ENDOCRINE SOCIETY
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Metastatic Pheochromocytoma in a Patient With Li-Fraumeni Syndrome
Sotiris Loizidis, 10 Christiana Matthaiou,1 Efrosini lacovou,2 Karel Pacak, 3,4[D and Ashley Grossman 5,6,7 İD
1Medical Oncology Department, Bank of Cyprus Oncology Center, Nicosia 2006, Cyprus
2Independent Histopathology Services, ECCLabs-IHCS, Nicosia 2020, Cyprus
3Center for Adrenal Endocrine Tumors, AKESO, Prague 155 00, Czech Republic
4Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20847, USA
5Centre for Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
6Green Templeton College, University of Oxford, Oxford 0X2 6HG, UK
7ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK
Correspondence: Sotiris Loizidis, MD, Bank of Cyprus Oncology Center, Acropoleos Avenue 32, Strovolos, Nicosia 2006, Cyprus. Email: Sotiris.Loizides@bococ.org.cy.
Abstract
Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome caused by genomic alterations in the tumor protein p53 (TP53) gene. The lifetime risk of developing cancer is very high, and carriers of germline TP53 pathogenic variants must be closely monitored starting from a young age. LFS is particularly associated with specific tumors, such as breast cancer, soft tissue and bone sarcomas, primary central nervous system cancers, acute leukemia, and adrenocortical carcinoma. Despite its association with a broad spectrum of malignancies, pheochromocytoma/ paraganglioma (PCC/PGL) is an unusual manifestation of LFS and has only rarely been reported. Here, we present a case of a 57-year-old female patient who is a carrier of a deleterious germline TP53 pathogenic variant and developed a PCC; several years later, she had lung and bone lesions compatible with metastatic PCC. We also discuss the most recent literature regarding the genomic landscape of PCCs/PGLs and their pathogenesis in connection with TP53 pathogenic variants.
Key Words: pheochromocytoma, paraganglioma, Li-Fraumeni syndrome, genetics, P53, molecular clusters
Abbreviations: DOTATATE, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate; GATA3, GATA-binding protein 3; IHC, immunohistochemistry; LFS, Li-Fraumeni syndrome; MRI, magnetic resonance imaging; PCC, pheochromocytoma; PET/CT, positron emission tomography/computer tomography; PGL, paraganglioma; PRRT, peptide receptor radionuclide therapy; WBMRI, whole-body magnetic resonance imaging.
Introduction
Li-Fraumeni syndrome (LFS) is a rare inherited cancer syndrome with an autosomal hereditary pattern. It was first described in 1969, while approximately 20 years later, germ- line tumor protein p53 (TP53) pathogenic variants were es- tablished as the cause of the syndrome [1, 2]. Individuals with LFS bear a markedly increased lifetime risk for neo- plasms such as early-onset breast cancer, soft tissue and bone sarcomas, primary central nervous system cancers, acute leukemia and adrenocortical carcinoma, requiring early and strict lifetime surveillance [3]. The TP53 gene, often referred to as the “guardian of the genome,” is dormant under physio- logical conditions. Cellular stress signals enable the binding of p53 protein to DNA, activating genes responsible for DNA re- pair, cycle arrest, and apoptosis, aiming to restore normality [4]. This safety brake is abolished by malfunctioning forms ☒ of the p53 protein, rendering cells highly vulnerable to DNA damage, ultimately leading to a cascade of tumorigenic events. Most LFS cases are inherited in an autosomal-dominant pattern; however, 7% to 20% of cases are attributed to de novo
mutations or mosaicism [5]. Developing a pheochromocytoma/ paraganglioma (PCC/PGL) represents a rather unusual pres- entation in TP53 carriers. We report a female patient with a germline TP53 pathogenic variant who developed metastatic PCC, and we discuss the current literature on this rare situation.
