Pediatr Dev Pathol
· 2025 · PMID 40270466
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BACKGROUND: Chorionic histiocytic hyperplasia (CHH) is a chronic inflammatory lesion (CIL) with a linear infiltrate of fetal histiocytes in the base of fetal or membranous chorion. We performed a retrospective study of p...BACKGROUND: Chorionic histiocytic hyperplasia (CHH) is a chronic inflammatory lesion (CIL) with a linear infiltrate of fetal histiocytes in the base of fetal or membranous chorion. We performed a retrospective study of placentas diagnosed since our last study period in order to analyze the strength of the association of CHH with other CIL. METHODS: Third trimester placentas diagnosed with CHH were identified in our LIS. Comparisons of incidence of associated lesions, including chronic villitis (CV), chronic deciduitis (CD), chronic chorioamnionitis (CC), eosinophilic/T-cell chorionic vasculitis (ETCV), and maternal and fetal acute inflammatory responses, between the prior and current studies were evaluated using the chi square statistic. RESULTS: CHH was present in 2.2% of placentas, significantly higher than 1.3% in the prior study period. A majority of CHH cases had accompanying CV (82.3%). CD was more often associated with CHH in the current study than in the prior study (49.1% vs 40.0%). CONCLUSIONS: The greater incidence of CHH in third trimester placentas diagnosed in the past 7.5 years may be due to greater recognition of the lesion by our pathologists. This study demonstrated the need for more research of CIL.
Mowat-Wilson Syndrome is an autosomal dominant disorder caused by de novo heterozygous mutations of on 2q22. It is characterized by developmental delay, Hirschsprung's disease, seizures, and a wide variety of malformati...Mowat-Wilson Syndrome is an autosomal dominant disorder caused by de novo heterozygous mutations of on 2q22. It is characterized by developmental delay, Hirschsprung's disease, seizures, and a wide variety of malformations affecting the neurologic, cardiac, and genitourinary systems. Reports describing the findings of Mowat-Wilson Syndrome at autopsy are sparse. Case reports of suprasellar spindle cell lipomas are even rarer, a circumstance that contributes to uncertainty regarding their etiology as true neoplasms rather than congenital malformations. Here we report the gross, histopathologic, and molecular findings of a 4-year-old female with Mowat-Wilson Syndrome presenting with sepsis in the setting of otitis media and incidentally found to have a rare suprasellar spindle cell lipoma demonstrating loss of by immunohistochemistry, suggestive of a neoplastic etiology.
Pediatr Dev Pathol
· 2025 · PMID 40243087
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BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder characterized by deficiency of branched-chain α-keto acid dehydrogenase complex. The affected patients can experience severe metab...BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder characterized by deficiency of branched-chain α-keto acid dehydrogenase complex. The affected patients can experience severe metabolic intoxication and encephalopathy in the first few years of life. Liver transplantation is an effective long-term treatment. There has been a lack of histologic description of explanted livers from MSUD patients in the literature. METHODS: A search of the medical record system was performed for cases carrying a diagnosis of MSUD between January 2003 and May 2024. Eight patients who underwent liver transplantation were identified. Their explanted livers were evaluated and their medical records were extensively reviewed. RESULTS: The weights of explanted livers were within normal range for patients' age. Histologic examination demonstrated features of nodular regenerative hyperplasia (NRH) in 5 (62.5%) liver explants. Other histologic findings included minimal to mild lymphocytic portal inflammation seen in 6 cases and mild steatosis in 2 cases. A detailed review of clinical histories revealed no signs of portal hypertension or specific underlying conditions conducive to NRH development. CONCLUSION: NRH is a frequent histologic finding in explanted livers from MSUD patients, although the underlying etiopathogenesis and clinical implication remain to be elucidated.
