The Natural History of Observed SDHx -Related Head and Neck Paragangliomas Using Three-Dimensional Volumetric Tumor Analysis.

OBJECTIVE: Characterize the natural history and clinical behavior of head and neck paragangliomas (HNPGLs) in subjects with succinate dehydrogenase ( SDHx ) pathogenic variants using volumetric tumor measurements. STUDY DESIGN: Cohort study. SETTING: Tertiary academic referral center. PATIENTS: Subjects with SDHx HNPGLs under observation for at least 6 months with 2 or more magnetic resonance imaging or computed tomography scans. INTERVENTIONS: Diagnostic interventions include next-generation sequencing, magnetic resonance imaging, and computed tomography. Therapeutic interventions include microsurgical resection or stereotactic radiosurgery. MAIN OUTCOME MEASURES: Radiographic progression was defined as a 20% or greater increase in volume. Cranial nerve (CN) functional outcomes were assessed using clinical documentation. RESULTS: A total of 19 subjects with 32 tumors met the inclusion criteria. Median radiographic follow-up was 2.2 years, and the median volumetric growth rate was 0.47 cm 3 /yr. Kaplan-Meier estimated rates of survival free of radiographic progression for all SDHx tumors at 1, 2, and 3 years were 69, 50, and 22%, respectively. No tumors developed new CN palsies during the period of observation. CONCLUSIONS: Over intermediate-term follow-up, observation of treatment-naive SDHx -related HNPGLs did not result in new cranial neuropathy. Although indefinite observation is only appropriate for select cases, these data support an interval of observation to characterize growth rate in asymptomatic to minimally symptomatic patients, who are at high risk of treatment-related morbidity. Given the early age at diagnosis and high risk of bilateral multifocal phenotypes in SDHx HNPGL mutation carriers, these data may aid in optimizing patient tumor control and CN functional preservation. Further studies are necessary to determine whether pretreatment growth rate is correlated with clinical outcomes.

Inherited TP53 Variants and Risk of Prostate Cancer.

BACKGROUND: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. OBJECTIVE: To determine whether gTP53 predisposes to prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer. RESULTS AND LIMITATIONS: We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis. CONCLUSIONS: Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. PATIENT SUMMARY: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Paraganglioma and other tumour detection rates in individuals with SDHx pathogenic variants by age of diagnosis and after the age of 50.

OBJECTIVE: Patients with SDHx germline mutations (SDHA, AF2, B, C, D) are at risk for paragangliomas (PGLs), renal cell carcinoma and gastrointestinal stromal tumours. The aim of this study was to evaluate the age of SDHx tumour diagnosis in those with pathogenic variants (PVs), notably tumour detection after the age of 50 years. STUDY DESIGN: Longitudinal retrospective observational analysis. PATIENTS: Individuals with SDHx PVs. MEASUREMENTS: Demographic, clinical, genetic, screening and tumour detection and treatment data were abstracted from the electronic medical record. Descriptive analysis was utilised. RESULTS: A total of 165 patients with SDHx PVs from 34 families were evaluated. Sixty-eight patients (41.2%) had at least one known SDHx-related tumour in their history, identified through symptoms, screening or incidentally. The average age of SDHx-related tumour diagnosis was 32.0 years. Age of diagnosis varied by the gene. Nine patients (n = 50; 18.0%) were identified with a tumour after the age of 50, identified via baseline screening after PV identification, or due to symptoms before molecular SDHx diagnosis. CONCLUSIONS: Though tumours were identified in individuals above the age of 50; they were all identified on baseline screening or due to symptoms, confirming that baseline screening is essential. Given the slow-growing nature of PGLs, these tumours might have been discovered before age 50 if molecular diagnosis and baseline screening had occurred earlier. Considering discontinuing screening after age 50 may be warranted if baseline screen imaging is negative and the individual does not have a prior tumour history.

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

PURPOSE: Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. METHODS: A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. RESULTS: Two hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens. CONCLUSION: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

Characterization of Malignant Head and Neck Paragangliomas at a Single Institution Across Multiple Decades.

