Metachronic breast and cerebellar neoplasm in a young patient / Neoplasias mamária e cerebelar metacrônicas em uma paciente jovem

Abstract Several factors trigger the development of genetic mutations that are responsible for causing a neoplasm. Medulloblastoma is a malignant and invasive cerebellar neoplasm, that affects children and young adults. Mucinous carcinoma is a special type of breast cancer. Being a special atypical subtype of invasive carcinoma, it most frequently affects women of advanced age and represents 1 to 7% of all breast cancers. The reported case aims to show the rarity of the occurrence of desmoplastic medulloblastoma and mammary mucinous carcinoma in a young patient in a short period of time, in different sites, without direct anatomical attachment and without occurrence of metastasis. Initially, this patient had a desmoplastic medulloblastoma and was treated with lumpectomy and radiotherapy. After 13 months, the patient was diagnosed with a mucinous breast carcinoma, underwent mastectomy, adjuvant chemotherapy and is currently undergoing endocrinotherapy. We conclude, based on the metachronous characteristic of the neoplasia and clinical characteristics, that the patient is likely to have Li-Fraumeni syndrome, an autosomal dominant disease with mutation of the TP53 gene, which is the the main involved. Because the patient does not present all the characteristics of the phenotype of the syndrome, she can thus be classified as having Li-Fraumeni variant or Li-Fraumeni-like syndrome.

Resumo Diversos fatores desencadeiam o desenvolvimento de mutações genéticas que são responsáveis por originar uma neoplasia. O meduloblastoma é uma neoplasia cerebelar maligna e invasiva que acomete crianças e adultos jovens. O carcinoma mucinoso é um tipo de câncer de mama especial por ser um subtipo atípico de carcinoma invasivo, que acomete com maior frequência mulheres de idade avançada e representa entre 1 a 7% do total de neoplasias mamárias. O caso relatado tem como objetivo mostrar a raridade da ocorrência do meduloblastoma desmoplásico e carcinoma mucinoso mamário em uma paciente jovem em um curto período de tempo, em diferentes sítios sem ligação anatômica direta e sem ocorrência de metástase. Inicialmente, esta paciente possuía um meduloblastoma desmoplásico e foi tratada com tumorectomia e radioterapia. Após 13 meses, a paciente foi diagnosticada com carcinoma mucinoso de mama, sendo submetida a mastectomia, quimioterapia adjuvante e atualmente está sendo tratada com endocrinoterapia. Concluímos, com base na característica metacrônica da neoplasia e características clínicas, que a paciente apresenta a síndrome de Li-Fraumeni, doença autossômica dominante com mutação do gene TP53, que é o principal gene envolvido nesta síndrome. Por não apresentar as características completas do fenótipo da síndrome, a paciente pode assim ser classificada como portadora de uma variante da síndorme de Li-Fraumeni ou síndrome do tipo Li-Fraumeni.

Caracterização clínica e histopatológica da síndrome de Li-Fraumeni e síndrome Li-Fraumeni like em pacientes brasileiros / Clinical and histopathologic characterization of Li-Fraumeni syndrome and Li-Fraumeni like syndrome in Brazilian patients

