RESUMO
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant familial cancer syndrome caused by germline mutations of the tumor protein p53 gene (TP53), which encodes the p53 transcription factor, also known as the "guardian of the genome." The most common types of cancer found in families with LFS include sarcomas, leukemia, breast malignancies, brain tumors, and adrenocortical cancers. Osteosarcoma and rhabdomyosarcoma are the most common sarcomas. Patients with LFS are at increased risk of developing early-onset gastric and colon cancers. They are also at increased risk for several other cancers involving the thyroid, lungs, ovaries, and skin. The lifetime risk of cancer in individuals with LFS is greater than 70% in males and greater than 90% in females. Some patients with LFS develop multiple primary cancers during their lifetime, and guidelines have been established for screening these patients. Whole-body MRI is the preferred modality for annual screening of these patients. The management guidelines for patients with LFS vary, as these individuals are more susceptible to developing radiation-induced cancers-for example, women with LFS and breast cancer are treated with total mastectomy instead of lumpectomy with radiation to the breast. The authors review the role of imaging, imaging guidelines, and imaging features of tumors in the setting of LFS. ©RSNA, 2024 Supplemental material is available for this article.
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Síndrome de Li-Fraumeni , Guias de Prática Clínica como Assunto , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Humanos , Feminino , MasculinoRESUMO
BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.
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Síndrome de Li-Fraumeni , Metformina , Adulto , Humanos , Camundongos , Animais , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/prevenção & controle , Metformina/efeitos adversos , Qualidade de Vida , Mutação em Linhagem Germinativa , Imageamento por Ressonância Magnética , Predisposição Genética para Doença , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoAssuntos
Leiomiossarcoma , Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Leiomiossarcoma/complicações , Leiomiossarcoma/diagnóstico por imagem , Leiomiossarcoma/cirurgia , Veia Axilar , Proteína Supressora de Tumor p53/genética , Genes p53RESUMO
Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%-4% initial, 6%-10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes. PREVENTION RELEVANCE: The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.
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Síndrome de Li-Fraumeni , Adulto , Humanos , Criança , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Detecção Precoce de Câncer/métodos , Imagem Corporal Total/métodos , Imageamento por Ressonância Magnética , Genótipo , Predisposição Genética para DoençaRESUMO
BACKGROUND: In recent decades, whole-body magnetic resonance imaging (WB-MRI) has become established as the modality of choice for the diagnosis, staging, and follow-up of oncological diseases as well as for the screening of cancer predisposition syndromes, such as Li-Fraumeni syndrome. METHODS: As a comprehensive imaging modality without ionizing radiation, WB-MRI can be used repetitively and because of its excellent soft tissue contrast and high resolution provides early and precise detection of pathologies. This article discusses the technical requirements, some examination strategies and the clinical significance of typical findings of WB-MRI in patients with cancer predisposition syndromes.
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Síndrome de Li-Fraumeni , Imagem Corporal Total , Humanos , Imagem Corporal Total/métodos , Imageamento por Ressonância Magnética/métodos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Predisposição Genética para Doença , GenótipoRESUMO
ABSTRACT: A 17-month-old girl underwent FDG PET/CT to evaluate a right adrenal lesion, which showed abnormal 18 F-FDG avidity. In addition, an unexpected lesion with mild 18 F-FDG uptake was noted in the right anterior thoracic wall. Pathology demonstrated adrenocortical carcinoma in the right adrenal and rhabdosarcoma in both the left forearm and right anterior thoracic wall. Gene analysis confirmed the diagnosis of Li-Fraumeni syndrome. The present case emphasized FDG PET/CT value of showing simultaneously multiple lesions in Li-Fraumeni syndrome, especially in the early stage without the gene analysis result.
