Orthopedic manifestations of Li-Fraumeni syndrome: Prevention and treatment of a polymorphic spectrum of malignancies

Abstract

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer predisposition syndrome characterized by a heightened risk of developing various malignancies at an early age. Emerging evidence suggests a correlation between LFS and orthopedic manifestations, underscoring the importance of orthopedic screening in individuals with this syndrome. Pediatric cancer is rare. It is estimated that more than 10%-15% of tumors are secondary to a pathogenic variant in a cancer predisposition gene. More than 100 cancer predisposition genes and their association with syndromes or isolated tumors have been identified. LFS is one of those who have been most widely described. Patients with this syndrome present a high risk of developing one or more tumors. Its knowledge enables the establishment of a follow-up protocol for the patient and affected family members, facilitating early detection of new tumors and reducing tumor and treatment-related morbidity and mortality. The primary objective of this invited editorial article is to provide a thorough review of the existing knowledge of LFS and its polymorphic spectrum of related malignancies, with a focus on aspects directly linked to orthopedic manifestations. Another objective is to offer an update on the most modern prevention, treatment and follow up guidelines that could be useful for the physicians dealing with this cohort of patients.

Key Words: Li-Fraumeni syndrome, Tumor protein P53, Orthopedic diseases, Osteosarcoma, Chondrosarcoma, Screening, Prevention

Core Tip: Modern screening approaches, including comprehensive genetic testing and advanced imaging modalities, offer promising avenues for early detection and intervention, ultimately improving outcomes in individuals with Li-Fraumeni syndrome (LFS). We advocate the need for internationally recognized and standardized guidelines for diagnosis, treatment and follow up of LFS and the need to form an international multidisciplinary network able to provide the highest level of expertise.

INTRODUCTION

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome first described by Frederick and Joseph in 1969. It is primarily caused by germline mutations in the tumor protein P53 (TP53), leading to an increased susceptibility to a broad spectrum of cancers, including sarcomas, breast cancer, brain tumors, adrenocortical carcinomas, and leukemia. While cancer is the hallmark of LFS, emerging evidence suggests a potential association between this syndrome and orthopedic manifestations, which necessitates further investigation and specialized screening approaches[1-3].

LFS is associated with an early onset in life, with the majority of cases occurring prior to the age of 46. The incidence of LFS is reported to range from 0.05% to 0.2% globally. These percentages make LFS as a truly rare condition[1-3].

Chompret criteria have been developed in order to make the LFS diagnosis. Patients should match at least one of the following criteria for the LFS diagnosis: (1) LFS diagnosis and associated malignancy before the age of 46; (2) Having 1 or more 1^st or 2^nd-degree relatives with LFS-associated malignancy before the age of 56; and (3) Having 1 or more 1^st or 2^nd-degree relatives with multiple tumors, independent from the age of onset[1]. These criteria are essential for identifying individuals who may have an inherited predisposition to LFS. It is thought that the most appropriate screening and application of preventive measures and treatments for LFS patients and their families could be allowed by the use of the above mentioned criteria, diagnosis strategies and genetic testing[1-3].

The primary objective of this invited editorial article is to provide a thorough review of the existing knowledge of LFS and its polymorphic spectrum of related malignancies, with a focus on aspects directly linked to orthopedic manifestations. Another objective is to offer an update on the most modern prevention, treatment and follow up guidelines that could be useful for the physicians dealing with this cohort of patients.

Pathogenesis of LFS

LFS is predominantly attributed to germline mutations in the TP53 gene, encoding the P53 protein, a critical regulator of cell cycle arrest, DNA repair, and apoptosis. The loss or dysfunction of P53 function disrupts cellular homeostasis, facilitating the accumulation of genetic alterations and predisposing individuals to cancer development[4].

During the past few years, a huge progress has been achieved with regards to new information. In fact, numerous genes that were associated with osteosarcoma and its clinical disease progression have been further studied and identified. These genes can be divided into subgroups: Self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue evasion and metastasis. Despite the fact that the full understanding of the process of osteosarcoma is still not fully clear, this new information might have the potential to improve the care for this cohort of patients in the future[5].

Clinical variability is commonly seen in LFS. Phenotypic heterogeneity is present among different families affected by the same pathogenic variant in the TP53 gene and among members of the same family. However, causes of this huge clinical spectrum have not been studied in depth. The real causes for this clinical heterogeneity are not clearly known yet; possible reasons should be sought among the different types of TP53 mutations that are involved in LFS[6].

Few studies have concluded that the general sex-specific P53 effect model was the most plausible model and that sex is not a predisposing factor for malignant cancer development in subjects carrying mutations.

However, the exact mechanisms underlying the diverse cancer spectrum observed in LFS remain incompletely understood, highlighting the complexity of this syndrome's pathogenesis and the need for further high levels of evidence in research[7,8].

Correlation between LFS and orthopedic diseases

Recent studies have elucidated a potential association between LFS and orthopedic manifestations, particularly osteosarcoma and chondrosarcoma. Osteosarcoma, a primary malignant bone tumor arising from osteoblasts, has been reported at an increased frequency in individuals with LFS, suggesting a predisposition to skeletal neoplasms.

Although the prognosis, diagnostic process, treatments and quality of life of patients with osteosarcoma were improved significantly during the past few years, the pathogenesis and etiology of this disease is still unclear. However, several etiologic agents have already been identified due to intense research and interest in the field.

Several chemical agents such as beryllium, viruses such as Finkel-Biskis-Jenkins murine osteosarcoma virus, a virus-induced osteosarcoma named after its discoverers (Finkel, Biskis, and Jinkins), subsequently found to contain the src-oncogene, and radiation were found to be among possible significant inducers of osteosarcoma. Less significant factors may include: Paget's disease, electrical burn and trauma. In the last few years, researchers have shown that an increased risk of osteosarcoma is carried by patients with hereditary diseases such as Rothmund-Thomson syndrome, Bloom syndrome, and LFS[5,9,10].

Recent studies have demonstrated the familial association of osteosarcoma. A higher-than-expected frequency of pathogenic or likely pathogenic variants has been observed in the LFS-associated gene, TP53, as well as in genes not traditionally associated with osteosarcoma, such as CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX[5,9,10].

The above concepts and considerations should drive the clinicians towards the belief that it is not just essential to search and identify genetic mutations in patients affected by osteosarcoma (osteosarcoma is a sentinel cancer in LFS), but it is paramount to prioritize early sarcoma detection in individuals with a family history of LFS or those diagnosed with LFS.

Similarly, to osteosarcoma, chondrosarcoma (characterized by the malignant transformation of cartilaginous tissue) has been documented in LFS cohorts, albeit with less frequency[11,12].

Approximately 27% of TP53 mutation carriers develop soft-tissue sarcomas (frequently rhabdomyosarcomas, but also liposarcomas or pleiomorphic sarcomas have been diagnosed)[13]. Studies have shown that greater than 5% of pediatric patients with rhabdomyosarcomas may have germline TP53 mutations. This discovery may help to increase suspicion of LFS among patients with these tumors[14-16].

These tumors of mesenchymal origin may arise from the skeletal muscle and can invade the adjacent neurovascular bundles. Although iso- to hypointense on T1-weighted imaging, they are either homogeneously or heterogeneously hyperintense on T2-weighted imaging with areas of necrosis and intrinsic soft-tissue signal intensity. Prominent flow voids and areas of hemorrhage have also been typically reported. Moreover, marked enhancement on contrast-enhanced T1-weighted imaging is considered among the radiological characteristics of these tumors[16-19].

These findings emphasize the importance of vigilant orthopedic monitoring in individuals with LFS. This proactive approach aims to enable early detection and intervention for diagnosing sarcomas at the earliest stage possible, and potentially implementing preventive strategies for patients with a family history or diagnosis of LFS.

MODERN SCREENING APPROACHES FOR PREVENTION

The autosomal dominant inherited LFS increases the lifetime risk of developing a malignancy to almost 100%. Although breast cancer, central nervous system tumors and sarcomas are particularly common, tumors can ultimately occur almost anywhere in the body. As causal therapy is not available, it seems that the only strategy able to improve prognosis is early cancer detection. In fact, current cancer surveillance recommendations include a series of examinations including genetic analysis and regular imaging that must be planned and carried out since birth[20].

Advancements in genomic technologies have revolutionized the screening and management of hereditary cancer syndromes, including LFS. Comprehensive genetic testing for TP53 mutations enables early identification of at-risk individuals, facilitating personalized risk assessment and tailored surveillance strategies. However, little information is available about TP53 pathogenic variants or phenotypes for LFS patients, making it difficult to provide precise genetic counseling with regard to long-term cancer risk[21-24].

It has been reported that significant factors able to influence the providers’ decision to offer TP53 testing are linked to the list of potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage[25].

Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, it could be very difficult to identify the patients that would require a genetics evaluation. The sarcoma clinic genetic screening questionnaire proved to be an efficient tool for identifying patients who would benefit most from a genetic evaluation. The tool allowed us to identify high-risk families fitting the criteria for Li-Fraumeni-like syndrome and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers[26].

Furthermore, advanced imaging modalities such as whole-body magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) offer sensitive methods for detecting occult tumors and monitoring disease progression in LFS patients. The most recent internationally accepted guidelines include an annual whole-body MRI among their recommendations in order to provide the most adequate screening for cancer patients carrying germline TP53[27].

Due to the wide range of tumor entities that can occur in individuals affected by LFS, a sensitive detection requires imaging of various tissue contrasts; however, because life-long screening is potentially initiated at a young age, this requirement for comprehensiveness must be balanced against the presumed high psychological burden associated with frequent or invasive examinations. It is well known that an increased radiation exposure could lead to a secondary increased risk of secondary tumors. Therefore, the need and use of CT and X-ray exams should be avoided as long as possible[28].

The use of annual whole-body MRI, given as propriety of not causing any radiation to the patients, is the exam of choice for this cohort of patients. However, due to the rarity of the syndrome, expertise is sometimes lacking and whole-body MRI examinations are performed heterogeneously and sometimes with limited diagnostic quality. Optimization and standardization of MRI protocols should therefore be studied and implemented. Moreover, the need for an intravenously administered contrast agent has not been conclusively clarified despite its high relevance[27,28].

After reviewing the most up to date literature and having discussed the above aspects, we believe that it is of utmost importance to form an international multidisciplinary network able to provide the highest level of expertise and integrate the studied modalities (genetic and radiological aspects) into routine screening protocols in order to achieve the earliest possible diagnosis and plan the most appropriate treatment course for all LFS patients. These future prospective holds promise for mitigating the morbidity and mortality associated with LFS-associated malignancies, including orthopedic tumors. To close the loop, we advocate the need for internationally recognized and standardized guidelines for diagnosis, treatment and follow up of LFS.

TREATMENT CHALLENGES

LFS is a rare inherited disease characterized by the early onset of multiple primary malignant tumors. Sarcomas account for more than 30% of all malignant tumors occurring at pediatric ages. Furthermore, it was shown that the rates of second cancer were higher in childhood cancer survivors[27,29,30].

The most difficult aspects with regards to orthopedic diseases related to LFS are related to the fact that LFS is a rare inherited disease characterized by the early onset of multiple primary malignant tumors. Unfortunately, it can happen that a patient is referred to a specialist center when they already have synchronous skeletal tumors. This situation has led to difficulties for the medical team in diagnosing malignancy and determining suitable surgical treatments, ultimately resulting in a poor prognosis for this group of patients[25,27,28-30].

It has been clearly shown that a multidisciplinary approach for diagnosis and treatment in reference centers improves survival of sarcoma patients. Therefore, early referral to a reference center is always advocated as soon as the suspicion of LFS is raised, possibly without having made any surgical intervention and prognosis[26-30].

Appropriate imaging screening is essential to plan the best treatment algorithm. The frequent discovery of multiple lesions after radiological follow up appointments with MRI scans highlights the importance of performing whole-body MRIs for the patients with germline TP53 mutations[26-30].

The discovery of multiple lesions whilst performing investigations on suspected LFS cases raises the problem of the surveillance of patients with germline TP53 mutations. Performing an appropriate cancer screening for these patients is truly challenging, mainly because of the very wide spectrum of cancer linked to TP53 mutations[1].

The treatment of the orthopedic diseases related to TP53 mutations is strictly related to the type of pathology. Malignant sarcomas should be treated in specialized centers according to the latest international guidelines. Consequently, a summary or algorithm with regards to LFS treatment cannot be drawn as every sarcoma has specific characteristics (particularly anatomical), and the surgical management strictly depends on these aspects. At the same time, radiotherapy, chemotherapy and any other cancer treatments are specifically planned on the basis of the type, stage, location of sarcoma and all other specific characteristics.

CONCLUSION

LFS represents a complex hereditary cancer predisposition syndrome characterized by a heightened risk of developing diverse malignancies, including those with orthopedic manifestations.

Emerging evidence suggests a potential correlation between LFS and skeletal neoplasms, emphasizing the importance of specialized orthopedic screening in affected individuals. Modern screening approaches, including comprehensive genetic testing and advanced imaging modalities, offer promising avenues for early detection and intervention, ultimately improving outcomes in individuals with LFS.

We advocate for internationally recognized and standardized guidelines for the diagnosis, treatment, and follow-up of LFS, emphasizing the importance of establishing an international, multidisciplinary network capable of delivering the highest level of expertise.

Further research is warranted to elucidate the mechanistic underpinnings of LFS-associated orthopedic diseases and optimize screening strategies for prevention and early intervention.