Multiple and hereditary renal tumors: a review for radiologists.

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of "sporadic" multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended. Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition. The concept of "non-hereditary" familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

Tumores renales múltiples y hereditarios. Revisión por y para radiólogos / Multiple and hereditary renal tumors: A review for radiologists

El 80% de los carcinomas renales (CR) se diagnostican incidentalmente por imagen. Se aceptan un 2-4% de multifocalidad «esporádica» y un 5-8% de síndromes hereditarios, probablemente con infraestimación. Multifocalidad, edad joven, historia familiar, datos sindrómicos y ciertas histologías hacen sospechar un síndrome hereditario. Debe estudiarse individualmente cada tumor y multidisciplinarmente al paciente, con estrategias terapéuticas conservadoras de nefronas y un abordaje diagnóstico radioprotector. Se revisan los datos relevantes para el radiólogo en los síndromes de von Hippel-Lindau, translocación de cromosoma-3, mutación de proteína-1 asociada a BRCA, CR asociado a déficit en succinato-deshidrogenasa, PTEN, CR papilar hereditario, cáncer papilar tiroideo-CR papilar, leiomiomatosis hereditaria y CR, Birt-Hogg-Dubé, complejo esclerosis tuberosa, Lynch, translocación Xp11.2/fusión TFE3, rasgo de células falciformes, mutación DICER1, hiperparatoridismo y tumor mandibular hereditario, así como los principales síndromes de predisposición al tumor de Wilms.(AU)

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of “sporadic” multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended. Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition. The concept of “non-hereditary” familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.(AU)

Caracterização clínica, molecular e genética de pacientes com câncer colorretal abaixo de 50 anos / Clinical, molecular and genetic characterization of colorectal cancer patients under 50 years of age

Introdução: Pacientes com câncer colorretal (CCR) em idade jovem (< 50 anos) apresentam maior risco de apresentar variantes germinativas em genes de predisposição ao câncer, entre eles os genes da Síndrome de Lynch (SL) (genes MMR - MLH1, MSH2, MSH6 e PMS2). Detectar a perda de expressão de proteínas de reparo de incompatibilidade de DNA (MMR) é altamente relevante para identificar pacientes com síndrome de Lynch. No entanto, a inativação de MLH1 devido à hipermetilação do promotor ocorre em 15% dos cânceres colorretais (CCRs) esporádicos e está correlacionada com mutações somáticas BRAF. Ainda, apesar das principais síndromes hereditárias de CCR representarem 15-19% dos casos de CCR de início precoce, a etiologia da maior parte dos CCRs nestes pacientes é desconhecida, mesmo com até 25% destes casos apresentando história familiar importante para essa neoplasia. Objetivo: Caracterizar o fenótipo clínico e molecular (somático e germinativo) de pacientes com CCR desenvolvido antes dos 50 anos tratados no A.C.Camargo Cancer Center. Materiais e Métodos: Pacientes com câncer colorretal <50 anos foram selecionados a partir do banco de dados do Departamento de Cirurgia Pélvica ou pelo encaminhamento do Departamento de Oncogenética. A análise de metilação do promotor de MLH1 foi realizada por sequenciamento de nova geração (NGS) a partir de DNA convertido por bissulfito de sódio, em uma metodologia desenvolvida e validada nesse estudo. A análise de mutação de BRAF foi realizada por NGS de amplicon. Para um subgrupo de pacientes com critérios clínicos e moleculares específicos (tumores MMR deficientes, história familiar positiva para CCR, mutação KRAS: G12C e/ou idade <40 anos) foi realizado o sequenciamento germinativo de genes de predisposição ao CCR. Na avaliação das variantes germinativas foi utilizado um painel multigênico com 62 genes de associação conhecida, emergente ou desconhecida para predisposição ao CCR. As variantes identificadas foram classificadas segundo os critérios sugeridos pelo American College of Medical Genetics (ACMG). Resultados: Para análise de metilação de MLH1 utilizamos DNA de tumores FFPE e saliva foi tratado com bissulfito, amplificado por PCR e avaliado por NGS. Em tumores deficientes em MLH1/PMS2, o estado de metilação de MLH1 foi concordante com o estado de mutação BRAF em 90% (18/20) dos casos. Nosso teste NGS baseado em amplicon mostrou uma grande sensibilidade e especificidade para detectar a metilação de MLH1 em amostras de CCR, com alta concordância com a avaliação da mutação BRAF. A avaliação das variantes germinativas foi realizada em 89 pacientes, e identificamos 24 (27%) pacientes com variantes patogênicas ou provavelmente patogênicas (P/PP). A maioria dos pacientes 53% (47/89) apresentaram variantes de significado incerto (VUS) e 18 (20%) pacientes apresentaram apenas variantes sem significado clínico para os 62 genes avaliados. Dos 24 pacientes com variantes patogênicas, 16 (66,6%) apresentaram variantes P/PP em genes da síndrome de Lynch. Cinco pacientes (20%) apresentaram variantes P/PP em MUTYH (3 bialélicos e 2 monoalélicos). Dois (8,3%) pacientes tinham variantes PP em FAN1. Um paciente apresentou uma variante PP em NTHL1 (monoalélica), e para os genes XRCC4 e RAD51C tivemos um paciente cada com alteração. Dois pacientes apresentaram variantes P/PP em mais de 1 gene (1 MLH1 com FAN1, 1 MUTYH com XRCC4). Conclusão: Em nosso trabalho fomos capazes de desenvolver com sucesso uma metodologia baseada em NGS para avaliação de metilação no promotor do gene MLH1, para caracterizar molecularmente as amostras tumorais do grupo de pacientes com deficiência nos genes de reparo relacionados a causas esporádicas (metilação de MLH1 e mutação de BRAF). Além disso, identificamos variantes germinativas com evidência definitiva de predisposição ao CCR em 1 a cada 4 pacientes da nossa coorte, além de termos identificado variantes patogênicas em genes com evidência limitada ou ausente de predisposição hereditária ao câncer CCR, como é o caso dos genes RAD51C, XRCC4 e FAN1.