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Fluordesoxiglucose F18 , Síndrome de Li-Fraumeni , Criança , Feminino , Humanos , Lactente , Síndrome de Li-Fraumeni/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The Toronto protocol for cancer surveillance in children with Li-Fraumeni syndrome has been adopted worldwide. OBJECTIVE: To assess the diagnostic accuracy of the imaging used in this protocol. MATERIALS AND METHODS: We conducted a blinded retrospective review of imaging modalities in 31 pediatric patients. We compared imaging findings with the reference standards, which consisted of (1) histopathological diagnosis, (2) corresponding dedicated imaging or subsequent surveillance imaging or (3) clinical outcomes. We individually analyzed each modality's diagnostic performance for cancer detection and assessed it on a per-study basis for chest and abdominal regional whole-body MRI (n=115 each), brain MRI (n=101) and abdominal/pelvic US (n=292), and on a per-lesion basis for skeleton/soft tissues on whole-body MRI (n=140). RESULTS: Of 763 studies/lesions, approximately 80% had reference standards that identified 4 (0.7%) true-positive, 523 (85.3%) true-negative, 5 (0.8%) false-positive, 3 (0.5%) false-negative and 78 (12.7%) indeterminate results. There were 3 true-positives on whole-body MRI and 1 true-positive on brain MRI as well as 3 false-negatives on whole-body MRI. Sensitivities and specificities of tumor diagnosis using a worst-case scenario analysis were, respectively, 40.0% (95% confidence interval [CI]: 7.3%, 83.0%) and 38.2% (95% CI: 29.2%, 48.0%) for skeleton/soft tissues on whole-body MRI; sensitivity non-available and 97.8% (95% CI: 91.4%, 99.6%) for chest regional whole-body MRI; 100.0% (95% CI: 5.5%, 100.0%) and 96.8% (95% CI: 90.2%, 99.2%) for abdominal regional whole-body MRI; sensitivity non-available and 98.3% (95% CI: 95.3, 99.4) for abdominal/pelvic US; and 50.0% (95% CI: 2.7%, 97.3%) and 93.8% (95% CI: 85.6%, 97.7%) for brain MRI. CONCLUSION: Considerations for optimizing imaging protocol, defining criteria for abnormalities, developing a structured reporting system, and practicing consensus double-reading may enhance the diagnostic accuracy for tumor surveillance.
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Síndrome de Li-Fraumeni , Criança , Detecção Precoce de Câncer/métodos , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Compostos Radiofarmacêuticos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Li-Fraumeni syndrome (LFS) is a rare autosomal-dominant inherited syndrome containing a germline mutation in the TP53 gene, which predisposes to oncogenesis. Leukemia and tumors of the brain, soft tissues, breasts, adrenal glands, and bone are the most common cancers associated with this syndrome. Patients with LFS are very susceptible to radiation, therefore the use of whole-body MRI is recommended for regular cancer screening. It is important to recognize the common tumors associated with LFS on MRI, and it is also important to be aware of the high rate of false-positive lesions. CONCLUSION: Whole-body MRI is useful for the detection of cancer in patients who come for regular screening; however, it is associated with pitfalls about which the radiologist must remain aware.
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Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/terapia , Humanos , Imageamento por Ressonância Magnética , Imagem Corporal TotalRESUMO
OBJECTIVE. Whole-body MRI is a valuable tool in the surveillance of cancer predisposition syndromes (CPSs). Because it allows wide-FOV imaging without ionizing radiation, whole-body MRI is ideal in pediatric patients, enabling efficient assessment of different organ systems for multifocal disease. This article summarizes the use of whole-body MRI in pediatric patients with CPSs for earlier detection of malignancy, provides evidence where available, and offers guidance where lacking because of the rarity of CPSs. Protocol modifications and technique performance in specific CPSs are also considered. CONCLUSION. Whole-body MRI is the preferred imaging modality for surveillance of pediatric patients with CPSs, and the growing literature supports its importance in presymptomatic cancer detection.
