NF2-related schwannomatosis is a tumor predisposition syndrome caused by diverse NF2 alterations, including truncating variants, copy-number changes, and non-truncating variants such as in-frame indels. Molecular and clinical correlations of these variant types remain incompletely defined, particularly for rare deletions. We present two distinct cases highlighting NF2 inactivation spectrum. Case 1 describes a 62-year-old man with a jugular foramen schwannoma harboring a novel somatic NF2 in-frame deletion (c.713_733del, p.Ala238_Tyr244del) resulting in complete Merlin expression loss. Structural modeling predicted FERM-C subdomain destabilization; copy-neutral loss of heterozygosity confirmed biallelic inactivation. Case 2 describes a 55-year-old woman with early-onset bilateral vestibular schwannomas caused by a germline whole-gene NF2 deletion, with additional somatic mutations (splice-site and frameshift) inactivating the second allele. Pedigree analysis demonstrated paternal inheritance, underscoring the relevance of genetic counseling. Both tumors displayed classical schwannoma histology with absent Merlin staining, confirming functional NF2 loss. These cases emphasize the necessity of comprehensive molecular testing-including targeted sequencing, whole-genome sequencing, and multiplex ligation-dependent probe amplification-to detect nucleotide-level and large-scale NF2 alterations; moreover, they expand the NF2 mutation spectrum, illustrate pathogenic mechanisms across germline and somatic contexts, and provide clinically actionable insights for Merlin-deficient tumors.

Background/AimNeurofibromatosis type 1 (NF1) is a tumor predisposition syndrome characterized by neoplasms originating from nerve sheath cells. The autosomal dominant hereditary disease also affects numerous developmental and metabolic processes, for example in the bones. The aim of the study was to document the diagnosis and treatment of an NF1 patient who had developed a space-occupying lesion at the base of the skull with noticeable mandibular changes.Case ReportThe patient, who presented for her initial examination as a teenager, had an asymmetrical lower face. The deformation of the lower jaw mainly affected the left ramus and was associated with a deviation of the chin region toward the affected side. MRI revealed a diffuse plexiform neurofibroma (PNF) on the left side, which spread within the dystrophic pterygoid muscles. Over a treatment interval of 21 years, the patient developed numerous PNF in various regions of the body. The extent of the skull base tumor and the degree of muscular dystrophy remained constant during this period. Similarly, the mandibular dysplasia already noted during the initial examination remained unchanged.ConclusionAlthough mandibular dysplasias associated with PNF are rare findings in patients with NF1, they often have a characteristic pattern and may remain unchanged for decades. Knowledge of tumor-associated mandibular dysplasia in patients with NF1 is essential for the differential diagnosis of tumors in this region which can become malignant.

Currently there are no therapeutic agents that are effective against both vestibular schwannoma and meningioma, the two most common tumour types affecting patients with the rare tumour predisposition syndrome NF2-related schwannomatosis. This study aimed to characterise the similarities and differences in the tumour immune microenvironments of meningioma and vestibular schwannoma to identify potential therapeutic targets viable for both tumour types. Publicly available bulk Affymetrix expression data for both meningioma (n = 22) and vestibular schwannoma (n = 31) were used to compare gene expression and signalling pathways, and deconvolved to predict the abundance of the immune cell types present. Publicly available single cell RNA sequencing data for both meningioma (n = 6) and vestibular schwannoma (n = 15) was used to further investigate specific T cell and macrophage subtypes for their signalling pathways, gene expression, and drug targets for predicted drug repurposing in both tumour types. Immune cells comprised a larger proportion of the vestibular schwannoma tumour microenvironment compared to meningioma and included a significantly higher abundance of alternatively activated macrophages. However, these alternatively activated macrophages, alongside other immune cell subtypes such as CD8 + T cells and classically activated macrophages, were predicted to be more active in meningioma than vestibular schwannoma. Despite these differences, T cells and tumour associated macrophages of both vestibular schwannoma and meningioma shared drug-target kinases amenable to drug repurposing with Food and Drug Administration (FDA) drugs approved for other conditions. These include bosutinib, sorafenib, mitoxantrone, and nintedanib which are yet to be clinically investigated for vestibular schwannoma or meningioma. Drug repurposing may offer an expedited route to the clinical translation of approved drugs effective for treating both meningioma and vestibular schwannoma to benefit NF2-related schwannomatosis patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02176-9.

