Avaliação e correlação clínica, laboratorial, radiológica, anátomo-patológica e genética de pacientes com feocromocitomas/paragangliomas esporádicos e familiais acompanhados na Unifesp/EPM
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Data
2023-12-01
Autores
Lima Junior, José Viana [UNIFESP]
Orientadores
Kater, Claudio Elias [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Manuscrito 1: “Síndrome Feocromocitoma/Paraganglioma: Um Panorama dos Mecanismos, Diagnóstico e Manuseio”
Os feocromocitomas/paragangliomas (PPGL) são tumores neuroendócrinos raros, metastáticos e potencialmente fatais, muitas vezes negligenciados por apresentarem sintomas semelhantes a outras condições clínicas prevalentes, como síndrome do pânico, tirotoxicose, ansiedade, hipoglicemia, etc., atrasando o diagnóstico e o tratamento. A taxa de diagnóstico de PPGL tem aumentado com a melhoria na dosagem dos metabólitos das catecolaminas e a crescente disponibilidade de procedimentos de imagem. Sua natureza genética essencial tem sido extensivamente investigada, compreendendo mais de 20 genes atualmente relacionados ao PPGL e provavelmente mais novos genes serão descobertos. Esta visão geral lançará alguma luz sobre o diagnóstico clínico, laboratorial, topográfico, genético e o manejo do PPGL.
Manuscrito 2: “Variantes genéticas germinativas em feocromocitoma/paraganglioma: Experiência de um centro isolado”
Feocromocitoma/paraganglioma (PPGL) são tumores neuroendócrinos raros sendo que em 25-40% dos casos possuem variantes genéticas patogênicas germinativas (VPG). Avaliamos o perfil molecular germinativo, clínico, laboratorial de 115 pacientes com diagnóstico patológico (quatorze pacientes eram parentes de 8 famílias diferentes recrutadas para pesquisa genética) confirmados com PPGL acompanhados em nossa instituição. Pacientes com fenótipos clássicos MEN2A/MEN2B e parentes em risco foram submetidos à análise direta do proto-oncogene RET, e os restantes tiveram amostras submetidas ao sequenciamento de próxima geração (NGS) completo visando 23 genes relacionados ao PPGL: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53 e VHL. . Também desenvolvemos um escore de julgamento clínico (CJS) para determinar a probabilidade de os pacientes terem uma doença potencialmente hereditária. O panorama genético resultante mostrou que 67 pacientes (58,3%) tinham variantes em pelo menos um gene: 34 (50,7%) tinham variantes exclusivamente patogênicas ou prováveis patogênicas, 13 (19,4%) variantes patogênicas ou provavelmente patogênicas e VUS e 20 (29,8%) carregavam apenas VUS. VPG foram encontrados em RET (N=18; 38,3%), VHL (N=10; 21,3%), SDHB e NF1 (N=8; 17% cada) e MAX, SDHD, TMEM127 e TP53 (N=1 ; 2,1% cada). O teste genético direto revelou sensibilidade de 91,3%, especificidade de 81,2% e valores preditivos positivos (VPP) e negativos (VPN) de 76,4% e 93,3%, respectivamente. O CJS para identificar pacientes que não se beneficiariam com testes genéticos apresentou sensibilidade de 75%, especificidade de 96,4% e VPP e VPN de 60% e 98,2%, respectivamente. Em resumo, o panorama das variantes do gene da linha germinativa PPGL de 115 pacientes brasileiros resultou em variantes patogênicas e provavelmente patogênicas com prevalência ligeiramente maior, especialmente no gene RET. Sugerimos que o CJS seja realizado para identificar pacientes com PPGL que não necessitariam de avaliação genética inicial, melhorando a especificidade do teste e reduzindo custos.