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Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Carcinoma Adenoide Cístico/diagnóstico por imagem , Síndrome de Li-Fraumeni/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Imagem Corporal Total , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms. METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up. RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations. CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
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Síndrome de Li-Fraumeni/diagnóstico , Imageamento por Ressonância Magnética , Neoplasias/diagnóstico , Proteína Supressora de Tumor p53/genética , Adulto , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Fatores de Risco , Imagem Corporal Total , Adulto JovemRESUMO
INTRODUCTION: Pleomorphic myxoid liposarcoma is a rare and aggressive cancer seen in the pediatric population that has been previously associated with hereditable cancer disorders like Li Fraumeni syndrome. We present a case report and review of the relevant literature. CASE PRESENTATION: Pleomorphic myxoid liposarcoma presenting as a second primary tumor in a child with a strong family history for cancer led to diagnosis of Li-Fraumeni syndrome, which is associated with TP53 tumor suppressor gene inactivation. MANAGEMENT AND OUTCOME: The tumor was fully excised, but postoperative radiation was deferred to limit future radiation-induced tumorgenesis. DISCUSSION: Pleomorphic myxoid liposarcoma is rare but aggressive, and should prompt caregivers to test for potential hereditable cancer disorders. Li-Fraumeni syndrome is associated with early onset neoplasia and development of recurrent primary tumors. Its presence affects treatment decisions and methods of surveillance. Chemoradiation should be used judiciously in this population.
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Neoplasias Faciais/diagnóstico , Síndrome de Li-Fraumeni/complicações , Lipossarcoma Mixoide/diagnóstico , Criança , Neoplasias Faciais/etiologia , Neoplasias Faciais/terapia , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/patologia , Lipossarcoma Mixoide/etiologia , Lipossarcoma Mixoide/terapia , Imageamento por Ressonância Magnética , MasculinoRESUMO
Imaging is fundamental to diagnosis and management of pediatric patients with cancer and cancer predisposition syndromes (CPSs). Whole-body MRI has emerged as a versatile tool for pediatric oncologic imaging, with the potential to spare children from ionizing radiation imparted by conventional modalities such as CT and PET. Whole-body MRI also enables simultaneous high-resolution local-regional staging and wide field-of-view distant staging in the same imaging session, with superior evaluation of the brain, spine, liver, and marrow. Recent technical advances have reduced imaging times and enhanced image quality, with continued advances on the near horizon. Pulse sequences such as whole-body diffusion-weighted imaging have also broadened the range of diagnostic information obtainable. In addition, increasing identification of children with CPSs has compelled efforts to establish surveillance imaging strategies for affected individuals, with whole-body MRI playing a pivotal role in screening algorithms for several CPSs. In light of these emerging trends, a working knowledge of oncologic whole-body MRI applications and evolving CPS surveillance algorithms is vital to providers who participate in the care of pediatric patients affected by or predisposed to cancer. Recognizing both the strengths and limitations of whole-body MRI not only enables more thoughtful implementation but also improves the accuracy of image interpretation. ©RSNA, 2019 See discussion on this article by Khanna .