Introduction: Patients with colorectal cancer (CRC) at a young age (< 50 years) are at greater risk of having germline variants in cancer predisposition genes, including Lynch Syndrome (LS) genes (MMR genes - MLH1, MSH2, MSH6 and PMS2). Detecting the loss of expression of DNA mismatch repair (MMR) proteins is highly relevant to identify patients with Lynch syndrome. However, inactivation of MLH1 due to promoter hypermethylation occurs in 15% of sporadic colorectal cancers (CRCs) and is correlated with somatic BRAF mutations. Also, although the main hereditary syndromes of CRC represent 15-19% of cases of early-onset CRC, the etiology of most CRCs in these patients is unknown, even with up to 25% of these cases presenting an important family history of this neoplasm. Objective: To characterize the clinical and molecular phenotype (somatic and germline) of patients with CRC developed before the age of 50 years treated at the A.C.Camargo Cancer Center. Materials and Methods: Colorectal cancer patients <50 years were selected from the database of the Department of Pelvic Surgery or by referral from the Department of Oncogenetics. MLH1 promoter methylation analysis was performed by next-generation sequencing (NGS) from DNA converted by sodium bisulfite, in a methodology developed and validated in this study. BRAF mutation analysis was performed by amplicon NGS. For a subgroup of patients with specific clinical and molecular criteria (MMR deficient tumors, positive family history for CCR, KRAS:G12C mutation, and/or age <40 years) germline sequencing of CRC predisposing genes was performed. In the evaluation of germline variants, a multigene panel with 62 genes of known, emerging or unknown association for CRC predisposition was used. The identified variants were classified according to the criteria suggested by the American College of Medical Genetics (ACMG). Results: For MLH1 methylation analysis we used DNA from FFPE tumors and saliva was treated with bisulfite, amplified by PCR and evaluated by NGS. In MLH1/PMS2 deficient tumors, MLH1 methylation status was concordant with BRAF mutation status in 90% (18/20) of cases. Our amplicon-based NGS test showed great sensitivity and specificity for detecting MLH1 methylation in CRC samples, with high agreement with the BRAF mutation assessment. The evaluation of germline variants was performed in 89 patients, and we identified 24 (27%) patients with pathogenic or probably pathogenic (P/PP) variants. Most patients 53% (47/89) had variants of uncertain significance (VUS) and 18 (20%) patients had only variants without clinical significance for the 62 genes evaluated. Of the 24 patients with pathogenic variants, 16 (66.6%) had P/PP variants in Lynch syndrome genes. Five patients (20%) had P/PP variants in MUTYH (3 biallelic and 2 monoallelic). Two (8.3%) patients had PP variants in FAN1. One patient had a PP variant in NTHL1 (monoallelic), and for the XRCC4 and RAD51C genes we had one patient each with alteration. Two patients had P/PP variants in more than 1 gene (1 MLH1 with FAN1, 1 MUTYH with XRCC4). Conclusion: In our work, we were able to successfully develop a methodology based on NGS for the evaluation of methylation in the promoter of the MLH1 gene, to molecularly characterize the tumor samples from the group of patients with deficiency in the repair genes related to sporadic causes (MLH1 methylation and BRAF mutation). In addition, we identified germline variants with definitive evidence of predisposition to CRC in 1 out of 4 patients in our cohort, in addition to having identified pathogenic variants in genes with limited or no evidence of hereditary predisposition to CRC cancer, such as the RAD51C genes, XRCC4 and FAN1.

