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Teratocarcinosarcoma is an extremely rare malignancy of the nasal cavity and paranasal sinuses. It exhibits both sarcomatous and carcinomatous components. Less than 100 cases are reported. It presents in adults with only two reported cases in infancy. Here we present a case of 3-week-old female with antenatally detected ocular mass. MRI revealed an exophytic right ocular mass (10 × 7.0 × 7.0 cm) with intracranial extension. The tumor consisted of malignant glands and mesenchymal elements of undifferentiated blastema-like cells and immature neuroepithelium. After an initial diagnosis and treatment for a Wilms tumor protocol, the mass showed no response. A second opinion rendered a diagnosis of sinonasal teratocarcinosarcoma. The patient underwent surgical resection and seven cycles of CNS ICE chemotherapy. A second debulking surgery revealed a very scant viable tumor with post-treatment changes. The patient is alive at 43 months on weekly vincristine maintenance. Molecular testing revealed a somatic CTNNB1 gene mutation. In conclusion, this is a rare and aggressive tumor which showed disease free survival beyond that reported in the literature with the appropriate use of multimodality therapy.

Supplementary Data from A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era

Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on “blastomas,” which variably recapitulate the morphologic maturation of organs from which they originate.Significance:In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.

Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous MYBPC3 variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the SMYD1 gene. The second patient, the proband’s sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous MYBPC3 variant. While this specific MYBPC3 variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel SMYD1 variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.

Nemaline Myopathy (NM) is a disorder of skeletal muscles caused by mutations in sarcomere proteins and characterized by accumulation of microscopic rod or thread-like structures (nemaline bodies) in skeletal muscles. Patients diagnosed with both NM and infantile cardiomyopathy are very rare. A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods. Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs. Both parents were heterozygous for the same variant but have no history of heart or muscle disease. Analysis of patient derived fibroblasts and cardiomyocytes derived from induced pluripotent stem cells confirmed the p.C430fs mutation (pathogenic variant), which appears to cause loss of both CAP2 protein and mRNA. The CAP2 gene encodes cyclase associated protein 2, an actin monomer binding and filament depolymerizing protein and CAP2 knockout mice develop severe dilated cardiomyopathy and muscle weakness. The patient underwent a heart transplant at 1 year of age. Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure. Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring. This is the first description of a patient presenting with nemaline myopathy associated with a pathogenic variant of CAP2.

17q12 deletion syndrome causes developmental abnormalities of the kidneys, pancreas, genital tract, and neurodevelopment, and it has a wide range of phenotypes ranging from fetal demise to normal adulthood with minimal renal impairment. Here we describe a rare case of 17q12 deletion diagnosed prenatally, complicated by anhydramnios and Potter sequence. The baby was born but necessitated life-saving interventions due to pulmonary and renal insufficiency and ultimately succumbed to multi-organ failure. We present full autopsy results describing findings linked to 17q12 deletion, including severe bilateral multicystic renal dysplasia, pancreatic hypoplasia, and cysts adjacent to the Fallopian tubes. We also describe pulmonary hypoplasia and Potter facies as consequences of anhydramnios. We correlate these findings to our current understanding of molecular signals altered by 17q12 deletion, notably affecting HNF1B and LHX1 genes, which are known to mediate renal and genitourinary tract development.

Background Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive β-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the β-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling. Methods Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy. Conclusion This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension. Clinical trial registration: The trial protocol was registered at clinicaltrials.gov (NCT04713657).

Linear Sebaceous Nevus Syndrome is a rare disorder that presents with nevus sebaceus in association with corneal dermoids, colobomas, choroidal osteomas, and arachnoid cysts. It is thought to represent a mosaic RASopathy. These are disorders characterized by postzygotic somatic mutation in genes involved in RAS/MAPK signaling pathway. In this report we describe two patients with linear sebaceous nevus syndrome found to have mutations in codon 146 of KRAS with evidence of mosaicism. This specific mutation has previously been reported in Oculoectodermal Syndrome and Encephalocraniocutaneous Lipomatosis, two other mosaic RASopathies with predominantly cerebrooculocutaneous manifestations. These findings suggest that, while initially classified as different syndromes, these disorders should be evaluated and managed as a spectrum of related disorders.

