Perivascular Epithelioid Cell-Family Tumors in Children, Adolescents and Young Adults:Clinicopathologic Features in 70 Cases.

CONTEXT.­: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented. OBJECTIVE.­: To describe a multi-institutional series of PEComas in children, adolescents, and young adults. DESIGN.­: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and authors' files. RESULTS.­: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominately in kidney (53 of 70), followed by liver (6 of 70). Thirty-four patients had confirmed tuberous sclerosis complex (TSC), 3 suspected TSC mosaicism, 2 Li-Fraumeni syndrome (LFS) and 1 neurofibromatosis type 1. Most common variants were classic (49 of 70) and epithelioid (8 of 70) AML. Among patients with AMLs, most (34 of 47) had TSC, and more TSC patients had multiple AMLs (15 of 36) than non-TSC patients (2 of 13). Two TSC patients developed malignant transformation of classic AMLs: 1 angiosarcomatous and 1 malignant epithelioid. Lymphangioleiomyomatosis (5 of 70) occurred in females only, usually in the TSC context (4 of 5). PEComas-NOS (6 of 70) occurred exclusively in non-TSC patients, 2 of whom had LFS (2 of 6). Three were malignant, 1 had uncertain malignant potential, and 2 were benign. All 4 PEComas-NOS in non-LFS patients had TFE3 rearrangements. CONCLUSIONS.­: Compared to the general population, TSC was more prevalent in our cohort; PEComas-NOS showed more frequent TFE3 rearrangements and possible association with LFS. This series expands the spectrum of PEComas in young patients and demonstrates molecular features and germline contexts that set them apart from older patients.

Gastrointestinal Tract Granular Cell Tumor in the Pediatric Population: A Multicenter Experience.

BACKGROUND: Pediatric granular cell tumors (GCT) involving the gastrointestinal tract (GIT) are rare with limited case report/series reported to date. METHODS: Multicenter retrospective study of pediatric GIT GCT. RESULTS: A total of 10 cases were included in the study with a median age of 13.5 years (range: 7-18 years) and were predominantly female patients (60%). In half of the patients no significant medical history was present with the remaining 5 having Crohn disease (10%), eosinophilic esophagitis (EoE) (10%), Crohn disease and EoE (10%), growth hormone deficiency (10%), and aplasia cutis congenita (10%). The GCT median size was 1.3 cm (range: 1-1.6 cm) and were more commonly located in the esophagus (70%) followed by the stomach (20%) and rectum (10%). Most of the cases showed round/polygonal tumor cells with abundant granular cytoplasm, and none of the cases had nuclear atypia, increased mitotic activity, or tumor cell necrosis. None of our cases received specific therapy for GCT other than clinical follow-up, and none of the patients had evidence of local recurrence or metastatic disease. CONCLUSION: We present our multicenter experience with GIT GCT, all cases had a benign course. Interestingly, 4 of the esophageal GCT cases (including 2 patients with EoE) showed an eosinophil-rich esophagitis in the underlying mucosa.

The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective.

CONTEXT.­: Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting. OBJECTIVE.­: To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage. DATA SOURCES.­: The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript. CONCLUSIONS.­: Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

ALK-Rearranged Epithelioid Mesenchymal Neoplasm: Expanding the Spectrum of Tyrosine Kinase-Altered Mesenchymal Tumors.

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.

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.

Acute Interstitial Nephritis in the Pediatric Population: A Review of Etiologic Associations, Histologic Findings, and Clinical Outcome.

BACKGROUND: Acute interstitial nephritis (AIN) is an infrequent cause of acute kidney injury in the pediatric population with a broad range of etiologies. This retrospective review attempts to characterize AIN in the pediatric population, delineate etiologic factors, histologic features, and clinical outcome. MATERIALS AND METHODS: Institutional pathology reports were queried for a diagnosis of AIN between 1/2010 and 10/2021. Archived slides and reports and clinical records were reviewed. RESULTS: Twenty-four patients were identified whose ages ranged from 5 to 20 years. A 8 cases (37.5%) were characterized as tubulointerstitial nephritis and uveitis (TINU), 4 cases (16.7%) were associated with an autoimmune disease, 4 cases (16.7%) were likely drug induced, and 8 cases (37.5%) had unclear etiology. DISCUSSION: Although all cases of drug induced interstitial nephritis contained eosinophils they were not exclusive to drug induced interstitial nephritis. A prominent plasma cell infiltrate was seen in both cases of Sjögren's associated interstitial nephritis. The vast majority (n = 18, 75%) showed an improved serum creatinine (<1 mg/dL) 1 year post diagnosis/at last follow-up. In this pediatric series of AIN, TINU contributed to a large subset of cases with known etiologies. On follow up, majority of the cases demonstrated recovery of renal function.

A Novel Tissue-Free Method to Estimate Tumor-Derived Cell-Free DNA Quantity Using Tumor Methylation Patterns.