Narrative review comparing the epidemiology, characteristics, and survival in sporadic colorectal carcinoma/Lynch syndrome / Revisão narrativa na comparação da epidemiologia, características e sobrevivência no Carcinoma Colorretal esporádico/Síndrome de Lynch

Abstract Introduction: Colorectal carcinoma is the third most prevalent neoplasm in the world, and the second cause of death by cancer. The most part of these neoplasms are sporadic by somatic mutations, but around 15% are hereditary, such as Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). Despite being the same tumor, it has differences between these two contexts as well as different prognosis. In Lynch syndrome cases, the survival of these individuals was greater than that observed in sporadic cases. Methods: This review focuses on the different characteristics and development of colorectal carcinoma in sporadic and Lynch syndrome cases, in order to conclude what may motivate the greater survival in the tumors associated with this syndrome. Results: Although the histopathological features drive into a worse prognosis, the colorectal carcinoma in the Lynch Syndrome presents a greater survival comparing to sporadic colorectal carcinoma. Discussion: The greater survival in the colorectal carcinoma in the HNPCC compared to the sporadic carcinomas has been linked to factors such as high microsatellite instability, diploid predominance, earlier screening for colo-rectal carcinoma, deficient DNA repair mechanism, low p53 mutation rate, and presence of lymphoid aggregates involving the neoplasm. Conclusion: Further studies should be conducted to provide new insights about survival of colorectal carcinoma in Lynch syndrome, as well as the therapeutic alternatives for this neoplasia.

Resumo Introdução: O carcinoma colorretal é a terceira neoplasia mais prevalente no mundo, bem como a segunda causa de morte por câncer. A maioria destas neoplasias são esporádicas, devidas a mutações somáticas, mas cerca de 15% são hereditárias como a síndrome de Lynch ou Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Apesar de ser a mesma neoplasia, esta apresenta características clinico-patológicas e moleculares distintas, bem como diferentes prognósticos. Nos casos de síndrome de Lynch, a sobrevida parece ser maior quando comparada com os carcinomas esporádicos. Métodos: Realizamos uma revisão bibliográfica sobre as diferentes características e desenvolvimentos do carcinoma colorretal esporádico e no contexto da síndrome de Lynch, para concluir o que causa a maior sobrevida no caso das neoplasias associadas a esta síndrome. Resultados: Apesar das características histopatológicas apontarem para um pior prognóstico, o HNPCC apresenta uma maior sobrevida em relação ao carcinoma colorretal esporádico. Discussão: A maior sobrevivência nos carcinomas colorretais associados ao HNPCC em comparação com os carcinomas colorretais esporádicos tem sido atribuída a fatores como a elevada instabilidade microssatélite, a predominância diploide, a realização de rastreio para o carcinoma colorretal mais precoce, deficiente mecanismo de reparação de DNA, menor taxa de mutação da p53 e existência de agregados linfoides a envolver a neoplasia. Conclusão: Consideramos que deve ser encorajado o estudo mais aprofundado dos fatores que levam à maior sobrevida do carcinoma colorretal na síndrome de Lynch, bem como de alternativas terapêuticas para esta neoplasia.

Extensive colectomy in colorectal cancer and hereditary nonpolyposis colorectal cancer - long-term results / Colectomia extensa em cancro colorretal e cancro colorretal hereditário sem polipose - resultados a longo prazo

ABSTRACT Background: Colorectal cancer survival is better in hereditary nonpolyposis colorectal cancer patients than in sporadic colorectal cancer patients and even for hereditary nonpolyposis colorectal cancer with colorectal cancer is not consensual that extensive colectomy is preferable to partial colectomy. This study analyzes and compares the long-term results of these two groups of patients submitted to curative subtotal colectomy or total colectomy. Methods: Between 2002 and 2018, 68 patients with colorectal cancer without familial adenomatous polyposis were submitted to a total or subtotal colectomy in a single tertiary center. The patients were divided in two groups: hereditary nonpolyposis colorectal cancer patients (with Amsterdam criteria) and sporadic colorectal cancer patients (the others). The presence of Amsterdam criteria for hereditary nonpolyposis colorectal cancer and germline mutation for mismatch repair genes was confirmed by clinical records. Results and survival were analyzed following surgery. Results: We obtained a sporadic colorectal cancer group with 31 patients and a hereditary nonpolyposis colorectal cancer group with 37 patients. The two groups differ in age but not in gender, tumor stage or surgical morbidity. The overall survival and disease-free survival were good in both groups but even better for hereditary nonpolyposis colorectal cancer group with statistical significance when comparing the two groups. Conclusion: Total or subtotal colectomy for colorectal cancer provides a good survival. These surgical procedures should be considered the first option for colorectal cancer in young hereditary non polyposis colorectal cancer patients. In those cases, they provide good long-term results, avoiding the risk of metachronous colorectal cancer and the surveillance is restricted only to the remaining need for rectum.

