BACKGROUND: Identifying the genetic signatures in bone and soft tissue tumors enhances our understanding of tumor biology and aids in the subclassification of tumors for personalized treatment. Histone H3.3 alterations p...BACKGROUND: Identifying the genetic signatures in bone and soft tissue tumors enhances our understanding of tumor biology and aids in the subclassification of tumors for personalized treatment. Histone H3.3 alterations play a pivotal role in K36M-mutant chondroblastomas and G34W/L-mutant giant cell tumors of the bone. METHODS AND RESULTS: In this report, we describe 2 cases of a distinct epithelioid neoplasm with K36M mutation but lacking features of chondroblastoma, which extends the spectrum of H3.3-mutant mesenchymal tumors. The 2 cases occurred in pediatric patients, had an aggressive clinical presentation, distinct epithelioid histomorphology with diffuse cytokeratin and TFE3 expression, and identical K36M mutations. No gene fusions were identified. Methylation analysis using the DKFZ sarcoma classifier v12.3 pipeline did not classify these tumors with known entities, suggesting the existence of non-chondrogenic mesenchymal tumors within the H3.3-mutant tumor spectrum. CONCLUSIONS: The distinctive histological and molecular features of these 2 cases expand the spectrum of H3.3-mutant tumors and call for further investigation of the biological underpinnings of this group of tumors.
Extra-testicular scrotal masses may be seen in young children, spanning a broad spectrum of lesions from benign entities to aggressive malignancies. Though rare, melanotic neuroectodermal tumor of infancy (MNTI) is a ver...Extra-testicular scrotal masses may be seen in young children, spanning a broad spectrum of lesions from benign entities to aggressive malignancies. Though rare, melanotic neuroectodermal tumor of infancy (MNTI) is a very important differential diagnosis of scrotal masses in infants due to its close histologic resemblance to more aggressive malignant small round cell tumors involving this region. An 18-month-old baby presented with a 10-month history of a scrotal mass, which was surgically excised and initially misdiagnosed as rhabdomyosarcoma, with a plan for post operative chemotherapy. Histopathologic review at our institute, with immunohistochemical support led to the correct diagnosis of MNTI, thus avoiding unnecessary chemotherapy. Morphologic findings and detailed differential diagnosis of this rare tumor are discussed.
Schiffer V, Thijs I, Al-Nasiry S
… +2 more, Teeffelen SV, Severens-Rijvers C
Pediatr Dev Pathol
· 2025 · PMID 40600612
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We present a unique case of a 33-year-old gravida that was referred to our hospital with an umbilical vessel aneurysm presenting as a large placental cyst on ultrasound. Although the 20-week anomaly scan showed no struct...We present a unique case of a 33-year-old gravida that was referred to our hospital with an umbilical vessel aneurysm presenting as a large placental cyst on ultrasound. Although the 20-week anomaly scan showed no structural abnormalities, routine fetal biometry scanning at 30 weeks of gestation revealed an abnormal placental cystic structure, located subchorionic under the umbilical cord insertion. Given the uncertainty of the origin of the structure's origin and its unpredictable evolution with possible adverse effect on the fetus, a cesarean section was performed delivering a healthy baby. Histopathological examination of the placenta showed an aneurysmal vein with thinning of the vessel wall and fragmented smooth muscle. Umbilical cord aneurysm represents an exceptionally rare placental anomaly, with umbilical vein aneurysms being associated with variable fetal mortality rates, ranging from those observed in uncomplicated pregnancies to 82% in documented cases. Therefore, a multidisciplinary approach is essential to optimize fetal outcomes.