Childhood cancer is a serious health issue that still does not receive sufficient attention on a global scale compared to cancer in adults. Specialized pediatric cancer registries play a crucial role in collecting detailed data on tumor types, treatment outcomes, genetic determinants, predisposition syndromes, and long-term treatment toxicity. The aim of this review is to emphasize the importance of collaboration between general and specialized pediatric cancer registries in epidemiological research of childhood malignancies and its impact on improving completeness of ascertainment, diagnosis, treatment, and follow-up care. The effective integration of data collected in general and pediatric cancer registries improves data quality and enables analysis of all relevant data, leading to advances in research, optimization of treatment, and improvement in the quality of care for pediatric cancer patients.

Introduction. Medulloblastomas (MB) of the SHH group account for 25–30% of all MBs and are associated with aberrant activation of the intracellular SHH signaling pathway. The incidence of tumor predisposition syndromes (TPS) in patients with MB of the SHH group is about 20%, and this is the highest rate among the other molecular genetic subgroups of MB. In addition, there is significant molecular genetic heterogeneity within the same group, which in turn contributes to variations in survival rates and prognosis. Objective – to analyze the clinical, molecular, and genetic characteristics of TPS in patients with SHH group MB. Materials and methods. This retrospective study included a cohort of 40 patients aged 0 to 18 years with SHH group MB who underwent molecular genetic diagnostic testing between 2018 and 2024 at the D. Rogachev National Medical Research Center. The MB group was determined using NanoString technology. To identify germline mutations, DNA isolated from peripheral blood was examined using the following methods: next-generation sequencing, whole genome sequencing, Sanger sequencing, multiplex ligation-dependent probe amplification. The amplification of the MYC and NMYC genes was detected using fluorescence in situ hybridization. This study did not require approval from the local Ethics Committee, as the analyzed data did not contain any personalized information. Consent was obtained for the peripheral blood testing for TPS and for the publication of the data. Statistical processing and analysis of the data obtained were carried out using the R package version 4.4.2. Overall survival was estimated using the Kaplan–Meier method, and the cumulative incidence of secondary tumors was estimated using the competing risk method. To calculate the overall survival, we used the time from the date of diagnosis to death, and for the cumulative incidence of secondary tumors, we used the time from the date of diagnosis to the development of a secondary tumor, while death was considered a competing event. Results. Fifteen out of 40 patients were diagnosed with TPS. Gorlin syndrome was diagnosed in 7 people, Li–Fraumeni syndrome in 4 patients, there was one case each of Lynch syndrome and neurofibromatosis type 1, and a mutation in the ELP1 gene. One child had a combination of two syndromes (Gorlin and Lynch). The incidence of TPS in the analyzed cohort of 40 people was 37.5%. Thirteen people are alive, 2 patients died. The overall 4-year survival rate was 93% (the 95% confidence interval 82–100). A secondary tumor developed in 4 patients. The 4-year cumulative incidence of secondary tumors was 31% (the 95% confidence interval 6.4–61.0). All patients who developed a secondary tumor had received radiation therapy. Conclusion. When detecting MB of the SHH, it is important to conduct molecular genetic testing for TPS, given their high frequency among patients with MB of this molecular subgroup. The data obtained will help optimize therapy (avoid radiation therapy for young children with confirmed Gorlin syndrome), as well as predict the course of the disease. In addition, genetic testing is necessary for follow-up of such patients and for counseling their parents regarding the familial forms of the described syndromes.