RESUMO Introdução: A sobrevivência do cancro colorretal é melhor em pacientes com cancro colorretal hereditário não associado a polipose do que em pacientes com cancro colorretal esporádico. Mesmo em casos de cancro colorretal hereditário sem polipose, a preferência pela colectomia total em relação à parcial não é consensual na literatura. Este estudo analisa e compara os resultados a longo prazo destes dois grupos de pacientes submetidos à colectomia curativa subtotal ou total. Métodos: Entre 2002 e 2018, 68 pacientes com cancro colorretal sem polipose adenomatosa familiar foram submetidos a colectomia total ou subtotal em um único centro terciário. Os pacientes foram divididos em dois grupos: aqueles com cancro colorretal hereditário sem polipose (de acordo com os critérios de Amsterdão) e os com cancro colorretal esporádico (os demais). Os critérios de Amsterdão para cancro colorretal hereditário sem polipose e a presença de mutação germinativa para os genes de reparação de ADN foram confirmados por consulta dos registros clínicos. Os resultados e a sobrevivência foram analisados após a cirurgia. Resultados: No presente estudo, 31 pacientes foram incluídos no grupo de cancro colorretal esporádico e 37 no grupo de cancro colorretal hereditário sem polipose. Diferenças significativas foram observadas em relação à idade, mas não ao gênero, estadio do tumor ou morbilidade cirúrgica. A sobrevivência global e a sobrevivência livre de doença foram boas em ambos os grupos, mas os resultados foram ainda melhores no grupo de cancro colorretal hereditário sem polipose, com significado estatístico. Conclusão: A colectomia total ou a colectomia subtotal para o cancro colorretal proporcionam uma boa sobrevivência e devem ser consideradas a primeira opção de tratamento em pacientes jovens com cancro colorretal hereditário sem polipose. Nestes pacientes, uma cirurgia cólica mais extensa permite a obtenção de bons resultados a longo prazo; reduz o risco de cancro colorretal metácrono e restringe a vigilância endoscópica ao reto remanescente.

Clinical practice guideline. Diagnosis and prevention of colorectal cancer. 2018 Update. / Guía de práctica clínica. Diagnóstico y prevención del cáncer colorrectal. Actualización 2018.

This document updates the recommendations made by the Spanish Society of Family and Community Medicine and the Spanish Association of Gastroenterology for the diagnosis and prevention of colorectal cancer (CRC). In order to evaluate the quality of the evidence and determine the recommendation levels of the interventions, we used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. This document establishes optimal delay intervals based on symptoms and the faecal immunochemical test (FIT) and recommends reducing the barriers for diagnostic confirmation in symptomatic subjects. With regard to CRC screening in the average-risk population, we propose strategies to achieve the universal implementation of organised CRC screening programmes based on biennial FIT and to increase the participation of the target population, including the involvement of Primary Healthcare. This Clinical Practice Guideline recommends universal screening for Lynch syndrome with mismatch repair proteins immunohistochemistry or microsatellite instability in incident CRCs and the use of gene panels in patients with adenomatous polyposis. It also updates the strategies to reduce the incidence and mortality of both CRC and other tumours associated with hereditary syndromes. Regarding non-hereditary familial CRC and surveillance after resection of adenomas, serrated lesions or CRC, we established the recommendations based on the attributable risk and the risk reduction of the proposed intervention. Finally, the document includes recommendations regarding surveillance intervals in inflammatory bowel disease and the attitude towards dysplasia.

Diagnosis and clinical behavior in patients with Lynch-like syndrome. / Diagnóstico y comportamiento clínico de pacientes con sospecha de síndrome de Lynch sin mutación conocida.

INTRODUCTION AND AIMS: Lynch-like syndrome is diagnosed when there is an expression deficit in DNA mismatch repair proteins but a normal genetic study. The behavior and management of that pathology are currently a subject of debate. We present herein the characteristics of patients with Lynch-like syndrome, together with a surveillance proposal. MATERIALS AND METHODS: Immunohistochemistry was carried out on families suspected of presenting with Lynch syndrome. Germline analysis was done if there was loss of mismatch repair protein expression and no BRAF mutation. RESULTS: Of the 148 patients that underwent immunohistochemistry testing, 23 presented with loss of mismatch repair protein expression. Seven of those patients were identified as having Lynch-like syndrome: 3had colon cancer, 2had endometrial tumor, and 2were healthy, with an affected relative. Mean patient age was 56.9 years and only one patient presented with another tumor associated with Lynch syndrome. CONCLUSIONS: Until there is a better understanding of the etiology of that heterogeneous entity, intermediate surveillance is an adequate strategy.

Síndrome de Lynch: aspectos genéticos, clínicos y diagnósticos / Lynch syndrome: genetic, clinical and diagnostic aspects

Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento.

This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos / Lynch syndrome: impact of the characterization of families based on genetic studies

El objetivo de este trabajo fue caracterizar demográfica y molecularmente las familias con diagnóstico de síndrome de Lynch en base a estudios genéticos. Se utilizó la base prospectiva del Registro de Epidemiología Molecular de Cáncer Colorrectal (REM-CCR) del Hospital Italiano de Buenos Aires (Clinical trials.gov NCT02781337). El criterio de inclusión fue que tuvieran hecho un estudio genético entre 1996 y 2017 (secuenciación y/o determinación de grandes rearreglos de al menos un gen reparador de error de apareamiento). Se analizaron 50 familias con los criterios de Amsterdam. En 23 (46%) se identificaron variantes patogénicas (n=19) y probablemente patogénicas (n=2). El 28.6% de las variantes patogénicas fueron originalmente descritas en esta serie, entre ellas la variante c.1911del en el exón 12 de MSH2 identificada en una familia con agregación de cáncer de mama. Fue identificada una mutación fundadora de Piamonte, Italia (c.2252_2253del). Los genes afectados incluyeron MSH2 (13 variantes) MLH1 (9 variantes) y PMS2 (1 variante). La tasa de detección de mutaciones fue del 46%. Entre las familias con mutación identificada (n=23), se detectó una edad mediana de inicio del cáncer menor (46 vs. 50 años, p=0.02) y mayor incidencia de tumores extra-colorrectales (90.5% vs. 45.8%, p <0.01), que las 27 sin mutaciones. La implementación de estudios genéticos permitió caracterizar variables demográficas en base a la identificación de mutaciones germinales asociadas al síndrome de Lynch, identificándose dos grupos diferenciados por la edad de afectación y la incidencia de tumores extracolónicos (AU)