Nagy A, Collins C, Szymanski LJ
… +10 more, Pawel BR, Kreiger PA, Bhatti T, Olivia M, Rudzinski E, Reyes J, Blessing M, Chikwava K, Putra J, Carreon CK
Pediatr Dev Pathol
· 2025 · PMID 40577397
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Protein-losing enteropathy (PLE) is a rare condition characterized by clinical findings such as edema, ascites, pleural effusion, and diarrhea due to excessive protein loss from the gastrointestinal system. Although syst...Protein-losing enteropathy (PLE) is a rare condition characterized by clinical findings such as edema, ascites, pleural effusion, and diarrhea due to excessive protein loss from the gastrointestinal system. Although systemic lupus erythematosus (SLE) is rare in childhood, PLE can be the first presenting feature; this condition is referred to as lupus-associated protein-losing enteropathy (LUPLE). Protein-losing enteropathy (PLE) is an uncommon condition resulting from excessive protein loss in the gastrointestinal system. Our case shows that PLE can be the initial presentation of SLE, which is a rare manifestation in childhood. PLE, a rare complication of lupus, tends to be more severe in children, and the diagnostic process can be challenging. This case report presents a 7-year-old girl who presented with abdominal distension, generalized edema, chronic diarrhea, and weakness. Despite treatment, the recurrence of symptoms and the addition of new joint findings led to further investigations, which revealed positive anti-dsDNA and low complement levels, resulting in a diagnosis of systemic lupus erythematosus. The patient's clinical condition improved with steroid, azathioprine, and hydroxychloroquine treatments. This case highlights the importance of considering SLE in the differential diagnosis of PLE and underscores the significance of recognizing the rare presentations of childhood lupus.
Lennox-Gastaut syndrome is a form of severe childhood epilepsy caused by a variety of etiologies including structural abnormalities, inflammatory conditions affecting the brain, malignancy, injury, or unknown causes. Sod...Lennox-Gastaut syndrome is a form of severe childhood epilepsy caused by a variety of etiologies including structural abnormalities, inflammatory conditions affecting the brain, malignancy, injury, or unknown causes. Sodium channelopathies have been linked to multiple seizure disorders, including Lennox-Gastaut syndrome, due to their role in action potential propagation in the brain. is one such voltage gated sodium channel found primarily in the central nervous system. We present a case of a 6-year-old female with Lennox-Gastaut syndrome and a heterozygous variant who became unresponsive during a supervised bath and later died. The neuropathologic exam was remarkable for dentato-olivary dysplasia, among other gross and microscopic abnormalities. We present this case highlighting rarely documented neuropathologic findings in Lennox-Gastaut syndrome associated with a channelopathy ( variant) as well as a review of literature of previously reported brain abnormalities in patients with variants.
BACKGROUND: Pulmonary agenesis is characterized by the absence of bronchi and lung parenchyma and it differs from pulmonary aplasia by the presence of rudimentary bronchial buds. SOX2 expression is observed during the no...BACKGROUND: Pulmonary agenesis is characterized by the absence of bronchi and lung parenchyma and it differs from pulmonary aplasia by the presence of rudimentary bronchial buds. SOX2 expression is observed during the normal course of lung development. The objective of this study is to investigate the expression of SOX2 and its regulation in the residual airway epithelium of pulmonary agenesis/aplasia. METHODS: Six cases of pulmonary agenesis/aplasia aged between 12 and 37 weeks of gestation and 6 age-matched controls were studied. Immunochemistry was performed using primary antibodies against SOX2, BMP4, FGF9, FGF10, TTF1, SHH, and beta-catenin. RESULTS: In sections of bronchi or trachea from lung agenesis or aplasia, the residual epithelium shows a high nuclear expression of SOX2 and an absence of expression of BMP4 as in the esophagus whereas in control cases, the airway epithelium shows an absence of expression of SOX2 and a high expression of BMP4. There were no differences between control and agenesis/aplasia cases concerning the expression of FGF9, FGF10, SHH, TTF1, and beta-catenin. CONCLUSION: The expression of SOX2 and BMP4 is strongly altered in pulmonary agenesis/aplasia. Thus, these proteins appear to regulate tissue-specific proliferative activity during early lung development.
