Appendiceal mucinous neoplasm in adolescence: Diagnosis, management, and surveillance.

This case report describes a 17-year-old patient with a low-grade appendiceal mucinous neoplasm. The patient presented with non-bloody diarrhea, abdominal pain, and weight loss. A colonoscopy revealed a cecal polypoid mass that required laparoscopic surgery. The residual appendix was dilated with myxoglobulosis and histopathology confirmed the diagnosis of a low-grade appendiceal mucinous neoplasm staged pT3Nx. The potential risk of pseudomyxoma peritonei is a serious complication of these tumors. Surveillance plans include computed tomography abdomen and pelvis, and tumor markers every 6 months for the next 2 years. This case highlights the importance of considering appendiceal malignancy in patients with abdominal pain and weight loss, despite the rarity of the disease. It also emphasizes the need for careful monitoring due to the possible complications associated with these tumors. Treatment and prognosis for appendiceal neoplasms depend on the histopathologic characteristics, tumor-nodes-metastasis stage, tumor grade, and presence of peritoneal disease.

Potential prognostic determinants for FET::CREB fusion-positive intracranial mesenchymal tumor.

Intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class "IMT, subclass B", one to "meningioma-benign" and one to "meningioma-intermediate". A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4-79 years) and a slight female predominance (female/male ratio = 1.55). Among the confirmed fusions, 25 (33.8%) featured an EWSR1::ATF1 fusion, 24 (32.4%) EWSR1::CREB1, 23 (31.1%) EWSR1::CREM, one (1.4%) FUS::CREM, and one (1.4%) EWSR1::CREB3L3. Among 66 patients with follow-up information available (median: 17 months; range: 1-158 months), 26 (39.4%) experienced progression/recurrences (median 10.5 months; range 0-120 months). Ultimately, three patients died of disease, all of whom underwent a subtotal resection for an EWSR1::ATF1 fusion-positive tumor. Outcome analysis revealed subtotal resection as an independent factor associated with a significantly shorter progression free survival (PFS; median: 12 months) compared with gross total resection (median: 60 months; p < 0.001). A younger age (< 14 years) was associated with a shorter PFS (median: 9 months) compared with an older age (median: 49 months; p < 0.05). Infratentorial location was associated with a shorter overall survival compared with supratentorial (p < 0.05). In addition, the EWSR1::ATF1 fusion appeared to be associated with a shorter overall survival compared with the other fusions (p < 0.05). In conclusion, IMT is a locally aggressive tumor with a high recurrence rate. Potential risk factors include subtotal resection, younger age, infratentorial location, and possibly EWSR1::ATF1 fusion. Larger case series are needed to better define prognostic determinants in these tumors.

An epigenetic clock for gestational age based on human umbilical vein endothelial cells from a diverse population of newborns.

Background: Epigenetic clocks are emerging as a useful tool in many areas of research. Many epigenetic clocks have been developed for adults; however, there are fewer clocks focused on newborns and most are trained using blood from European ancestry populations. In this study, we built an epigenetic clock based on primary human umbilical vein endothelial cells from a racially and ethnically diverse population. Results: Using human umbilical vein endothelial cell [HUVEC]-derived DNA, we calculated epigenetic gestational age using 83 CpG sites selected through elastic net regression. In this study with newborns from different racial/ethnic identities, epigenetic gestational age and clinical gestational age were more highly correlated (r = 0.85), than epigenetic clocks built from adult and other pediatric populations. The correlation was also higher than clocks based on blood samples from newborns with European ancestry. We also found that birth weight was positively associated with epigenetic gestational age acceleration (EGAA), while NICU admission was associated with lower EGAA. Newborns self-identified as Hispanic or non-Hispanic Black had lower EGAA than self-identified as non-Hispanic White. Conclusions: Epigenetic gestational age can be used to estimate clinical gestational age and may help index neonatal development. Caution should be exercised when using epigenetic clocks built from adults with children, especially newborns. We highlight the importance of cell type-specific epigenetic clocks and general pan tissue epigenetic clocks derived from a large racially and ethnically diverse population.

Endobronchial mucoepidermoid carcinoma in a pediatric patient: A case report.

Mucoepidermoid carcinoma (MEC) is an uncommon type of salivary gland tumor that can present as an endobronchial neoplasm, most commonly in the adult population. Neuroendocrine carcinoid tumors comprise the majority of bronchial neoplasms in the pediatric population and are nearly indistinguishable from MEC on imaging. We present a rare case of MEC in a 3-year-old presenting with recurrent symptoms of lower airway obstruction and discuss its typical associated symptoms and imaging features.

The long noncoding RNA lnc-HLX-2-7 is oncogenic in Group 3 medulloblastomas.