Case Presentation
A 57-year-old woman with LFS was under surveillance at our center. Her past medical history was remarkable for type 2 dia- betes mellitus, hypertension, and various malignancies. In 2009, she was diagnosed with papillary thyroid cancer (pT1bN0) and treated with near-total thyroidectomy followed by radioactive iodine therapy. In 2014, a 10-cm asymptomatic adrenal mass was incidentally discovered. Magnetic resonance imaging (MRI) of the abdomen suggested a pheochromocytoma, while suspicious para-aortic lymphadenopathy was noted. The pre- operative hormonal profile for catecholamine hypersecretion was negative. The patient underwent surgery, revealing a 9-cm well-circumscribed mass composed of large polygonal cells
arranged in nests (Zellballen pattern), a low proliferation index (Ki-67=1%-3%), rare mitoses (<2 mitoses/10 high-power fields), absence of necrosis, and low cellularity. Three lymph no- des were negative for metastases. Immunohistochemistry (IHC) was positive for synaptophysin, chromogranin A, S100, and GATA-binding protein 3 (GATA3). The pathology features were consistent with PCC (pT2N0). The Pheochromocytoma of the Adrenal gland Scaled Score (PASS) was 2, and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) had a score of 1, both indicating a low probability for metastasis. In 2015, she was diagnosed with high-grade ductal carcinoma in situ (DCIS) of the left breast. She underwent a partial mastectomy followed by radiation ther- apy and initiated adjuvant endocrine treatment with tamoxifen. A few months later, multiple lesions were identified in the left breast, and a subsequent biopsy showed an invasive breast carcinoma (triple-negative breast cancer). She underwent a left mastectomy and axillary lymph node removal [pT2(m)N1] followed by adjuvant chemotherapy. The presence of multiple malignancies prompted targeted genetic testing (Sanger sequencing) for BRCA1/2 and TP53 gene alterations. Testing revealed a substitution in exon 6 (c.743G>A) of the TP53 gene, resulting in arginine substitution by glutamine at codon 248 (p.Arg248Gln). This missense mutation represents an established pathogenic variant, and the patient was placed on a surveillance program [6]. In 2018, she underwent a prophylactic right mastectomy. Her daughter and 2 sisters tested negative for the TP53 mutation, while her parents have not been assessed due to their advanced age. Her family history includes only one cancer case: her niece, with an un- known genetic background, was diagnosed with dermatofibro- sarcoma protuberans.
Diagnostic Assessment
In 2023, her annual whole-body MRI (WBMRI) showed suspi- cious lung lesions warranting further investigation (Fig. 1A). A subsequent fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computer tomography (PET/CT) scan
revealed multiple bilateral lung nodules (Fig. 1B). Following the imaging results, a CT-guided biopsy demonstrated infiltration by nests of tumor cells with eosinophilic cytoplasm and no mitot- ic activity. The IHC was positive for GATA3 and the neuroendo- crine markers chromogranin A and synaptophysin, and negative for cytokeratin 7 (CK7), anti-cytokeratin 5.2 (CAM 5.2), cyto- keratin AE1/3, cytokeratin 5/6 (CK5/6), thyroid transcription factor 1 (TTF-1), tumor protein 63 (p63), and estrogen receptor (ER). These findings were compatible with metastatic PCC (Fig. 2). Given the neuroendocrine nature of the neoplasm, a gallium-68 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (68Ga-DOTATATE) PET/CT scan was performed. It confirmed the presence of somatostatin receptor-expressing tumor tissue in the lungs and in the first lum- bar vertebrae (L1) (Fig. 1C and 1D). Clinically, the patient did not report any signs or symptoms due to excessive catecholamine secretion. A 24-hour urine collection for fractionated metanephr- ine, normetanephrine and 3-methoxytyramine was ordered, and the results were within normal limits (Table 1). Moreover, new germline testing was performed using a next-generation sequen- cing (NGS) assay (NextSeq 2000, Illumina, Inc.), interrogating a broad spectrum of genes related to PCCs/PGLs (EGLN1, FH, MAX, MEN1, NF1, RET, SDHA, SDHA2, SDHB, SDHC, SDHD, TMEM127, VHL). Testing was negative for any germ- line mutations other than TP53. The tissue sample was tested for additional somatic mutations (NextSeq 2000, Illumina, Inc.) and copy number variations (MLPAR, MRC Holland) with negative results.
Treatment
Given the absence of symptoms and signs and no evidence of cat- echolamine overproduction, the patient continued with follow- up and strict surveillance. A few months later, a new 24-hour urine test showed an increase in metanephrine levels, leading to the decision to start the patient on subcutaneous lanreotide auto- gel, 120 mg monthly. A WBMRI did not demonstrate any radiological disease progression. Subsequent repeat testing indi- cated a further rise in 24-hour urinary metanephrine levels,
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accompanied by blood pressure dysregulation. Antihypertensive therapy was modified to include doxazosin, 2 mg daily.