BACKGROUND: Umbilical cord consists of 2 arteries and 1 vein embedded in Wharton's jelly. Umbilical cord weight has not been examined for fetal growth and placental pathology. MATERIALS AND METHODS: We have assessed umbi...BACKGROUND: Umbilical cord consists of 2 arteries and 1 vein embedded in Wharton's jelly. Umbilical cord weight has not been examined for fetal growth and placental pathology. MATERIALS AND METHODS: We have assessed umbilical cord by measuring the weight and the length during placental examination. The cord weight index (CWI) was defined as an average weight of 10 cm cord, and the normal ranges of cord diameter and CWI were established as 10th to 90th percentile. RESULTS: A total of 520 cases of umbilical cord were examined. Normal ranges of 10th to 90th percentile of cord diameter and CWI were established. Light cord was defined as less than 10th percentile and heavy cord was greater than 90th percentile of CWI. Light cord was significantly associated with decreased cord diameter, lower placental and fetal birth weight, female sex, nuchal cord, and IUGR, while heavy cord was significantly associated with increased cord diameter, increased BMI, male sex, diabetes mellitus, and decreased maternal and fetal inflammatory responses. CONCLUSION: Our data demonstrated that CWI is a novel and superior measure of cord development to diameter, and CWI can add value, providing preliminary evidence for more rigorous study and for incorporating CWI in placental examination.
BACKGROUND: Stillbirth continues to pose a significant public health challenge. Autopsy and placental assessments are recognized as the gold standard for stillbirth investigation. The utility of these procedures can vary...BACKGROUND: Stillbirth continues to pose a significant public health challenge. Autopsy and placental assessments are recognized as the gold standard for stillbirth investigation. The utility of these procedures can vary based on the quality of the examination. The aim of this study is to determine the quality of placenta pathology reporting in Australia in the context of a stillbirth. MATERIALS AND METHODS: Placenta pathology reports from stillbirths were reviewed from 18 maternity hospital from 2013 to 2018. The Khong tool was used to produce a placenta quality score (PQS), by a blinded panel of assessors to the cause of death. Outcome measures were the number of reports achieving the minimal acceptable score (MAS) of 75% or a poor score (PS) of 50% of the PQS. RESULTS: 560 placental pathology reports of which 494 were singleton and 66 were twin placentas. 282 (50%) achieved the MAS score. Macroscopic items were recorded well and microscopic items recorded poorly. CONCLUSIONS: The standard of placenta pathology reporting can be improved in Australia. The use of templates or checklists for both macroscopic descriptions and histological reporting is recommended to ensure all key components are described.
Kaposi sarcoma (KS) is a rare, human herpesvirus-8 (HHV-8)-associated vascular tumor that primarily affects the skin but can involve visceral organs, particularly in immunosuppressed patients. While iatrogenic KS is well...Kaposi sarcoma (KS) is a rare, human herpesvirus-8 (HHV-8)-associated vascular tumor that primarily affects the skin but can involve visceral organs, particularly in immunosuppressed patients. While iatrogenic KS is well-documented in adults, isolated gastrointestinal involvement in pediatric cases remains unreported. We describe a 16-year-old HIV-negative male with chronic granulomatous disease (CGD) who initially presented with inflammatory bowel disease-like symptoms and was treated with immunosuppressive therapy. Over 17 months, he developed recurrent infections, hepatosplenomegaly, and ultimately intestinal perforation, necessitating emergency colectomy. Histopathology confirmed iatrogenic KS, highlighting the need for increased awareness of this rare malignancy in immunocompromised pediatric patients and carefully balancing the risks of long-term immunosuppressive therapy.
