Pediatric hepatic vascular tumors: clinicopathologic characteristics of 33 cases and proposed updates to current classification schemes.

Pediatric hepatic vascular tumors (HVTs) are rare neoplasms with features distinct from their cutaneous counterparts. Their behavior ranges from benign to malignant, with each subtype having therapeutic differences. Histopathologic descriptions of large cohorts are scarce in the literature. Thirty-three putative HVTs diagnosed from 1970 to 2021 were retrieved. All available clinical and pathologic materials were reviewed. Lesions were reclassified according to the World Health Organization (WHO) classification of pediatric tumors [1] as hepatic congenital hemangioma (HCH; n = 13), hepatic infantile hemangioma (HIH; n = 10), hepatic angiosarcoma (HA; n = 3), and hepatic epithelioid hemangioendothelioma (HEH; n = 1). Vascular malformations (n = 5) or vascular-dominant mesenchymal hamartoma (n = 1) were excluded. HCH frequently showed involutional changes, whereas HIH often had anastomosing channels and pseudopapillae formation. HA had solid areas with epithelioid and/or spindled endothelial morphology, significant atypia, increased mitoses, high proliferation index, and occasionally necrosis. On morphology analysis, a subset of HIH showed features worrisome for progression to HA including solid glomeruloid proliferation, increased mitoses, and epithelioid morphology. The widely metastatic and fatal HEH was observed in a 5-year-old male with multiple liver lesions. Immunohistochemically, HIHs and HA were Glucose transporter isoform 1 (GLUT-1) positive. One HIH patient died from postoperative complications, whereas 3 are alive without disease. Five HCH patients are alive and well. Two of three HA patients died of disease, and 1 is alive without recurrence. To our knowledge, this is the largest series of pediatric HVTs reviewing clinicopathologic features based on current Pediatric WHO nomenclature [1]. We highlight diagnostic challenges and propose inclusion of an intermediate category between HIH and HA which warrants closer follow-up.

Focal Nodular Hyperplasia-Like Lesions With Glypican-3 Positivity in Infancy.

PURPOSE AND CONTEXT: Glypican-3 is often used to discriminate between neoplastic and nonneoplastic liver. In focal lesions, positivity may be considered suggestive of a malignancy such as hepatoblastoma. However, glypican-3 is also normally expressed in the immature liver. We present a series of 5 cases of focal nodular hyperplasia (FNH)-like lesions arising in very young patients with glypican-3 expression and highlight the challenges these lesions present in the differential diagnosis of hepatoblastoma. METHODS: Cases were obtained from the files of 3 tertiary pediatric hospitals. Clinical data were obtained from the electronic medical record and histopathologic material including immunohistochemical stains were reviewed. KEY RESULTS: Patients were aged 2 weeks to 6 months with peak AFP levels ranging from 88.6 to 204,696 ng/mL. Microscopically, all were variably demarcated hepatocellular lesions with cords of hepatocytes, marked sinusoidal dilatation, and occasional fibrous bands and areas reminiscent of central scar with bile ducts. No significant cytologic atypia or increased mitotic activity were present. All showed glypican-3 expression and were negative for nuclear beta-catenin with intact reticulin framework. CONCLUSIONS: Our study highlights the pitfalls of evaluating focal liver lesions in infants when high AFP levels and glypican-3 expression may reflect immaturity rather than neoplasia.

Teratoid Hepatoblastoma-Our Experience.

Hepatoblastomas (HB) are the most common pediatric liver tumor with several subgroups described, of which teratoid HB is the rarest. The aim of this study is to characterize the histologic and phenotypic spectrum of teratoid HB in order to better understand the biology and behavior of these tumors. A retrospective analysis of all teratoid HB diagnosed at a major pediatric hospital as well as the consultation files of one of the authors (SR) was performed with the available clinical data and surgical pathology material reviewed. A detailed immunohistochemical workup was also performed. A total of 28 cases were included from patients ranging from 5 to 84 months of age and a M:F ratio of 1.07:1. Four patients had syndromic associations. In 14/28 cases, the tumors contained primitive glandular elements with histologic and immunophenotypic overlap with the yolk sac tumor which in two cases became predominant in metastatic sites. One case had extensive primitive neural epithelium mimicking a primitive neuroectodermal tumor (PNET). Other unique elements included melanin, mature neuroglial tissue, rhabdomyoblastic differentiation, and neuroendocrine carcinoma-like areas (n = 2). In conclusion, this study provides the largest series of teratoid HB to date with clinical and outcome data, highlights previously undescribed or under-recognized histologic patterns in these tumors, and describes the immunohistochemical profile of these tumors to aid in diagnosis.