Capozzi A, Jansen FA, Smetsers SE
… +6 more, Bakhuizen JJ, Hiemcke-Jiwa LS, Kranendonk MEG, Flucke U, Alaggio R, de Krijger RR
Pediatr Dev Pathol
· 2025 · PMID 40231379
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syndrome is a heterogeneous cancer predisposition syndrome, characterized by a large variety of benign and malignant tumor types, and caused by germline heterozygous pathogenic variants in the gene, which is essential i...syndrome is a heterogeneous cancer predisposition syndrome, characterized by a large variety of benign and malignant tumor types, and caused by germline heterozygous pathogenic variants in the gene, which is essential in miRNA processing and RNA interference. The clinical manifestations are diverse, with pleuropulmonary blastoma, Sertoli-Leydig cell tumor, cystic nephroma, uterine cervical embryonal rhabdomyosarcoma, and thyroid follicular nodular disease being the most prevalent tumor types. Since these neoplasms are rare and particularly occur in the pediatric population, pathologists should be aware of the potential relationship of these tumors with an underlying syndrome in order to perform or suggest additional molecular pathologic analysis and refer patients and their parents for genetic counseling and testing. This review describes the various -related tumor types with emphasis on the histological features, reflects on the molecular pathogenesis of , and aims to raise awareness of this syndrome to facilitate earlier diagnosis.
BACKGROUND: Colonic graft-versus-host disease (GVHD) is rare in children. The goal of this study was to evaluate the Lerner and the Farooq grade in pediatric patients. METHODS: Retrospective multicenter study including a...BACKGROUND: Colonic graft-versus-host disease (GVHD) is rare in children. The goal of this study was to evaluate the Lerner and the Farooq grade in pediatric patients. METHODS: Retrospective multicenter study including all biopsies with a diagnosis of GVHD. RESULTS: 101 patients were included (median age: 8.9 years) with a male predominance (59%). 71% of patients had extracolonic GVHD. 98% and 54% of cases had apoptotic bodies and >6 apoptotic bodies, respectively. Crypt dropout was seen in 53% of cases and ulceration in 19%. Using the Lerner grade, 47% of cases were grade 1, 13% grade 2, 20% grade 3 and 20% grade 4; and using the Farooq grade, 35% were indeterminate for GVHD, 25% low, 27% intermediate and 14% high grade. There was moderate agreement ( = 0.47) between the system. 67% of the Lerner grade 1 cases were considered indeterminate for GVHD using the Farooq grade. No difference was seen with GVHD-related death and the grading systems. GVHD-related death was associated with extraintestinal involvement ( = .04), and with treatment response ( < .01). CONCLUSIONS: Although neither system was associated with GVHD-related death, given the more comprehensive approach, the authors suggest utilizing the Farooq grading system.
Osteopetrosis is a rare metabolic bone disease that can lead to progressive bone marrow failure if left untreated. Resulting cytopenia and extramedullary hematopoiesis are frequently encountered in autosomal recessive fo...Osteopetrosis is a rare metabolic bone disease that can lead to progressive bone marrow failure if left untreated. Resulting cytopenia and extramedullary hematopoiesis are frequently encountered in autosomal recessive form of the disease (ARO) and may result in death. Recurrent bone fractures and skeletal deformities are mostly seen in autosomal dominant form osteopetrosis (ADO) and cause significant morbidity. In this report, clinical, laboratory, and radiological findings of 5 patients with osteopetrosis were presented. Three had cytopenias, typical peripheral smear, and bone marrow aspiration findings regarding bone marrow failure as well as extensively increased bone density which was a classical radiological appearance. Two of them had mutations associated with ARO, died because of severe infections. One with certain findings of ARO without genetic analysis is alive after hematopoietic stem cell transplantation. Two siblings had novel variants of (NM_001114331) p.Val755Serfs*4 (c.2263del) heterozygocity, associated with ADO and severe skeletal problems. One had been followed up also for nephrotic syndrome. Detection of genetic abnormalities is important as well as typical physical examination findings and, presence of hematological or radiological indicators in definitive diagnosis of the disease. Although osteopetrosis is rare, it is a potentially fatal disease that should be considered in the differential diagnosis.