Acinic cell carcinoma (AciCC) is the second most common pediatric malignant salivary gland tumor. However, there are limited pathology publications about this tumor in the pediatric population.We describe four pediatric AciCC cases diagnosed between 2000 and 2021 in our institute. Reticulin histochemistry plus immunohistochemistry for NR4A3 and DOG1 were performed on all cases.Histologically, all four cases featured a tumor-associated lymphoid proliferation and collagenous stroma, in which two formed central scars. The tumors were predominantly solid, with a lobular pattern and variably sized dilated spaces, including one case with focal microcysts. High-grade transformation was not observed in any of our cases. Reticulin stain and immunohistochemistry for NR4A3 showed distinct features between AciCC and non-neoplastic salivary gland parenchyma. DOG1 immunohistochemistry confirmed the acinar origin of AciCC.Our study reveals that pediatric AciCCs often present with tumor-associated lymphoid proliferation (TALP) and sclerosis. Special stains such as reticulin histochemistry and NR4A3 immunohistochemistry are helpful to separate tumor from adjacent benign parenchyma. The ancillary study is helpful for the diagnosis of small specimens. Our study is limited by its low case number, but we hope that our results will promote more studies on this rare salivary gland tumor in the pediatric population.

Teratocarcinosarcoma is an extremely rare malignancy of the nasal cavity and paranasal sinuses. It exhibits both sarcomatous and carcinomatous components. Less than 100 cases are reported. It presents in adults with only two reported cases in infancy. Here we present a case of 3-week-old female with antenatally detected ocular mass. MRI revealed an exophytic right ocular mass (10 × 7.0 × 7.0 cm) with intracranial extension. The tumor consisted of malignant glands and mesenchymal elements of undifferentiated blastema-like cells and immature neuroepithelium. After an initial diagnosis and treatment for a Wilms tumor protocol, the mass showed no response. A second opinion rendered a diagnosis of sinonasal teratocarcinosarcoma. The patient underwent surgical resection and seven cycles of CNS ICE chemotherapy. A second debulking surgery revealed a very scant viable tumor with post-treatment changes. The patient is alive at 43 months on weekly vincristine maintenance. Molecular testing revealed a somatic

Myoepithelial tumors of soft tissue are rare mesenchymal neoplasms that overlap with their salivary gland and skin counterparts at both the histopathologic and molecular levels. EWSR1 gene rearrangements with various fusion partners represent a common genetic event in myoepithelial tumors of soft tissue, whether benign or malignant, and may prove useful as a diagnostic tool in difficult cases. However, the number of diagnostic entities with EWSR1 gene rearrangements has grown considerably in recent years, and there is significant morphologic and immunophenotypic overlap amongst this group, underscoring the importance of fusion testing to detect fusion partners that are characteristic of discrete diagnostic entities. Herein, we report a malignant myoepithelial tumor of soft tissue/myoepithelial carcinoma with an undifferentiated round cell morphology arising in a pediatric patient with a EWSR1-ATF1 gene fusion.

Duchenne muscular dystrophy (DMD) is characterized by progressive systemic muscle wasting, leading to respiratory paralysis and early death. This X-linked disease is caused by DMD mutations, encoding dystrophin. 1 There is little information regarding gastrointestinal abnormalities in patients with DMD. However, since the esophageal wall includes smooth and skeletal muscle it is also vulnerable to suffering the effects of muscle wasting in patients with DMD. After finding dyskeratosis and parakeratosis restricted to the proximal and middle esophagus with distal sparing in an 18-year-old patient with DMD, we performed an archive search of a large academic hospital and identified four additional patients with DMD who had also undergone esophageal biopsy. The patients consisted of five boys, ranging from 7 to 19 years of age. Esophageal injury was present in two patients, consisting of mild esophagitis in one, and spongiosis with dyskeratosis and parakeratosis in another. These patients were both older and had been diagnosed with DMD for greater than 15 years, while the three patients with histologically normal biopsies were younger and been diagnosed with DMD for 7, 9, and 13 years, respectively. Although the data is limited and the changes are subtle, they can be explained by the underlying muscular dystrophy pathophysiology.

Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome resulting from defective cytotoxicity. A previously healthy 3-month-old female presented with fever, irritability, abdominal distention, and tachypnea. She ultimately met all eight HLH-2004 diagnostic criteria, accompanied by elevated CXCL9. Initial empiric anti-inflammatory treatment included anakinra and IVIg, which stabilized ferritin and cytopenias. She had molecular and genetic confirmation of perforin deficiency and was started on dexamethasone and etoposide per HLH-94. She clinically improved, though CXCL9 and sIL-2Ra remained elevated. She was readmitted at week 8 for relapsed HLH without clear trigger and HLH-94 induction therapy was reinitiated. Her systemic HLH symptoms failed to respond and she soon developed symptomatic CNS HLH. She was incidentally found to have multifocal lung and kidney nodules, which were sterile and consisted largely of histiocytes and activated, oligoclonal CD8 T cells. The patient had a laboratory response to salvage therapy with alemtuzumab and emapalumab, but progressive neurologic decline led to withdrawal of care. This report highlights HLH foci manifest as pulmonary/renal nodules, demonstrates the utility of monitoring an array of HLH biomarkers, and suggests possible benefit of earlier salvage therapy.

Introduction Somatic internal tandem duplication of 3’ of BCOR ( BCOR ITD) has been found in clear cell sarcomas of the kidney (CCSK), soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and a subgroup of central nervous system high-grade neuroepithelial tumors (CNS-HGNET). BCOR ITD+ tumors share morphologic features. Expression of OLIG2 and epidermal growth factor receptor (EGFR) has been reported in CNS-HGNET with BCOR ITD. Here, we characterize OLIG2 and EGFR expression in URCS/PMMTI with BCOR ITD. Methods Paraffin blocks of 9 polymerase chain reaction-confirmed soft tissue BCOR ITD+ tumors (URCS/PMMTI) were immunophenotyped for OLIG2 and EGFR expression and scored semiquantitatively by percentage of positive cells and intensity of staining as negative, 1+, 2+, and 3+. Fluorescence in situ hybridization (FISH) for EGFR amplification was performed (amplification EGFR/CEP7 ratio ≥2.0). Results All 9 tumors showed membrane/cytoplasmic expression of EGFR, strong and diffuse (3+) in 8 cases; weak (+2) in 1. FISH detected no EGFR amplification. OLIG2 was negative in all. Conclusions EGFR is overexpressed in pediatric URCS/PMMTI with BCOR ITD and may be related to transcriptional upregulation of EGFR by BCOR ITD. OLIG2 negative staining differentiates URCS/PMMTI from CNS-HGNET. This finding may further support the possibility that these tumors have a different stem cell of origin.

In inflammatory dermatoses, dermal melanophages (MLP) are ascribed to "pigment incontinence," with melanin "dropping down" from the epidermis. Although this is analogous to the "dropping down" of melanocytic nevus cells (Abtropfung), MLP in ordinary nevi have not been systematically studied-so "pigment incontinence" may not apply to MLP in nevi. A total of 31 childhood nevi identified by pediatricians and family practitioners were evaluated for the distribution of MLP. We tested the hypothesis that a dermal origin of the melanin in MLP is more likely than dropping down from the epidermis. In our cohort, 90.3% (28/31) of childhood nevi had dermal MLP, a significantly higher frequency, compared to 31/60 ordinary adult nevi (P < 0.0001). Superficial dermis was the most common location (P < 0.001). However, only six specimens had MLP restricted to the superficial dermis, significantly less than predicted by the theory that melanin drops down from the epidermis (P < 0.00001). We also evaluated perivascular MLP, since nerves run together with vessels in neurovascular bundles (NVB), and it has been showed that precursors of melanocytes migrate from the neural crest to the skin as nerve sheath stem cells. Superficial NVB MLP correlated with deep NVB bundle MLP (P < 0.05), suggesting that NVB MLP represent "tombstones" for superficial and deep dermal nevus cells. Deep dermal, deep NVB, and deep periadnexal MLP may be valid biological criteria for diagnosis of congenital type (prenatal) nevi. Viewing prenatal nevi in children as a neurocristopathy fits a major principle of pediatric pathology: childhood diseases should be studied and understood based on what happens during tissue development.

Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference.

Calyceal diverticula (CD) are relatively uncommon urologic conditions that generally follow an asymptomatic course and rarely require medical intervention. CD are thought to have a congenital origin due to abnormalities during the process of ureteral bud formation. Clinically and radiologically, they can mimic multiple neoplastic and non-neoplastic renal processes, with potentially relevant differences in the management of these patients. Symptoms are usually associated with the presence of stones, obstruction to the drainage of the diverticulum, large size, or secondary infection. In chronic cases, surgery might become necessary, creating an opportunity to examine the histopathological characteristics of this condition. Although these are benign in the majority of patients, some rare instances of malignancy arising from the CD have been reported. In this series, we addressed the clinical, radiological, and histopathological findings of CD.

A 15 - month-old full-term male of African descent with an asymptomatic sickle cell trait, presented with episodes of transient erythematous subcutaneous nodules involving the entire body except the face, since 2 weeks of age. The skin lesions evolved to areas of lipoatrophy and hyperpigmentation. An initial skin biopsy, studied at a different Department at 2 months of age, was initially misinterpreted as subcutaneous fat necrosis of the newborn despite the lack of the typical radiated crystals and needle-shaped clefts characterizing that entity. At 4 months of age, he developed systemic inflammatory manifestations including fever, a new rash, significant periorbital edema, and failure to thrive. An extensive workup showed leukocytosis, hypercalcemia, elevated inflammatory markers, hypertriglyceridemia, and transaminitis. A new skin biopsy of the eyelid was diagnosed as neutrophilic lobular panniculitis with necrotic adipocytes. An initial whole-exome sequencing did not identify any causative mutations, but a WES reanalysis focused on autoinflammatory disorders was requested based on additional clinicopathologic data, and revealed a mosaic intronic mutation in IKBKG c. 671+3G>C. This mutation encodes an mRNA missing exon 5 resulting in NEMO Δ-exon 5 Autoinflammatory Syndrome (NDAS). NEMO-NDAS is one of the systemic autoinflammatory diseases (SAIDs) that may appear as an unexplained panniculitis in young children, who should be monitored for immunodeficiency and/or autoinflammatory disease. The differential diagnosis of autoinflammatory disorders should be considered in such cases incorporating the use of the whole genome/ exome sequencing in the investigation. The Inhibitor of Kappa-B Kinase Regulatory Subunit Gamma (IKBKG) is located on chromosome Xq28 and encodes the NF-κB essential modulator (NEMO), a critical molecule upstream of NF-kB activation.

Rhabdomyomatous mesenchymal hamartomas (RMHs), also termed striated muscle hamartomas, are rare benign tumors of skin and subcutis, which mostly occur at birth with a predilection for the head and neck. Simple surgical excision is the treatment modality of choice with excellent prognosis.To review the spectrum of the different clinical and pathologic features of RMHs in pediatric patients and recognize their characteristics to avoid confusion with other lesions in their list of differential diagnosis.Six cases of RMH diagnosed at our institution from 2009 to 2021 were retrieved from our files and reviewed retrospectively after anonymization by an honest broker. This review is IRB-approved by the University of Pittsburgh School of Medicine, study STUDY19080192.The patients' age ranged from 6 days to 8 years, with a female predominance (2:1). In all cases, the lesion was present at birth. All lesions, except for 2, occurred in the head and neck regions. One patient had multiple additional small nodules in the face, whereas all others presented with solitary RMHs. The size of the lesions varied, and their composition included bundles of skeletal muscle (the landmark finding) associated with variable amounts of adipose, fibrous, vascular, nerve, and adnexal structures.RMH is a benign hamartomatous lesion with a variable phenotypic spectrum. RMHs predominate in the head and neck. Familiarity with these lesions, including their presentation in less frequent anatomical sites, is important to avoid diagnostic misinterpretations and potential overtreatment. This study represents one of the largest series of RMHs in the literature, including an unusual case in a perianal location.

