Oncological and endocrinological outcomes for children and adolescents with testicular and ovarian sex cord-stromal tumors. Results of the TGM13 National Registry.

RATIONALE: Sex cord-stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes. METHOD: Patients (< 19 years) registered in the TGM13 registry between 2014 and 2021 for SCST were selected. RESULTS: Sixty-three ovarian SCST (juvenile granulosa tumor (JGT) n = 34, Sertoli-Leydig cell tumor (SLCT) n = 17, other SCST n = 12) were included. Median age was 13.1 years (0.4-17.4). Germline DICER1 pathogenic variant was present in 9/17 SLCT. Sixty-one were FIGO stage I (IC n = 14). Adjuvant chemotherapy was administered for 15. Seven had recurrence (FIGO IA n = 3, IX n = 2, III n = 2), leading to one death. With a median follow-up of 42 months (2.5-92), the 3-year progression-free survival (PFS) was 89% (95% CI 76%-95%). Median age was 6.4 years (0.1-12.9) among the 15 testicular SCST (Leydig cell tumor n = 6, JGT n = 5, Sertoli cell tumor n = 3, mixed SCST n = 1). Tumor-nodes-metastases (TNM) stage was pSI in 14. Eight underwent a tumorectomy, 7 an orchiectomy. None experienced recurrence. Endocrinological data were reviewed for 41 patients (18 prepubescent). Endocrine symptoms were present at diagnosis in 29/34 females and 2/7 males (gynecomastia). After a median follow-up of 11 months, 15 patients had persistent endocrine abnormalities: gynecomastia/breast growth (2 males, 1 prepubescent female), precocious/advanced puberty (4 prepubescent females), and hirsutism/menstruation disorders/voice hoarseness/hot flashes (8 pubescent females). The mean height at the last follow-up was within normal ranges (+0.3 standard deviation). CONCLUSIONS: SCSTs have a favorable prognosis. Tumorectomy appears safe with testicular primary. Endocrinological disorders, common at diagnosis, may persist warranting endocrinological follow-up.

Fungal Integrated Histomolecular Diagnosis Using Targeted Next-Generation Sequencing on Formalin-Fixed Paraffin-Embedded Tissues.

Histopathology is the gold standard for fungal infection (FI) diagnosis, but it does not provide a genus and/or species identification. The objective of the present study was to develop targeted next-generation sequencing (NGS) on formalin-fixed tissue samples (FTs) to achieve a fungal integrated histomolecular diagnosis. Nucleic acid extraction was optimized on a first group of 30 FTs with Aspergillus fumigatus or Mucorales infection by macrodissecting the microscopically identified fungal-rich area and comparing Qiagen and Promega extraction methods through DNA amplification by A. fumigatus and Mucorales primers. Targeted NGS was developed on a second group of 74 FTs using three primer pairs (ITS-3/ITS-4, MITS-2A/MITS-2B, and 28S-12-F/28S-13-R) and two databases (UNITE and RefSeq). A prior fungal identification of this group was established on fresh tissues. Targeted NGS and Sanger sequencing results on FTs were compared. To be valid, the molecular identifications had to be compatible with the histopathological analysis. In the first group, the Qiagen method yielded a better extraction efficiency than the Promega method (100% and 86.7% of positive PCRs, respectively). In the second group, targeted NGS allowed fungal identification in 82.4% (61/74) of FTs using all primer pairs, in 73% (54/74) using ITS-3/ITS-4, in 68.9% (51/74) using MITS-2A/MITS-2B, and in 23% (17/74) using 28S-12-F/28S-13-R. The sensitivity varied according to the database used (81% [60/74] using UNITE compared to 50% [37/74] using RefSeq [P = 0.000002]). The sensitivity of targeted NGS (82.4%) was higher than that of Sanger sequencing (45.9%; P < 0.00001). To conclude, fungal integrated histomolecular diagnosis using targeted NGS is suitable on FTs and improves fungal detection and identification.