Neuroblastoma (NB) is the most common extracranial solid neoplasm affecting the pediatric population. It shows a high prevalence of bone marrow infiltration (BMI), which substantially impacts the disease's staging and pr...Neuroblastoma (NB) is the most common extracranial solid neoplasm affecting the pediatric population. It shows a high prevalence of bone marrow infiltration (BMI), which substantially impacts the disease's staging and prognostic assessment. Conventional methodologies, including bone marrow biopsy (BMB) and aspirate (BMA), have been extensively employed; nevertheless, the advent of novel technologies presents a promising avenue for diagnostic accuracy. This systematic review is designed to critically analyze and compare the established techniques (BMB and BMA) versus novel diagnostic approaches-such as immunocytology, RT-qPCR, and multiparametric flow cytometry (FCM), along with functional imaging like MIBG scintigraphy and FDG-PET/CT-in assessing BMI in pediatric NB. An exhaustive search was performed across the PubMed and Embase databases, identifying 2694 scholarly articles. Following a meticulous screening process and the application of inclusion criteria centered on diagnostic accuracy, sensitivity, and specificity about BMI, a total of 140 articles were selected for qualitative analysis. While BMB remains the gold standard for diagnosing and staging BMI in NB, recent advances in molecular techniques and functional imaging have shown superior sensitivity and specificity. Immunocytology and RT-qPCR can detect minimal residual disease (MRD) with higher sensitivity compared to traditional methods. Functional imaging modalities, particularly FDG-PET/CT and MIBG scintigraphy, have demonstrated improved accuracy in assessing bone marrow involvement with the added advantage of evaluating the entire bone marrow, overcoming the limitations of focal sampling in BMB. The integration of advanced molecular diagnostics and functional imaging with traditional biopsy methods enhances the accuracy of BMI in NB.
Celiac disease (CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Association of CD and aplastic anemia (AA) has been reported in the literature, yet t...Celiac disease (CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Association of CD and aplastic anemia (AA) has been reported in the literature, yet this association remains rare in children. The authors report a case of a previously healthy 4-year-old boy with 1-month history of diarrhea, asthenia, loss of appetite, and weight loss. Laboratory evaluation showed bicytopenia with very severe aregenerative anemia and neutropenia. Bone marrow aspirate and biopsy were performed with findings suggestive of bone marrow aplasia. Further etiological research showed IgA deficiency and increased plasma concentrations of anti-tissue transglutaminase IgG antibodies (anti-tTG IgG 336 U/mL). Patient underwent upper digestive endoscopy confirming diagnosis of CD. The child started a gluten-free diet (GFD) with subsequent clinical and serological improvement. At 12-month post-hospitalization follow-up, the child was asymptomatic, with normal growth rate, resolution of bicytopenia, and anti-tTG IgG lower but still positive (151 U/ml) due to partial adhesion to GFD. To the best of author's knowledge, this is the eighth published pediatric case describing the association of CD with AA. The pathogenesis of this association is not yet fully understood. The authors suggest that CD screening should be considered in patients with unexplained hematological abnormalities.
Expression of glypican-3 is seen in a variety of malignant liver neoplasms, such as hepatoblastoma and hepatocellular carcinoma. It is generally not expressed in benign neoplasms and is therefore used as a reliable immun...Expression of glypican-3 is seen in a variety of malignant liver neoplasms, such as hepatoblastoma and hepatocellular carcinoma. It is generally not expressed in benign neoplasms and is therefore used as a reliable immunohistochemical marker for distinguishing benign from malignant liver neoplasms. Its expression can also be seen normally in the liver during embryonic development. It has not been described in non-neoplastic liver outside of embryonic development. We present 2 cases of glypican-3 positivity in the background non-neoplastic liver parenchyma of 2 pediatric patients with liver masses.
The oral mucosal calcified nodule (OMCN) is a rare soft tissue lesion with only 7 cases reported in the English literature. It typically presents in the pediatric population as an asymptomatic submucosal nodule of less t...The oral mucosal calcified nodule (OMCN) is a rare soft tissue lesion with only 7 cases reported in the English literature. It typically presents in the pediatric population as an asymptomatic submucosal nodule of less than 2 cm size affecting the maxillary ridge or palate, though other sites are reported. The histopathology displays stratified squamous epithelium overlying fibrous connective tissue with embedded calcified aggregates bordered by variable numbers of multinucleated giant cells. Surgical excision is curative. In this report, we present a new case of OMCN, outline the characteristic histopathologic features and review the cases reported in the English literature.