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Imageamento por Ressonância Magnética/métodos , Neoplasias/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/diagnóstico por imagem , Imagem Corporal Total/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Masculino , Oncologia , Estadiamento de Neoplasias/métodos , Neurofibromatoses/diagnóstico por imagem , Paraganglioma/diagnóstico por imagem , Pediatria , Feocromocitoma/diagnóstico por imagemAssuntos
Doença de Bowen/genética , Síndrome de Li-Fraumeni/genética , Segunda Neoplasia Primária/genética , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Biópsia , Doença de Bowen/diagnóstico por imagem , Doença de Bowen/cirurgia , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/cirurgia , Masculino , Segunda Neoplasia Primária/diagnóstico por imagem , Segunda Neoplasia Primária/cirurgia , Pele/patologia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/cirurgia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Li-Fraumeni syndrome is a genetic disease that is caused by mutation of the tumor suppressor gene TP53. Patients with this syndrome may develop multiple malignant neoplasms including brain tumors. We herein report the first case of Li-Fraumeni syndrome in which development of supratentorial anaplastic ependymoma led to difficulty in terms of selecting the optimal postoperative therapeutic protocol. CASE DESCRIPTION: A 7-year-old boy experiencing a convulsive attack was brought to our institute. He underwent surgical tumor resection, and magnetic resonance imaging of the head revealed a tumor-like lesion in the right parietal lobe. Although adjuvant radiotherapy was performed after total tumor resection, a focal recurrent lesion appeared soon afterward. We initiated chemotherapy with bevacizumab after resection of the recurrent lesion, but bevacizumab was unable to control tumor progression. At this writing, he remains bedridden and requires tube feeding and artificial ventilation. CONCLUSION: Since Li-Fraumeni syndrome is a genetic disease that is caused by mutation of the tumor suppression gene TP53, patients should generally not be treated with radiotherapy or alkylating agents that induce deoxyribonucleic acid damage. However, if the prognostic benefit of postoperative adjuvant therapies is thought to surpass the risk of long-term secondary cancer, it is appropriate to consider these therapies after consultation with the patient and family. Postoperative treatment protocols are controversial, and their role should be further explored in cases of Li-Fraumeni syndrome complicated with malignant gliomas.
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Ependimoma/complicações , Síndrome de Li-Fraumeni/complicações , Neoplasias Supratentoriais/complicações , Criança , Diagnóstico Diferencial , Gerenciamento Clínico , Ependimoma/diagnóstico por imagem , Ependimoma/patologia , Ependimoma/terapia , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/patologia , Síndrome de Li-Fraumeni/terapia , Masculino , Neoplasias Supratentoriais/diagnóstico por imagem , Neoplasias Supratentoriais/patologia , Neoplasias Supratentoriais/terapiaRESUMO
Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous hereditary syndrome with predominantly oncological manifestations, which is associated with mutations in the TP53, MDM2, and CHEK2 genes. The most common variant is a TP53 mutation. OBJECTIVE: To analyze the literature and present a clinical case of a patient with Li-Fraumeni syndrome and multiple anaplastic oligodendrogliomas of the brain. CLINICAL CASE: A 42-year-old male patient presented with complaints of headaches, word finding difficulty, memory loss, right hemianopsia, and generalized convulsive attacks. For 10 years, he underwent multiple interventions and chemotherapy courses for colon adenocarcinoma and recurrent B-cell lymphoma. MRI revealed multiple space-occupying lesions of the cerebraln hemispheres, which were located in the left temporo-occipital and right frontal regions. RESULTS: The patient underwent resection of multiple space-occupying lesions of the left temporo-occipital and right frontal regions. The postoperative period proceeded without complications. The histological diagnosis was WHO grade III anaplastic oligodendroglioma. The patient and one of his sons were detected with a R248W missense mutation in the TP53 gene. The patient underwent six courses of temozolomide chemotherapy. At a follow-up examination 20 months after surgery and chemotherapy, the patient's condition was satisfactory; he returned to work. Control MRI of the brain revealed no signs of continued tumor growth. CONCLUSION: An analysis of the literature and the clinical case indicate the success of multiple surgical interventions and chemotherapy courses performed for a long time in the patient with Li-Fraumeni syndrome manifested by colon adenocarcinoma, recurrent B-cell lymphoma, and multiple anaplastic oligodendroglioma of the brain. The patient had a good quality of life and returned to professional activity.