BACKGROUND: Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs. METHODS: Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq. RESULTS: Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7-deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression. CONCLUSIONS: Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.

Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.

Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection.

Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.

Solitary Duodenal Ulcer Causing Biliary Obstruction Requiring Rendezvous Procedure in a Pediatric Patient With Eosinophilic Gastroenteritis.

Eosinophilic gastroenteritis (EGE) is an uncommon disease characterized by immune cell-mediated inflammation of the gastrointestinal (GI) tract resulting in vague abdominal symptoms, most commonly nausea, vomiting, diarrhea, and abdominal pain. We report the case of a 16-year-old male presenting with a six-week history of progressive pruritus, jaundice, fatigue, abdominal pain, acholic stools, and dark-colored urine. This patient was diagnosed via endoscopy with biliary obstruction caused by a large, solitary, duodenal ulcer secondary to EGE. This is a severe complication of EGE and to our knowledge, this is the first reported case of biliary obstruction caused by a duodenal ulcer in a pediatric patient with EGE. Additionally, we describe the first pediatric combined percutaneous-endoscopic rendezvous technique after failed therapeutic endoscopic retrograde cholangiography (ERCP) to relieve the biliary obstruction.

TRIM28 congenital predisposition to Wilms' tumor: novel mutations and presentation in a sibling pair.

Wilms' tumor is the most common renal malignancy in children. In addition to staging, molecular risk stratification, such as loss of heterozygosity (LOH) in Chromosomes 1 and 16, is being increasingly used. Although genetic predisposition syndromes have been well-characterized in some Wilms' tumors, recent sequencing and biology efforts are expanding the classification of this malignancy. Here we present a case of siblings with remarkably similar presentations of bilateral Wilms' tumor at ∼12 mo of age. Thorough exam after the younger sibling was diagnosed did not reveal any signs to suggest one of the known Wilms' predisposition syndromes. Both were treated with standard therapies with good response and long-term sustained complete remission of 53 and 97 mo, respectively. Whole-exome sequencing was performed on a tumor sample from each patient and matched blood from one, revealing a shared truncation mutation of TRIM28 in all three samples with heterozygosity in the germline sample. TRIM28 loss has been recently implicated in early-stage Wilms' tumors with epithelioid morphology. These siblings expand the phenotype for presentation with multifocal disease with retained excellent response to standard therapy.

Chondroblastoma of bone in the extremities: a multicenter retrospective study.

BACKGROUND: Chondroblastoma is a rare benign cartilage tumor that commonly occurs in children and adolescents. This study was designed to review the epidemiologic characteristics and outcomes of surgical management in a large series of patients with extremity chondroblastoma. METHODS: We performed a multicenter retrospective analysis of 199 patients with extremity chondroblastoma. Clinical data, radiographic images, histological findings, treatment, and outcome were analyzed. RESULTS: There were 145 male patients and fifty-four female patients with a mean age of 18.0 years. The most commonly involved bone was the proximal part of the tibia (fifty-five patients [27.6%]), followed by the proximal part of the femur (fifty-two patients [26.1%]) and the distal part of the femur (thirty-eight patients [19.1%]). Prior to presentation, 73.4% (146 of 199 patients) experienced pain. The mean duration of pain and other symptoms was 8.7 months. The physis was open in 25.7%, it was closing in 22.2%, and it was closed in 52.1% of the patients at the time of presentation. One hundred and twenty-six patients had at least twenty-four months of follow-up; their mean follow-up duration was 62.1 months (range, twenty-four to 190 months). Initial treatment was curettage for 119 patients (94.4%) and en bloc resection for seven patients (5.6%). The local recurrence rate was 5.0% after curettage and 0% after resection. The only significant factor related to recurrence was the location of the lesion in the proximal part of the humerus (p = 0.001). CONCLUSIONS: Chondroblastoma occurs most frequently in the proximal part of the tibia and the proximal part of the femur with significant male predilection. In this series, recurrence was most frequent in the proximal part of the humerus. Our results suggest that curettage and bone-grafting provide favorable local control and satisfactory functional outcome for patients with this disease. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Primary Burkitt's lymphoma of the colon--an uncommon cause of acute constipation and abdominal pain.

Constipation is a common problem in children and adolescents, accounting for over 25% of all visits to pediatric gastroenterologists. Approximately 95% of childhood constipation is functional in nature. Primary gastrointestinal malignancies are rare in childhood and adolescence. When present in the gastrointestinal tract, Burkitt's lymphoma is typically located in the ileocecal region. We present a case of primary Burkitt's lymphoma of the transverse colon in an adolescent presenting with acute exacerbation of constipation, abdominal pain, and later, rectal bleeding and progressive weight loss.

Subcutaneous panniculitis-like T-cell lymphoma in a child with trisomy 21.

