Melanoma in patients with Li‑Fraumeni syndrome (Review)
- Authors:
- Published online on: November 24, 2021 https://doi.org/10.3892/etm.2021.10998
- Article Number: 75
Abstract
1. Introduction
Li-Fraumeni syndrome (LFS) is a cancer prone, autosomal dominant, hereditary syndrome (1). Patient with LFS have a very early onset of underlying neoplasia during life; 10-15% of all malignancies in the pediatric population are found associated with LFS in addition to more than 100 gene anomalies, including the TP53 gene (1,2). Starting from childhood, early diagnosis of brain cancer, leukemia in addition to sarcomas of the skeleton and soft tissue, and adrenocortical cancer have been reported (3). In young females, there is a higher risk of mammary cancer (1). This particular aspect needs to be differentiated from other gynecological cancers with a hereditary pattern such as Peutz-Jeghers syndrome, Lynch syndrome, BRCA1- and BRCA2-associated disease, and Cowden syndrome (4).
Specific protocols of screening, management and lifelong surveillance for LFS patients have been developed (5). A large study on 286 subjects carrying a TP53 mutation (from 107 families) showed a cumulative cancer incidence of 100% (by the age of 70 years), and 50% by the age of 46 (males) and 31 years (females). Women have the most increased incidence of malignancy after the age of 20 years (because of mammary cancer, with a cumulative incidence of 54% by the age of 70) while men exhibit a high incidence early during childhood and later during adulthood. The cumulative incidence (by the age of 70 years) for females and males was found to be 15 and 22% respectively for soft tissue sarcoma, 5 and 11% respectively for osteosarcoma, 6 and 19% respectively for central nervous system tumors; with a second tumor diagnosed after a median of a decade in almost half of patients (6).
2. Aim of the review
The present review was designed with an aim to introduce a practical overview of published data regarding LFS and associated malignancies focusing on melanoma. This is a brief narrative review of literature underling a PubMed research on LFS and associated malignancies, especially malignant melanoma (MM). Most of the published papers involving specific data on LFS and melanoma were found to be of a low level of evidence, mainly case reports or cases series, but also we found two retrospective studies. The perspective of approach was clinical and multidisciplinary. The inclusion criteria of the citations were full-length English papers that were recently published with the majority of the 61 articles published within the last three years. Due to the rarity of the topic, a heterogeneous level of statistical evidence was used in order to offer a real-life medical picture of the selected topic.
3. Genetic background: TP53 mutations
LFS is related to germline mutations of the TP53 gene (chromosome 17) with high penetrance. TP53 is a tumor-suppressor gene that encodes the p53 protein with a major role in apoptosis, DNA repair and cell cycle regulation (7). While germline mutations cause LFS, sporadic mutations are related to almost half of global cancers (mostly non-syndromic presentation), because the p53 protein in addition to p73 protein represent essential players in human body anticancer protection at the cellular level (8). The p53 protein is responsible for cell cycle function in order either to maintain adequate homeostasis or to induce cell cycle arrest thus causing cell death (9).
The mutation profile is a prognostic factor in associated malignancies; tumor heterogeneity being related to incomplete protein inactivation (7). Hotspot variant and truncating variants are correlated with a higher incidence of cancer and an earlier age at presentation (10). Dominant negative variant is generally recognized with an overall higher cancer risk (1). TP53 (R337H) mutation is particularly prevalent in Brazil where population clusters of pediatric adrenocortical carcinomas or sarcomas have been described (11). Not all TP53 carriers develop tumors through their entire lifespan, but those who do, are associated with a clinical picture of an 80-100% penetrance by the age of 70 years (12). Some aspects of the genotype-phenotype correlations are well known until present but there are still open issues (12). The timing of tumors in LFS includes the following: between birth and 15 years, adrenocortical carcinoma in association with choroid plexus carcinoma are prominent; between 16 and 50 years, breast cancers in females, sarcomas, astrocytoma, and leukemia are prominent; between 51 and 80 years, pancreatic carcinoma in both sexes and prostate cancer in males are prominent (12).
4. Tumorigenesis in Li-Fraumeni syndrome
We mention the importance of a general picture in LFS, which represents a standard multidisciplinary approach, both in terms of diagnosis and therapy (1). Yearly magnetic resonance imaging (MRI) is recommended for tumor screening (13). Whole-body sequences are mostly useful and, since the technique is not radiant, it is feasible in the pediatric population (14). In subjects with positive TP53 mutations, the protocol of imaging follow-up during childhood includes: annual whole body and brain MRI from the first year of life (and bi-annual abdominal ultrasound). In adults, yearly brain MRI should be implemented until the age of 50 years in addition to annual whole body MRI. For women, this should include annual mammary MRI until the age of 65-70 years (1).