Immunohistochemical procedures are complex, multiparameter assays that must take into account many factors during protocol development. The overall goal of a successful immunohistochemistry protocol is to produce a specific, sensitive, robust, and reproducible stain. Each step in the protocol has an important role in this outcome. This chapter focuses on primary antibody selection and techniques for blocking various undesired staining reactions.

Immunohistochemical procedures are complex, multiparameter assays that must take into account many factors during protocol development. The overall goal of a successful immunohistochemistry protocol is to produce a specific, sensitive, robust, and reproducible stain. Each step in the protocol has an important role in this outcome. This chapter focuses on primary antibody selection and techniques for blocking various undesired staining reactions.

Disorders of sex development (DSD) are a group of congenital conditions associated with anomalous development of internal and external genital organs. Ovotesticular disorder of sex development (OT-DSD) is a condition in which a child is born with both testicular tissue (that possesses variable fertility potential within seminiferous tubules) and ovarian tissue (with primordial follicles). These tissues may be co-existent in the same gonad (ovotestis) or independently in separate gonads. Here, we report the clinical case of a 21-month-old boy that we met during a humanitarian surgical mission performed at Hospital Dr. Francisco Moscoso Puello, Santo Domingo, Dominican Republic. The child was referred for management of hypospadias, cryptorchidism, and symptomatic right inguinal and umbilical hernias. With further chromosomal evaluation, the diagnosis of SRY-negative OT-DSD was made, and shared decision-making was used to determine the timing of gender assignment, reconstruction, and the child’s long-term care team. OT-DSD is an uncommon condition with unclear causes. Once a DSD condition is suspected at birth, a complete investigation should be performed, encompassing a descriptive examination, a basic electrolyte and hormonal profile, genetic assessment, and pelvic ultrasound. Consultation with a multidisciplinary team is warranted, including pediatric urology or pediatric surgery with urologic training, endocrinology, genetics, psychology, pathology, and the patient’s pediatrician at minimum before surgical reconstruction. It is crucial to involve the patient and their family with shared decision-making before surgery or gender assignment.

The lysine methyltransferase SMYD1 was first identified in mice and shown to be important for embryonic cardiac development. Subsequently, we reported the first analysis of SMYD1 in adult myocardium and demonstrated that cardiomyocyte-specific loss of SMYD1 lead to progressive cardiac hypertrophy and heart failure, and showed that this enzyme is necessary to maintain metabolic homeostasis through transcriptional regulation of mitochondrial energetics in adult mice. While SMYD1 has been the subject of several additional studies in zebrafish and mice, since it was first identified, only in the last few years have human patients been identified with variants in the SMYD1 gene thought to be responsible for their cardiomyopathies. Specifically, two patients have been identified to date, the first patient displaying hypertrophic cardiomyopathy had a de novo heterozygous variant (c.814T>C) and the second patient with left ventricular non-compaction cardiomyopathy and arrhythmias had a truncating heterozygous variant (c.675delA). Here we report a third patient with biventricular heart failure containing a homozygous variant (c.302A>G; p.Asn101S) in the SMYD1 gene which was identified by a whole exome sequencing. Our histopathological analysis of cardiac tissue and skeletal muscle from the proband showed abnormalities in myofibrillar organization in both cardiac and skeletal muscle suggesting that SMYD1 is necessary for sarcomere assembly and organization. In addition, we observe markedly abnormal myocardium with extensive fibrosis and multifocal calcification, and our ultrastructural (EM) analysis revealed presence of abnormal mitochondria with reduced and irregular or lost cristae. Lastly, we have performed structural modeling of SMYD1 containing the p.Asn101Ser variant (N101S) and report how this variant may affect the enzymatic activity of SMYD1 due to its proximity to the substrate binding site. The identification of this novel variant constitutes the third patient with a SMYD1 variant displaying cardiomyopathy and provides insights into the molecular functionality of this protein. In addition, this is the first analysis of tissue from a patient expressing a SMYD1 variant which provides critical insights into the role of SMYD1 in the heart and how loss of function mutations can effect cardiac physiology.

Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on “blastomas,” which variably recapitulate the morphologic maturation of organs from which they originate. Significance: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.

Background Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. Methods We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. Results Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. Conclusion We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.

In the past decade, there have been major advances in knowledge related to mesenchymal tumors, and new genetic alterations are being delineated. We report a mesenchymal spindle cell neoplasm harboring a novel gene fusion in an infant. Histopathologically, the neoplasm shared some features with sclerosing perineurioma, but immunohistochemically, EMA was negative, whereas GLUT1, NK1-C3, and BCOR were positive. Next-generation sequencing revealed a PCMTD1-pleomorphic adenoma gene 1 (PLAG1) fusion. PLAG1 contributes to the expression of a variety of genes implicated in regulating cell proliferation, and PCMTD1 has been related to the development of certain carcinomas. Recently, other soft tissue tumors in young children associated with PLAG1 fusion variants have been reported. Perhaps, mesenchymal neoplasms presenting PLAG1 fusions with different genes would confirm a specific group (PLAG mesenchymal tumours or "plagomas") in the near future.

Renal mass lesions with a follicular architecture resembling atrophic kidney have been described, but their distinction from thyroid-like follicular carcinoma of the kidney remains controversial. We collected 8 cases of this purported "atrophic kidney"-like lesion to fully describe their clinical and histologic spectrum, their possible etiology, and to discuss their distinction from other renal neoplasms. Eight total cases were identified with patient ages ranging from 9 to 48 years (mean: 29 y; median: 28.5 y). Four patients were female and 4 were male. The tumors were unifocal and size ranged from 1.6 to 4.9 cm (mean: 3.4 cm; median: 3.4 cm). All 8 tumors had a remarkably similar histology. Each was enveloped by a smooth muscle rich capsule and had an overall low power "follicular" architecture. The luminal spaces of the "follicles" (or cysts) contained eosinophilic secretions and the lining epithelium was often flattened and atrophic, but some had more rounded cells with a distinctive hobnail arrangement. Many cysts contained discohesive round cells floating within the eosinophilic material, and some contained small intraluminal tufts with features of markedly atrophic glomeruli. Periodic acid-Schiff stains highlighted basement membrane material extending into these glomerular-like tufts, and some contained small distinct capillaries surrounded by endothelial cells, interspersed mesangial-like cells, and rare surrounding podocyte-like cells, providing additional evidence for glomerulocystic structures. Scattered calcifications were present within cysts (or within cyst walls) in varying numbers and were characterized by 2 types: psammoma body-like or more amorphous deposits. The tissue between cystic glomeruli contained predominantly small atrophic tubular structures, but collagenized stroma and smaller collapsed glomeruli were also present. The 2 tumors from the oldest 2 patients (48 and 39 y) had a more striking degree of stromal hyalinization. Immunohistochemically, the cyst lining cells had a predominant WT-positive/PAX-8 negative/CK7-negative phenotype, while tubules were typically WT-1 negative/PAX-8 positive/CK7-positive. Upon comparison to a control group of 10 kidneys containing incidental non-mass-forming glomerulocystic change, the morphologic features and immunophenotype were identical. To date, no patient has had any recurrence or aggressive clinical behavior based on follow status in 7 of 8 cases (follow-up range: 9 to 168 mo; median: 24 mo; mean: 40 mo). In summary, we describe the clinicopathologic features of 8 unique, benign "atrophic kidney"-like lesions that may simply represent a non-neoplastic form of organizing tubular atrophy and glomerulocystic change, and emphasize their distinction from thyroid-like follicular carcinoma of the kidney.