Ferreira EO, Del Bigio MR, Morin J
… +1 more, Frosk P
Pediatr Dev Pathol
· 2025 · PMID 40415601
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Glutaredoxin 5 (GLRX5) is a mitochondrial protein encoded by the GLRX5 gene, which is essential for cellular redox homoeostasis, lipoic acid synthesis, and iron-sulfur cluster transfer. Rare cases of pathogenic GLRX5 mut...Glutaredoxin 5 (GLRX5) is a mitochondrial protein encoded by the GLRX5 gene, which is essential for cellular redox homoeostasis, lipoic acid synthesis, and iron-sulfur cluster transfer. Rare cases of pathogenic GLRX5 mutations have been associated with sideroblastic anemia and non-ketotic hyperglycinemia with progressive spasticity and cavitating leukoencephalopathy. We report an 11-month-old child, who died following aspiration, with severe cardiomyocyte mitochondrial abnormalities and cerebral white matter degeneration in the context of a homozygous GLRX5 variant (c.208A>G, p.S70G).
Children with Trisomy 21 (T21) have an increased incidence of pulmonary hypertension (PHTN); most commonly due to congenital heart/lung diseases but also in conjunction with other T21-associated gastrointestinal and meta...Children with Trisomy 21 (T21) have an increased incidence of pulmonary hypertension (PHTN); most commonly due to congenital heart/lung diseases but also in conjunction with other T21-associated gastrointestinal and metabolic abnormalities. This report describes a 2 days old, full-term male neonate with T21, without significant cardiac anomalies presenting with severe hypoxic respiratory failure eventually leading to death. Autopsy confirmed T21-associated dysmorphic features and revealed both extra and intrahepatic congenital portosystemic shunts (CPSS). Additionally, the liver demonstrated dilated hepatic and portal veins and mildly altered lobular architecture without any focal lesions. Bilateral lungs showed mild alveolar maldevelopment, double capillary loops, and normal lung to body weight ratio without vascular hypertensive changes. This case underscores the importance of careful examination of the liver hilum and considering CPSS as a potential etiology of PHTN in neonates with T21 in the absence of cardiac defects or significant lung disease.
BACKGROUND: Gallbladders are a commonly encounter specimen in pediatric pathology practice. In the adult population, intestinal metaplasia (IM) in the gallbladder is associated with the development of dysplasia and adeno...BACKGROUND: Gallbladders are a commonly encounter specimen in pediatric pathology practice. In the adult population, intestinal metaplasia (IM) in the gallbladder is associated with the development of dysplasia and adenocarcinoma; however, in children its significance is unknown, and the appropriate sampling has not been described which is the goal of this study. METHODS: Twenty-five routine pediatric cholecystectomy cases with IM were identified, and their clinical and histologic findings were reviewed. RESULTS: Of these 25 cases, 23 were female (92%). The most common indication for surgery was cholelithiasis (84%). Stones were present in 21 cases (84%). Twenty-three cases (92%) had additional sections submitted with an average of 3.9 slides (range = 3-6), and 52% had IM in additional blocks. However, no dysplasia or carcinoma was identified in any case. CONCLUSION: IM in the gallbladder is frequently seen in the setting of gallstones and chronic inflammation. Based on our experience, no additional sampling is required when incidentally identified.
Teratocarcinosarcoma is rare malignant sinonasal neoplasm with immature and malignant endodermal, mesodermal, and neuroepithelial elements resembling immature teratoma, commonly with loss or activating mutation. The ca...Teratocarcinosarcoma is rare malignant sinonasal neoplasm with immature and malignant endodermal, mesodermal, and neuroepithelial elements resembling immature teratoma, commonly with loss or activating mutation. The carcinoma component may be either squamous or adenocarcinoma and the mesenchymal component may be composed of spindle cells, cartilage, bone, smooth muscle, or skeletal muscle. Due to the uncommon nature of this malignancy, there are frequently diagnostic difficulties that result in management problems. Herein we report a teratocarcinosarcoma arising in the nasal cavity of a 13-year-old boy with activating mutation and copy number variations by next-generation sequencing along with an abnormal karyotype. This tumor must be included in the differential of neoplasms with immature elements, more likely seen in pediatric patients.