INTRODUÇÃO: a Síndrome de Li-Fraumeni (LFS; OMIM#151623) é uma síndrome rara de predisposição hereditária ao câncer, de caráter autossômico dominante e de alta penetrância, relacionada a mutações germinativas no gene TP53. Os tumores típicos da LFS são sarcomas de partes moles e ósseos, leucemias, tumores do sistema nervoso central (SNC), tumores adrenocorticais e tumores de mama. No entanto, há uma variação no espectro tumoral de acordo com o genótipo. No Brasil, há uma alta prevalência da mutação germinativa p.R337H (presente em 0.3% da população do Sul e Sudeste) devido a um efeito fundador. O conhecimento do real espectro tumoral da síndrome associada a esta mutação fundadora ainda é objeto de discussão. PACIENTES E MÉTODOS: foram avaliados dados clínicos, retrospectivamente, a partir de prontuários médicos, de 247 pacientes com LFS e LFS portadores de mutações germinativas no gene TP53, atendidos no Departamento de Oncogenética do A.C.Camargo Cancer Center de 2001 a 2015. As características dos tumores apresentados pelos pacientes portadores de mutação (espectro tumoral, idade do diagnóstico do primeiro tumor e dos tumores subsequentes, tipo histológico dos tumores) foram comparadas entre o grupo de portadores da mutação p.R337H e o grupo de pacientes com as demais mutações patogênicas no gene TP53. As taxas de frequência das mutações (p.R337H versus outras mutações), assim como sexo (masculino e feminino) foram correlacionados com o status de óbito, desenvolvimento ou não de câncer, a idade do diagnóstico do primeiro câncer, tempo do primeiro câncer até aparecimento do segundo câncer, através do teste qui-quadrado ou teste exato de Fisher. Foi aplicado o Teste T para amostras independentes. O estimador de Kaplan-Meier e o teste de log rank foram utilizados para avaliar a influência das variáveis nos tempos de sobrevida global, tempo de aparecimento do primeiro câncer e tempo do primeiro câncer até aparecimento do segundo câncer. RESULTADOS: de 247 portadores de LFS incluídos no estudo, 193 pacientes eram portadores da mutação p.R337H. Deste total de 193 portadores da mutação p.R337H, 101 pacientes apresentaram câncer (52.3%) e 23,8% dos pacientes com câncer tiveram dois ou mais tumores ao longo da vida; enquanto dos 54 pacientes portadores de outras mutações no gene TP53 (21.9% da população total), 39 pacientes tiveram câncer (72.2%), p=0.009. A idade média de diagnóstico do primeiro câncer nos portadores da mutação p.R337H foi de 30.8 anos, comparada a 28.9 anos nos portadores de outras mutações no gene TP53, p=0.604. nos portadores da mutação p.R337H, o primeiro tumor também ocorreu em idade mais precoce nas pacientes femininas (média de 34.7 anos versus 50.4 anos, p<0.001). Em relação ao espectro dos tumores p.R337H na nossa população, câncer de mama e sarcoma de partes moles foram os tumores mais frequentes, seguidos de carcinoma adrenocortical, perfazendo 70,5% dos tumores apresentados nesta população. Nos portadores de outras mutações no gene TP53 , câncer de mama, sarcoma de partes moles, tumor de sistema nervoso central e sarcoma ósseo corresponderam a 69.3% de todos os tumores observados. Nossos dados revelam uma alta frequência de carcinoma adrenocortical (21.5%), carcinoma papilífero de tireoide (6.8%), adenocarcinoma de pulmão (4.9%) e carcinoma renal (4.3%) nos portadores da mutação p.R337H. Interessantemente carcinoma colorretal foi observado apenas nos portadores de outras mutações não-p.R337H. O sarcoma de partes moles nos portadores p.R337H mais frequente foi o leiomiossarcoma e a idade média de diagnóstico foi 46.8 anos; nos portadores das outras mutações, rabdomiossarcoma e leiomiossarcoma foram os subtipos mais frequentes e a idade média do diagnóstico foi 24 anos (p=0.001). A idade média de diagnóstico de câncer de mama foi 42.8 anos nos portadores da mutação p.R337H e 37 anos nos portadores das demais mutações no gene TP53 (p=0.029). O câncer de mama nos portadores das outras mutações apresentavam hiperexpressão de HER2 em 62.5% dos casos, comparado a 19% nos tumores de mama das portadoras da mutação p.R337H. CONCLUSÕES: nossos dados mostram um espectro tumoral distinto para os portadores da LFS com a mutação p.R337H. Esses dados podem ajudar a estabelecer um programa de rastreamento para esses portadores diferente do preconizado para os portadores das demais mutações no gene TP53.