Extracranial germ cell tumours in children and adolescents: Results from the French TGM13 protocol.

BACKGROUND: Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more. PROCEDURE: Patients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine-bleomycin-cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide-cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups. RESULTS: One hundred fifteen patients were included: median age of 12.8 years (0.4-18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80-92) and 95% (89-98), respectively (median follow-up: 3.5 years, range: 0.2-5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84-93), 5-year OS 93% (89-95), p = .561). The 5-year EFS were 93% (95% CI: 80-98), 88% (71-95) and 79% (62-90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p = .02) according to the risk groups: 90% (66-97), 64% (30-85), 95% (72-99) and 87% (74-94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003-1.007). CONCLUSION: Risk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.

Testicular Sertoli cell tumour and potentially testicular Leydig cell tumour are features of DICER1 syndrome.

DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.

Delaying testicular sperm extraction in 47,XXY Klinefelter patients does not impair the sperm retrieval rate, and AMH levels are higher when TESE is positive.

STUDY QUESTION: Should testicular sperm extraction (TESE) in non-mosaic 47,XXY Klinefelter syndrome (KS) patients be performed soon after puberty or could it be delayed until adulthood? SUMMARY ANSWER: The difference in sperm retrieval rate (SRR) in TESE was not significant between the 'Young' (15-22 years old) cohort and the 'Adult' (23-43 years old) cohort of non-mosaic KS patients recruited prospectively in parallel. WHAT IS KNOWN ALREADY: Several studies have tried to define predictive factors for TESE outcome in non-mosaic KS patients, with very heterogeneous results. Some authors have found that age was a pejorative factor and recommended performing TESE soon after puberty. To date, no predictive factors have been unanimously recognized to guide clinicians in deciding to perform TESE in azoospermic KS patients. STUDY DESIGN, SIZE, DURATION: Two cohorts (Young: 15-22 years old; Adult: 23-43 years old) were included prospectively in parallel. A total of 157 non-mosaic 47,XXY KS patients were included between 2010 and 2020 in the reproductive medicine department of the University Hospital of Lyon, France. However 31 patients gave up before TESE, four had cryptozoospermia and three did not have a valid hormone assessment; these were excluded from this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data for 119 patients (61 Young and 58 Adult) were analyzed. All of these patients had clinical, hormonal and seminal evaluation before conventional TESE (c-TESE). MAIN RESULTS AND THE ROLE OF CHANCE: The global SRR was 45.4%. SRRs were not significantly different between the two age groups: Young SRR=49.2%, Adult SRR = 41.4%; P = 0.393. Anti-Müllerian hormone (AMH) and inhibin B were significantly higher in the Young group (AMH: P = 0.001, Inhibin B: P < 0.001), and also higher in patients with a positive TESE than in those with a negative TESE (AMH: P = 0.001, Inhibin B: P = 0.036). The other factors did not differ between age groups or according to TESE outcome. AMH had a better predictive value than inhibin B. SRRs were significantly higher in the upper quartile of AMH plasma levels than in the lower quartile (or in cases with AMH plasma level below the quantification limit): 67.7% versus 28.9% in the whole population (P = 0.001), 60% versus 20% in the Young group (P = 0.025) and 71.4% versus 33.3% in the Adult group (P = 0.018). LIMITATIONS, REASONS FOR CAUTION: c-TESE was performed in the whole study; we cannot rule out the possibility of different results if microsurgical TESE had been performed. Because of the limited sensitivity of inhibin B and AMH assays, a large number of patients had values lower than the quantification limits, preventing the definition a threshold below which negative TESE can be predicted. WIDER IMPLICATIONS OF THE FINDINGS: In contrast to some studies, age did not appear as a pejorative factor when comparing patients 15-22 and 23-44 years of age. Improved accuracy of inhibin B and AMH assays in the future might still allow discrimination of patients with persistent foci of spermatogenesis and guide clinician decision-making and patient information. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from the French Ministry of Health D50621 (Programme Hospitalier de Recherche Clinical Régional 2008). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: NCT01918280.