Large viral meningoencephalitis CSF serologic panel lacks utility in clinical decisions and outcomes.

INTRODUCTION: Accurate diagnosis of viral meningoencephalitis (VMe) and identification of the etiologic agent has clinical importance and large serology panels are available to aid in the detection of several viral pathogens. However, such panels are often send-out testing, with prolonged time to results, thus impacting the actionability of test results. We hypothesized these panels may not contribute to patient care and lack clinical utility. METHODS: A retrospective review of all VMe CSF serology panels ordered at one pediatric (n = 53; 2017-2019) and two adult (n = 200; 2019-2020) tertiary care hospitals was performed to assess test clinical utility. Panels included serology for: Adenovirus, coxsackie and echoviruses, influenza, measles, lymphocytic choriomeningitis virus, herpes simplex virus, mumps, varicella zoster, encephalitis viruses. Clinical data collected included diagnostic test results, symptoms, comorbidities, and interventions. RESULTS: In 129/200 (64.5 %) of adult cases and 37/53 (69.8 %) of pediatric cases CSF had a WBC less than 5 cells/mm2. In total, 127 (63.5 %, 127/200) adult panels had at least one positive target with 49 panels having more than one positive (38.6 %, 49/127). In 99.5 % of adult and 100 % of pediatric cases there was no change to decisions regarding starting, discontinuing, continuing, or changing antimicrobial therapy based on panel results. In no cases were potentially immunosuppressive therapies like steroid or IVIG administration delayed while awaiting the results of the panel. CONCLUSIONS: While all patients presented with neurologic symptoms, poor pre-screening for CNS inflammation using CSF WBC analysis likely contributed to poor clinical utility of the VMe panels. Large CSF serologic panels for VMe did not contribute to or add value to clinical decision making in our cohort.

Pediatric Benign Tumors With a Skeletal Muscle Component: Myogenin Expression, Diagnostic Pitfalls, and New Molecular Insights.

OBJECTIVES: Benign tumors with skeletal muscle differentiation are rare and their characterization in the literature is limited. We present a series of twelve pediatric benign tumors with rhabdomyomatous differentiation including seven rhabdomyomatous mesenchymal hamartomas, four fetal rhabdomyomas, and one benign triton tumor, analyzing myogenic markers as well as clinicopathologic and molecular features. A review of the literature was also performed with an emphasis on myogenic marker expression and correlation with molecular features. METHODS AND RESULTS: Cases obtained from three tertiary pediatric hospitals were retrospectively reviewed. Eleven of twelve cases expressed myogenin in rare to greater than 15% of cells. Five of nine cases had rare to 70-80% of cells positive for MyoD1. One fetal rhabdomyoma demonstrated homozygous deletions in ZEB2. The benign triton tumor harbored a CTNNB1 mutation. Review of the literature identified 160 pediatric benign tumors with skeletal muscle differentiation of which 9 reported myogenin positivity. CONCLUSIONS: Myogenin and MyoD1 may be variably expressed in benign lesions with skeletal muscle differentiation. Recognition of key morphologic features remains critical to diagnose these lesions and, in rhabdomyoma, to exclude malignancy. Our series expands the knowledge of the relationship between rhabdomyoma and rhabdomyosarcoma (RMS) by identifying a shared molecular alteration in ZEB2.

Fibrous histiocytoma/dermatofibroma in children: the same as adults?