Background Mesenchymal chondrosarcoma is a rare and aggressive bone tumor with few reports of primary tumor in the chest wall. Case We report a case of a 17‐year‐old male presenting with back pain and a posterior mediastinal mass. Imaging demonstrated what was thought to be a benign chondral tumor. The patient underwent resection which confirmed extraskeletal mesenchymal chondrosarcoma. The patient declined proposed adjuvant chemotherapy and underwent multiple resections for rapid local reoccurrence. He ultimately elected for hospice care. Conclusion The case highlights the importance of close disease monitoring and exploration of treatment options, given lack of established guidelines and consistent tumor features.

Objectives Very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD) is a disorder of fatty acid oxidation. Symptoms are managed by dietary supplementation with medium‐chain fatty acids that bypass the metabolic block. However, patients remain vulnerable to hospitalisations because of rhabdomyolysis, suggesting pathologic processes other than energy deficit. Since rhabdomyolysis is a self‐destructive process that can signal inflammatory/immune cascades, we tested the hypothesis that inflammation is a physiologic dimension of VLCADD. Methods All subjects (n = 18) underwent informed consent/assent. Plasma cytokine and cytometry analyses were performed. A prospective case analysis was carried out on a patient with recurrent hospitalisation. Health data were extracted from patient medical records. Results Patients showed systemic upregulation of nine inflammatory mediators during symptomatic and asymptomatic periods. There was also overall abundance of immune cells with high intracellular expression of IFNγ, IL‐6, MIP‐1β (CCL4) and TNFα, and the transcription factors p65‐NFκB and STAT1 linked to inflammatory pathways. A case analysis of a patient exhibited already elevated plasma cytokine levels during diagnosis in early infancy, evolving into sustained high systemic levels during recurrent rhabdomyolysis‐related hospitalisations. There were corresponding activated leukocytes, with higher intracellular stores of inflammatory molecules in monocytes compared to T cells. Exposure of monocytes to long‐chain free fatty acids recapitulated the cytokine signature of patients. Conclusion Pervasive plasma cytokine upregulation and pre‐activated immune cells indicate chronic inflammatory state in VLCADD. Thus, there is rationale for practical implementation of clinical assessment of inflammation and/or translational testing, or adoption, of anti‐inflammatory intervention(s) for personalised disease management., Very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD), an incurable inborn error of fatty acid oxidation, is traditionally considered a disease of energy deficit. Symptoms are managed by dietary supplementation of medium‐chain fatty acids, but patients remain vulnerable to hospitalisations because of recurrent rhabdomyolysis. This study shows for the first time that chronic inflammation is a novel physiologic dimension of VLCADD, which provide rationale for personalised adoption of anti‐inflammatory intervention(s) in disease management.

Salivary gland secretory carcinoma (SSC) is a neoplasm with characteristic histologic features, similar to those of secretory carcinoma of the breast. Only a few pediatric SSC cases have been reported, all with ETV6-NTRK3 fusion. We present four new pediatric SSC examples, one with a novel ETV6-RET fusion. Four cases of SSC were diagnosed between 2010 and 2020: 2 boys, 7 and 9 year-old with parotid tumors (1.5 and 1.3 cm, respectively); and two 14 year-old girls: one with a submandibular tumor (2.1 cm), and one with a parotid lesion (1.2 cm). Histologically, all tumors were similar: well-circumscribed lesions composed by mid-size, monotonous cells with eosinophilic and sometimes vacuolated cytoplasm. The nuclei are oval to round with open chromatin and a single nucleolus. There are duct-like structures and microcysts with colloid-like material. Immunohistochemically, tumor cells are positive for S100, CK7, mammaglobin and GATA3. A classic ETV6-NTRK3 translocation was confirmed in the three parotid tumors; an ETV6-RET fusion was demonstrated in the submandibular lesion. All patients underwent complete surgical resection and are alive without tumor recurrence after a follow-up time ranging from one to 4 years. Pediatric SSC is extremely rare but their characteristic morphology and immunohphenotype facilitate their diagnosis. We describe the first pediatric case with the recently reported ETV6-RET fusion. Similar to adult cases, this tumor is morphologically undistinguishable from those carrying the classic ETV6–NTRK3 translocation. Thus, in pediatric cases with morphology suggestive of SSC and negative ETV6-NTRK3 by RT-PCR, other possible fusions should be investigated.