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Genes p53/genética , Síndrome de Li-Fraumeni/diagnóstico por imagem , Oligodendroglioma/diagnóstico por imagem , Adulto , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/cirurgia , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Oligodendroglioma/genética , Oligodendroglioma/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant disease that is associated with germline TP53 mutations and it predisposes affected individuals to a high risk of developing multiple tumors. In Brazil, LFS is characterized by a different pattern of TP53 variants, with the founder TP53 p.R337H mutation being predominant. The adoption of screening strategies to diagnose LFS in its early stages is a major challenge due to the diverse spectrum of tumors that LFS patients can develop. The purpose of this study was to evaluate two rounds of whole-body magnetic resonance imaging (WB-MRI) which were conducted as a screening strategy for LFS patients. METHODS: Over a 4-year period, 59 LFS patients underwent two rounds of WB-MRI. Each MRI was characterized as positive or negative, and positive cases were further investigated to establish a diagnosis. The parameters used to evaluate the WB-MRI results included: positive rate, number of invasive investigations of positive results, and cancer detection rate. RESULTS: A total of 118 WB-MRI scans were performed. Positive results were associated with 11 patients (9.3%). Seven of these patients (11.8%) were identified in the first round of screening and 4 patients (6.7%) were identified in the second round of screening. Biopsies were performed in three cases (2.5%), two (3.4%) after the first round of screening and one (1.7%) after the second round of screening. The histopathological results confirmed a diagnosis of cancer for all three cases. There was no indication of unnecessary invasive procedures. CONCLUSIONS: WB-MRI screening of LFS carriers diagnosed cancers in their early stages. When needed, positive results were further examined with non-invasive imaging techniques. False positive results were less frequent after the first round of WB-MRI screening.
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Síndrome de Li-Fraumeni/diagnóstico por imagem , Imageamento por Ressonância Magnética , Imagem Corporal Total , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development. MATERIALS AND METHODS: We first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice. We then exposed a total of 208 Trp53Δ/Δ, wt/Δ or wt/wt mice to clinical doses of X-rays or genotoxic or non-genotoxic chemotherapies. Tumour development was monitored using whole-body magnetic resonance imaging and pathological examination at death. RESULTS: X-rays and conventional chemotherapies, except mitotic spindle poisons, were found to be genotoxic in both p53 genotoxicity assays. Exposition to X-rays and the topoisomerase inhibitor etoposide, analysed as genotoxic anticancer treatment, drastically increase the tumour development risk in Trp53Δ/Δ and wt/Δ mice (hazard ration [HR] = 4.4, 95% confidence interval [CI] [2.2-8.8], p < 0.001*** and HR = 4.7, 95% CI [2.4-9.3], p < 0.001***, respectively). In contrast, exposure to the non-genotoxic mitotic spindle poison, docetaxel, had no impact on tumour development. CONCLUSIONS: This study shows that radiotherapy and genotoxic chemotherapies significantly increase the risk of tumour development in a LFS mice model. These results strongly support the contribution of genotoxic anticancer treatments to MPC development in LFS patients. Therefore, to reduce the risk of MPCs in germline TP53 mutation carriers, radiotherapy should be avoided whenever possible, surgical treatment prioritised, and non-genotoxic treatments considered.
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Antineoplásicos/toxicidade , Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni/genética , Neoplasias Primárias Múltiplas/genética , Proteína Supressora de Tumor p53/genética , Terapia por Raios X/efeitos adversos , Animais , Antineoplásicos/uso terapêutico , Predisposição Genética para Doença/genética , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/terapia , Imageamento por Ressonância Magnética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Primárias Múltiplas/etiologia , Fatores de Risco , Análise de Sobrevida , Irradiação Corporal Total/efeitos adversos , Terapia por Raios X/métodosRESUMO
BACKGROUND: Medulloblastomas are common childhood central nervous system tumors that are prone to leptomeningeal spread. Intramedullary dissemination is rare with very few case reports existing in the available literature. CASE DESCRIPTION: The authors here present a case of a 14-year-old boy with Li-Fraumeni syndrome and medulloblastoma who underwent surgical resection of spinal intramedullary spread. Histopathology revealed the tumor to be anaplastic medulloblastoma, same as the intracranial lesions. Genetic testing of the metastatic deposit revealed loss of functions mutations in SUFU, NOTCH3, and TP53 and TERC amplification. An improvement in ambulatory function at short-term follow-up was noted before the patient died of disseminated disease. CONCLUSIONS: Intramedullary metastasis of medulloblastoma remains a rare disease. Surgical resection might play a possible role in management in addition to radiation and chemotherapy.