Broadening the Clinical and Molecular Spectrum of BAP1 Tumor Predisposition Syndrome: Findings from the First Reported Turkish Cohort

DICER1 syndrome is a relatively recently identified hereditary tumor predisposition syndrome, strongly associated with pleuropulmonary blastoma (PPB) and other neoplasms, but its actual status in Japan is unclear. We retrospectively performed germline DICER1 gene analysis in patients with suspected PPB at our institute between 2003 and 2022. Relevant clinical data were extracted from the medical records. Six patients with PPB were identified, of whom four harbored pathogenic germline variants in DICER1. Only one patient had a family history of childhood or juvenile cancer. Genetic testing of unaffected family members was performed in two families, revealing three asymptomatic carriers, including one infant carrier. Two of the three carriers underwent active surveillance, and no new tumors were detected on follow-up at 6 and 2.5years after diagnosis, respectively. A high prevalence of DICER1 germline variants was observed in patients with PPB, consistent with previous studies. Family history alone may be insufficient to suspect DICER1 syndrome, and thus, proactive genetic testing of family members is advisable in all cases of PPB.

Background:BAP1-tumor predisposition syndrome (BAP1-TPDS) is associated with four main cancers: uveal melanoma, cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. However, there are additional cancers found more rarely in BAP1-TPDS patients. The aim of this study was to investigate the association, clinical, and pathologic characteristics of meningioma in BAP1-TPDS.Methods:We conducted a retrospective chart review of meningiomas in two independent cohorts of patients with germline BAP1 pathogenic or likely pathogenic (P/LP) variants at The Ohio State University Wexner Medical Center and at the Memorial Sloan Kettering Cancer Center from October 1st, 2010 date to April 21st, 2025. Additionally, we conducted a literature review of meningioma case studies for individuals with germline BAP1 (P/LP) variants.Results:In a cohort of 237 subjects with BAP1-TPDS, we identified 6.8% (16/237) with history of meningiomas. The average age of diagnosis was 45.8 years (17–71). For patients with available pathology, 61.5% (8/13) of the tumors were grade II/III. Patients with available tumor tissue 83.3% (5/6) showed evidence of BAP1 biallelic inactivation. Family history of meningioma was reported in 18.8% (3/16) of patients. Three cases of meningioma were identified during meningioma surveillance imaging. Published cases were consistent with the early age of onset, high-grade tumors, and clinical phenotype of tumors.Conclusions:This study provides additional evidence that high-grade brain and spinal meningiomas are part of the clinical spectrum of BAP1-TPDS. Craniospinal imaging surveillance in the BAP1-TPDS population should be considered starting around puberty, enabling early detection and management for individuals with BAP1-TPDS.

The DICER1 gene, essential for microRNA biogenesis and posttranscriptional gene regulation, has been implicated in a variety of benign and malignant neoplasms, particularly within the context of the DICER1-related tumor predisposition syndrome. While DICER1-associated rhabdomyosarcomas (RMS) are predominantly documented in the genitourinary tract, we present the first case of a DICER1-mutated embryonal-like (botryoid-like) RMS of the nasal fossa. A 63-year-old woman without relevant family history presented with nasal obstruction, headaches, and epistaxis and underwent resection of a polypoid sinonasal mass. Histopathological analysis revealed a spindle cell neoplasm with prominent botryoid growth, rhabdomyogenic features, and foci of metaplastic cartilage. Immunohistochemistry demonstrated positivity for desmin, myogenin, and MyoD1, prompting molecular testing that confirmed pathogenic DICER1 and KRAS mutations. Germline testing was negative for DICER1 alterations, and the DICER1 variant was determined to be somatic. The covering respiratory epithelium showed prominent hyperplastic changes, in areas closely mimickingbiphenotypic sinonasal sarcoma. Targeted RNA sequencing revealed no gene fusions involving MAML3, FOXO1, PAX3, or other genes. This case underscores the broad differential diagnosis of spindle cell lesions of the sinonasal tract and highlights the utility of combined morphology, immunohistochemistry, and molecular testing in establishing a diagnosis. Notably, the presence of cartilage foci within a RMS-like neoplasm represents a strong clue to an underlining DICER1 alteration. The rarity of this presentation in the nasal fossa at this age, coupled with its implications for diagnosis, treatment, and familial screening, emphasizes the need for awareness ofthe morphology patterns of DICER1-associated neoplasms across diverse anatomical sites.

Do urinary bladder smooth muscle neoplasms show morphologic and immunophenotypic features of their uterine fumarate hydratase-deficient counterparts?