Sakhuja S, Patel KR, Goss M
… +5 more, Munoz FM, Wortham G, Crawford M, Goss JA, Galvan NT
Pediatr Dev Pathol
· 2025 · PMID 40152442
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The COVID-19 pandemic presents several challenges during pregnancy including thromboembolic complications, direct placental infection, transplacental transmission, and systemic hyperinflammatory state. The liver is the s...The COVID-19 pandemic presents several challenges during pregnancy including thromboembolic complications, direct placental infection, transplacental transmission, and systemic hyperinflammatory state. The liver is the second most commonly affected organ in SARS-CoV-2 infection after the lungs. Mechanisms of liver injury in COVID-19 patients can include: direct viral cytopathic effect, worsening of underlying liver disease, cytokine storm, hypoxic ischemic injury, and cholangiopathy leading to persistent marked cholestasis. Here we describe 3 infants at Texas Children's Hospital with perinatal SARS-CoV-2 exposure with persistent cholestasis and histologic evidence of extrahepatic biliary obstruction suggesting underlying biliary atresia (BA) with some atypical features possibly exacerbated by SARS-CoV-2 infection. All 3 patients described in this case series developed liver failure in the setting of low GGT cholestasis, and all 3 required liver transplantation within the first year of life. Though post-COVID cholangiopathy is described in adults in the literature, none of the infants in our series had moderate or severe COVID infection but still progressed to advanced liver disease. Instead it is very likely that the patients in our series had underlying BA with some atypical features, with the commonality of having been exposed perinatally to SARS-CoV-2 Though further studies are needed to determine causality, our case series raises the question of if the timing of exposure/infection plays a role in prognosis.
In this report, we describe a case of classic Hodgkin lymphoma presenting with lytic bone lesions and pancytopenia, but with no significant lymphadenopathy or mediastinal mass. We report detailed clinical, radiologic, an...In this report, we describe a case of classic Hodgkin lymphoma presenting with lytic bone lesions and pancytopenia, but with no significant lymphadenopathy or mediastinal mass. We report detailed clinical, radiologic, and pathologic findings. We discuss the scant medical literature of similar cases. We conclude that such cases often represent diagnostic challenges at the clinical and microscopic levels. We emphasize that awareness of this rare presentation of Hodgkin lymphoma is key to avoid diagnostic delay or interpretation pitfalls.
BACKGROUND: Bile acids in the ileum act as a feedback regulator of their own synthesis by inducing the release of ileal fibroblast growth factor 19 (FGF19), which inhibits the cholesterol-7-alpha hydroxylase enzyme. In c...BACKGROUND: Bile acids in the ileum act as a feedback regulator of their own synthesis by inducing the release of ileal fibroblast growth factor 19 (FGF19), which inhibits the cholesterol-7-alpha hydroxylase enzyme. In cholestasis, this feedback mechanism is dysregulated. FGF19 is not expressed in the healthy liver. We aimed to assess the hepatic expression of FGF19 in neonatal cholestasis (NC) and its relation to serum bile acids. METHODS: The study included 41 patients with NC. FGF19 immunohistochemical staining in liver tissue (hepatocytes, endothelial cells, bile ducts, and bile canaliculi) was evaluated as negative, weak, moderate, and strong staining. FGF19 staining in 6 liver samples from explants of children with Crigler-Najjar syndrome type-1 served as controls. RESULTS: Hepatocyte, endothelial, and canalicular FGF19 expression was significantly higher in cholestasis group compared to controls ( = .039, .006, and .028 respectively). Serum bile acids had significant correlation with hepatocyte FGF19, endothelial, and bile duct FGF19 expressions ( = .002, .003, and .01, respectively) but not with canalicular FGF19 expression. Hepatocyte FGF19 expression significantly associated with cholestasis severity in terms of serum total bilirubin, direct bilirubin, and aspartate transaminase levels ( = .01, .02, and .02, respectively). CONCLUSION: Hepatic FGF19 expression significantly upregulated in NC and correlated with cholestasis severity.
Ilori EO, Kahlow C, Garcia R
… +3 more, Ahmed S, Timmons C, Nesterenko TH
Pediatr Dev Pathol
· 2025 · PMID 40008593
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Acute respiratory distress in a neonate is a potentially critical condition with multiple possible causes. Developmental etiologies are particularly problematic by virtue of being refractory to routine modalities for enh...Acute respiratory distress in a neonate is a potentially critical condition with multiple possible causes. Developmental etiologies are particularly problematic by virtue of being refractory to routine modalities for enhancing ventilation and oxygen exchange. Some genetic causes of neonatal respiratory distress, such as surfactant protein deficiencies and alveolar capillary dysplasia with misalignment of pulmonary veins, are well known, and sequencing panels have been formulated to detect them. We present a case of fatal neonatal respiratory insufficiency in which the autopsy showed primary pulmonary hypoplasia and congenital alveolar dysplasia. A sequencing panel of genes associated with heritable pulmonary disorders gave a normal result; however, a chromosomal microarray identified a heterozygous deletion encompassing the gene on chromosome 17. Haploinsufficiency for is a known cause of disturbed pulmonary development. This case illustrates why work-up of pulmonary developmental disorders must look beyond standard sequencing panels in some instances, if rare causes of pulmonary maldevelopment such as deletions causing haploinsufficiency are not to be missed.