INTRODUCTION: Li Fraumeni syndrome (LFS, OMIM #151623) is a rare autosomal dominant genetic disorder inherited by germline TP53 mutations. Carriers have a high lifetime risk of developing multiple early-onset childhood and adult cancers, including soft tissue and bone sarcomas, central nervous system (CNS) tumors, adrenocortical tumors (ACT), breast cancer and leucemia. However, tumor spectrum may have difference according to genotype. In Brazil, it is observed a high prevalence of a founder germline mutation p.R337H (present in 0.3% of the population in South and Southeast). The exact tumor profile associated to p.R337H carriers is unknown. PATIENTS AND METHODS: we have analyzed medical records of a cohort of 247 germline TP53 mutation carriers, members of Brazilian families who fulfilled LFS/LFL clinical criteria, between 2001 and 2015 from the Oncogenetics Department at A.C.Camargo Cancer Center, Sao Paulo, Brazil. Clinical data were retrospectively evaluated and the tumor characteristics of carriers (tumor spectrum, age at diagnosis, histological subtype) were compared between p.R337H carriers and carriers of other mutations in TP53 gene. The mutation status (p.R337H and other mutations) and gender (male and female) were correlated with death rate, cancer risk, age at diagnosis of cancer, interval between the first and the second cancer diagnosis, using the chi-squared test or Fisher's exact test. The T test was used for independent samples analysis. The Kaplan-Meier and log rank test were used to evaluate the influence of variables on overall survival, time and cancer the first time until onset of the second cancer. RESULTS: the study evaluated 247 patients with LFS, 193 patients had the mutation p.R337H. Among 193 p.R337H carriers, 101 patients had cancer (52.3%) and 23.8% of cancer-affected carriers had two or more tumors lifetime; whereas from 54 non-p.R337H mutation carriers, 39 patients were cancer-affected (72.2%), p = 0.009. The mean age at diagnosis of first cancer in p.R337H carriers was 30.8 years old (yo) compared to 28.9 yo in non-p.R337H mutation carriers, p = 0.604. In p.R337H patients, the first tumor occurred at an earlier age in female patients (mean age at 34.7 yo vs. 50.4 yo, p <0.001). Regarding the tumor spectrum in p.R337H carriers, breast cancer and soft tissue sarcoma were the most frequent tumors, followed by adrenocortical carcinoma (70.5% of the total of tumors). In non-p.R337H mutation carriers, breast cancer, soft tissue sarcoma, central nervous system tumor and bone sarcoma accounted for 69.3% of all tumors observed. Our results showed a high frequency of adrenocortical carcinoma (21.5%), papillary thyroid carcinoma (6.8%), lung adenocarcinoma (4.9%) and renal cell carcinoma (4.3%) in p.R337H patients. Interestingly, colorectal carcinoma was observed only in nonp.R337H mutation patients. Leiomyosarcoma was the most frequent sarcoma subtype in p.R337H carriers and the mean age at diagnosis was 46.8 yo; in non-p.R337H mutation patients, rhabdomyosarcoma and leiomyosarcoma were the most frequent subtypes and the mean age at diagnosis was 24 yo (p = 0.001). The mean age at diagnosis of breast cancer was 42.8 yo in p.R337H patients and 37 yo in non-p.R337H mutation patients (p = 0.029). The breast cancer in non-p.R337H mutation patients showed overexpression of HER2 in 62.5% of cases, compared to 19% in breast tumors from p.R337H carriers. CONCLUSIONS: our clinical cohort revealed a different tumor spectrum associated with p.R337H TP53 mutation. The major limitation in our study was the relatively small sample of nonp.R337H mutation carriers to compare with p.R337H carriers. Notwithstanding, our findings offer insight into exploring a distinct cancer screening protocol for p.R337H mutation carriers in Brazil.

Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome

BACKGROUND: Little is known of the mutation and tumor spectrum of Korean patients with Li-Fraumeni syndrome (LFS). Owing to the rarity of LFS, few cases have been reported in Korea thus far. This study aimed to retrospectively review the mutations and clinical characteristics of Korean patients with LFS. METHODS: TP53 mutation was screened in 89 unrelated individuals at the Samsung Medical Center in Korea, from 2004 to 2015. Six additional mutation carriers were obtained from the literature. RESULTS: We identified nine different mutations in 14 Korean patients (male to female ratio=0.3:1). Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel. The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys). The median age at the first tumor onset was 25 yr. Ten patients (71%) developed multiple primary tumors. A diverse spectrum of tumors was observed, including breast (n=6), osteosarcoma (n=4), brain (n=4), leukemia (n=2), stomach (n=2), thyroid (n=2), lung (n=2), skin (n=2), bladder (n=1), nasal cavity cancer (n=1), and adrenocortical carcinoma (n=1). CONCLUSIONS: There was considerable heterogeneity in the TP53 mutations and tumor spectrum in Korean patients with LFS. Our results suggest shared and different LFS characteristics between Caucasian and Korean patients. This is the first report on the mutation spectrum and clinical characteristics from the largest series of Korean LFS patients.