The aim of this study was to characterize demographically and molecularly families diagnosed with Lynch syndrome based on genetic studies. Families with a genetic study performed between 1996 and 2017 (sequencing and/or determination of large rearrangements of a mismatch repair gene at least) were selected from the prospective database REM-CCR of Hospital Italiano de Buenos Aires (Clinical trials. Gov NCT02781337). Fifty families fulfilled Amsterdam criteria were analyzed. Pathogenic variants were found in 23 out of 50 (46%) families, being 21 pathogenic and 2 likely pathogenic. The 28.6% of the pathogenic variants were originally described in this series. Among them, the variant c.1911del in MSH2 in a family with breast cancer aggregation and a founder MLH1 mutation from Piedmont, Italy (c.2252_2253del) were identified. Affected genes include MSH2 (13 variants), MLH1 (9 variants), PMS2 (1 variant). Mutations detection rates was 46%. Those families with an identified mutation (n=23) had a lower median age of cancer onset (46 vs. 50 years, p=0.02) and a higher incidence of extra-colorectal tumors (90.5% vs. 45.8%, p<0.01) than those without identified mutations (n=27). The implementation of genetic studies allowed characterizing demographic variables based on the identification of germline mutations associated with Lynch syndrome. Two groups, Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos 3 differentiated by the age of cancer onset and the incidence of extracolonic tumors were characterized (AU)

Current evidence for universal molecular testing for colorectal cancer patients / Evidências atuais para testes moleculares universais para pacientes com câncer colorretal

Abstract Background Risk assessment for Lynch Syndrome may be a complex and challenging task. Demonstration of germline mutations has the benefits of confirming Lynch Syndrome diagnosis and may also provide screening and surgical orientation for affected members and relief for non-affected relatives. Objective The present paper aimed to critically review the criteria to diagnose Lynch Syndrome, focusing the attention on the new perspective of adopting universal screening for patients diagnosed with colorectal cancer. Methods We performed a literature review about the rationale and preliminary results of universal testing for Lynch Syndrome. Results The use of selective eligibility criteria to determine who should undergo Lynch Syndrome testing may fail in a substantial proportion of cases. Moreover, universal strategy is feasible, cost-effective and more sensitive than previous methods. However, there still exist problems regarding clinical practice implementation and compliance either by medical doctors and patients. Conclusions Standard guidelines for colorectal cancer screening are not ideal to provide early detection of Lynch Syndrome patients. And although universal screening has been associated with an increased identification of Lynch Syndrome patients, a successful implementation of this approach is still limited by the lack of clinical expertise among physicians, and also requires standardization of the existing protocols for routine genetic screening.

Resumo Introdução A avaliação de risco para síndrome de Lynch (SL) pode ser tarefa complexa e desafiadora. A demonstração de mutações na linha germinal resulta em benefícios, como a confirmação do diagnóstico de SL e também pode proporcionar orientações para a triagem e procedimentos cirúrgicos para os membros afetados, além de trazer alívio para os parentes não afetados. Objetivo Este artigo teve por objetivo oferecer uma revisão crítica dos critérios para o diagnóstico de SL, com enfoque na atenção sobre a nova perspectiva de adoção da triagem universal para pacientes diagnosticados com câncer colorretal (CCR). Métodos Procedemos a uma revisão da literatura com ênfase nas justificativas e resultados preliminares de testes universais para SL. Resultados O uso de critérios seletivos de qualificação, com vistas a determinar quem deveria passar por um teste para SL, pode ser malsucedido em substancial percentual de casos. Foi também constatado que a estratégia universal é exequível, com bom custo-benefício e com maior sensibilidade, em comparação com os métodos previamente utilizados. Contudo, ainda existem problemas concernentes à sua implementação na prática clínica e também na cooperação de médicos e de pacientes. Conclusões As orientações padronizadas para a triagem de CCR não são ideais, em termos de se obter a imediata detecção de pacientes com SL. Por outro lado, embora a triagem universal tenha sido associada a um aumento na identificação de pacientes com SL, a bem-sucedida implementação dessa abordagem fica ainda limitada pela pouca experiência clínica entre os médicos e, além disso, também há a necessidade de padronização dos protocolos existentes para a triagem genética de rotina.