Evolution of humoral lesions on follow-up biopsy stratifies the risk for renal graft loss after antibody-mediated rejection treatment.

BACKGROUND: The standard-of-care protocol, based on plasma exchanges, high-dose intravenous immunoglobulin and optimization of maintenance immunosuppression, can slow down the evolution of antibody-mediated rejection (AMR), but with high interindividual variability. Identification of a reliable predictive tool of the response to AMR treatment is a mandatory step for personalization of the follow-up strategy and to guide second-line therapies. METHODS: Interrogation of the electronic databases of 2 French university hospitals (Lyon and Strasbourg) retrospectively identified 81 renal transplant recipients diagnosed with AMR without chronic lesions (cg score ≤1) at diagnosis and for whom a follow-up biopsy had been performed 3-6 months after initiation of therapy. RESULTS: The evolution of humoral lesions on follow-up biopsy (disappearance versus persistence versus progression) correlated with the risk for allograft loss (logrank test, P = .001). Patients with disappearance of humoral lesions had ∼80% graft survival at 10 years. The hazard ratio for graft loss in multivariate analysis was 3.91 (P = .04) and 5.15 (P = .02) for patients with persistence and progression of lesions, respectively. The non-invasive parameters classically used to follow the intensity of humoral alloimmune response (evolution of immunodominant DSA mean fluorescence intensity) and the decline of renal graft function (estimated glomerular filtration rate decrease and persistent proteinuria) showed little clinical value to predict the histological response to AMR therapy. CONCLUSION: We conclude that invasive monitoring of the evolution of humoral lesions by the mean of follow-up biopsy performed 3-6 months after the initiation of therapy is an interesting tool to predict long-term outcome after AMR treatment.

High-dose chemotherapy followed by autologous stem cell rescue in Wilms tumors: French report on toxicity and efficacy.

BACKGROUND: Heterogeneous data have been reported on high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in Wilms tumors (WTs). We aimed to define its safety and efficacy in the French cohort, and to compare this management to current international recommendations. METHODS: Data prospectively collected from children, adolescents, and young adults with WT treated with HDCT/ASCR between 2000 and 2016 in French centers were retrospectively analyzed. Toxicity was reported according to CTCAE v4.03. RESULTS: Fifty-four patients received HDCT/ASCR (first line, n = 13; recurrence, n = 41). Their median age at the time of ASCR was 5.3 years (range 2.2-21.6). Main nonhematological acute grades 3-4 toxicities were digestive and renal. No significant difference of toxicity rate was observed among HDCT regimens and schedules. Two patients died shortly after ASCR (renal and multiorgan failure), and one heavily pretreated patient died of late respiratory failure. The selection criteria applied to define those patients eligible for HDCT/ASCR retrospectively matched to those currently used in the International Society of Pediatric Oncology (SIOP) UMBRELLA protocol for 38 patients, with encouraging survival rates compared to published data. The objective response rate to HDCT was 21%, with a disease control rate after HDCT of 85%. After a median follow-up of 7 years, the 5-year event-free survival (EFS) and overall survival (OS) were 54% (95% CI: 32%-76%) and 62% (95% CI: 31%-82%) for frontline patients, and 57% (95% CI: 39%-71%) and 69% (95% CI: 52%-81%) at recurrence. CONCLUSION: HDCT was feasible and showed encouraging results in well-defined settings. Data from the current prospective protocol will help to better evaluate HDCT impact on survival.

Lessons from a large nationwide cohort of 350 children with ovarian mature teratoma: A study in favor of ovarian-sparing surgery.