Pediatric cancer and Li-Fraumeni/Li-Fraumeni-like syndromes: a review for the pediatrician / Câncer pediátrico e síndrome de Li-Fraumeni/Li-Fraumeni- like: uma revisão para o pediatra.

Summary Introduction: cancer is the second leading cause of death in children between the ages of 0 and 14 years, corresponding to approximately 3% of all cases diagnosed in Brazil. A significant percentage (5-10%) of pediatric cancers are associated with hereditary cancer syndromes, including Li-Fraumeni/Li-Fraumeni-like syndromes (LFS/LFL), both of which are caused by TP53 germline mutations. Recent studies have shown that a specific TP53 mutation, known as p.R337H, is present in 1 in 300 newborns in Southern and Southeast Brazil. In addition, a significant percentage of children with LFS/LFL spectrum tumors in the region have a family history compatible with LFS/LFL. Objective: to review clinical relevant aspects of LFS/LFL by our multidisciplinary team with focus on pediatric cancer. Methods: the NCBI (PubMed) and SciELO databases were consulted using the keywords Li-Fraumeni syndrome, Li-Fraumeni-like syndrome and pediatric cancer; and all manuscripts published between 1990 and 2014 using these keywords were retrieved and reviewed. Conclusion: although LFS/LFL is considered a rare disease, it appears to be substantially more common in certain geographic regions. Recognition of population- specific risks for the syndrome is important for adequate management of hereditary cancer patients and families. In Southern and Southeastern Brazil, LFS/ LFL should be considered in the differential diagnosis of children with cancer, especially if within the spectrum of the syndrome. Due to the complexities of these syndromes, a multidisciplinary approach should be sought for the counseling, diagnosis and management of patients and families affected by these disorders. Pediatricians and pediatric oncologists in areas with high prevalence of hereditary cancer syndromes have a central role in the recognition and proper referral of patients and families to genetic cancer risk evaluation and management programs. .

Resumo Introdução: o câncer é a segunda principal causa de morte em crianças com idades entre 0 e 14 anos, correspondendo a cerca de 3% de todos os casos diagnosticados no Brasil. Um percentual significativo (5-10%) dos cânceres pediátricos são associados a síndromes hereditárias para câncer, incluindo Li-Fraumeni/Li-Fraumeni-like síndromes (LFS/LFL), causadas por mutações germinativas no gene TP53. Estudos recentes têm demonstrado que uma mutação específica em TP53, conhecida como p.R337H, está presente em 1 em 300 recém-nascidos no Sul e Sudeste do Brasil. Além disso, um percentual significativo de crianças com tumores do espectro LFS/LFL na região têm uma história familiar compatível com a síndrome. Objetivos: revisão dos aspectos clínicos relevantes da LFS/LFL por equipe multidisciplinar, com foco no câncer pediátrico. Métodos: o NCBI (PubMed) e SciELO foram consultados, usando as palavras-chave síndrome de Li-Fraumeni, síndrome de Li-Fraumeni-like e câncer pediátrico. Todos os artigos publicados entre 1990 e 2014 usando essas palavras- chave foram recuperados e revisados. Conclusão: apesar de LFS/LFL ser considerada uma doença rara, ela parece ser mais frequente em certas regiões. Reconhecer os critérios e condutas para identificação de pacientes em risco para LFS/LFL é fundamental para o manejo adequado dos pacientes com câncer hereditários e suas famílias. Devido à complexidade dessas síndromes, a abordagem multidisciplinar deve ser realizada. Pediatras e oncologistas pediátricos em áreas com alta prevalência de síndromes hereditárias de câncer têm um papel central no reconhecimento e encaminhamento adequado dos pacientes e famílias para programas de avaliação do risco de câncer genético e de gestão. .