Subcutaneous Panniculitis-Like T-cell Lymphoma (SPTCL) is a rare lymphoma with fewer than twenty cases reported in children less than 18 years of age. Trisomy 21 is a chromosomal abnormality associated with a risk of malignancy that differs from their normal counterparts. Leukemia is diagnosed 10-20 times over the general population while solid tumors are underrepresented. The risk for Lymphoma historically has been elevated as well. We describe a case of a 3 year-old girl with Down syndrome who was successfully treated for SPTCL.

Histologic assessment of thermal injury to tonsillectomy specimens: a comparison of electrocautery, coblation, harmonic scalpel, and tonsillotome.

OBJECTIVES/HYPOTHESIS: To determine the extent of thermal injury to the tonsillar tissue following the use of various types of instrumentation. To determine if tonsillectomy specimens routinely contain tissue other than lymphoid tissue. STUDY DESIGN: Retrospective histologic analysis. METHODS: A histologic analysis performed on 228 tonsillectomy specimens removed by use of an electrocautery in 132 specimens, harmonic scalpel in 46, coblation device in 24, and a tonsillotome in 26. The specimens were evaluated for presence and percentage of skeletal muscle and depth of thermal tissue injury. RESULTS: The mean percentage of skeletal muscle present in the specimens was 0.79% for electrocautery, 1.74% for harmonic scalpel, 0.97% for coblation device, and 1.66% for the tonsillotome. Skeletal muscle was absent in only 8 of 228 specimens (3.5%). Electrocautery has a statistically significant (P < .05) lower percentage of muscle tissue compared to harmonic scalpel and the tonsillotome. There was no statistically significant difference in the mean depth of thermal injury among the harmonic scalpel (0.68 mm), electrocautery (0.58 mm), and coblation device (0.71 mm) specimens. The tonsillotome specimens had no thermal injury. CONCLUSIONS: Attempts to remove the entire tonsil results in a similar depth of thermal injury to tonsillectomy specimens when using the harmonic scalpel, electrocautery, and coblation device. Skeletal muscle is a nearly ubiquitous finding in routine tonsillectomy specimens. The use of an electrocautery with a needle point may allow for a more precise dissection as it results in tonsillectomy specimens with a smaller percentage of muscle present.

Novel pathologic findings associated with urinary retention in a mouse model of mucopolysaccharidosis type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome type B) is a metabolic disorder with devastating clinical characteristics starting in early childhood and leading to premature death. A knockout mouse strain was developed that models this disease. Mice of the strain B6.129S6- Naglu(tm1Efn)/J are invaluable for investigating pathogenesis and possible treatment modalities. However, the mouse strain also exhibits some objectionable phenotypic features. One such feature, urinary retention, not only is atypical of human MPS IIIB but often leads to early termination of experiments due to animal welfare concerns. The aim of this study was to investigate abnormalities associated with the urinary retention. Necropsies were performed on 9-mo-old mice; urinalysis, hematology and blood chemistry parameters were evaluated, and urogenital specimens were microscopically examined. Histopathologic examinations of urinary tract specimens proved illuminating regarding pathology in the urinary tract. A large mononuclear cell infiltrate was discovered in mutant mice of both sexes, more pronounced in females compared with male mice. The infiltrate comprises of large rounded or polygonal cells with generous variably vacuolated, granular eosinophilic cytoplasm and small round vesicular nuclei. These cells were present throughout and expand the interstitium of the lower urinary tract. Either this results in extrinsic compression of the lumen of the urethra, eventually leading to obstructive uropathy, bladder hyperdistension, and urinary retention or possibly interferes with the neurogenic component of micturition needs to be further investigated. The novel finding of an unexpected mononuclear cell infiltrate in the urinary tract in the knockout mice B6.129S6- Naglu(tm1Efn)/J is reported.

Clinicopathologic conference: Pulmonary tumor in a thirteen-year-old child.

An inflammatory myofibroblastic tumor as a distinct clinicopathologic entity in the lung has gained wide acceptance. The majority of these tumors are either contained within a single segment or pulmonary lobe and may cross the interlobar fissure and/or extend into the mediastinum, especially if arising in a perihilar location. We describe the case of a 13-year-old male with a 4-year history of an unresponsive lung mass in the left hemithorax. The resected tumor showed the typical morphology of a fasciculated fibroblastic/myofibroblastic lesion.

Surgical management of perineal masses in patients with anorectal malformations.