Cáncer colorrectal hereditario no asociado a poliposis o síndrome de Lynch / Hereditary colorectal cancer not associated with polyposis or Lynch syndrome

El cáncer colorrectal hereditario no asociado a poliposis, también llamado síndrome de Lynch, es reconocido como un síndrome hereditario de patrón autosómico dominante de penetrancia incompleta, en el cual hay mutación en los genes reparadores del ADN. De 2 a 3 % de todos los tumores colorrectales se originan por este síndrome hereditario que predispone a su desarrollo. El síndrome Lynch, el más frecuente de los síndromes genéticos, incrementa, además del riesgo de desarrollar cáncer de colon, el de cáncer metacrónico y otros tipos de cáncer no colorrectal como los de endometrio, de intestino delgado, de uréter o de la pelvis renal. Por lo tanto, es indispensable reconocerlo e identificar a los individuos en riesgo de presentarlo para prevenir, diagnosticar y tratar de manera precoz la aparición de estas neoplasias, y poder disminuir las tasas de morbilidad y mortalidad asociadas

Hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome is recognized as an autosomal dominant hereditary syndrome of incomplete penetrance characterized by mutations in DNA repair genes. It is the most frequent of all the hereditary syndromes, and increases the likelihood of developing colorectal cancer, thus representing 2-3% of all colorectal cancers (CRC). This syndrome predisposes to metachronous (CRC) and other extracolonic cancers, as endometrium, small bowel, ureter and renal pelvis, among others. Therefore, it is necessary to recognize this syndrome and identify individuals with HNPCRC to prevent, diagnose and provide, if possible, early treatment in an effort to decrease its morbidity and mortality

Hereditary forms of colorectal cancer. / Formas hereditarias de cáncer colorrectal.

Colorectal cancer is one of the most frequent neoplasms in western countries; it is the third most common cancer in men after prostate and lung cancer and the second most common in women after breast cancer. Colorectal cancer is usually sporadic but in a small proportion is hereditary. The genetic cause is well established, allowing pre-symptomatic diagnosis in at-risk relatives. The present article reviews the most novel findings presented at the latest meeting of the American Gastroenterological Association on hereditary forms of colorectal cancer, especially Lynch syndrome and MUTYH-associated polyposis, as well as diverse organisational aspects that can favour the correct management of these patients and their relatives.

Molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome) / Diagnóstico molecular del cáncer colorrectal no polipósico hereditario (síndrome de Lynch)

Abstract Lynch syndrome is the most common cause of inherited colorectal cancer, totaling 5 to 8% of all the cases with high susceptibility to this type of cancer and extracolonic cancer. It is related to germinal mutations taking place at mismatch repair genes. The diagnosis of Lynch syndrome is essential for both monitoring patients with this disease and detecting asymptomatic carriers, in order to establish appropriate clinical monitoring, preventive management and genetic counseling. Although clinical criteria have been standardized by implementing Amsterdam I and II, as well as Bethesda guidelines, the detection rate of mutations in these genes only varies between 20% and 60%. The objective of this research was to review the state of the art regarding molecular diagnosis of Lynch syndrome; thus, a review of the literature published from 1995 to 2015 in PubMed database was performed by using the criteria "lynch syndrome molecular screening". 19 articles were selected and reviewed, and the relevant bibliography related to such articles was also reviewed. This paper presents different approaches proposed by several researchers on molecular algorithms to improve the efficiency of Lynch syndrome diagnosis.

Resumen El síndrome de Lynch es la causa más frecuente de cáncer colorectal (CCR) hereditario y representa el 5-8% de los casos con alta susceptibilidad a CCR y cánceres extracolónicos. Este síndrome se relaciona con mutaciones germinales en genes de reparación de malos apareamientos (MMR); su diagnóstico es fundamental, tanto para el seguimiento de los afectados como para la detección de portadores asintomáticos, y tiene el propósito de instaurar un adecuado seguimiento, un manejo preventivo y un asesoramiento genético. Si bien los criterios clínicos han sido estandarizados con la implementación de las guías de Amsterdam I y II y Bethesda, la tasa de detección de mutaciones en estos genes solo varía entre 20% y 60%. El objetivo de esta investigación fue revisar el estado del arte con relación al diagnóstico molecular del síndrome de Lynch, para lo cual se realizó una revisión de la literatura publicada entre 1995 y 2015 en la base de datos PubMed usando como criterio de revisión: "Lynch syndrome molecular screening". Se escogieron y revisaron 19 artículos y además se revisó y escogió la bibliografía pertinente de los artículos. Se presentan propuestas de varios autores sobre los algoritmos moleculares para mejorar la eficiencia del diagnóstico del síndrome de Lynch.

Mutación fundadora en síndrome de Lynch tipo II / Founder mutation in Lynch syndrome