Angiosarcoma in previously irradiated breast in patient with Li-Fraumeni syndrome. A case report / Angiossarcoma em mama previamente irradiada em paciente portadora da síndrome de Li-Fraumeni. Um relato de caso

CONTEXT: Li-Fraumeni syndrome is a rare disease with an autosomal dominant inheritance pattern and high penetrance that defines a 50% chance of developing cancer before the age of 30 years, including cases of breast sarcoma. Patients with this syndrome who require radiotherapy have an increased risk of developing secondary malignancies including angiosarcomas. CASE REPORT: This was a case report on a female patient with Li-Fraumeni syndrome. In October 2005, she was diagnosed with invasive ductal carcinoma of the right breast and underwent sectorectomy. She then received chemotherapy and adjuvant radiotherapy. Trastuzumab and tamoxifen were also part of the treatment. She recently sought care at our hospital, complaining of hyperemia and nodulation in the right breast, and underwent surgical resection that revealed epithelioid angiosarcoma. CONCLUSIONS: When genetic predisposition due to Li-Fraumeni syndrome is documented, the therapy should be adapted so as to minimize the risk. Thus, conservative surgical treatments should be avoided and mastectomy without radiation should be prioritized. In cases in which use of radiotherapy is justified, patients should be followed up intensively. .

CONTEXTO: A síndrome de Li-Fraumeni é doença rara que apresenta padrão de herança autossômica dominante e alta penetrância, definindo possibilidade de 50% no desenvolvimento de neoplasias antes dos 30 anos, incluindo nesses casos os sarcomas em mama. Pacientes portadoras dessa síndrome que requerem tratamento radioterápico têm risco aumentado de desenvolver neoplasias secundárias, incluindo os angiossarcomas. RELATO DE CASO: Este é um relato de caso de paciente feminina, portadora da síndrome de Li-Fraumeni. Em outubro de 2005, ela teve diagnóstico de carcinoma ductal invasor da mama direita, sendo submetida à setorectomia. Recebeu quimioterapia e radioterapia adjuvante; trastuzumabe e tamoxifeno também fizeram parte do tratamento. Recentemente, procurou atendimento em nosso serviço, com queixa de hiperemia e nodulação em mama direita, e foi submetida a ressecção cirúrgica que revelou angiossarcoma epitelioide. CONCLUSÕES: Quando a predisposição genética da síndrome de Li-Fraumeni está documentada, devese adequar a terapêutica a fim de minimizar riscos, evitando tratamentos cirúrgicos conservadores e priorizando a mastectomia sem radioterapia. Nos casos em que se justifica o uso de radioterapia, os pacientes devem ser acompanhados de forma intensiva. .

Mutacao do gene p53 induzindo predisposicao hereditaria ao cancer: relato de um caso da sindrome de Li-Fraumeni / P53 gene mutation inducing hereditary cancer predisposition: case report of Li-Fraumeni syndrome

A sindrome de Li-Fraumeni e uma sindrome de predisposicao familiar ao cancer, caracterizada pela...

Familial cancers

Although cancer is common in the general population, only a small proportion is thought to be due to highly penetrant cancer genes. Families with a highly penetrant cancer predisposing gene may be recognised by the presence of a high number of individuals within the family with a particular cancer type, or individuals with features associated with rare inherited cancers, such as retinal changes or multiple colonic polyps. It is likely that there are many other less penetrant genes, which, in combination with environmental influences, will confer a greater lifetime predisposition to cancers. These genes are currently being identified through epidemiological studies

Li-fraumeni syndrome in pediatric patients with soft tissue sarcoma or osteosarcoma

Family history of cancer and features of the Li-Fraumeni syndrome (LFS) were investigated in 42 patients with soft tissue sarcoma or osteosarcoma in a pediatric hospital in Mexico City, and compared with 42 non-cancer children. Six subjects with cancer were found among 204 first-degree relatives of cancer patients while there were none among 183 first-degree relatives of non-cancer children. In three families, the proband had two affected relatives, and the type of neoplasia as well as the age of onset suggested the clinical diagnosis of LFS. Our results show that 7.1 percent of our pediatric patients with soft tissue sarcoma or osteosarcoma may belong to LFS families. The authors encourage pediatric and adult oncologist to pay more attention to the history of cancer in nuclear families for eventual hereditary cancer syndrome identification and cancer prevention