A central pathology or site reading of biopsy slides is used in liver transplant clinical trials to determine rejection. We evaluated interrater reliability of readings of "rejection or not" using digitized slides from the Medication Adherence in Children who had a Liver Transplant (MALT) study. Four masked experienced pathologists read the digitized slides and then reread them after a study-specific histologic endpoint development program. Agreement was expressed throughout as a Kappa or Fleiss Kappa statistic (ҡ). A ҡ>0.6 was predefined as desirable. Readings were correlated with immunosuppressant adherence (the Medication Level Variability Index, [MLVI]), and maximal liver enzyme levels during the study period. Interrater agreement between site and central review in MALT, and between 4 pathologists later on, was low (ҡ=0.44, Fleiss ҡ=0.41, respectively). Following the endpoint development program, agreement improved and became acceptable (ҡ=0.71). The final reading was better-aligned with maximal gamma-glutamyl transferase levels and MLVI as compared with the original central reading. We found substantial disagreement between experienced pathologists reading the same slides. A unique study-specific procedure improved interrater reliability to the point it was acceptable. Such a procedure may be indicated to increase reliability of histopathologic determinations in future research, and perhaps also clinically.

Capillary hemangioma is a rare benign lesion in the testicle, particularly in pediatrics. It can mimic malignancy, leading to radical orchiectomy. We present a case of a testicular hemangioma in a child, and review the literature on testicular hemangiomas in this age group. A hypervascular testicular lesion without elevated tumor markers may warrant intraoperative biopsy to direct surgical management, which may include testis-sparing surgery if amenable.

Background Omipalisib has been found to affect the viability of cancer cells. However, its effect on clonogenicity - a feature of cancer stem cells, is not clear. Cells isolated from neurocutaneous melanocytosis (NCM) patients' lesions grow clonogenically. The aim of this study was to investigate the effect of omipalisib treatment on clonogenic growth of NCM cells in vitro. Materials and methods Clonogenic growth efficiency was evaluated by colony formation assays with or without specific growth factors. Activation of MEK and Akt was determined by immunoblots. Colony formation and cell viability were assessed upon pharmacological inhibition of MEK, Akt and mToR. Results Clonogenicity appeared to depend on bFGF and IGF1signaling through ERK and Akt. Omipalisib treatment prevented colony formation and induced autophagic cell death. Conclusion Signaling through Akt is important for survival of clonogenic cells in NCM, and omipalisib treatment as a monotherapy or in combination with MEK162 could be an effective therapeutic strategy to inhibit clonogenic growth.

Background The XX male disorder of sex development (DSD) is a rare condition that is most commonly associated with the presence of the SRY gene on one of the X chromosomes due to unequal crossing-over between sex chromosomes during spermatogenesis. However, in about 20% of the XX male individuals, SRY is missing, although these persons have at least some testis differentiation. The genetic basis of genital ambiguity and the mechanisms triggering testis development in such patients remain unknown. Methods The proband with 46,XX SRY-negative testicular DSD was screened for point mutations by whole exome sequencing and CNVs using a high-resolution DSD gene-targeted and whole genome array comparative genomic hybridisation. The identified Xp21.2 genomic alteration was further characterised by direct sequencing of the breakpoint junctions and bioinformatics analysis. Results A unique, 80 kb microdeletion removing the regulatory sequences and the NR0B1 gene was detected by microarray analysis. This deletion disturbs the human-specific genomic architecture of the Xp21.2 dosage-sensitive sex (DSS) reversal region in the XX patient with male-appearing ambiguous genitalia and ovotestis. Conclusions Duplication of the DSS region containing the MAGEB and NR0B1 genes has been implicated in testis repression and sex reversal. Identification of this microdeletion highlights the importance of genomic integrity in the regulation and interaction of sex determining genes during gonadal development.