BACKGROUND: The aim of this study was to review the outcome of surgical management of various types of perineal masses encountered in patients with anorectal malformations (ARM). METHODS: Retrospective review from 2 large pediatric anorectal referral centers. RESULTS: Twenty-two patients with a perineal mass were identified in more than 2000 patients treated for an ARM over a 15-year period. The 22 patients (4 men) represented all levels of severity of ARMs. The lesions were of 3 types: lipomas (n = 10), vascular anomalies (n = 4), and hamartomas/choristomas (n = 8). The lipomas were carefully removed from between the muscle fibers during the posterior sagittal anorectoplasty. The vascular anomalies (3 of 4 were hemangiomas) underwent magnetic resonance imaging preoperatively, but none were found to invade deeply and all were excised at the time of the posterior sagittal anorectoplasty. The hamartomas/choristomas all occurred in women, and 50% arose as a pedunculated mass from the vulva. The lesions contained tissues such as glia, osteoid, nephrogenic rests, and endocervical-type mucosa. One was initially misinterpreted as a teratoma, prompting a wider excision. This and all subsequent patients have been correctly diagnosed pathologically as having either hamartomas or choristomas, which were not widely excised. Follow-up ranges from 5 months to 12 years. Six of the 10 lipoma patients are continent. One vascular anomaly was re-excised and there was minor wound separation in another. None of the hamartoma/choristoma lesions recurred. CONCLUSION: The presence of unusual perineal masses can add to the complexity of ARMs; however, most of these lesions can be carefully excised with preservation of the muscle complex and ultimate continence. Hamartomatous lesions can be mistaken for teratomas but do not require aggressive excision with clear margins.

Obstruction in modified Blalock shunts: a quantitative analysis with clinical correlation.

BACKGROUND: Despite numerous reports describing the clinical course of patients undergoing a modified Blalock-Taussig shunt (MBTS), there is limited information on shunt obstruction. No studies have quantified MBTS stenosis histopathologically and correlated that with demographic and clinical risk factors. METHODS: From June 2001 to June 2003, 155 patients had MBTS takedown. The shunt operation (at median age 6 days; shunt size 3.5 mm in 56 [36%]; 4 mm in 84 [54%]; 5 mm in 15 [10%]) was performed on cardiopulmonary bypass (CPB) in 96 patients (62%). At elective takedown (at median 8.1 months), the shunt was excised and histopathologically analyzed for maximal narrowing. Demographics and clinical variables including age, weight, shunt size and duration, diagnosis, use of cardiopulmonary bypass, blood products, anastomosis sites, and concomitant antegrade flow were then tested for correlation with shunt stenosis. RESULTS: The mean value for maximal narrowing of the shunt lumen was 34% +/- 22%, and 32 patients (21%) had greater than 50% stenosis. Myofibroblastic proliferation, often associated with organized thrombus, caused the obstruction. Smaller shunt size (<4 mm) was a statistically significant risk factor for stenosis greater than 50% (odds ratio [OR] = 2.51; p = 0.028). Other variables that showed a clinically important association with obstruction but did not reach statistical significance included age less than 14 days at shunt (OR = 2.08, confidence interval [CI] 0.8 to 5.2), shunt on bypass (OR = 2.07, CI 0.9 to 4.8), and platelet use at shunt operation (OR = 1.96, CI 0.9 to 4.4). CONCLUSIONS: Most MBTS develop stenosis by the time of takedown, and 21% have greater than 50% obstruction. Shunt size less than 4 mm is a risk factor for high-grade stenosis. Younger age, CPB, and use of platelets are other clinically important factors. Better conduits and suppression of intimal proliferation could potentially improve outcomes.

Ewing sarcoma/peripheral primitive neuroectodermal tumor: adult abdominal tumors with an Ewing sarcoma gene rearrangement demonstrated by fluorescence in situ hybridization in paraffin sections.

The differential diagnosis of small round cell tumors is exhaustive and requires ancillary studies. Relatively recently, fluorescence in situ hybridization (FISH) using probes for specific gene rearrangements has gained wide acceptance. This technique is particularly useful in the differential diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) and desmoplastic small round-cell tumor (DSRCT). In ES/PNET, the EWS gene is juxtaposed to the FLI-1 gene in 85% of cases and to the ERG gene in another 7% of cases; the EWS gene is juxtaposed to the WTI gene in DSRCT. Documentation of the EWS gene rearrangements in EWS/PNET has previously been demonstrated in frozen tissue. We report 2 unusual cases of EWS/PNET diagnosed in abdominal tumors in adults. Although the immunohistochemical results supported a diagnosis of ES/PNET, 1 case morphologically resembled DSRCT. The diagnosis in these 2 cases was confirmed by the FISH demonstration of EWS/FLI-1 gene fusion in paraffin-embedded tissue. Thus, the usefulness of FISH demonstration of an EWS gene rearrangement with these specific probes in such unusual cases is supported and is demonstrated in paraffin-embedded tissue.