Outcome and Follow-Up
The patient continues to be closely monitored for signs and symp- toms of catecholamine excess. At present, she is asymptomatic, and her blood pressure is well-controlled. She undergoes regular WBMRI scanning; in due course, 68Ga-DOTATATE PET/CT will be repeated. In case of disease progression, further treatment options include radioisotope therapy with peptide receptor radio- nuclide therapy (PRRT) or iodine-131 meta-iodobenzylguanidine (131I-MIBG), systemic chemotherapy (cyclophosphamide-
vincristine-dacarbazine, or temozolomide monotherapy), and molecular targeted therapy (cabozantinib, sunitinib).
Discussion
PCCs/PGLs are rare neuroendocrine tumors arising from the adrenal medulla or extra-adrenal paraganglia. They are in- creasingly being discovered incidentally and predominantly produce catecholamines responsible for their symptomatol- ogy [7]. According to the latest World Health Organization (WHO) classification, virtually all PCCs/PGLs have metastat- ic potential, and the terms benign and malignant are no longer advised [8].
| Urine catecholamines | Results (SI units) | Normal range (SI units) |
|---|---|---|
| First 24-hour urine collection (November 2023) | ||
| Metanephrine | 62 µg/24 hours (314.3 nmol/day) | 45-290 µg/24 hours (228.1-1470.3 nmol/day) |
| Normetanephrine | 112 µg/24 hours (611.3 nmol/day) | 75-400 µg/24 hours (409.3-2183.2 nmol/day) |
| Dopamine | 68 µg/24 hours (443.9 nmol/day) | 65-400 µg/24 hours (424.3-2611.2 nmol/day |
| Second 24-hour urine collection (May 2024) | ||
| Metanephrine | 191 µg/24 hours (968.4 nmol/day) | 45-290 µg/24 hours (228.1-1470.3 nmol/day) |
| Normetanephrine | "913 µg/24 hours (4983.1 nmol/day) | 75-400 µg/24 hours (409.3-2183.2 nmol/day) |
| Dopamine | 73 µg/24 hours (476.5 nmol/day) | 65-400 µg/24 hours (424.3-2611.2 nmol/day) |
| Third 24-hour urine collection (October 2024) | ||
| Metanephrine | "522 µg/24 hours (2646.5 nmol/day) | 45-290 µg/24 hours (228.1-1470.3 nmol/day) |
| Normetanephrine | "1600 µg/24 hours (8732.8 nmol/day) | 75-400 µg/24 hours (409.3-2183.2 nmol/day) |
Abbreviation: SI, Système International.
“Abnormal values are shown in bold font.
| First author, year of publication [reference] | Demographics: age, gender | Type (PCC/ PGL), stage | Catecholamine phenotype | TP53 mutation, classification |
|---|---|---|---|---|
| Hu et al., 2016 [13] | 3 yo, female | PCC, local | NA | c.730G>A; p. (Gly244Ser), exon 6, PV |
| Gniado et al., 2020 [14] | 39 yo, male | PCC, metastatic | NMN + MN | c.743G>A; p. (Arg248Gln), exon 6, PV |
| Seo et al., 2020 [15] | 43 yo, female | PGL, local | NMN + MN | c.566C>T; p. (Ala189Val), exon 6, VUS |
| Choi et al., 2021 [16] | 30 yo, female | PGL, metastatic | Functional tumor | c.725G>A; p. (Cys247Tyr), exon 7, PV |
| Choi et al., 2021 [16] | 49 yo, female | PCC, metastatic | Functional tumor | c.31G>C p. (Glu11Gln), exon 18, VUS |
| Lima et al., 2023 [17] | 32 yo, female | PCC, local | NMN + MN | c.1010G>A; p. (Arg337His), exon 9, PV/LP |
| Stojiljkovic et al., 2024 [18] | 19 yo, female | PCC, local | Functional tumor | c.376-2A>G, intronic region (splice acceptor), PV/LP |
Abbreviations: LP, likely pathogenic; MN, metanephrine; NA, not applicable; NMN, normetanephrine; PCC/PGL, pheochromocytoma/paraganglioma; PV, pathogenic variant; VUS, variant of undetermined significance.