El síndrome de Lynch es la más frecuente de las neoplasias colorrectales hereditarias. Se origina por mutaciones germinales deletéreas familia-específicas en los genes que codifican proteínas de reparación del ADN: MLH1 (homólogo humano de mutL), MSH2 y MSH6 (homólogo humano de mutS 2 y 6, respectivamente), PMS2 (homólogo humano de PMS1 2) y MUTYH (homólogo humano de la ADN-glycosilasa mutY). La mutación c.2252_2253delAA, p.Lys751Serfs*3 en el exón 19 del gen MLH1 segrega con un haplotipo descripto en la región norte de Italia y cuyo origen fue atribuido a un efecto fundador. Esta mutación co-segrega con características típicas del síndrome de Lynch, incluyendo afectación temprana y múltiples tumores primarios en el mismo individuo, una alta frecuencia de cáncer pancreático, elevada inestabilidad microsatelital y falta de expresión de PMS2. En el presente trabajo se comunica dicha mutación en una paciente argentina con adenocarcinoma endometroide de útero en cuya historia familiar existen antecedentes de cáncer de colon diagnosticado antes de los 50 años en familiares de primer grado, reuniendo los criterios de Ámsterdam I y síndrome de Lynch II. Los polimorfismos presentes en la paciente coinciden con el haplotipo descripto en una región del norte de Italia. El alto grado de patogenicidad asociada a esta mutación hace imprescindible el estudio de todos los integrantes de las familias con cáncer hereditario permitiendo el diagnóstico genético pre-sintomático, la instauración de tratamientos o conductas preventivas y su seguimiento.

Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase).The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments.

[Prevalence of altered mismatch repair protein nuclear expression detected by immunohistochemistry on adenomas with high-grade dysplasia and features associated with this risk in a population-based study]. / Prevalencia de alteración de expresión nuclear de proteínas reparadoras con inmunohistoquímica sobre adenomas con displasia de alto grado y características asociadas a dicho riesgo en un estudio de base poblacional.

INTRODUCTION: Alteration of mismatch repair system protein expression detected by immunohistochemistry (IHQ) in tumoural tissue is a useful technique for Lynch Syndrome (LS) screening. A recent review proposes LS screening through immunohistochemical study not only in all diagnosed cases of colorectal cancer (CRC) but also in advanced adenomas, especially in young patients. OBJECTIVE: To assess the prevalence of altered IHQ carried out in all adenomas with high-grade dysplasia (HGD) diagnosed in our community in 2011, as well as the variables associated with this alteration. METHODS: We included all the cases of adenomatous polyps with HGD diagnosed in the three public pathology laboratories of Navarre during 2011 and performed a statistical study to assess the association between different patient and lesion characteristics and altered IHQ results. RESULTS: A total of 213 colonic adenomas with HGD were diagnosed, and 26 (12.2%) cases were excluded from the final analysis (2 known LS, 22 without IHQ study and 2 with inconclusive IHQ studies). The final number of adenomas included was 187. Pathologic results were found in 10 cases (5.35%)-6 cases in MLH1 and PMS2, 2 cases in PMS2, 1 case in MSH6 and 1 case in MSH2 and MSH6. The factors showing a statistically significant association with the presence of abnormal proteins were the synchronous presence of CRC, the presence of only one advanced adenoma, proximal location of HGD and age <50 years. CONCLUSIONS: The percentage of pathologic nuclear expression found in IHQ is high. Consequently, screening of all diagnosed HGD could be indicated, especially in young patients, with a single AA and proximal HGD.

[New advances in hereditary colorectal cancer]. / Novedades en el cáncer colorrectal hereditario.

Colorectal cancer is the most frequent malignancy in both sexes in Spain. Between 20% and 25% of affected individuals have a family history of the disease, and 5% to 6% have a germ mutation, i.e. the disease develops in the context of a hereditary syndrome. The importance of identifying patients with hereditary syndromes predisposing them to colorectal cancer lies in the possibility of applying preventive measures, screening, and more appropriate management of both patients and their families. The present article outlines the most important studies presented at the congress of the American Gastroenterological Association.

[Hereditary and familial colorectal cancer]. / Cáncer colorrectal familiar y hereditario.

Up to 5% of all colorectal cancer cases are caused by a known hereditary syndrome. These hereditary types often need a higher degree of clinical suspicion to be diagnosed and require specific and specialized management. In addition, diagnosing hereditary colorectal cancer has significant consequences not only for the patient, for whom there are effective preventative measures, but also for their families, who could be carriers of the condition. The most significant advances in the field of colorectal cancer have come from the diagnosis and characterization of these syndromes.

Identificación de cáncer colorrectal hereditario / Identification of heredity colorectal cancer: Lynch Syndrome

El síndrome de Lynch representa aproximadamente 4% de todos los tipos de cáncer colorrectal. Este síndrome se manifiesta en las familias de manera autosómica dominante y predispone a los individuos al desarrollo de cánceres temprano en la vida. El síndrome de Lynch es causado por mutaciones en la línea germinal de los genes que codifican las proteínas responsables de la reparación del daño al ADN, MLH1, MSH2, MSH6 y PMS2. La correcta historia familiar es en la actualidad el principal método para la identificación de pacientes con alto riesgo de presentar esta enfermedad, no obstante existen criterios clínicos ya establecidos. Es muy importante establecer medidas de vigilancia y monitoreo en los personas identificadas como portadoras de este síndrome, con la finalidad de ofrecer un programa de diagnóstico a sus familiares, ya que ayuda a reducir la morbimortalidad. El objetivo de esta revisión es describir los nuevos avances y conceptos sobre el síndrome de Lynch, su espectro tumoral, las características clínicas-patológicas, la correlación genotipo-fenotipo, los métodos de diagnóstico e identificación de mutaciones, así como resaltar su impacto en salud pública.