Importance: Malignant head and neck paragangliomas (HNPGLs) are rare entities, and there are limited data regarding optimal treatment recommendations to improve clinical outcomes. Objective: To classify succinate dehydrogenase (SDH) germline mutations associated with malignant HNPGLs, evaluate time from diagnosis to identification of malignant tumor, describe locations of metastases and the functional status of malignant HNPGLs, and determine the role of selective neck dissection at the time of initial surgical resection. Design, Setting, and Participants: A retrospective cohort study was completed of patients diagnosed with paragangliomas on various sites on the body at an academic tertiary cancer hospital between the years 1963 and 2018. A subanalysis of HNPGLs was also completed. Data regarding diagnosis, gene and mutation, tumor characteristics and location, and treatments used were reviewed between February 2017 and March 2018. Main Outcomes and Measures: Mutations of SDH genes associated with benign and malignant HNPGLs, treatments used, time to the discovery of malignancy, and location of metastasis. Results: Of the 70 patients included in the study, 40 (57%) were male, and the mean (SD) age was 47 (21.1) years. Of patients with tumors isolated to the head and neck, 38 (54%) had benign HNPGLs, which were associated with mutations in the genes SDH subunit B (SDHB) (n = 18; 47%), SDH subunit C (n = 2; 5%), and SDH subunit D (n = 18; 47%). Among those with malignant HNPGLs, all but 1 patient had mutations in SDHB (n = 5; 83%); 1 patient had no mutation associated with their disease. The average age at diagnosis for malignant HNPGLs was 35 years, while benign tumors were diagnosed at an average age at 36 years. All patients with malignant disease underwent surgery. Four patients were found to have metastasis at the time of selective neck dissection. Among patients with malignant HNPGLs, 5 (83%) were treated with adjuvant radiation, and 1 (17%) was treated with adjuvant chemotherapy. Conclusions and Relevance: Malignant HNPGLs are rare entities that are difficult to diagnose and are typically identified by the presence of regional or distant metastasis. The results of this study found the prevalence of malignant HNPGLs to be 9%. These data suggest that it is beneficial to perform a selective neck dissection at the time of tumor excision. All patients with malignant HNPGLs but 1 had SDHB mutations.

Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis.

Importance: Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in surveillance of this high-risk population. Objective: To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline. Data Sources: Clinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium. Study Selection: Cohorts that incorporated WBMRI for individuals with germline TP53 mutations from January 1, 2004, through October 1, 2016, were included. Data Extraction and Synthesis: Data were extracted by investigators from each cohort independently and synthesized by 2 investigators. Random-effects meta-analysis methods were used to estimate proportions. Main Outcomes and Measures: The proportions of participants at baseline in whom a lesion was detected that required follow-up and in whom a new primary malignant neoplasm was detected. Results: A total of 578 participants (376 female [65.1%] and 202 male [34.9%]; mean [SD] age, 33.2 [17.1] years) from 13 cohorts in 6 countries were included in the analysis. Two hundred twenty-five lesions requiring clinical follow-up were detected by WBMRI in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%). Conclusions and Relevance: These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population.

Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.

BACKGROUND: Carriers of a germline TP53 pathogenic variant have a substantial lifetime risk of developing cancer. In 2011, we did a prospective observational study of members of families who chose to either undergo a comprehensive surveillance protocol for individuals with Li-Fraumeni syndrome or not. We sought to update our assessment of and modify the surveillance protocol, so in this study we report both longer follow-up of these patients and additional patients who underwent surveillance, as well as update the originally presented surveillance protocol. METHODS: A clinical surveillance protocol using physical examination and frequent biochemical and imaging studies (consisting of whole-body MRI, brain MRI, breast MRI, mammography, abdominal and pelvic ultrasound, and colonoscopy) was introduced at three tertiary care centres in Canada and the USA on Jan 1, 2004, for carriers of TP53 pathogenic variants. After confirmation of TP53 mutation, participants either chose to undergo surveillance or chose not to undergo surveillance. Patients could cross over between groups at any time. The primary outcome measure was detection of asymptomatic tumours by surveillance investigations. The secondary outcome measure was 5 year overall survival established from a tumour diagnosed symptomatically (in the non-surveillance group) versus one diagnosed by surveillance. We completed survival analyses using an as-treated approach. FINDINGS: Between Jan 1, 2004, and July 1, 2015, we identified 89 carriers of TP53 pathogenic variants in 39 unrelated families, of whom 40 (45%) agreed to surveillance and 49 (55%) declined surveillance. 19 (21%) patients crossed over from the non-surveillance to the surveillance group, giving a total of 59 (66%) individuals undergoing surveillance for a median of 32 months (IQR 12-87). 40 asymptomatic tumours have been detected in 19 (32%) of 59 patients who underwent surveillance. Two additional cancers were diagnosed between surveillance assessments (false negatives) and two biopsied lesions were non-neoplastic entities on pathological review (false positives). Among the 49 individuals who initially declined surveillance, 61 symptomatic tumours were diagnosed in 43 (88%) patients. 21 (49%) of the 43 individuals not on surveillance who developed cancer were alive compared with 16 (84%) of the 19 individuals undergoing surveillance who developed cancer (p=0·012) after a median follow-up of 46 months (IQR 22-72) for those not on surveillance and 38 months (12-86) for those on surveillance. 5 year overall survival was 88·8% (95% CI 78·7-100) in the surveillance group and 59·6% (47·2-75·2) in the non-surveillance group (p=0·0132). INTERPRETATION: Our findings show that long-term compliance with a comprehensive surveillance protocol for early tumour detection in individuals with pathogenic TP53 variants is feasible and that early tumour detection through surveillance is associated with improved long-term survival. Incorporation of this approach into clinical management of these patients should be considered. FUNDING: Canadian Institutes for Heath Research, Canadian Cancer Society, Terry Fox Research Institute, SickKids Foundation, and Soccer for Hope Foundation.