BACKGROUND: Sloughing esophagitis (esophagitis dissecans superficialis) is a benign, self-limited condition of uncertain etiology. It is most common in adults; pediatric literature is limited. METHODS: Ten years of recor...BACKGROUND: Sloughing esophagitis (esophagitis dissecans superficialis) is a benign, self-limited condition of uncertain etiology. It is most common in adults; pediatric literature is limited. METHODS: Ten years of records were queried for esophageal biopsies containing terms "sloughing" and/or "dissecans." Histologic inclusion criteria were "two-tone" appearance, sloughing/flaking of superficial epithelium, and parakeratosis. Degree of inflammation was documented and medical records were reviewed. RESULTS: Fourteen patients were identified ranging from 1 to 19 years (mean = 14 years) and included 3 males and 11 females. Two patients were excluded due to lack of histologic criteria/unavailability of slides for review. Of the 12 cases evaluated, 6 showed a classic inflammation pattern, 5 had minimal or no inflammation, and 1 displayed severe acute inflammation. Endoscopy did not correlate with histology. Sloughing esophagitis is traditionally associated with Selective serotonin reuptake inhibitors (SSRI) use; though 5/12 patients were taking medication for anxiety or depression, only 3 were taking SSRIs. Five patients had marijuana/cannabinoid exposure. CONCLUSION: Sloughing esophagitis can present in the pediatric population across a wide age range. Similar to the adult population, etiology may be linked to medications. Additional associations such as marijuana/cannabinoid exposure need further clinical investigation. A subset of patients had a history of or subsequently developed eosinophilic esophagitis.
We report a teenage patient with a delayed diagnosis of compound heterozygous pathogenic variants [( c. 1943 C>G, p.P648R) and ( c. 679 C>T, p.R227W)] who presented with fatigue and neuropathy, as well as long standing...We report a teenage patient with a delayed diagnosis of compound heterozygous pathogenic variants [( c. 1943 C>G, p.P648R) and ( c. 679 C>T, p.R227W)] who presented with fatigue and neuropathy, as well as long standing malnutrition and cachexia, erroneously attributed to an eating disorder. She experienced multiple bowel perforations and pathologic examination revealed jejunal diverticula and features of visceral neuromyopathy. In addition to ganglion cell mega-mitochondrial inclusions, there were multiple foci of interrupted muscularis mucosae, an alteration not previously recognized in the intestines of patients with primary mitochondrial disorders. We provide a detailed account of the gastrointestinal pathologic findings in this patient and compare with prior cases of Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) phenotypes.
Okotcha N, Guerina N, de la Monte S
… +1 more, Patil R
Pediatr Dev Pathol
· 2025 · PMID 39945430
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Acute necrotizing encephalopathy (ANE) is a rare immune-mediated disease in children that could progress rapidly, and lead to significant morbidity or mortality. ANE's diagnostic challenges render it difficult to recogni...Acute necrotizing encephalopathy (ANE) is a rare immune-mediated disease in children that could progress rapidly, and lead to significant morbidity or mortality. ANE's diagnostic challenges render it difficult to recognize and treat in a timely and effective manner. Although infantile-onset cases have been reported, the presentation of ANE in preterm neonates has not been described. Herein, we report a case of a preterm newborn who had a relatively stable clinical course in the first week of life, after which the neonate exhibited sudden deterioration due to progressive encephalopathy with refractory status epilepticus. Despite aggressive management of seizures and sepsis, the patient succumbed. Whole-exome sequencing analyses of the patient and parents were negative. Viral and metabolic testing were non-contributory. An autopsy showed evidence of acute to subacute fulminant liquefactive necrosis with extensive hemorrhage diffusely in the cortex with relative sparing of the cerebellum and the brainstem. A major consideration highlighted by this case is that the adaptive immune response to the immune-mediated or cytokine storm-related proposed etiology of acute necrotizing encephalopathy may differ in preterm compared with full-term infants due to properties dictated by their innate immune responses. Clinical suspicion of ANE should be heightened whenever preterm neonates with early sepsis continue to deteriorate despite aggressive management.