BACKGROUND: Ovarian mature teratoma (OMT) is a common ovarian tumor found in the pediatric population. In 10%-20% of cases, OMT occurs as multiple synchronous or metachronous lesions on ipsi- or contralateral ovaries. Ovarian-sparing surgery (OSS) is recommended to preserve fertility, but total oophorectomy (TO) is still performed. DESIGN: This study reviews the clinical data of patients with OMT, and analyzes risk factors for second events. A national retrospective review of girls under 18 years of age with OMTs was performed. Data on clinical features, imaging, laboratory studies, surgical reports, second events and their management were retrieved. RESULTS: Overall, 350 children were included. Eighteen patients (5%) presented with a synchronous bilateral form at diagnosis. Surgery was performed by laparotomy (85%) and laparoscopy (15%). OSS and TO were performed in 59% and 41% of cases, respectively. Perioperative tumor rupture occurred in 23 cases, independently of the surgical approach. Twenty-nine second events occurred (8.3%) in a median time of 30.5 months from diagnosis (ipsilateral: eight cases including one malignant tumor; contralateral: 18 cases; both ovaries: three cases). A large palpable mass, bilateral forms, at diagnosis and perioperative rupture had a statistical impact on the risk of second event, whereas the type of surgery or approach did not. CONCLUSION: This study is a plea in favor of OSS as the first-choice treatment of OMT when possible. Close follow-up during the first 5 years is mandatory considering the risk of 8.3% of second events, especially in cases with risk factors.

Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection.

BACKGROUND: Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. METHODS AND RESULTS: Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. CONCLUSIONS: The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.

Disorder of sex development with germ cell tumors: Which is uncovered first?

BACKGROUND: Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery. DESIGN/METHODS: All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed. RESULTS: Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age. CONCLUSION: DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.

Pure pediatric ovarian immature teratomas: The French experience.

OBJECTIVE: To describe characteristics and outcome of pediatric ovarian immature teratomas (IT) to better define the place of chemotherapy. METHODS: Children with ovarian IT enrolled in TGM95 and TGM2013 studies were analyzed. Norris grading and International Federation of Gynecology and Obstetrics staging system were used. RESULTS: Thirty-six cases were identified with a median age of 11 years (range = 1-18): 35 of 36 stage I (17 stage IA, 13 stage IC, and 5 stage IX), including seven patients with gliomatosis peritonei (GP), and 1 stage IIIB (IT peritoneal implants). Centrally reviewed Norris grading was performed in 31 cases: 14 grade I and 17 grade II/III tumors. All patients underwent upfront surgery: 19 unilateral oophorectomy, 14 unilateral adnexectomy, 2 unilateral cystectomy, and 1 bilateral cystectomy. No extensive GP surgery was performed. Six patients received adjuvant vinblastin, bleomycin, and cisplatinum because of tumor rupture (n = 5, including two patients with GP) or stage III (n = 1). After a median follow-up of 39.5 months (range = 6-238), two events occurred 10 and 11 months after diagnosis: one bilateralization (initial stage IX, grade I) and one IT peritoneal relapse (initial stage IA, grade II), respectively. Both were successfully rescued by platinum-based chemotherapy and delayed surgery. No stage IC patients treated without adjuvant chemotherapy relapsed (four grade I and three grade III). None of the seven patients with GP progressed. Five-year event-free survival and overall survival were 94% (95% CI = 81-98%) and 100%. CONCLUSIONS: The current series confirms the excellent prognosis of pediatric ovarian IT, arguing for conservative surgical approach in GP and against systematic adjuvant chemotherapy, even in ruptured tumors.

Liver metastasis at diagnosis in children with nephroblastoma enrolled in SIOP2001 protocol: A French multicentric study.

