With the increasing use of magnetic resonance imaging (MRI) in the evaluation of children with endocrine disorders, pituitary stalk thickening (PST) poses a clinical conundrum due to the potential ...for underlying neoplasms and challenges in obtaining a tissue biopsy. The existing literature suggests Langerhans cell histiocytosis (LCH) to be the commonest (16%) oncologic cause for PST, followed by germ cell tumors (GCTs, 13%) (CCLG 2021). As the cancer epidemiology varies according to ethnicity, we present herein the incidence and predictors for oncologic etiologies in Hong Kong Chinese children with PST.
Based on a territory-wide electronic database, we reviewed patients aged < 19 years who presented to three referral centers with endocrinopathies between 2010 and 2022. Records for patients who underwent at least one MRI brain/pituitary were examined (
= 1670): those with PST (stalk thickness ≥ 3 mm) were included, while patients with pre-existing cancer, other CNS and extra-CNS disease foci that were diagnostic of the underlying condition were excluded.
Twenty-eight patients (M:F = 10:18) were identified. The median age at diagnosis of PST was 10.9 years (range: 3.8-16.5), with central diabetes insipidus (CDI) and growth hormone deficiency (GHD) being the most frequent presenting endocrine disorders. At a median follow-up of 4.8 years, oncologic diagnoses were made in 14 patients (50%), including 13 GCTs (46%; germinoma = 11, non-germinoma = 2) and one LCH (4%). Among patients with GCTs, 10 were diagnosed based on histology, two by abnormal tumor markers and one by a combination of histology and tumor markers. Three patients with germinoma were initially misdiagnosed as hypophysitis/LCH. The cumulative incidence of oncologic diagnoses was significantly higher in boys and patients with PST at presentation ≥6.5 mm, CDI or ≥2 pituitary hormone deficiencies at presentation and evolving hypopituitarism (all
< 0.05 by log-rank).
A higher rate of GCTs was observed in Chinese children with endocrinopathy and isolated PST. The predictors identified in this study may guide healthcare providers in Asia in clinical decision making. Serial measurement of tumor markers is essential in management.
This paper examines the link between CNS tumor biology and heterogeneity and the use of genome-wide DNA methylation profiling as a clinical diagnostic platform. CNS tumors are the most common solid ...tumors in children, and their prognosis remains poor. This study retrospectively analyzed pediatric patients with CNS embryonal tumors in Hong Kong between 1999 and 2017, using data from the territory-wide registry and available formalin-fixed paraffin-embedded tumor tissue. After processing archival tumor tissue via DNA extraction, quantification, and methylation profiling, the data were analyzed by using the web-based DKFZ classifier (Molecular Neuropathology (MNP) 2.0 v11b4) and t-SNE analysis. Methylation profiles were deemed informative in 85 samples. Epigenetic data allowed molecular subgrouping and confirmed diagnosis in 65 samples, verified histologic diagnosis in 8, and suggested an alternative diagnosis in 12. This study demonstrates the potential of DNA methylation profiling in characterizing pediatric CNS embryonal tumors in a large cohort from Hong Kong, which should enable regional and international collaboration in future pediatric neuro-oncology research.
Background
Despite neoadjuvant chemotherapy and wide surgical ablation, 15% to 25% of patients with primary osteosarcoma will relapse (local recurrence or metastases). Neither chemotherapy nor ...radiation therapy alone will render a patient disease-free without concomitant surgical ablation of relapse. We prefer excision of relapse when possible. However, it is unclear whether excision enhances survival.
Questions/purposes
We therefore determined (1) onset, location, and treatments for relapse; (2) postrelapse disease-free survival of patients who underwent surgical ablation and those who did not; and (3) relapse-free interval between initial diagnosis and first relapse in survivors and in those who died of their disease.
Methods
We retrospectively reviewed 15 children who initially presented with localized, nonmetastatic extremity osteosarcoma and attained initial complete remission after neoadjuvant chemotherapy, wide local resection, postoperative chemotherapy, and subsequently developed disease relapse. Relapse occurred at a median of 28 months, although late relapse after 5 years occurred in three. We resected the recurrent tumor in nine patients and treated six nonoperatively.
Results
Seven of nine surgically treated patients had a postrelapse disease-free survival ranging from 3 to 14 years and an overall survival ranging from 7 to 16 years. Patients not surgically treated all died within 40 months of their relapse. The median relapse-free interval in patients who survived was longer 34 months (range, 17–152 months) as compared with 17 months (range, 7–40 months) in those who died of their disease.
Conclusions
Our data confirm the importance of surgery in patients with relapsed osteosarcoma. Disease-free survival in patients with relapsed osteosarcoma is only possible if complete remission is attained. Patients with late relapse may have a better chance of survival.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Minimal residual disease, or MRD, is an important prognostic indicator in childhood acute lymphoblastic leukemia. In ALL-IC-BFM 2002 study, we employed a standardized method of flow cytometry MRD ...monitoring for multiple centers internationally using uniformed gating, and determined the relevant MRD-based risk stratification strategies in our local patient cohort. We also evaluated a novel method of PCR MRD quantitation using peripheral blood plasma. For the bone marrow flow MRD study, patients could be stratified into 3 risk groups according to MRD level using a single time-point at day-15 (Model I) (I-A: <0.1%, I-B: 0.1-10%, I-C: >10%), or using two time-points at day-15 and day-33 (Model II) (II-A: day-15<10% and day-33<0.01%, II-B: day-15 ≥ 10% or day-33 ≥ 0.01% but not both, II-C: day-15 ≥ 10% and day-33 ≥ 0.01%), which showed significantly superior prediction of relapse (p = .00047 and <0.0001 respectively). Importantly, patients with good outcome (frequency: 56.0%, event-free survival: 90.1%) could be more accurately predicted by Model II. In peripheral blood plasma PCR MRD investigation, patients with day-15-MRD ≥ 10(-4) were at a significantly higher risk of relapse (p = 0.0117). By multivariate analysis, MRD results from both methods could independently predict patients' prognosis, with 20-35-fold increase in risk of relapse for flow MRD I-C and II-C respectively, and 5.8-fold for patients having plasma MRD of ≥ 10(-4). We confirmed that MRD detection by flow cytometry is useful for prognostic evaluation in our Chinese cohort of childhood ALL after treatment. Moreover, peripheral blood plasma DNA MRD can be an alternative where bone marrow specimen is unavailable and as a less invasive method, which allows close monitoring.