Muir-Torre syndrome (MTS) is a hereditary tumor predisposition syndrome associated with sebaceous neoplasms. Immunohistochemistry (IHC) for loss of mismatch repair (MMR) proteins in these tumors is used as a screening test, but its diagnostic accuracy has not been rigorously assessed. We conducted a meta-analysis of 25 studies involving 692 patients who underwent IHC testing for MMR protein loss in sebaceous neoplasms. The pooled sensitivity was 0.84 (95% CI: 0.75-0.90) and specificity was 0.46 (95% CI: 0.28-0.66), with significant inter-study heterogeneity in specificity (I2, 77%). Restricting the meta-analysis to more rigorous studies with exposure-based designs and germline mutation as the reference standard yielded higher sensitivity (0.91; 95% CI: 0.83-0.96) and lower specificity (0.14; 95% CI: 0.06-0.27). Hypothetically restricting testing to patients under 60 years or tumors outside the head/neck locations increased specificity (0.87 and 0.88, respectively) but reduced sensitivity (0.60 and 0.37, respectively). A two-antibody panel (MSH6 and PMS2) performed equivalently to a four-antibody panel (MLH1, MSH2, MSH6, and PMS2). IHC testing can discriminate between sporadic and MTS-associated sebaceous neoplasms, but diagnostic utility is limited by low specificity. Most MMR-deficient cases are not due to MTS.

Schwannomatosis refers to a group of rare genetic syndromes characterized by a predisposition to develop nerve sheath tumors, specifically schwannomas. Although germline and mosaic (described in the NF2 gene) pathogenic variants in NF2, SMARCB1, and LZTR1 account for the majority of cases, a subset of affected individuals remains without a definitive molecular diagnosis, including those associated with 22q loss of heterozygosity at the tumor level. The absence of a specific disease cause limits effective risk assessment, clinical surveillance, and genetic counselling. In recent years, advances in sequencing technologies have facilitated the identification of novel candidate driver genes. However, the rarity of these findings makes it challenging to establish their pathogenic relevance. This review aims to evaluate the current knowledge of genetic contributors to schwannomatosis in patients for whom routine genetic testing fails to detect a molecular cause in the known associated genes. On chromosome 22, DGCR8 and SOX10 have emerged as novel susceptibility genes, supported by accumulating molecular and clinical data. In addition, genes such as CDKN2A and SMARCA4 may also contribute to schwannomatosis in the context of broader tumor predisposition syndromes. These emerging genetic associations may help explain a proportion of schwannomatosis cases that currently lack a molecular diagnosis, while there is still room for the discovery of non-coding alleles or mosaic forms of known schwannomatosis-related conditions as well as novel genes that could explain unresolved cases.

Onychocytic matricoma (OCM) is an acquired benign onychogenic tumor producing a localized thickening of the nail plate that usually presents as longitudinal pachymelanonychia. However, longitudinal pachyleukonychia as the presenting sign of OCM is increasingly recognized in clinical practice. To our knowledge, polydactylous OCM has not previously been reported in the literature. This study aims to describe a new nail genodermatosis presenting as polydactylous longitudinal leukonychia with histology typical of OCM. Four cases were identified. The previously unreported familial nail abnormality occurred in at least 2 first-degree relatives. Longitudinal white bands located exclusively on the fingernails were the only characteristic of this disease. The longitudinal bands varied in number from 2 to 4 per nail. Nail changes may appear during childhood, but most cases were observed between the ages of 20 and 50 years. The multiple longitudinal bands corresponded histologically to multiple OCM. Three cases in this series had no relevant personal of family history of neoplasm, but only 2 generations were analyzed. In 1 family, polydactylous OCM was associated with a family history of melanoma and renal cell carcinoma. The genomic profile of this single family allowed a diagnosis of OCM associated with BRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS). Our results are limited by incomplete follow-up and the small size of this retrospective case series. As such tumors are rare, additional cases need to be collected to clarify the role of onychocytic hamartoma as an early indicator of BAP1 TPDS.