Adenocarcinoma del intestino delgado asociado al síndrome de Lynch / Adenocarcinoma of the small intestine associated with Lynch syndrome

El síndrome de Lynch (SL) es una enfermedad autosómica dominante causada por una mutación en los genes de reparación del ADN que predispone al cáncer colorrectal (CCR) y a otros tumores extracolónicos. Entre estos predominan los del endometrio, estómago, tracto urinario alto y ovario. La incidencia de los tumores de intestino delgado (TID) si bien es baja (0,4-2,9%), supera en más de 25 veces a la de la población general. El objetivo de este trabajo es presentar un caso de carcinoma del duodeno en un paciente masculino de 47 años con criterios de Amsterdam II, y discutir las características de los TID en el SL.

Lynch Syndrome (LS) is an autosomal dominant condition caused by mutations in the mismatch repair genes that predispose to colorectal cancer (CRC) and other extracolonic tumors. Among these, endometrial, gastric, ovarian, and urinary tract tumors are the commonest. The incidence of small bowel tumors (SBT), although low (0.4-2.9%), exceeds in more than 25 times that of the general population. The purpose of this paper is to communicate a case of carcinoma of the duodenum in a 47 years old male with Amsterdam II criteria, and discuss the characteristics of SBT in LS.

Caracterização funcional de variantes de patogenicidade incerta, MLH1 LEU676PRO E MSH2 MET729ILE, encontradas em pacientes diagnosticados com síndrome de Lynch / Functional characterization of variants of uncertain pathogenicity, MLH1 Leu676Pro and MSH2 Met729Ile, found in patients diagnosed with Lynch syndromeneoplasias and uterine cervix squamous cell carcinoma

O melanoma cutâneo é uma neoplasia que acomete indivíduos jovens e apresenta comportamento agressivo quando diagnosticado tardiamente. Sendo assim, novos métodos diagnósticos auxiliares ao exame clínico, como a dermatoscopia e a microscopia confocal in vivo (MC), têm sido desenvolvidos com o objetivo de melhorar a acurácia diagnóstica desse tumor. Semelhante à dermatoscopia, a MC revela detalhes morfológicos da arquitetura tecidual no plano paralelo à pele e, além disso, fornece imagens instantâneas com alta magnificação e resolução celular. A realização de cortes histológicos transversais (mesmo plano da dermatoscopia e MC) poderia contribuir para melhor caracterizar os achados observados tanto na dermatoscopia quanto na MC. Não existem relatos na literatura médica comparando as características dermatoscópicas, a MC e os achados histopatológicos em cortes transversais. O objetivo deste estudo foi descrever a técnica para realização dos cortes histológicos transversais e comparar as principais características dermatoscópicas do melanoma cutâneo à MC e à histopatologia em cortes perpendiculares e transversais, no intuito de oferecer uma interpretação mais precisa dos achados celulares e arquiteturais observados in vivo. Foram avaliadas 65 lesões com diagnóstico dermatoscópico de melanoma cutâneo de 63 pacientes recrutados no Núcleo de Câncer de Pele e Dermatologia do A.C. Camargo Cancer Center no período de junho de 2011 a abril de 2013. Uma forma fácil, segura e confiável para a realização dos cortes histológicos transversais foi apresentada. Os aspectos celulares e arquiteturais no exame de MC das principais características dermatoscópicas do melanoma cutâneo foram determinados e comparados aos achados histopatológicos nos cortes transversais e perpendiculares. A MC permitiu a identificação de uma nova estrutura chamada de “papila em mitocôndria” que pode representar um critério adicional para o diagnóstico do melanoma in situ. Os cortes histológicos...

Cutaneous melanoma is a cancer that affects young individuals and shows aggressive behavior when diagnosed lately. Therefore, new diagnostic tools to unaided eye, such as dermoscopy and in vivo reflectance confocal microscopy (RCM), have been developed with the aim of improving the diagnostic accuracy of this tumor. Similarly to dermoscopy, RCM reveals morphological details of tissue architecture in parallel plane to the skin and, moreover, provides instant images with high magnification and cellular level resolution. The performance of transverse histopathological sections (same plane of dermoscopy and RCM) could help to better characterize the features observed in both dermoscopy and RCM. There are no reports in the medical literature comparing dermoscopic, RCM and histopathological features in transverse sections. The purpose of this study was to describe the technique for acquiring the transverse sections and compare the main dermoscopic features of cutaneous melanoma to the RCM and histopathology in perpendicular and transverse sections, in order to offer a more precise interpretation of the cellular and architectural features observed in vivo. This study included 65 lesions with dermoscopic diagnosis of cutaneous melanoma in 63 patients recruited at the Dermatology Center of the AC Camargo Cancer Center from June 2011 to April 2013. An easy, safe and reliable way for handle the transverse sections was presented. The RCM cellular and architectural aspects of the main melanoma dermoscopic features were determined and compared to histopathological findings in the transverse and perpendicular sections. We described a new structure called “papillae in mitochondria” which may represent an additional clue for the melanoma in situ diagnosis. The transverse sections allowed a more precise interpretation of the main RCM features in cutaneous melanoma...