Secreted-frizzled related proteins (SFRPs) are modulators of the Wnt signaling pathway that is closely involved in normal and malignant hematopoiesis. Epigenetic deregulation of Wnt modulators ...leading to aberrant signaling has been reported in adult patients with acute myeloid leukemia (AML), but its occurrence in childhood patients with AML and the role of individual modulators are unclear. In this study, we examined SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in 83 patients with AML (59 children and 24 adults) and found preferential SFRP1 methylation and mRNA down-regulation in the prognostically favorable subgroup of AML with t(8;21) translocation. Among the 4 genes, SFRP1 methylation independently predicted prolonged event-free and relapse-free survivals in childhood patients with nonacute promyelocytic leukemia with nonadverse cytogenetics. Mechanistically, we further demonstrated that RUNX1-ETO, the t(8;21) fusion product, specifically bound the SFRP1 promoter and repressed its transcription via a consensus RUNX binding site. In t(8;21)–leukemia cells, SFRP1 selectively inhibited canonical Wnt signaling and cellular proliferation that were associated with concomitant down-regulation of Wnt/β-catenin target genes, including CCND1 and MYC. Taken together, we identified SFRP1 as a transcriptional repression target of the t(8;21) fusion protein and demonstrated a novel mechanism of Wnt activation in a specific subtype of AML.
We report an unusual case of a pelvic extraovarian moderately differentiated Sertoli-Leydig cell tumor arising in a 4-yr-old female. The tumor contained a DICER1 pathogenic variant which was absent ...in the germline ruling out DICER1 syndrome. In reporting this case, we discuss the differential diagnosis and possible histogenesis and review reported cases of extraovarian Sertoli-Leydig cell tumor.
Despite being the most common pediatric solid tumors, incidence and outcome of CNS tumors in Chinese children have not been systematically reported. We addressed this knowledge gap by comparing the ...epidemiology of pediatric CNS tumors in Hong Kong and the United States.
Data between 1999 and 2016 from a population-based cancer registry in Hong Kong, China, on patients < 18 years old with CNS tumors (Hong Kong cohort) and from the US SEER Program (Asian/Pacific Islander and all ethnicities) were compared. Incidence and overall survival (OS) by histology were evaluated.
During the study period, 526 children were newly diagnosed with CNS tumors in Hong Kong (crude incidence rate, 2.47 per 100,000; 95% CI, 2.26 to 2.69). Adjusted incidences were significantly lower in the Hong Kong (2.51; 95% CI, 2.30 to 2.74) than in the SEER (Asian/Pacific Islander: 3.26; 95% CI, 2.97 to 3.57;
< .001; all ethnicities: 4.10 per 100,000; 95% CI, 3.99 to 4.22;
< .001) cohorts. Incidences of germ cell tumors (0.57
0.24;
< .001) were significantly higher, but those of glial and neuronal tumors (0.94
2.61;
< .001), ependymomas (0.18
0.31;
= .005), and choroid plexus tumors (0.08
0.16;
= .045) were significantly lower in Hong Kong compared with SEER (all ethnicities) cohorts. Compared with the SEER (Asian/Pacific Islander) cohort, histology-specific incidences were similar except for a lower incidence of glial and neuronal tumors in Hong Kong (0.94
1.74;
< .001). Among cohorts, OS differed only for patients with glial and neuronal tumors (5-year OS: Hong Kong, 52.5%; SEER Asian/Pacific Islander, 73.6%; SEER all ethnicities, 79.9%;
< .001).
We identified important ethnic differences in the epidemiology of CNS tumors in Chinese children. These results will inform the development of pediatric neuro-oncology services in China and aid further etiologic studies.
RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by 2 promoters P1 and P2, RUNX3 is frequently inactivated by P2 methylation in solid tumors. Growing ...evidence has suggested a role of this transcription factor in hematopoiesis. However, genetic alterations have not been reported in blood cancers. In this study on 73 acute myeloid leukemia (AML) patients (44 children and 29 adults), we first showed that high RUNX3 expression among childhood AML was associated with a shortened event-free survival, and RUNX3 was significantly underexpressed in the prognostically favorable subgroup of AML with the t(8;21) and inv(16) translocations. We further demonstrated that this RUNX3 repression was mediated not by P2 methylation, but RUNX1-ETO and CBFβ-MYH11, the fusion products of t(8;21) and inv(16), via a novel transcriptional mechanism that acts directly or indirectly in collaboration with RUNX1, on 2 conserved RUNX binding sites in the P1 promoter. In in vitro studies, ectopically expressed RUNX1-ETO and CBFβ-MYH11 also inhibited endogenous RUNX3 expression. Taken together, RUNX3 was the first transcriptional target found to be commonly repressed by the t(8;21) and inv(16) fusion proteins and might have an important role in core-binding factor AML.
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