LFS-related cancers, especially pediatric cancers are highly sensitive to radiotherapy (15). On the other hand, an alarming risk of radiation-induced second malignancy has been reported in carriers of TP53 germline mutations, as well as a higher risk in tumorigenesis caused by conventional genotoxic chemotherapy (16). For instance, the prevalence of secondary sarcoma is higher than that noted in the general population (15). It is essential to identify the TP53 status in patients with different malignancies who otherwise would be candidates for radiotherapy and genotoxic chemotherapy, because these therapeutic procedures should be avoided, if possible (1).
As mentioned, the large area of LFS-related tumorigenesis is extended as following. Osteosarcoma, the most frequent primary malignancy of the skeleton in children and teenagers and the third most frequent in adults, involves TP53 mutations in the majority of cases (17). RB1 mutations (retinoblastoma syndrome) are described in almost one-fifth of osteosarcoma cases, while other rarer syndromic circumstances involve Werner syndrome or Bloom syndrome (18).
Hereditary syndrome-related primary genitourinary rhabdomyosarcoma needs to be differentiated from DICER1 mutations, Noonan syndrome, Costello syndrome, neurofibromatosis type 1, and Beckwith-Wiedemann syndrome (19,20).
Since TP53 mutations represent an important cause of breast cancer before the age of 31 years, for cases with a positive TP53 mutation, annual screening should be performed as well as in TP53-positive patients who are survivors of mammary cancer (21). Overall, half of female patients with TP53 germline mutations present with breast cancer by the age of 70 years (22). On the other hand, in females presenting with a mammary malignancy at an early age and unknown genetic background, TP53 analysis should be assessed, especially if testing for BRCA1 and BRCA2 mutations is negative (23). A TP53 carrier, regardless of the full manifestation of LFS, has a 3 times higher risk of breast cancer when compared to the global population (except for BRCA1 and BRCA2 carriers) (24). Radiotherapy may be useful in breast cancer related to LFS or Li-Fraumeni-like syndrome, but the rate of radiotherapy-related malignancy represents a massive concern (25).
LFS is associated with a higher risk of tumors located in the central nervous system (such as astrocytoma, glioblastoma and choroid plexus carcinoma) and close surveillance is necessary (26). Loss of TP53 function and gain of function in mutant variants are both connected with brain cancers (27).
Hematological malignancies associated with LFS have also reported. These include leukemia of lymphoid type (acute lymphoblastic leukemia) and of myeloid type (acute myeloid or chronic myeloid leukemia), and myelodysplastic syndrome and less often lymphoma (28). The potential of inducing these disorders may be related to the actual therapy which is applied for some concurrent solid cancers (such as radiotherapy or certain types of chemotherapy) (29).
LFS has a dramatic impact on adrenocortical carcinoma incidence; 50-80% of subjects diagnosed with LFS during infancy have syndromic TP53 mutation, while 10% of adult cases have a genetic anomaly, either LFS or Lynch syndrome (30). A high index of suspicion is necessary in cases of children diagnosed with adrenal cancer and unknown family medical history; TP53 analysis is indicated under these circumstances (31,32).
5. Melanoma in patients with Li-Fraumeni syndrome
Patients with LFS have an increased lifetime cumulative rate of different familial cancers as mentioned before; yet the exact epidemiological data concerning skin cancers, especially MM, are limited (33). Generally, it is considered that melanoma is diagnosed less frequently in TP53 carriers when compared to the previously mentioned neoplasias, but more frequent when compare to the general population (33,34). Melanoma in the pediatric population with LFS has also been reported (34). Exceptional cases with multiple melanoma have been found, as well (35,36). In addition, pediatric Spitzoid melanoma which is not typically involved in syndromic associations, was reported in a young patient with TP53 mutation, also associated with choroid plexus carcinoma and myelodysplasic syndrome (37).
