contrast medium on T1-weighted images. The mean tumour size was 1.5+/-0.5 cm. (18)F-DOPA PET seems to be a highly sensitive metabolic imaging procedure for the detection of glomus tumours and may have potential as a screening method for glomus tumours in patients with SDHD gene mutations.
Assuntos
Tumor do Corpo Carotídeo/diagnóstico por imagem , Di-Hidroxifenilalanina/análogos & derivados , Tumor Glômico/diagnóstico por imagem , Tomografia Computadorizada de Emissão/métodos , Adulto , Idoso , Tumor do Corpo Carotídeo/diagnóstico , Tumor do Corpo Carotídeo/genética , Feminino , Tumor Glômico/diagnóstico , Tumor Glômico/genética , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico , Paraganglioma/diagnóstico por imagem , Paraganglioma/genética , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Método Simples-CegoRESUMO
PURPOSE: To evaluate fluorine 18 ((18)F) dihydroxyphenylalanine (DOPA) whole-body positron emission tomography (PET) as a biochemical imaging approach for detection of pheochromocytomas. MATERIALS AND METHODS: (18)F DOPA PET and magnetic resonance (MR) imaging were performed in 14 consecutive patients suspected of having pheochromocytomas (five sporadic, nine with von Hippel-Lindau disease); metaiodobenzylguanidine (MIBG) scintigraphy was performed in 12 of these patients. The individual imaging findings were assessed in consensus by specialists in nuclear medicine and radiologists blinded to the results of the other methods. The findings of the functional imaging methods were compared with those of MR imaging, the reference standard. Histologic verification could be obtained in eight patients with nine tumors. RESULTS: Seventeen pheochromocytomas (11 solitary, three bifocal; 14 adrenal, three extraadrenal) were detected with MR imaging. (18)F DOPA PET and MR imaging had concordant results in all 17 tumors. In contrast, MIBG scintigraphy had false-negative results in four patients with three adrenal tumors smaller than 2 cm and one extraadrenal tumor with a diameter of 3.6 cm. On the basis of these data, sensitivities of 100% for (18)F DOPA PET and of 71% for MIBG scintigraphy were calculated. Specificity was 100% for both procedures. CONCLUSION: (18)F DOPA PET is highly sensitive and specific for detection of pheochromocytomas and has potential as the functional imaging method of the future.