Fibrous histiocytoma (FH) or dermatofibroma is a common cutaneous lesion mostly seen in adults and rare in the first two years of life. Two hundred sixty-seven patients younger than 18 years with a diagnosis of FH or dermatomyofibroma, a lesion with morphologic overlap with FH, were identified from the files of a single institution, with only 13 (4.8%) occurring in patients younger than 5 years. Ten patients had either underlying neurologic, autoimmune, or metabolic disorders or a family history of autoimmune conditions. Histologic review of hematoxylin and eosin staining and immunostaining on 75 FHs and dermatomyofibroma in 70 patients showed the following results: 33 classic FHs, 8 classic FHs characterized by a peculiar retiform morphology with thin fascicles of elongated cells forming a network reminiscent of the eruptive variant of FH, 19 deep/cellular variants, 5 aneurysmal variants, 3 lipidized variants (including two lesions in a patient affected by mucopolysaccharidosis IV), 3 dermatomyofibromas, and 4 isolated cases of hemosiderotic, granular cell atypical, and epithelioid FH. Immunostaining for factor XIIIa highlighted a dense network of dendritic cells in FH, which was significantly reduced in the FH with retiform morphology. Smooth muscle actin staining was positive in a high percentage of FHs (85.3%). The current series demonstrates that FH in children may show unique clinical and morphologic features. The retiform pattern with decreased dendritic cells found in congenital lesions and in two older patients with lesions in two locations might have a different pathogenesis, probably related to an altered immune response in very young patients.

SOX9 Immunohistochemistry in the Distinction of Angiomatoid Fibrous Histiocytoma From Histologic Mimics: Diagnostic Utility and Pitfalls.

Angiomatoid fibrous histiocytoma (AFH) can be diagnostically difficult because of its varied histologic appearance and potential to occur at unusual sites. The identification of recurrent rearrangements (EWSR1-CREB1, EWSR1-ATF1, and FUS-ATF1) is a helpful diagnostic tool. Additional immunohistochemical markers in AFH could aid in restricting the differential diagnosis and selecting appropriate cases for targeted molecular studies. SOX9 is a transcription factor that is crucial for chondrogenesis and is expressed in neoplasms with chondroid differentiation, and other malignant bone and soft tissue tumors. Recently a role of EWS in regulation of SOX9 expression has been reported, the rearrangements typical of AFH may play a role in SOX9 expression. In this study, we analyzed SOX9 expression in 13 pediatric AFH with varying histology, and an additional 80 cases of other myofibroblastic or fibrohistiocytic lesions. SOX9 expression was present in 11 of 13 AFH, 2 of 53 dermatofibroma (1 aneurysmal and 1 cellular) and 1 calcifying aponeurotic fibroma. The remaining tumors were negative. SOX9 is selectively expressed in AFH and may be a useful maker in combination with desmin, CD99, CD68, and EMA in small biopsies, especially in cases with unusual morphologic features. SOX9 appears to be highly specific for AFH, being weakly expressed in a subset of aneurysmal dermatofibroma and absent in other myofibroblastic lesions, except calcifying aponeurotic fibroma. It should be used with caution when differentiating AFH from malignant neoplasms such as Ewing sarcoma.

Early Bilateral Gonadoblastoma Associated With 45,X/46,XY Mosaicism: The Spectrum of Undifferentiated Gonadal Tissue and Gonadoblastoma in the First Months of Life.

45,X/46,XY mosaicism is one of a heterogenous group of congenital conditions known as differences (disorders) of sex development (DSD) that results in abnormal development of internal and external genitalia. Patients with DSD, particularly those with segments of the Y chromosome, are at increased risk for germ cell tumors including gonadoblastoma. Gonadoblastoma is a neoplasm comprised of a mixture of germ cells and elements resembling immature granulosa or Sertoli cells with or without Leydig cells or lutein-type cells in an ovarian type stroma. Gonadoblastoma has an increased prevalence of 15% to 40% in patients with 45,X/46,XY mosaicism and has been previously reported in patients as young as 5 months of age with that karyotype. Herein, we describe a 3-month-old child with 45,X/46,XY karyotype who was referred for the evaluation of asymmetric labia majora. Additional evaluation revealed left streak gonad and right dysplastic/dysgenetic testis. Both gonads contained foci of cells typical for gonadoblastoma as well as undifferentiated gonadal tissue, underscoring the potential for very early infantile gonadoblastoma and the spectrum of developmental anomalies associated with this karyotype.