Hirschsprung disease (HD) is a disorder caused by the failed migration of neural crest cells, resulting in abnormal innervation of the colon. Histologic hallmarks include the absence of ganglion cells and the presence of...Hirschsprung disease (HD) is a disorder caused by the failed migration of neural crest cells, resulting in abnormal innervation of the colon. Histologic hallmarks include the absence of ganglion cells and the presence of hypertrophic nerve fibers. At present, an immunostain for calretinin is the most used ancillary study. The supportive staining pattern for HD is the absence of immunoreactive ganglion cells and mucosal nerve fibers (neurites). While studying a patient with mantle cell lymphoma involving the colon, we observed a similar immunoreactive pattern for ganglion cells and neurites with anti-BCL-1 and hypothesize that this immunostain might complement calretinin staining. To test this hypothesis, we prospectively collected biopsy and resection specimens from patients clinically suspected of having HD. BCL-1 immunoreactive ganglion cells and/or mucosal neurites were observed in 10 biopsy specimens of patients without HD while these elements were absent in biopsy and affected areas of resection specimens in 12 patients with HD. The staining of ganglion cells and neurites dependent of the source of the antibody used. The parallel negative staining of neural elements with 2 unrelated antibodies provides credence to the absence of immunoreactivity for calretinin in the diagnostic workup of patients suspected of having HD.
INTRODUCTION: We describe placental findings associated with SARS-CoV-2 infection in pregnancy and any differences between trimester of infection. METHODS: We included 314 pregnant patients who tested positive for SARS-C...INTRODUCTION: We describe placental findings associated with SARS-CoV-2 infection in pregnancy and any differences between trimester of infection. METHODS: We included 314 pregnant patients who tested positive for SARS-CoV-2 during pregnancy and had their placenta submitted for pathology examination. Trimester of infection was based on the gestational age at the time of infection. Placental pathology was categorized into acute inflammation (AI), chronic inflammation (CI), maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), and divided into none, low-grade, and high-grade. RT-PCR for SARS-CoV-2 was performed on placenta tissue in 238/314 (75%) cases. RESULTS: The prevalence of AI, CI, FVM, and MVM did not differ by trimester of infection. However, high-grade inflammatory and/or vascular pathology were more prevalent with earlier infection in pregnancy (1st trimester (27/40, 67.5%), 2nd trimester (37/67, 55.2%), and 3rd trimester (82/207, 39.6%, < .01). Third trimester infection ≤10 days before delivery was associated with a higher prevalence of FVM compared to infection more remote from delivery (46/134, 34.3% vs 14/73, 19.2%; < .02). We detected SARS-CoV-2 RNA in placenta, in 8/238 (3.4%) of cases. CONCLUSION: High-grade inflammatory and/or vascular placental pathology are more prevalent with earlier SARS-CoV-2 infection in pregnancy.
Campomelic dysplasia (CD) is a rare skeletal dysplasia typically associated with a high neonatal mortality rate due to respiratory insufficiency. The condition is due to mutations in the SOX9 gene, which affects skeletal...Campomelic dysplasia (CD) is a rare skeletal dysplasia typically associated with a high neonatal mortality rate due to respiratory insufficiency. The condition is due to mutations in the SOX9 gene, which affects skeletal and sexual development. Mutations further away from this gene result in a milder condition, and thus some of those affected live into adulthood. Due to SOX9's effect on sexual development, there is sex reversal in approximately 75% of genotypic males (46XY). This report presents a unique case of a 1-year-old phenotypic female with a 46XY karyotype, diagnosed with CD, gonadal dysgenesis, and bilateral gonadoblastoma. The patient exhibited non-ambiguous female genitalia and a uterus but had undescended streak gonads. The streak gonads were surgically removed due to the increased risk of malignancy. Histological analysis revealed a right-sided streak gonad with multiple foci of dissecting gonadoblastoma and a left-sided streak gonad with classic gonadoblastoma. While the patients' gene break point lies at the 17q23.1 locus, outside of the widely accepted SOX9 region, there may be reason to believe her mutation is affecting the SOX9 gene. This case shows the importance of early diagnosis and intervention with gonadectomy in patients with campomelic dysplasia or other sex reversal disorders.
