Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders.

BACKGROUND/OBJECTIVES: Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls). METHODS: This study analysed 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analysed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale and compared between cases and controls with a propensity score weighting method. RESULTS: The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% to 3.8%): three BRCA2, three PMS2, two SDHB, and one each in BRCA1, MLH1 and RAD51C. Among the relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 vs 16.2 in MICRA total score, 6.3 vs 4.2 in the distress subscale, and 8.3 vs 6.6 in the uncertainty subscale; all p<0.001). CONCLUSION: SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history.

Epstein-Barr virus-associated risk factors for post-transplant lymphoproliferative disease in pediatric liver transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) are the most common de novo malignancies after liver transplantation (LT) in children. The aim of our study was to assess the role of pre-LT EBV status and post-LT EBV viral load as risk factors for developing PTLD in a cohort of pediatric LT recipients. METHODS: Data of all children who underwent LT between January 2002 and December 2019 were collected. Two cohorts were built EBV pre-LT primary infected cohort and EBV post-LT primary infected cohort. Moreover, using the maximal EBV viral load, a ROC curve was constructed to find a cutoff point for the diagnosis of PTLD. RESULTS: Among the 251 patients included in the study, fifteen PTLD episodes in 14 LT recipients were detected (2 plasmacytic hyperplasia, 10 polymorphic PTLD, 2 monomorphic PTLD, and 1 Classical-Hodgkin's lymphoma). Patients of the EBV post-LT primary infected cohort were 17.1 times more likely to develop a PTLD than patients of the EBV pre-LT primary infected cohort (2.2-133.5). The EBV viral load value to predict PTLD was set at 211 000 UI/mL (93.3% sensitivity and 77.1% specificity; AUC 93.8%; IC 0.89-0.98). In EBV post-LT primary infected cohort, patients with a viral load above 211 000 were 30 times more likely to develop PTLD than patients with a viral load below this value (OR 29.8; 3.7-241.1; p < 0.001). CONCLUSIONS: The combination of pretransplant EBV serological status with EBV post-transplant viral load could be a powerful tool to stratify the risk of PTLD in pediatric LT patients.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

INTRODUCTION: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. METHOD: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. RESULTS: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. CONCLUSION: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.

BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

Ultrasound criteria (EU-TIRADS) to identify thyroid nodule malignancy risk in adolescents. Correlation with cyto-histological findings.

INTRODUCTION: Thyroid nodule (TN) harbouring a thyroid carcinoma are more common in paediatric than adult patients. In paediatric population, the evaluation of a TN should require specific paediatric tools for its diagnostic and therapeutic management. High-resolution ultrasonography and cytological evaluation after fine-needle aspiration biopsy (FNAB) remain the cornerstones of evaluation of TN. OBJECTIVES: To evaluate in paediatric TN for the first time the usefulness and precision of the ultrasound criteria defined by the "Thyroid Imaging Reporting and Data System (EU-TIRADS) 2017 in adults" to establish the ultrasound indication for the practice of FNAB and stratify the risk of malignancy. PATIENTS AND METHODS: 24 paediatric patients under age 18 years with thyroid nodules were attended in the last 15 years, 24 of them (31 nodules; age: 15.2 ±â€¯2.2 years; 18 women) met the inclusion criteria: FNAB with Bethesda classification and ultrasound with EU-TIRADS score. EU-TIRADS score were evaluated retrospectively. Fourteen patients underwent surgery and the definitive histological diagnosis was obtained, this allowed the calculations of sensitivity, specificity and positive and negative predictive values of the EU-TIRADS and Bethesda classification. Data on the largest diameters of the nodules were collected. RESULTS: Of the overall 31 nodules, the distribution by EU-TIRADS (T) category was: T1 (3.2%), T2: 2 (6.4%), T3: 7 (22.6%), T4: 16 (51.6%) and T5: 5 (16.1%). All malignant nodules were included in EU-TIRADS category 4 or 5. By the other hand, 13 of the 25 benign nodules were also included in the EU-TIRADS 4 category, and one in the 5. The distribution by categories of Bethesda's classification (B): BI: 6 (19.4%), BII: 14 (45.2%), BIII: 5 (16.1%), BIV: 2 (6.5%), BV: 0 and BVI: 4 (12.9%). The pathological diagnosis of the 14 patients who underwent surgery was: 6 papillary carcinomas and 8 with benign lesions: 6 nodular hyperplasia and 2 follicular adenoma. The percentage of malignancy was 42%. The sensitivity of the EU-TIRADS classification to detect malignant nodules was 100%, the specificity was 25%, PPV 44% and NPV 100%. The sensitivity of the Bethesda classification to detect malignant nodules was 86%, the specificity was 75%, PPV 67% and NPV 90%. The analysis of the largest diameter of the nodules did not show statistically significant differences between benign and malignant lesions. CONCLUSIONS: EU-TIRADS for ultrasonographic criteria classification in combination with the clinical history is an adequate and reproducible method to estimate suspicion of malignancy of paediatric TN. It is also a reliable diagnostic tool to decide which nodules will be candidates for FNAB.

Ultrasound criteria (EU-TIRADS) to identify thyroid nodule malignancy risk in adolescents. Correlation with cyto-histological findings. / Criterios ecográficos (EU-TIRADS) para identificar el riesgo de malignidad de los nódulos tiroideos en adolescentes. Correlación con los hallazgos cito-histológicos.

INTRODUCTION: Thyroid nodule (TN) harboring a thyroid carcinoma are more common in pediatric than adult patients. In pediatric population, the evaluation of a TN should require specific pediatric tools for its diagnostic and therapeutic management. High-resolution ultrasonography and cytological evaluation after fine-needle aspiration biopsy (FNAB) remain the cornerstones of evaluation of TN. OBJECTIVES: To evaluate in pediatric TN for the first time the usefulness and precision of the ultrasound criteria defined by the"Thyroid Imaging Reporting and Data System (EU-TIRADS) 2017 in adults" to establish the ultrasound indication for the practice of FNAB and stratify the risk of malignancy. PATIENTS AND METHODS: 24 pediatric patients under age 18 years with thyroid nodules were attended in the last 15 years, 24 of them (31 nodules; age: 15.2 ± 2.2 years; 18 women) met the inclusion criteria: FNAB with Bethesda classification and ultrasound with EU-TIRADS score. EU-TIRADS score were evaluated retrospectively. Fourteen patients underwent surgery and the definitive histological diagnosis was obtained, this allowed the calculations of sensitivity, specificity and positive and negative predictive values of the EU-TIRADS and Bethesda classification. Data on the largest diameters of the nodules were collected. RESULTS: Of the overall 31 nodules, the distribution by EU-TIRADS (T) category was: T1 (3.2%), T2: 2 (6.4%), T3: 7 (22.6%), T4: 16 (51.6%) and T5: 5 (16.1%). All malignant nodules were included in EU-TIRADS category 4 or 5. By the other hand, 13 of the 25 benign nodules were also included in the EU-TIRADS 4 category, and one in the 5. The distribution by categories of Bethesda's classification (B): BI: 6 (19.4%), BII: 14 (45.2%), BIII: 5 (16.1%), BIV: 2 (6.5%), BV: 0 and BVI: 4 (12.9%). The pathological diagnosis of the 14 patients who underwent surgery was: 6 papillary carcinomas and 8 with benign lesions: 6 nodular hyperplasia and 2 follicular adenoma. The percentage of malignancy was 42%. The sensitivity of the EU-TIRADS classification to detect malignant nodules was 100%, the specificity was 25%, PPV 44% and NPV 100%. The sensitivity of the Bethesda classification to detect malignant nodules was 86%, the specificity was 75%, PPV 67% and NPV 90%. The analysis of the largest diameter of the nodules did not show statistically significant differences between benign and malignant lesions. CONCLUSIONS: EU-TIRADS for ultrasonographic criteria classification in combination with the clinical history is an adequate and reproducible method to estimate suspicion of malignancy of pediatric TN. It is also a reliable diagnostic tool to decide which nodules will be candidates for FNAB.

Long-term follow-up of differentiated thyroid carcinoma in children and adolescents.

Objectives The aims were to analyze the clinical features, response to treatment, prognostic factors and long-term follow-up of children and adolescents with differentiated thyroid carcinoma (DTC). Methods Eighty patients with DTC were studied retrospectively. All underwent total or near-total thyroidectomy, and in 75 cases, ablative iodine therapy was recommended. Patients were assessed periodically by tests for serum thyroglobulin levels and whole-body iodine scans. Age, gender, initial clinical presentation, histology, tumor stage, postoperative complications, radioiodine treatment protocol, treatment response, thyroglobulin (Tg), recurrence and long-term disease progression were evaluated. Results Seventy patients completed >2 years of follow-up (23 males, 47 females; median age: 14 years; range: 3-18 years). Sixty-two patients showed papillary DTC and eight, follicular DTC. Sixty-five percent presented nodal metastasis and 16%, pulmonary metastasis at diagnosis. Six months after first radioiodine treatment, 36.2% of patients were free of disease. Seven recurrences were documented. At the end of follow-up, overall survival was 100%, and 87.2% of patients were in complete remission. Nine patients had persistent disease. We found a significant association between stage 4 and persistent disease. Hundred percent of patients with negative Tg values at 6 months posttreatment were documented free of disease at the end of the follow-up. The analysis of disease-free survival based on radioiodine treatment protocols used showed no statistically significant differences. Conclusions DTC in children and adolescents is frequently associated with presence of advanced disease at diagnosis. Despite this, complete remission was documented after treatment in most cases, with a good prognosis in the long-term follow-up. Negative posttreatment thyroglobulin and stage 4 at diagnosis were significant prognostic variables.