Hereditary renal cell carcinoma (RCC) accounts for approximately 5-8% of all renal cancers. This review provides a comprehensive overview of the seven hereditary RCC syndromes recognized by the National Comprehensive Cancer Network: Tuberous Sclerosis Complex (TSC), Von Hippel-Lindau (VHL), Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), Hereditary Papillary Renal Carcinoma (HPRC), Birt-Hogg-Dubé syndrome (BHDS), Succinate dehydrogenase (SDH)-deficient RCC/Hereditary Paraganglioma/Pheochromocytoma (PGL/PCC) syndrome, and BAP1 tumor predisposition syndrome (BAP1-TPDS). For each syndrome, the underlying inheritance, epidemiology, and clinicopathologic features of their associated RCCs are detailed. Furthermore, radiographic challenges faced in the diagnosis of RCC in some of these syndromes are discussed, including differentiating RCC from the more common lipid-poor AML in TSC, distinguishing papillary RCC from hemorrhagic cysts in HPRC, and discerning chromophobe RCC from oncocytomas in BHDS. Radiologists are integral to the multidisciplinary management of hereditary RCC, as they are often the first to identify clinicopathologic features suggestive of an underlying genetic syndrome. Recognizing these patterns is crucial for prompting timely genetic evaluation, guiding decisions for nephron-sparing interventions, and establishing appropriate surveillance for patients and their at-risk family members. Advances in radiogenomics and artificial intelligence hold promise for further refining non-invasive diagnosis and personalizing patient care.

Recent developments in genetic testing have demonstrated that cancer predisposition syndrome (CPS) is present in approximately 15% of pediatric central nervous system (CNS) tumors; however, the optimal eligibility and timing of germline genetic testing in these patients have not been determined yet. We retrospectively examined the clinical and genetic characteristics of pediatric CNS tumor patients diagnosed with CPS at Saitama Children's Medical Center between December 2016 and December 2022. Among approximately 83 pediatric CNS tumor patients at our institution, 12 (14.5%) were diagnosed with CPS. Only 2 patients had a family history of cancer. A total of 6 patients were identified with CPS before developing a tumor, including 4 with neurofibromatosis type 1, one with 22q11.2 deletion syndrome, and one with von Hippel-Lindau disease. The remaining 6 patients were identified as having CPS only after the development of tumors in 2 with Li-Fraumeni syndrome, one with familial adenomatous polyposis, one with Cowden disease, one with rhabdoid tumor predisposition syndrome, and one with Gorlin syndrome. Cancer gene panel testing discovered germline mutations in 4 patients. Notably, one patient with a lateral ventricle tumor was provisionally diagnosed with choroid plexus carcinoma following the finding of a TP53 germline mutation by liquid biopsy. Another patient with 22q11.2 deletion syndrome developed pineoblastoma, with confirmed biallelic inactivation of DGCR8. A subset of CPS in pediatric CNS tumors was challenging to diagnose before tumor development. These findings highlight the need for refined genetic screening criteria to enhance CPS diagnosis and management.

Abstract Neurofibromatosis type 1 (NF-1) is an autosomal dominant tumor predisposition syndrome caused by germline mutation of the NF1 tumor suppressor gene, yet NF-1 individuals exhibit marked clinical heterogeneity. We identified 220 people (median age: 34, age range: 5-81 years) treated at the University of California San Francisco between 2015-2025 who met the clinical diagnostic criteria for NF-1. Comprehensive clinical data were extracted from the medical record, spanning dermatologic, skeletal, cardiovascular, neurocognitive, and tumor-related features. DNA mutation analysis was performed for a subset using either a CLIA certified targeted DNA sequencing assay (n=94, 43%) or whole exome sequencing (n=18, 8%). Consistent with NF-1 epidemiology, the most prevalent non-tumor findings were café-au-lait macules (n=192, 87%), axillary/inguinal freckling (n=171, 77%), neurocognitive delay (n=53, 24%), scoliosis (n=29, 13%), cardiovascular abnormalities (n=20, 9%) and long bone dysplasia (n=6, 3%). The most common tumors were cutaneous neurofibromas (n=172, 78%), plexiform neurofibromas (n=138, 63%), non-optic gliomas (n=48, 22%), and optic pathway gliomas (n=30, 14%). MPNSTs (n=64, 29%) were enriched compared to reported NF-1 epidemiology (10%). There were no statistically significant differences in age, biologic sex, or race between patients who developed MPNSTs and those who did not. Across the entire cohort, molecularly detected NF1 variants comprised nonsense (n=29, 26%), missense (n=23, 21%), frameshift (n=28, 25%), splice-site (n=22, 20%) mutations, or deletions (n=10, 9%). Patients who developed MPNSTs commonly harbored a definitive loss of function deletion, nonsense, or frameshift variant (n=34/39, or 87%) and were significantly less likely to harbor missense variants (n=3/39 versus n=20/73 in patients without MPNST; p=0.01, chi-square test). In sum, our single institution cohort enriched for aggressive tumor phenotypes in people with NF-1 identifies NF1 variants associated with MPNSTs, providing a unique resource for defining biomarkers of malignant tumor development in this common neurogenetic cancer predisposition syndrome.