Manuscrito 3: “Retrato de uma grande série de pacientes com feocromocitoma/ paraganglioma estudados em um centro de referência em São Paulo”
Feocromocitomas (Pheo) e paragangliomas (PGL) são tumores secretores de catecolaminas. A confirmação do PPGL funcional depende fortemente do achado de metanefrinas (MN) plasmáticas e/ou urinárias elevadas em 24 horas. Apresentamos os aspectos clínicos, hormonais e de imagem de 116 pacientes estudados em nosso centro de referência endócrina em São Paulo, Brasil, nos quais foi confirmado o diagnóstico de PPGL (94 Pheo, 22 PGL). A hipertensão arterial sistêmica (HAS) esteve presente em 81% dos pacientes, 42,6% tinham HAS estágio 3; 9,5% eram pré-hipertensos e 9,5% eram normotensos. A HAS foi acompanhada de paroxismos em 58,5% dos pacientes com PPGL e foi sustentada exclusivamente nos outros 41,5%. HAS resistente foi observada em 27,7%, principalmente associada à HAS paroxística e combinada. A hipotensão ortostática esteve presente em 64,7% dos pacientes, seis dos quais não apresentavam hipertensão. Para identificar lesões funcionantes, utilizamos um valor de corte de 885 mcg/24 horas para MN urinário total (100% de sensibilidade [S] e 92,5% de especificidade [E]) e um ponto de corte de 1,5 nmol/L para lesões totais. MN plasmático (100% S e 97,3% E). A ressonância magnética (RM) foi o principal procedimento de imagem. Foram identificados 18 Pheo bilaterais (19,2%), 53 (56,4%) Pheo no lado direito e 23 (24,5%) no lado esquerdo. Treze (56,5%) PGL eram retroperitoneais e 10 (43,5%) eram cervicais. O tamanho do tumor foi positivamente correlacionado com a excreção urinária total de MN. A concordância entre a ressonância magnética e a cintilografia com 131I-mIBG, realizada em 57 pacientes com PPGL (52,3%), foi de quase 100%.
Manuscript 1: “The Pheochromocytoma/Paraganglioma Syndrome: An Overview on Mechanisms, Diagnosis and Management” Pheochromocytomas/paragangliomas (PPGL) are rare, metastatic, and potentially fatal neuroendocrine tumors, often neglected because they present symptoms similar to other prevailing clinical conditions such panic syndrome, thyrotoxicosis, anxiety, hypoglycemia, etc., delaying diagnosis and treatment. The rate of diagnosis of PPGL has been increasing with the improvement in the measurement of catecholamine metabolites and the expanding availability of imaging procedures. Its essential genetic nature has been extensively investigated, comprising more than 20 genes currently related to PPGL and more new genes will probably be revealed. This overview will shed some light on the clinical, laboratory, topographical, genetic diagnosis, and management of PPGL. Manuscript 2: “Germline genetic variants in pheochromocytoma/ paraganglioma: Single-center experience” Pheochromocytoma/paraganglioma (PPGL) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGV). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (fourteen patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remained had samples submitted to complete Next Generation Sequencing (NGS) aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) pathogenic or likely pathogenic variants and VUS and 20 (29.8%) carried only VUS. PGV were found in RET (N=18; 38.3%), VHL (N=10; 21.3%), SDHB and NF1 (N=8; 17% each), and MAX, SDHD, TMEM127, and TP53 (N=1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive (PPV) and negative (NPV) predictive values, respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs. Manuscript 3: “Portrait of a large series of patients with pheochromocytoma/ paraganglioma studied in a reference center in São Paulo” Pheochromocytomas (Pheo) and paragangliomas (PGL) are catecholamine-secreting tumors. Confirmation of functional PPGL strongly relies on the finding of elevated plasma and/or 24-h urinary metanephrines (MN). We present the clinical, hormonal, and imaging aspects of 116 patients studied in our endocrine reference center in São Paulo, Brazil, in whom a diagnosis of PPGL (94 Pheo, 22 PGL) was confirmed. Systemic arterial hypertension (SAH) was present in 81% patients, 42.6% had stage 3 SAH; 9.5% were prehypertensive, and 9.5% were normotensive. SAH was accompanied by paroxysms in 58.5% PPGL patients and was exclusively sustained in the other 41.5%. Resistant SAH was observed in 27.7%, mostly associated with paroxysmal and combined SAH. Orthostatic hypotension was present in 64.7% patients, six of whom did not have hypertension. To identify functioning lesions, we used a cut-off value of 885 mcg/24-h for total urinary MN (100% sensitivity [S] and 92.5% specificity [E]) and a cut-off of 1.5 nmol/L for total plasma MN (100% S and 97.3% E). Magnetic resonance imaging (MRI) was the major imaging procedure. It identified 18 bilateral Pheo (19.2%), 53 (56.4%) Pheo on the right side and 23 (24.5%) on the left side. Thirteen (56.5%) PGL were retroperitoneal and 10 (43.5%) were cervical. Tumor size was positively correlated with total urinary MN excretion. The concordance between MRI and 131I-mIBG scintigraphy, performed in 57 PPGL patients (52.3%), was almost 100%.