BACKGROUND: Liver metastases are rare in children with Wilms tumor (WT), and their impact on the outcome is unclear. PATIENTS AND METHODS: The French cohort of patients with WT presenting liver metastases at diagnosis and enrolled in the International Society of Pediatric Oncology (SIOP) 2001 study was reviewed. RESULTS: From 2002 to 2012, 906 French patients were enrolled in the SIOP2001 trial. Among them, 131 (14%) presented with stage IV WT and 18 (1.9%) had liver metastases at diagnosis. Isolated liver metastases were displayed in four of them. After preoperative chemotherapy, persistent liver disease was reported in 14/18 patients, and 13 of them underwent metastasectomy after nephrectomy. In resected liver lesions, the same histology of the primary tumor was reported for three patients, blastemal cells without anaplasia were identified in one patient with DA-WT, and post-chemotherapy necrosis/fibrosis was identified for the other 10 patients. For the four patients who had liver and lung surgery, both sites had nonviable cells with post-chemotherapy necrosis/fibrosis. Six patients had hepatic radiotherapy. Sixteen patients achieved primary complete remission and were alive at the last follow-up (median follow-up: 6.4 years). The only two deceased patients presented diffuse anaplasia histology. The five-year EFS and OS were 83% (60%-94%) and 88% (66%-97%), respectively. CONCLUSION: Liver involvement does not appear to be an adverse prognostic factor in metastatic WT. The role of hepatic surgery and radiotherapy remains unclear, and should be carefully considered in case of persistent liver metastases, according to histology and radiological response to other metastatic sites.

Exploring heterogeneity of adrenal cortical tumors in children: The French pediatric rare tumor group (Fracture) experience.

INTRODUCTION: Pediatric adrenal cortical tumors are characterized by a wide spectrum of behavior. Questions remain regarding intermediate disease stages with isolated tumor rupture or relapse. OBJECTIVES: To describe clinical characteristics, treatment strategy, and outcome of patients depending on disease stage, tumor rupture, or in case of a refractory tumor, to discuss optimal management. MATERIAL AND METHODS: Pediatric patients with histological material reviewed and treated between 2000 and 2018 in 23 French oncology centers were included. RESULTS: Among 95 cases, 59% of patients had stage I tumors (n = 55), 16% had stage II tumors (n = 16), 19% had stage III tumors (n = 17), and 5% had stage IV tumors (n = 5) (missing data: 2). Overall, 27% of patients (n = 25) had an unfavorable histology. Initial tumor resection was performed for 90% of patients (n = 86). Systemic therapies included mitotane in 20 cases and chemotherapy in 13 cases. Among 17 stage III patients, 12 had microscopic residual tumor due to an initial biopsy (n = 5), intraoperative rupture (n = 8), or surgical resection with microscopic residue or tumor spillage surgery (n = 1) (two patients with two modalities). After a median follow-up of 96 months (25-119), four early progressions and two relapses occurred. A total of seven patients died, including five of disease. Stage III diseases due to microscopic residual disease correlated with a worse prognosis: 5-year progression-free survival 44% (95% CI, 22-87%) versus 82% (95% CI, 73-91%) for the whole cohort (P < .0001). Among the 14 patients with refractory disease, only 3 were alive and free of disease after multimodal second-line therapy. CONCLUSIONS: Stage III diseases due to a microscopic residual tumor have a dismal prognosis, arguing for the systematic use of adjuvant therapy. Patients with a relapsed disease should be included in experimental studies.

Revisiting the role of the pathological grading in pediatric adrenal cortical tumors: results from a national cohort study with pathological review.

The prognosis of malignant pediatric adrenocortical tumors is closely related to disease stage, which is used to guide perioperative treatment recommendations. However, current scoring systems are inadequate to distinguish between benign and malignant adrenocortical tumors. Robust microscopic prognostic features that could help determine perioperative therapy are also lacking. The aim of this national study was to review the prognostic value of the Wieneke scoring criteria and Ki67 labeling index in unselected pediatric adrenocortical tumors. Using strict definitions previously defined by expert pathologists, a Wieneke score was re-attributed to each tumor after an independent and centralized review. In addition, Ki67 proliferation index was performed and reviewed for each case. A total of 95 cases were selected; all were treated between 2000 and 2018 and had histopathologic material and sufficient outcome-related information available. Localized disease was found in 88% of patients. Among those with advanced disease, 6% had tumor extension into adjacent organs and 5% had metastases at diagnosis. Median follow-up was 5 years and 3 months. The 5-year PFS was 82%, 95% CI [73%-91%]. Tumor stage significantly correlated with PFS (p < 0.0001). Tumor weight up to 200 g, extra-adrenal extension and initial non-complete surgical resection were statistically associated with worse outcomes. No recurrences nor metastases occurred when the Ki67 index was < 15%. Up to two of the following five factors including tumor necrosis, adrenal capsular invasion, venous invasion, mitotic count > 15/20 high-power fields, and Ki67 index > 15%, significantly correlated with worse outcomes. We propose a pathological scoring system incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection. These results should be validated in an independent cohort.