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome associated with pathogenic variants affecting the GTPase-activating protein neurofibromin. Genetic variants affect neurofibromin through targeted protein degradation, failed aggregation of the monomers or failure of specific domains depending on the functional state. In addition to the occurrence in NF1, there is evidence of pathogenic variants occurring in various solid tumors. We collected data from 63 patients from our molecular tumor board for NF1 gene sequencing and detected 72 NF1 variants, thereby 32% of those being pathogenic. They occurred most often in lung cancer, glioma, melanoma, sarcoma, and gynecological cancer and affected women more often. Pathogenic NF1 variants appeared at low frequency except in malignant melanoma and glioma (10%). We present common pathogenic variants, their types, and association with tumor entities, their frequency, and domain localization and focus on common recurrent variants and their probable result and predictive quality in somatic mutation screening. We detected variants in different tumor entities without NF disease, covering more frequent truncating mutations than reported for germline. We question whether all NF1 variants reported in tumors without the presence of NF1 are somatic. To conclude, recognition of NF1 mosaicism requires multitissue sampling, precise sequencing technologies, and inclusion of genetic counseling.

<i>Introduction</i>: Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome is a rare tumour predisposition and polyposis syndrome that presents in childhood. It is caused by mutations in mismatch repair (MMR) genes that result in a tumour spectrum including colorectal cancers, high-grade gliomas, non-Hodgkin T-cell lymphomas and leukaemias. It is characterized by biallelic germline mutation of one of four MMR genes that can be identified by immunohistochemistry. Immunohistochemistry is used in screening for Lynch syndrome (LS); however, the pattern of loss-of-staining in the background, non-tumour tissue is unique to CMMR-D syndrome. CMMR-D syndrome is seen in LS families and occurs as a result of consanguinity or founder effect. In South Africa, LS families in the Western and Northern Cape Provinces show a unique <I>MLH1</I> c1528C>T mutation. The diagnosis of CMMR-D syndrome includes clinical findings outlined in the European Consortium’s Care of CMMRD document and confirmation of biallelic mutation in one MMR gene. Immunohistochemistry can be used in the diagnosis of CMMR-D syndrome by identifying cases for targeted molecular genetic tests. Loss of staining of the affected gene in the background, non-tumour tissue, is a key feature of CMMR-D syndrome. <i>Methods</i>: A retrospective analysis of archival, formalin fixed paraffin embedded tissue was performed on specimens of children attending Red Cross Children’s Hospital with tumours that form part of the CMMR-D spectrum, outlined by the Care for CMMRD criteria. We used the criteria of high-grade gliomas (WHO Grade III or IV) occurring before 25 years of age, cutaneous lesions suggestive of CMMR-D syndrome and patients with a first or second degree relative diagnosed with LS. Immunohistochemistry was performed and the staining pattern was documented using a modified Allred Scoring system. Specific attention was given to the characterization of the staining pattern of the background normal tissue. <i>Results</i>: 21 samples evaluated from 18 patients. 16 samples represented brain tumours. Three inadequate samples were excluded. 12 samples showed intact staining. Two samples showed staining of unknown significance. Four samples from 3 different patients showed staining patterns compatible with MMR deficiency. Of these four samples, three samples showed loss of staining in background non-tumour tissue with positive external control. <i>Conclusion</i>: MMR immunohistochemistry can be used in the evaluation of CMMR-D syndrome. The pattern and scoring of both the tumour and the background non-tumour tissue is critical. The diagnosis of CMMR-D syndrome depends on clinical application of Care for CMMRD criteria, MMR immunohistochemistry in conjunction with molecular genetic testing.