Manuscript 1: “The Pheochromocytoma/Paraganglioma Syndrome: An Overview on Mechanisms, Diagnosis and Management” Pheochromocytomas/paragangliomas (PPGL) are rare, metastatic, and potentially fatal neuroendocrine tumors, often neglected because they present symptoms similar to other prevailing clinical conditions such panic syndrome, thyrotoxicosis, anxiety, hypoglycemia, etc., delaying diagnosis and treatment. The rate of diagnosis of PPGL has been increasing with the improvement in the measurement of catecholamine metabolites and the expanding availability of imaging procedures. Its essential genetic nature has been extensively investigated, comprising more than 20 genes currently related to PPGL and more new genes will probably be revealed. This overview will shed some light on the clinical, laboratory, topographical, genetic diagnosis, and management of PPGL. Manuscript 2: “Germline genetic variants in pheochromocytoma/ paraganglioma: Single-center experience” Pheochromocytoma/paraganglioma (PPGL) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGV). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (fourteen patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remained had samples submitted to complete Next Generation Sequencing (NGS) aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) pathogenic or likely pathogenic variants and VUS and 20 (29.8%) carried only VUS. PGV were found in RET (N=18; 38.3%), VHL (N=10; 21.3%), SDHB and NF1 (N=8; 17% each), and MAX, SDHD, TMEM127, and TP53 (N=1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive (PPV) and negative (NPV) predictive values, respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs. Manuscript 3: “Portrait of a large series of patients with pheochromocytoma/ paraganglioma studied in a reference center in São Paulo” Pheochromocytomas (Pheo) and paragangliomas (PGL) are catecholamine-secreting tumors. Confirmation of functional PPGL strongly relies on the finding of elevated plasma and/or 24-h urinary metanephrines (MN). We present the clinical, hormonal, and imaging aspects of 116 patients studied in our endocrine reference center in São Paulo, Brazil, in whom a diagnosis of PPGL (94 Pheo, 22 PGL) was confirmed. Systemic arterial hypertension (SAH) was present in 81% patients, 42.6% had stage 3 SAH; 9.5% were prehypertensive, and 9.5% were normotensive. SAH was accompanied by paroxysms in 58.5% PPGL patients and was exclusively sustained in the other 41.5%. Resistant SAH was observed in 27.7%, mostly associated with paroxysmal and combined SAH. Orthostatic hypotension was present in 64.7% patients, six of whom did not have hypertension. To identify functioning lesions, we used a cut-off value of 885 mcg/24-h for total urinary MN (100% sensitivity [S] and 92.5% specificity [E]) and a cut-off of 1.5 nmol/L for total plasma MN (100% S and 97.3% E). Magnetic resonance imaging (MRI) was the major imaging procedure. It identified 18 bilateral Pheo (19.2%), 53 (56.4%) Pheo on the right side and 23 (24.5%) on the left side. Thirteen (56.5%) PGL were retroperitoneal and 10 (43.5%) were cervical. Tumor size was positively correlated with total urinary MN excretion. The concordance between MRI and 131I-mIBG scintigraphy, performed in 57 PPGL patients (52.3%), was almost 100%.
Descrição
Citação
LIMA JUNIOR, José Viana. Avaliação e correlação clínica, laboratorial, radiológica, anátomo-patológica e genética de pacientes com feocromocitomas/paragangliomas esporádicos e familiais acompanhados na Unifesp/EPM. Tese (Doutorado em Endocrinologia e Metabologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2023.