PCCs/PGSs have one of the highest genetic predispositions among all tumors, and international guidelines strongly en- dorse genetic testing. Approximately 30% to 40% of cases are associated with inherited syndromes harboring a germline mutation in genes related to PCCs/PGLs, while an additional 35% to 40% of tumors bear a somatic driver mutation [9]. Intriguingly, in 10% to 13% of seemingly sporadic cases, a germline pathogenic mutation in a culprit genetic locus is de- tected [10, 11]. Recent advances in molecular biology have en- abled the in-depth characterization of the molecular background of these neoplasms. PCCs/PGLs can be assigned to 1 of 3 clusters based on the molecular pathway of tumori- genesis. Cluster 1, or the pseudo-hypoxic cluster, comprises genes that activate pathways resembling hypoxia signaling: these genes include SDHA-D, FH, MDH2, SLC25A11, and VHL, and are predominantly correlated with germline muta- tions. Cluster 2 includes genes implicated in tyrosine kinase signaling, such as RET, HRAS, NF1, TMEM127, MAX, and FGFR1. Mutations for some genes could be either germ- line or somatic, while for others, they are exclusively somatic. Cluster 3 is related to ß-catenin/Wnt-signaling activation and comprises the MAML3 fusion gene and CSDE1; mutations in this group are solely somatic [12].
The genetic landscape of PCCs/PGLs has largely been deci- phered, but associations with TP53 mutations have not been frequently observed. LFS appears to be strongly related to
numerous types of cancer; however, the connection with PCCs/PGLs is infrequent and is only noted in sporadic case re- ports (Table 2). In 2016, Hu et al reported the first Chinese family with LFS, where one of the affected members was diag- nosed with PCC at the age of 3 years [13]. A case of metastatic PCC in the context of LFS was reported by Gniado et al in 2021; however, the authors noted that the patient also carried another germline mutation in the SDHB gene, which is well known to be associated with PCC [14]. Seo et al reported a single TP53 germline mutation in 36 patients with PCCs/ PGLs [15]. Two cases of germline TP53 mutations were re- ported in a North Korean series of 15 cases [16]. In a series of 101 PCCs/PGLs reported by Lima et al, there was one case of a germline TP53 carrier, but the authors stated that the patient also had a germline pathogenic mutation in the TMEM127 gene [17]. A case from Serbia was published re- garding a carrier of a germline TP53 pathogenic variant with a history of PCC [18].
As noted above, extensive molecular profiling has greatly illu- minated the genomic blueprint of PCCs/PGLs. Although the loss of the short arm of chromosome 17, which contains the gen- etic locus of TP53, is considered a frequent genomic event in PCCs/PGLs, more specific TP53 genomic alterations have also been identified [10, 19]. The French COMETE cohort was one of the first initiatives aiming to shed light on the genomic landscape of PCCs/PGLs. A multi-omics analysis of 202 samples
| (germline/somatic) Other co-mutations | 1 RET-G (VUS) 3 SDHB->G (1 NA, 2 PV) | 1 NF1-S 1 TMEM127-G (PV) 1 NF2->G (BV) 1 SDHB-+G (PV) 1 NF1-S 1 SDHB-S 1 HRAS-S | ||
|---|---|---|---|---|
| status (%) Functional | (40) 4/10 | (100) 6/6 | ||
| Metastatic sites | Kidneys, LNs | Bones, lungs, LNs | ||
| disease (%) Local/metastatic | L:5 (50) M:3(30) | L:4 (57.1) M:3(42.9) | ||
| mutations | (%/%) Type (PCC/PGL) | (70/30) 7/3 | (71.4/28.6) 5/2 | |
| somatic | age | |||
| germline and | Median (range) | (25-66) 42 | (3-49) 37 | |
| with TP53 | Gender (M/F) | 2/6 | 1/6 | |
| Characteristics of PCCs/PGLs | Number [ref.] | @10 [10, 16, 20-24] | [13-18] @7 | |
| Table 3. | Somatic | Germline | ||
Abbreviations: BV, benign variant; F, female; G, germline; L, local; LNs, lymph nodes; M, male; M, metastatic; NA, not applicable; PCC/PGL, pheochromocytoma/paraganglioma; PV, pathogenic variant; S, somatic; VUS, variant of undetermined significance.