Pediatr Dev Pathol
· 2025 · PMID 40353490
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Pulmonary cystic lesions in infants are uncommon and can present diagnostic challenges due to overlapping radiologic features with other cystic lung conditions. We present 2 cases of left lung cystic lesions in infants....Pulmonary cystic lesions in infants are uncommon and can present diagnostic challenges due to overlapping radiologic features with other cystic lung conditions. We present 2 cases of left lung cystic lesions in infants. Initial high-resolution computed tomography (HRCT) suggested differential diagnoses, including pneumatocele, type I congenital pulmonary airway malformation (CPAM), or a solitary cystic lymphangioma. Definitive diagnosis was achieved through histopathological examination after left lower lobectomy and resection of the lesion. These cases highlight the challenges in accurately diagnosing pulmonary cystic lesions, given the limitations of imaging alone.
Pediatric pancreatic acinar cell carcinoma (PACC) is a rare malignancy, comprising 5-15% of pediatric pancreatic tumors. rearrangement is found in 20%-30% of PACC cases. We report a case of PACC with a novel fusion and...Pediatric pancreatic acinar cell carcinoma (PACC) is a rare malignancy, comprising 5-15% of pediatric pancreatic tumors. rearrangement is found in 20%-30% of PACC cases. We report a case of PACC with a novel fusion and independent amplifications in and . A 10-year-old male presented with 6 months of weight loss, back pain, and loose stools. Imaging demonstrated concentric soft tissue thickening around the superior mesenteric artery, prompting biopsy of a periaortic lymph node showing metastatic PACC. Pancreaticoduodenectomy revealed PACC and metastatic deposits in multiple lymph nodes and retroperitoneal soft tissue. Fluorescence hybridization of both the periaortic lymph node and pancreaticoduodenectomy specimens demonstrated gene rearrangement, with the partner identified as by next generation sequencing and fusion assays. Chromosomal microarray analysis demonstrated amplification of in the periaortic lymph node biopsy and amplification of in the resection specimen. The patient was treated with neoadjuvant chemotherapy, radiation, and a pan-RAF inhibitor, but developed new widespread metastasis and was deceased 22 months after presentation. The combination of the primary fusion with secondary amplification of and is likely to drive the aggressive behavior and metastasis in this case of PACC.
Kan SY, Scarpini CG, Ward D
… +13 more, Fleming B, Cheow HK, Jalloh I, Tadross JA, Watkins J, Roberts T, Trotman J, Tarpey P, Coleman N, Hook CE, Burns C, Trayers C, Murray MJ
Pediatr Dev Pathol
· 2025 · PMID 40277298
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NUT carcinoma is challenging to diagnose and may mimic a germ cell tumor (GCT) due to raised serum alpha-fetoprotein (AFP). A 15-year-old patient presented with back pain and cough. Investigation revealed a mediastinal m...NUT carcinoma is challenging to diagnose and may mimic a germ cell tumor (GCT) due to raised serum alpha-fetoprotein (AFP). A 15-year-old patient presented with back pain and cough. Investigation revealed a mediastinal mass and multiple bone metastases. Serum AFP was highly elevated, consistent with a metastatic malignant nonseminomatous GCT. Aggressive chemotherapy was initiated with initial response, unfortunately not sustained. Diagnostic biopsy showed undifferentiated tumor cells with weak GCT immunophenotype but was ultimately non-diagnostic. Serum miR-371a-3p levels, highly sensitive/specific for malignant GCTs, were negative casting diagnostic suspicion. Routine use of agnostic molecular investigations, including whole genome sequencing, identified a chromosome 15:19 translocation, with gene fusion on RNA sequencing, confirming NUT carcinoma. Subsequent NUTM1 immunohistochemistry was positive. A high index of clinical suspicion is required for non-pathologically/molecularly confirmed diagnoses. Serum miR-371a-3p quantification ruled out malignant GCT and routine agnostic molecular studies identified the correct diagnosis; a low threshold for NUTM1 immunohistochemistry is thus recommended.