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Neoplasias Cerebelares/cirurgia , Síndrome de Li-Fraumeni/cirurgia , Meduloblastoma/cirurgia , Neoplasias da Medula Espinal/cirurgia , Adolescente , Neoplasias Cerebelares/diagnóstico por imagem , Evolução Fatal , Humanos , Síndrome de Li-Fraumeni/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Masculino , Meduloblastoma/diagnóstico por imagem , Neoplasias da Medula Espinal/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgiaRESUMO
BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 gene and a high risk of childhood-onset malignancies. Cancer surveillance is challenging in pediatric mutation carriers given the anatomic spectrum of malignancies and young age of onset. Whole-body magnetic resonance imaging (WB-MRI) may provide an acceptable method for early cancer detection. PROCEDURE: We conducted a prospective feasibility pilot study of pediatric subjects (age < 18 years) with LFS to determine return rates for annual WB-MRI scan. Secondary objectives included characterization of incident cancers (and how they were detected). RESULTS: Forty-five WB-MRI scans in 20 subjects were performed over 5 years; two patients enrolled without subsequently undergoing scans. Eighty-nine percent of participants scanned (95% confidence interval: 67-99%) returned for second examinations. Fifty-five percent of participants required general anesthesia, which was well tolerated in all cases. Six patients required dedicated follow-up imaging. One participant required biopsy of a detected brain lesion; pathology demonstrated reactive gliosis. Another participant, with prior choroid plexus carcinoma, had a new brain lesion detected on clinical follow-up MRI not seen on WB-MRI 6 months prior. All other participants remain well (median: 3 years, range: 0.08-4 years). CONCLUSIONS: WB-MRI in pediatric subjects is a well-tolerated approach to cancer surveillance despite the need for general anesthesia in some patients. A large multicenter trial would determine true test characteristics and efficacy of this approach for early cancer detection in children at high cancer risk.
Assuntos
Síndrome de Li-Fraumeni/diagnóstico por imagem , Imageamento por Ressonância Magnética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Projetos Piloto , Estudos ProspectivosRESUMO
Individuals with Li-Fraumeni syndrome (LFS) have a significantly increased lifetime cancer risk affecting multiple organ sites. Therefore, novel comprehensive screening approaches are necessary to improve cancer detection and survival in this population. The objective of this study was to determine the diagnostic performance of whole body MRI (WB-MRI) and dedicated brain MRI screening as part of a comprehensive screening clinic called Li-Fraumeni Education and Early Detection (LEAD) at MD Anderson Cancer Center. Adult (≥21 year old) and pediatric (<21 year old) patients were referred to the LEAD clinic by healthcare providers or self-referred and screened at 6 month intervals. During the study period, 63 LFS individuals were seen in the LEAD clinic including 49 adults (11 male, 38 female) and 14 children (7 male, 7 female). Fifty-three of 63 potentially eligible individuals underwent baseline WB-MRI (41 adults and 12 children) with primary tumors detected in six patients, tumor recurrence in one patient and cancer metastases in one patient. Thirty-five of 63 patients (24 adults and 11 children) underwent baseline brain MRI with primary brain tumors detected in three individuals, also noted on subsequent WB-MRI scans. Three additional tumors were diagnosed that in retrospect review were missed on the initial scan (false negatives) and one tumor noted, but not followed up clinically, was prospectively found to be malignant. The high incidence of asymptomatic tumors identified in this initial screening (13%), supports the inclusion of WB-MRI and brain MRI in the clinical management of individuals with LFS.