Introduction: In children, papillary thyroid cancer (PTC) is generally sporadic and may, less frequently, be part of an undiagnosed hereditary tumor predisposition syndrome (HTPS). Somatic molecular testing is useful to understand tumor etiology and behavior, predict prognosis, and possibly guide development of novel treatment strategies. The aims of our study were to analyze the findings of a next-generation sequencing (NGS) panel in a cohort of pediatric PTC from Argentina according to age at presentation, recurrence risk, and response to treatment. Methods: A retrospective descriptive study was conducted of 63 consecutive pediatric patients with PTC seen at a single center in whom a DNA-based NGS panel was performed. The patients were classified according to the ATA-2015 recurrence risk stratification into a low (n = 10), an intermediate (n = 13), and a high-risk group (n = 40). All patients were treated with total thyroidectomy and radioiodine. At the last follow-up, patients were classified as excellent response (ER) or having persistent disease (PD). Results: In 70% (44/63) of the samples, a pathogenic somatic variant was detected; the most frequent alterations were RET fusions (20%). Fusions were more frequent in younger patients (median age 11.45 vs. 13.7 years; p = 0.048), in diffuse sclerosing subtype histology (p = 0.01) and in the high-recurrence risk group (p < 0.014). The risk of PD was higher in patients in the high-risk group (odds ratio, 9.2). When evaluating treatment response based on molecular findings, we found that among the 25 patients who achieved ER, 12 (48%) had fusions and 13 (52%) had point variants, with no statistically significant difference. However, among the 19 patients with PD, 12 (64%) had fusions and 7 (36%) had point variants, a difference that was statistically significant (p < 0.01). In 5/63 (8%), pathological germline mutations were observed in genes associated with HTPSs: DICER1 (n = 2), PTEN (n = 1), and MSH6 (n = 2). Conclusions: Interestingly, in our PTC cohort, the NGS panel was highly specific to detect molecular alterations. Fusions were more frequent at a younger age and in the ATA-2015 high-recurrence-risk group; however, it was not a determining factor to predict PTC outcome. Finally, detection of pathological germline mutations in genes involved in HTPS was useful for genetic counseling.

Renal haemangioblastoma is a very rare mesenchymal neoplasm that remains incompletely characterized despite its inclusion in the WHO classification. In this study, we investigate the clinicopathologic and molecular features of renal haemangioblastoma. The cohort comprised 8 patients (six male, two female) with a median age of 47 years (range: 29-63). No patients had a known history of a tumour predisposition syndrome. The tumours ranged in size from 1.3 to 8.0 cm (median: 4.0 cm). Histologically, the tumours were well circumscribed and composed of epithelioid/polygonal cells with clear-to-palely eosinophilic and often multivacuolated cytoplasm. In other areas, the tumour cells were more spindled. A prominent vascular pattern was frequently present. Two tumours were closely associated with renal cell carcinoma (RCC); the latter demonstrated features characteristic of RCC with fibromyomatous stroma (FMS). Targeted DNA sequencing was successfully performed on 7 tumours, revealing that most (5/7; 71%) harboured one or more alterations involving mTOR pathway genes. A total of 9 mTOR pathway alterations were identified, affecting MTOR (n = 3), TSC1 (n = 4), TSC2 (n = 1) and PTEN (n = 1). Immunohistochemistry for glycoprotein nonmetastatic B (GPNMB) was positive in 5/6 tumours assessed, including one tumour that lacked an identifiable mTOR pathway alteration by sequencing. This study contributes further understanding to the pathogenesis of renal haemangioblastoma and supports that it exists on a spectrum with RCC with haemangioblastoma-like features and RCC with FMS.