Aggressive large B-cell lymphoma triggered by a parvovirus B19 infection in a previously healthy child.

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.

Mutiple DICER1-related lesions associated with a germline deep intronic mutation.

Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli-Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.

Hyperphosphatemic tumoral calcinosis caused by FGF23 compound heterozygous mutations: what are the therapeutic options for a better control of phosphatemia?

BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes encoding FGF23 or its regulators, and leading to functional deficiency or resistance to fibroblast growth factor 23 (FGF23). Subsequent biochemical features include hyperphosphatemia due to increased renal phosphate reabsorption, and increased or inappropriately normal 1,25-dihydroxyvitamin D (1,25-D) levels. CASE-DIAGNOSIS/TREATMENT: A 15-year-old girl was referred for a 1.2-kg-calcified mass of the thigh, with hyperphosphatemia (2.8 mmol/L); vascular impairment and soft tissue calcifications were already present. DNA sequencing identified compound heterozygous mutations in the FGF23 gene. Management with phosphate dietary restriction, phosphate binders (sevelamer, aluminum, nicotinamide), and acetazolamide moderately decreased serum phosphate levels; oral ketoconazole was secondary administered, leading to significantly decreased 1,25-D levels albeit only moderate additionally decreased phosphate levels. However, therapeutic compliance was questionable. Serum phosphate levels always remained far above the upper normal limit for age. The patient presented with two relapses of the thigh mass, requiring further surgery. CONCLUSIONS: We suggest that control of phosphate metabolism is crucial to prevent recurrences and vascular complications in HFTC; however, the medical management remains challenging.

Computer-assisted topological analysis of renal allograft inflammation adds to risk evaluation at diagnosis of humoral rejection.

Antibody-mediated rejection is associated with heterogeneous kidney allograft outcomes. Accurate evaluation of risk for graft loss at time of diagnosis is necessary to offer personalized treatment. In contrast with serological and molecular assessment, morpho-histological evaluation of antibody-mediated rejection lesions has not significantly evolved. This relies on Banff classifications designed to be of diagnostic discriminatory power rather than prognostic and face quantitative and qualitative limitations. Here we developed a method of Computer-assisted Analysis of Graft Inflammation (CAGI) to improve the classification of allograft inflammation. Digitization of immunostained biopsy sections, image processing and algorithm-driven analysis allowed quantification of macrophages, T cells, B cells, and granulocytes per unit surface of interstitium, capillaries or glomeruli. CAGI was performed on biopsy specimens of 52 patients with extensively phenotyped antibody-mediated rejection. Macrophage numbers in capillaries and interstitium, but not Banff scores or the amount of other immune cell subsets, correlated with donor-specific antibody (DSA) mean fluorescence intensity and DSA-C3d status. The quantity of macrophages in the interstitium and DSA-C3d status were the only independent predictors for significant allograft loss at the time of antibody-mediated rejection diagnosis (hazard ratio 3.71 and 2.34, respectively). A significant strategy integrating the DSA-C3d assay and the quantification of interstitial macrophages allowed identification of three groups with distinct renal prognosis: DSA-C3d-, DSA-C3d+/macrophages-low and DSAC3d+/macrophages-high. Thus, CAGI brings a missing piece to the antibody-mediated rejection puzzle by identifying morpho-histological processes that bridge in vitro parameters of DSA pathogenicity and graft loss. Hence, this approach could be useful in future integrated strategies of risk evaluation.

A novel disorder of sex development, characterized by progressive regression of testicular function and cystic leukoencephalopathy.

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc.