Gender-Affirming Care in a Transgender Young Woman With Li-Fraumeni Syndrome: A Case Report.

The number of youths who identify with a gender different from their sex designated at birth is increasing. Youth account for about 4% of all cancer diagnoses in the United States. Some youths may want gender-affirming medical treatment, such as puberty blockers and/or hormone therapy, which may exacerbate cancer and/or increase cancer development risk. No studies assess the impact of estrogen-based treatment in gender-diverse youth with a history of Li-Fraumeni syndrome. This case report will discuss gender-affirming care and shared decision-making in a youth with a history of Li-Fraumeni syndrome and increased risk for breast cancer.

Correlation between choroid plexus carcinoma and Li-Fraumeni syndrome: implications of TP53 mutations and management strategies-a case-based narrative review.

BACKGROUND: Choroid plexus carcinomas (CPCs) are rare, aggressive grade 3 tumors of the central nervous system associated with Li-Fraumeni syndrome (LFS) in a notable percentage of cases due to TP53 germline mutations. Understanding the correlation between CPCs and LFS is crucial for tailored management strategies. However, distinguishing CPCs from benign choroid plexus papillomas (CPPs) remains challenging, relying largely on histologic features. This study aimed to explore the association between CPCs and LFS, emphasizing the impact of TP53 mutations on diagnosis, treatment, and clinical outcomes. MATERIALS AND METHODS: Scientific databases such as PubMed, Scopus, and Web of Science were systematically searched up to January 2024 using keywords related to CPCs, LFS, TP53 mutation, and central nervous system tumors. Selection criteria included studies investigating the link between CPCs and LFS, their management approaches, and genetic implications of TP53 mutations. Ten relevant studies were selected for analysis after screening titles, abstracts, and full-text articles. Data extraction focused on clinical, genetic, and management factors related to CPCs associated with LFS. RESULTS: The review highlighted the strong association (36%) between CPCs and LFS, primarily due to TP53 germline mutations. Studies emphasized the need for genetic testing in patients with CPCs, especially in pediatric cases, to identify LFS implications. Furthermore, the impact of TP53 mutations on treatment strategies was emphasized, recommending irradiation-sparing therapies due to inferior survival rates associated with radiotherapy in LFS patients with CPCs. Cases illustrated the challenges in diagnosing CPCs and the importance of immunohistochemistry and genetic testing for TP53 mutations. CONCLUSION: CPCs pose challenges in diagnosis and management, particularly in distinguishing them from benign tumors. The association with LFS, often due to TP53 germline mutations, underscores the importance of genetic testing for early detection and tailored treatment strategies. Irradiation-sparing therapies are recommended for LFS-associated CPCs to mitigate the risk of secondary malignancies. Comprehensive profiling of CPC patients, especially in pediatric cases, is crucial for early detection and management of potential secondary cancers associated with LFS.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Pediatric pituitary adenoma and medulloblastoma in the setting of p53 mutation: case report and review of the literature.

Li-Fraumeni syndrome is a cancer predisposition condition associated with various tumor types. We present the case of a 6-year-old boy who initially presented with a pituitary adenoma that was successfully treated with surgery. It ultimately recurred, requiring further surgical intervention followed by proton beam therapy. He later developed a medulloblastoma, and genetic testing revealed TP53 germline mutation. The patient underwent gross total resection of this medulloblastoma, followed by proton-based craniospinal irradiation and adjuvant chemotherapy. He remained disease-free 12 months after radiation and 7 months after chemotherapy. Current literature does not report pituitary adenoma as the initial central nervous manifestation in Li-Fraumeni syndrome. Early genetic testing should be considered in pediatric patients who present with such rare tumor types to help identify cancer predisposing conditions. Furthermore, as evidenced by our case, the management of multiple brain tumors in the pediatric population poses challenges. A multidisciplinary approach involving neurosurgery, pediatric oncology, pathology, and radiation oncology remains crucial to optimize patient outcomes.

Psychosocial interventions and needs among individuals and families with Li-Fraumeni syndrome: A scoping review.

Li-Fraumeni syndrome (LFS), a rare cancer predisposition syndrome caused by germline mutations in the TP53 gene, is associated with significant lifetime risk of developing cancer and warrants extensive and long-term surveillance. There are psychosocial impacts on individuals and families living with this condition, from the initial diagnosis throughout multiple stages across the lifespan, but these impacts have not been systematically reviewed and organized. The objective of this scoping review was to synthesize and characterize the literature on psychosocial screening and outcomes, educational needs, support services, and available interventions for patients and families with LFS. A systematic search of six databases was most recently conducted in August 2020: (PubMed/MEDLINE (NLM), EMBASE (Elsevier), Cochrane Library (Wiley), CINAHL (EBSCO), PsycINFO (OVID), and Web of Science (Clarivate Analytics). A total of 15 757 titles were screened, and 24 articles included. Several important themes were identified across studies: factors associated with TP53 genetic testing, LFS surveillance, psychological outcomes, and communication. Findings related to these themes were organized into age-specific categories (age agnostic/across the lifespan, childhood, adolescence and young adulthood, and adulthood).

Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.

[Report of Multidisciplinary Treatment for Sisters with Li-Fraumeni Syndrome].

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Case 1: A 22- year-old woman who was diagnosed with LFS by genetic test when she developed upper rectal cancer. Her rectal tumor with marked bilateral lateral lymph node dissection was successfully removed by low anterior resection with extensive lateral lymph node dissection. She underwent resection for ovarian metastasis followed by chemotherapy and radiotherapy but subsequently died by the disease 32 months postoperatively. Case 2(elder sister of Case 1): A brain tumor was identified in the left high frontal lobe to the parietal lobe because of consciousness disorder, after the genetic diagnosis of LFS. The brain tumor was successfully resected. Histological examination revealed diffuse astrocytoma(WHO grade Ⅱ). Local recurrence was observed 46 months later, and radiation therapy was performed. Six months have passed since radiation therapy, no exacerbation of local recurrence has been observed.

[Li-Fraumeni syndrome in adult patients with acute lymphoblastic leukemia].

BACKGROUND: LiFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome. AIM: Describe clinical observations of patients with acute lymphoblastic leukemia (ALL) and LFS and consider general issues of diagnosis and treatment of adult patients with LFS and ALL. MATERIALS AND METHODS: TP53 gene mutations were screened using Sanger sequencing in 180 de novo patients with Ph-negative (B- and T-cell) and Ph-positive ALL treated by Russian multicenter protocols (ALL-2009, ALL-2012, ALL-2016) at the National Research Center for Hematology, Moscow, Russia, and at the hematology departments of regional clinics of Russia (multicenter study participants). RESULTS: TP53 gene mutations were found in 7.8% (n=14) of de novo ALL patients. In patients, whose biological material was available TP53 gene mutational status was determined in non-tumor cells (bone marrow and peripheral blood during remission, bone marrow samples after allogeneic hematopoietic stem cells transplantation and in tissue of non-hematopoietic origin) for discriminating germline mutations. The analysis included 5 patients (out of 14 with TP53 mutations), whose non-tumor biological material was available for research. Germline status was confirmed in 4 out of 5 B-cell ALL (n=3), T-cell ALL (n=1) investigated patients. CONCLUSION: Practical value of the research is the observation that the greater part of TP53 gene mutations in patients with Ph-negative B-cell ALL are germinal and associated with LFS.

Li-Fraumeni Syndrome and Whole-Body MRI Screening: Screening Guidelines, Imaging Features, and Impact on Patient Management.

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.

Re-irradiation using proton therapy for radiation-induced secondary cancer with Li-Fraumeni syndrome: A case report and review of literature.

Li-Fraumeni syndrome (LFS) is a genetic disease that is hypersensitive to radiotherapy. Proton therapy (PT) was strongly recommended for pediatric and radiation-sensitive tumors. However, there is little information on PT for LFS. The patient was a 7-year-old girl with LFS who was diagnosed with radiation-induced right shoulder blade osteosarcoma and left chest wall malignant fibrous histiocytoma. Both tumors were in the area that had previously been irradiated (36-45 Gy by photon radiotherapy). Sixty-six GyE in 30 fractions was planned for both tumors. We set the clinical target to the minimum gross tumor volume. To comprehensively assess any adverse events, PT was conducted under hospital administration. Cisplatin was used as simultaneous combination chemotherapy. Although administration of granulocyte-colony stimulating factor was necessary for myelosuppression by chemotherapy, PT was completed without interruption. Acute radiation toxicity was observed as Grade 1 dermatitis. The dermatitis became exacerbated 2 weeks after PT but subsequently improved with conservation treatment alone. Twenty-three months after PT, magnetic resonance imaging showed an increase in the tumor on the right shoulder. A histological examination was not conducted as the family declined, but secondary cancer was suggested rather than recurrent osteosarcoma, as the tumor developed mainly from the soft tissue. Additional surgical treatment and radiotherapy were not indicated, and the patient died of tumor progression and sepsis caused by myelosuppression 27 months after undergoing PT. Up to 23 months after PT, there were no signs of Grade 2 or more late toxicities. This represents the first reported case of PT for a patient with LF to treat radiation-induced secondary cancer.

Health professionals' practice for young people with, or at risk of, Li-Fraumeni syndrome: An Australasian survey.

Li-Fraumeni syndrome (LFS), a rare cancer syndrome caused by pathogenic germline variants in TP53, has serious implications for adolescents and young adults (AYAs; aged 15-39 years). The early-onset and multi-organ cancer risk associated with LFS means health professionals must concurrently contend with the developmental needs of individuals who are diagnosed from a young age, and recent changes in practice due to advances in whole-body cancer surveillance. To help understand how current practice meets the developmental needs of AYAs with, or at risk of, LFS, we conducted a national online survey to explore the experiences of health professionals who care for this population in Australia and New Zealand. Forty-three respondents completed the survey (56% genetic counselors), one-third of whom had facilitated predictive TP53 testing for minors (n = 14/43, 33%). In hypothetical scenarios describing 15-year-olds eligible for predictive TP53 testing, respondents were more supportive of testing for emotionally mature compared to immature minors (p = .009); and more supportive of adolescent wishes compared to parental wishes for testing (p = .020) when families held discordant views on testing. Genetic health professionals were more likely than oncology health professionals to address psychological (p = .017) and information needs about reproductive options for LFS during consultations than to refer them on (p = .004). All respondents supported comprehensive risk management for LFS, but noted important medical, logistical, and psychosocial limitations for AYAs. This study offers valuable insight into developmentally appropriate practices of Australasian health professionals who care for AYAs with, or at risk of, LFS. These findings suggest they may foster the autonomy of minors undergoing predictive TP53 genetic testing and be supportive of new whole-body risk management guidelines.