“Data for some cases were inadequate.
revealed somatic mutations in the TP53 gene in only 2 cases [20]. Another initiative was launched by the Cancer Genome Atlas (TCGA) research network by conducting a comprehensive molecular characterization of 173 PCCs/PGLs. No germline TP53 germline pathogenic variants were detected, while somat- ic alterations were found in just one case [10]. A large cohort conducted in the United Kingdom that included 141 individuals with PCCs/PGLs aimed to investigate the clinical utility of som- atic sequencing: 45 patients harbored germline mutations, but none involving the TP53 gene, and while 37 had pathogenetic somatic mutations, only one referred to TP53 [21]. Other small- er studies have confirmed the rarity of germline and somatic TP53 mutations [16, 22-24].
Searching the literature, we detected 7 germline TP53 var- iants (0.74%) in 942 PCCs/PGLs with germline investigation [10, 13-18, 20-24], while of 788 cases with somatic testing, 10 bore somatic variants (1.27%) [10, 16, 20-24]. Table 3 summarizes the characteristics of PCCs/PGLs with TP53 alter- ations. Most carriers with germline mutations are female and tend to develop PCCs (71.4%), which are functional tumors (100%) with mixed catecholamine secretion profiles. When metastatic, the tumors tended to metastasize primarily to bones and lungs. In 2 cases, germline co-mutations with SDHB and TMEM127 genes were detected. Both genes are related to the development of PCCs/PGLs, and the contribution of the TP53 mutation to tumorigenesis in this context is unclear.
In our case, the knockout of the wild-type TP53 allele, lead- ing to loss of heterozygosity, could represent a potential tumorigenesis mechanism. However, molecular investigation of the tumor did not reveal a deleterious mutation or loss of the genetic locus of the wild-type TP53 gene; thus, epigenetic silencing of the wild-type TP53 allele could be speculated as a possible mechanism. Geli et al showed that PCCs/PGLs ex- hibit an extensive epigenomic dysregulation, leading to epi- genetic silencing of tumor suppressor genes and correlating with aggressive disease [25]. Furthermore, mutations in genes related to epigenetic regulation, such as ATRX, SETD2, and KMT2D, have been described in PCCs/PGLs [12]. It has also been demonstrated that PCCs/PGLs with gene mutations included in Cluster 1 exhibit a profound hypermethylation phenotype [26]. Another theory supports the concept that deleterious germline TP53 mutations exert a predominantly dominant-negative effect on the wild-type TP53 allele, abro- gating normal protein function [27].
Our patient was exposed to radiation following the diagnosis of DCIS, and a few months later she developed invasive carcin- oma. Although the evidence regarding the impact of radiation on TP53 carriers is scarce, radiotherapy appears to further in- crease the risk of secondary malignancies, particularly for soft tissue sarcomas [28]. PRRT is an established treatment for PCCs/PGLs. Typically, the recommended schedule for PRRT with lutetium-177 (177Lu)-DOTATATE consists of 4 fixed cycles of 7.4 GBq (200 mCi) infusions every 6 to 12 weeks. Nevertheless, the effects of the emitted radiation from this type of therapy in LFS individuals remain unknown, and its pos- sible future use in this patient would need to be more carefully considered than in patients with other types of mutation.
Learning Points
· LFS is associated with a broad spectrum of malignancies. PCCs/PGLs represent infrequent manifestations of the syndrome (~1%).
· Carriers of deleterious germline TP53 variants should be closely monitored from a young age. Screening recommen- dations propose comprehensive physical examination, ultrasound of the abdomen and pelvis every 3 to 4 months, and annual WB-MRI for carriers starting at birth.
· Based on the existing literature, we recommend periodic blood pressure monitoring and consideration of assess- ments of metanephrines secretion wherever there is clinical suspicion. Where positive, one could proceed to careful evaluation of WBMRI for adrenal lesions and 68Ga-DOTATATE PET/CT scanning may be useful.
Contributors
All authors made individual contributions to authorship. S.L., C.M., and A.G. were involved in the diagnosis and manage- ment of this patient; E.I. was involved in histopathology pic- tures presentation; and K.P. and A.G. were involved in manuscript editing and correction. All authors reviewed and approved the final draft.
Funding
No public or commercial funding.
Disclosures
None declared.
Informed Patient Consent for Publication
Signed informed consent has been obtained directly from the patient.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
References
1. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neo- plasms. A familial syndrome? Ann Intern Med. 1969;71(4):747-752.
2. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a fa- milial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233-1238.
3. Schneider K, Zelley K, Nichols KE, Schwartz Levine A, Garber J. GeneReviews: Li-Fraumeni Syndrome. University of Washington; 1993.
4. Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 2016;6(5):a026062.
5. Renaux-Petel M, Charbonnier F, Théry JC, et al. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet. 2018;55(3):173-180.
6. ClinVar. National Center for Biotechnology Information. Updated April 20, 2025. Accessed April 21, 2025. https://www.ncbi.nlm. nih.gov/clinvar/variation/12356/
7. Aggarwal S, Prete A, Chortis V, et al. Pheochromocytomas most commonly present as adrenal incidentalomas: a large tertiary center experience. J Clin Endocrinol Metab. 2023;109(1):e389-e396.
8. Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol. 2022;33(1):90-114.
9. Sbardella E, Cranston T, Isidori AM, et al. Routine genetic screen- ing with a multi-gene panel in patients with pheochromocytomas. Endocrine. 2018;59(1):175-182.
10. Fishbein L, Leshchiner I, Walter V, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31(2):181-193.
11. Brito JP, Asi N, Bancos I, et al. Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. Clin Endocrinol (Oxf). 2015;82(3):338-345.
12. Nölting S, Bechmann N, Taieb D, et al. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev. 2022; 43(2):199-239.
13. Hu H, Liu J, Liao X, et al. Genetic and functional analysis of a Li Fraumeni syndrome family in China. Sci Rep. 2016;6(1):20221.
14. Gniado E, Carracher CP, Sharma S. Simultaneous occurrence of germ- line mutations of SDHB and TP53 in a patient with metastatic pheo- chromocytoma. J Clin Endocrinol Metab. 2020;105(4):dgz269.
15. Seo SH, Kim JH, Kim MJ, et al. Whole exome sequencing identifies novel genetic alterations in patients with pheochromocytoma/para- ganglioma. Endocrinol Metab (Seoul). 2020;35(4):909-917.
16. Choi YM, Lim J, Jeon MJ, et al. Mutation profile of aggressive pheochromocytoma and paraganglioma with comparison of TCGA data. Cancers (Basel). 2021;13(10):2389.
17. Lima JV Jr, Scalissi NM, de Oliveira KC, et al. Germline genetic var- iants in pheochromocytoma/paraganglioma: single-center experi- ence. Endocr Oncol. 2023;3(1):e220091.
18. Stojiljković D, Cvetković A, Jokić A, et al. Li-fraumeni syndrome with six primary tumors-case report. Case Rep Oncol Med. 2024;2024:6699698.
19. Petri BJ, Speel EJ, Korpershoek E, et al. Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas. Mod Pathol. 2008;21(4):407-413.
20. Castro-Vega LJ, Letouzé E, Burnichon N, et al. Multi-omics ana- lysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6(1):6044.
21. Winzeler B, Tufton N, S Lim E, et al. Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort. Clin Endocrinol (Oxf). 2022;97(4):448-459.
22. Ma X, Ling C, Zhao M, et al. Mutational profile and potential mo- lecular therapeutic targets of pheochromocytoma. Front Endocrinol (Lausanne). 2022;13:921645.
23. Luchetti A, Walsh D, Rodger F, et al. Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next gener- ation sequencing analysis. Int J Endocrinol. 2015;2015:138573.
24. Gieldon L, William D, Hackmann K, et al. Optimizing genetic work- up in pheochromocytoma and paraganglioma by integrating diag- nostic and research approaches. Cancers (Basel). 2019;11(6):809.
25. Geli J, Kiss N, Karimi M, et al. Global and regional CpG methyla- tion in pheochromocytomas and abdominal paragangliomas: asso- ciation to malignant behavior. Clin Cancer Res. 2008;14(9): 2551-2559.
26. Chatzikyriakou P, Brempou D, Quinn M, et al. A comprehensive characterisation of phaeochromocytoma and paraganglioma tu- mours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide. Clin Epigenetics. 2023; 15(1):196.
27. Monti P, Perfumo C, Bisio A, et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011;9(3):271-279.
28. Thariat J, Chevalier F, Orbach D, et al. Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and herit- able TP53-related cancer syndromes. Lancet Oncol. 2021;22(12): e562-e574.