Atypical forms of melanoma have been reported with a very low level of evidence (38). A first case of mucosal melanoma was reported in a female of 21 years as a first presentation of LFS; hematologic malignancies were subsequently identified among other family members caring the TP53 mutation (39). Uveal MM has been described in a few cases (40). An analysis of LFS and POT1 gene anomalies was assessed and incidental diagnosis of melanoma was pointed out (41). A cases series on two 28-year-old twins with LFS found familial melanoma, suggesting that follow-up of moles based on dermoscopy and total-body photography is helpful for early recognition of melanoma in such cases (42). An unusual case of primary skin leiomyosarcoma was reported in 2018 in regards to a patient with TP53 mutation (loss of heterozygosity) presenting with LFS (43).
A retrospective Dutch study based on national registry data included 71 patients diagnosed with different skin cancers from 33 families with LFS; 59% of the subjects with skin cancers and LFS were females; the cumulative risk of skin cancers of these patients depending on age was 10.4% at 40 years, 25.2% at 60 years, and 44.6% at 70 years; the median age at diagnosis of the dermatological malignancies was 41 years, independent of other LFS-related cancers (44). In addition, by the age of 70 years, the cumulative risk for specific cancers was higher than the general population for the same geographic area: 12.6% for melanoma and 34.6% for basal cell carcinoma (44).
Another retrospective single center study on 89 subjects diagnosed between 2004 and 2015 with LFS showed a median age at first tumor diagnosis (regardless of the site and the type) of 25 years: 71% of individuals had primary multiple tumors and 2/89 patients had skin cancer, with a similar incidence for stomach, thyroid, lung carcinomas and leukemia in this mentioned cohort (45).
For the differential diagnosis of a patient with melanoma and tumors related to LFS including brain cancer, a case must be mentioned concerning melanoma-astrocytoma syndrome underlying CDKN2A tumor-suppressor gene mutations (chromosome 9) (46).
On the other hand, non-syndromic mutations of the TP53 gene have been reported in many melanoma studies, as well as the immunohistochemistry expression of p53 which generally is associated with a poor prognosis (47). A genetic analysis of 154 patients with metastatic disease from different carcinomas, adenocarcinomas and melanomas identified TP53 out of 790 mutations as the most common driven pathway correlated with metastatic potential and drug resistance (48). A study of 38 subjects with desmoplastic melanoma showed a correlation between the depth of invasion and TP53 gene mutation (P=0.002) (49). The p53 protein is related to skin tumorigenesis, in terms of both melanoma and non-melanoma, and it may represent a future target of standard therapy (50). For instance, S-petasin is a molecule that activates the p53 pathway inducing anti-proliferative effects in melanoma cell lines (51).
6. Future considerations
Overall, LFS represents a very challenging condition for patients and physicians, as noted in other multiple endocrine and non-endocrine tumor combinations based on a common genetic background (52,53). The timing of surgery, whether it includes adrenalectomy or melanoma removal, requires a multidisciplinary team of evaluation for improving the outcome but also the quality of life, not only the life span of the patients (54,55). Whether or not hormonally active tumors such as adrenal neoplasia and related neuroendocrine anomalies promote the growth of MM, as suggested by some studies, is still a matter of discussion (56,57). In addition, whether or not the phenotype of MM is more severe or atypical in relationship to the presence of other tumors and/or genetic anomalies is an open issue; on the one hand the patient has multiple associated tumors thus a more severe overall prognosis; but, on the other hand, since the patient has been diagnosed with a genetic condition, he/she may be re-assessed more frequently for serial check-ups (58,59). Various biomarkers such as the E-cadherin family or TIMP proteins are suggested in order to be used as prognostic factors for MM (60,61).
7. Conclusions
An important level of awareness involves skin cancer in LFS, particularly melanoma, despite the fact that it is not a part of the typical malignancy-containing picture. Patients with LFS seem to have a higher risk of developing MM when compared to the general population. The level of statistical evidence requires additional data to be conclusive. However, at least one dermatologic control is the first step in the multidisciplinary panel of surveillance of these patients; but in cases with benign and pre-malign pigmentations, serial dermatoscopy and full body photography are recommended for early melanoma detection in order to improve the prognosis and to reduce the overall malignancy burden.
Acknowledgements
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Funding
Funding: No funding was received.
Availability of data and materials
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Authors' contributions
FS drafted the manuscript and critically revised the final form. MCD is the corresponding author and revised the references. AP researched the literature, MC drafted the manuscript in light of the literature data, RCP researched the literature data, and AG approved the final form after review of the literature data. All the authors read and approved the final form of the manuscript for publication.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare they have no competing interests.
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