[Li-Fraumeni syndrome]. / Li­Fraumeni-szindróma.

Li-Fraumeni syndrome is a rare genetic disorder predisposing the individual to multiple different cancer types, caused by a germline mutation of the TP53 or CHEK2 genes inherited in an autosomal dominant manner. We hereby describe the case of a family with Li-Fraumeni syndrome. An asymptomatic 40-year-old female was diagnosed with primary lung leiomyosarcoma (T3N0), adenocarcinoma (T1aN0), and inflammatory myofibroblastic tumor, which were surgically removed without further treatment. Twenty months later she underwent surgery for retroperitoneal liposarcoma and even though she received adjuvant chemotherapy, deceased shortly after. Due to family history, the patient underwent TP53 mutation testing, using peripheral blood genomic DNA, which identified a heterozygous, likely pathogenic missense mutation (c.722C>G p.Ser241Cys) in case of the mother and her son. Three years after the patient's death, her 17-year-old son was diagnosed with a 3.5 cm osteosarcoma of the right second rib, which was surgically removed, followed by adjuvant chemotherapy. However, despite treatment, he deceased after two years. Throughout four generations of the patient's family, 10 malignant tumors (stomach-, breast-, 2 lung-, and colon cancer, leukemia, leiomyosarcoma, liposarcoma and 2 osteosarcoma) were diagnosed with a mean age of 43.2 (13-70 years) years. The simultaneous appearance of primary lung leiomyosarcoma, inflammatory myofibroblastic tumor and adenocarcinoma in the same organ is extremely rare. When possible, surgical resection should be carried out. Genetic testing for TP53 is recommended when family history is suggestive of Li-Fraumeni syndrome. Prognosis remains poor. Orv Hetil. 2019; 160(6): 228-234.

Pediatric Case of Li-Fraumeni Syndrome Complicated with Supratentorial Anaplastic Ependymoma.

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.

Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations.

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.

Li-Fraumeni Syndrome-related Malignancies Involving the Genitourinary Tract: Review of a Single-institution Experience.

OBJECTIVE: To report a case of pelvic angiosarcoma in a 27-year-old man with Li-Fraumeni Syndrome (LFS) and evaluate the presentation and timeline of genitourinary (GU) tract involvement in LFS patients. METHODS: We retrospectively identified 39 LFS patients treated at our institution between 2000 and 2014; 7 (18%) had experienced a GU malignancy or an LFS-related malignancy involving the GU tract. Clinical characteristics, including dates of onset of first GU tract malignancies; pathologic findings; multimodal management; and familial history of LFS were reviewed. RESULTS: Median age at first malignancy was 14.0 years (interquartile range [IQR] 5.5-24.0). There was a slight male predominance (4 of 7). Median time between first malignancy and the malignancy involving the GU tract was 10.1 years (IQR 8.0-19.5). Six of the 7 patients (86%) had a form of sarcoma involving the GU tract; 1 developed adrenocortical carcinoma. The cancer pedigree of all patients showed LFS-associated malignancies in family members. Multimodal management included surgical resection in 6 patients with adjuvant chemotherapy or radiotherapy in 1 patient each. One patient received chemotherapy only. Following diagnosis of malignancy involving the GU tract, 5 of the 7 patients developed additional primary malignancies. At a median follow-up of 4.7 years (IQR 3.0-12.1), 2 patients are alive, 3 died of disease, and 1 died of unknown cause. One patient was lost at follow-up. CONCLUSION: Continued follow-up of LFS cancer patients aimed at the determination of optimal screening, management, and surveillance protocols is recommended and may result in longer survival expectations.

Successful Treatment of Recurrent Li-Fraumeni Syndrome-related Choroid Plexus Carcinoma.

The management of choroid plexus carcinoma (CPC) is challenging and multifaceted. Here, we discuss a 3-year-old girl with CPC and Li-Fraumeni syndrome who achieved full remission after surgery and chemotherapy, with radiation therapy spared. At recurrence, we used a novel, standard-dose cytotoxic chemotherapy regimen, focal proton radiation therapy, and targeted agents based on morphoproteomic analysis to achieve long-term survival. We highlight the rationale for our therapy at recurrence, as well as the risk-benefit analyses necessary in decision making for these patients. Our strategy may be effective in managing other patients with recurrent CPC and Li-Fraumeni syndrome.

Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy.

Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( Ptrend < .001) and breast cancer ( Ptrend < .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( Pdifference = .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( Ptrend = .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.