Hypoplastic right heart syndrome (HRHS) is an uncommon congenital cardiac defect, characterized by variable underdevelopment of the right-sided heart structures. We report on a case of HRHS in a 25-week female fetus. Pre...Hypoplastic right heart syndrome (HRHS) is an uncommon congenital cardiac defect, characterized by variable underdevelopment of the right-sided heart structures. We report on a case of HRHS in a 25-week female fetus. Prenatal karyotype was normal. Autopsy performed following pregnancy termination demonstrated characteristic craniofacial dysmorphism and complex congenital heart disease encompassing severe hypoplasia of the right ventricle, main pulmonary artery and tricuspid valve, ostium secundum atrial septal defect, and ductus arteriosus agenesis. Macroscopic and histologic examinations of the brain and organs were unremarkable. Post-mortem array CGH didn't detect any unbalanced chromosomal abnormalities. Exome and Sanger sequencing revealed a novel de novo heterozygous missense variant in (NM_005257.6:c.1385A>G) which is located in the hotspot exon 4 encoding the highly conserved C-terminal zinc finger domain. This report ascertains that GATA6 haploinsufficiency may cause a cardiocraniofacial syndrome consisting of distinctive craniofacial dysmorphism and HRHS.
Chen H, Putra J, Nagy A
… +13 more, Terry J, El Demellawy D, de Nanassy J, Schollenberg E, Haig A, Stefanovici C, Whelan K, Poulin A, Dal Soglio D, Chen Z, Smith B, Fiore C, Somers GR
Pediatr Dev Pathol
· 2025 · PMID 39927568
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BACKGROUND: Digital pathology facilitates remote pathology consultations. Pediatric pathologists in Canada formed a nationwide digital pathology consultation network, mostly for second opinion review of pediatric cancer...BACKGROUND: Digital pathology facilitates remote pathology consultations. Pediatric pathologists in Canada formed a nationwide digital pathology consultation network, mostly for second opinion review of pediatric cancer cases. Validation of such a large network for clinical use is challenging. Here we report our unique validation process of this digital pathology network. METHOD: This study was designed in keeping with the College of American Pathologist (CAP) guidelines, and included 14 pathologists from 9 hospitals across Canada. All cases are pediatric pathology cases. Each pathologist reviewed multiple digital cases and the corresponding glass slide cases. For each review, intra-observer concordance (diagnosis on digital case versus diagnosis on glass slide case) was recorded, creating a data point. RESULT: The study generated 269 valid diagnostic data points. Out of the 269 data points, 257 were concordant (95.5% concordance), exceeding the CAP recommendation of 95% concordance. Thus, the network was successfully validated. CONCLUSION: This is a unique validation study for a large nationwide digital pediatric pathology network. The study involved all pathologists/hospitals in the network, closely emulating real world clinical process. The network was successfully validated.
Harris JC, Schubert J, Lockhart B
… +13 more, Olson R, Paessler ME, Margolskee E, Pillai V, Wu J, Golenberg N, Chen J, Denenberg EH, Luke T, Luo M, Zhong Y, Li MM, Wertheim GB
Pediatr Dev Pathol
· 2025 · PMID 39898462
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We report a case of acute myeloid leukemia with megakaryoblastic differentiation (AMKL) that developed after an initial B-lymphoblastic leukemia (B-ALL) with low hypodiploidy. Although the AMKL was initially thought eith...We report a case of acute myeloid leukemia with megakaryoblastic differentiation (AMKL) that developed after an initial B-lymphoblastic leukemia (B-ALL) with low hypodiploidy. Although the AMKL was initially thought either to be a phenotypic change from the original B-ALL or to have arisen as a result of treatment (acute myeloid leukemia, post cytotoxic therapy, AML-pCT [WHO]; AML, therapy related [ICC]), genetic evaluation of both the AMKL and the B-ALL suggest that neither of these considerations was correct. Rather, the AMKL did not harbor the most common genetic hallmark of AML-pCT-rearrangement of and was genetically distinct from the B-ALL. Both the B-ALL and the AMKL, however, showed an identical mutation by next generation sequencing (NGS), while germline testing was negative for this mutant allele. Hence, either the patient had a tissue restricted constitutional mutation or had a somatic mutation in a multipotent hematopoietic precursor. This case highlights the necessity for close monitoring of patients with -mutant tumors, as they may develop multiple lesions despite negative germline testing.