Estimating the abundance of cell-free DNA (cfDNA) fragments shed from a tumor (i.e., circulating tumor DNA (ctDNA)) can approximate tumor burden, which has numerous clinical applications. We derived a novel, broadly applicable statistical method to quantify cancer-indicative methylation patterns within cfDNA to estimate ctDNA abundance, even at low levels. Our algorithm identified differentially methylated regions (DMRs) between a reference database of cancer tissue biopsy samples and cfDNA from individuals without cancer. Then, without utilizing matched tissue biopsy, counts of fragments matching the cancer-indicative hyper/hypo-methylated patterns within DMRs were used to determine a tumor methylated fraction (TMeF; a methylation-based quantification of the circulating tumor allele fraction and estimate of ctDNA abundance) for plasma samples. TMeF and small variant allele fraction (SVAF) estimates of the same cancer plasma samples were correlated (Spearman's correlation coefficient: 0.73), and synthetic dilutions to expected TMeF of 10-3 and 10-4 had estimated TMeF within two-fold for 95% and 77% of samples, respectively. TMeF increased with cancer stage and tumor size and inversely correlated with survival probability. Therefore, tumor-derived fragments in the cfDNA of patients with cancer can be leveraged to estimate ctDNA abundance without the need for a tumor biopsy, which may provide non-invasive clinical approximations of tumor burden.

Solid pancreatic masses in children: A review of current evidence and clinical challenges.

Pancreatic tumors in children are infrequently encountered in clinical practice. Their non-specific clinical presentation and overlapping imaging characteristics often make an accurate preoperative diagnosis difficult. Tumors are categorized as epithelial or non-epithelial, with epithelial tumors further classified as tumors of the exocrine or endocrine pancreas. Although both are tumors of the exocrine pancreas, solid pseudopapillary neoplasm is the most prevalent solid pancreatic tumor in children, while pancreatoblastoma is the most common malignant tumor. Insulinoma is the most common pediatric pancreatic tumor of the endocrine pancreas. Malignant tumors require a complete, often radical, surgical resection. However, pancreatic parenchyma-sparing surgical procedures are utilized for benign tumors and low-grade malignancy to preserve gland function. This review will discuss the epidemiology, pathophysiology, clinical and diagnostic characteristics, and management options associated with both common and rare solid pancreatic masses in children. We will also discuss current challenges encountered in their evaluation and treatment.

Evaluation of cell-free DNA approaches for multi-cancer early detection.

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.

Placental Pathology and the Developing Brain.

Abnormal neurodevelopmental outcomes are associated with multiple factors including prematurity, intrauterine infection, maternal comorbidities as well as fetal anomalies. Within the past decade, new standardized terminology in placental pathology has emerged, emphasizing the current understanding of processes that play a role in placental dysfunction. Factors playing a major role in the abnormal development of the placenta include abnormalities in blood flow and perfusion of the fetal and maternal compartments of the placenta termed fetal vascular malperfusion and maternal vascular malperfusion, respectively. Concepts reviewed include massive perivillous fibrin deposition, chronic villitis, meconium-associated injury as well as chorioamnionitis. Each have a temporal effect on the placental vascular tree and may reflect an altered maternal inflammatory response. In this article we highlight pathologic placental findings which when present can serve to explain, at least in part, altered neurodevelopment in the child, adolescent and adult. Lesions with a propensity for recurrence in future pregnancies are discussed.

Syringocystadenocarcinoma Papilliferum in a Fifteen-Year-Old Girl: A Case Report and Review of the Literature.

Syringocystadenocarcinoma papilliferum (SCACP) is a rare malignant neoplasm arising from adnexal tissues and is the malignant complement to the benign neoplasm syringocystadenoma papilliferum (SCAP). SCACP lesions appear as raised nodules or inflammatory plaques and can be associated with SCAP or nevus sebaceous. There have been fewer than 100 described cases of this neoplasm in the literature, and all previously published cases have been described in adults, with the majority occurring in the elderly. We present a case of an adolescent female with a syringocystadenocarcinoma papilliferum arising from a large thigh mass harboring an in-frame alteration in MAP2K1 along with a brief review of the literature.

Pediatric Hypersensitivity Pneumonitis: Clinicopathologic Characteristics of Two Cases with Fungal Triggers.

Background Hypersensitivity pneumonitis (HP) infrequently presents in childhood. Asthma or a pneumonia-like clinical presentation may lead to diagnostic delay, especially in children. Case Report: We present two cases of HP, a 6-year-old (Case 1) male and a 5-year-old (Case 2) female. Both cases had a negative infectious work-up and patchy ground glass lung opacities on chest computed tomography. Lung biopsies demonstrated lymphocytic bronchiolitis with granulomatous interstitial and peribronchial inflammation. Serology demonstrated elevated immunoglobulin precipitins toward Thermoactinomyces and Aspergillus species in Case 1 and Aspergillus fumigatus in Case 2. Both patients received steroid therapy and had symptom resolution. Conclusions: A diagnosis of HP should be considered in pediatric lung biopsies with granulomatous interstitial and peribronchial inflammation, if infectious etiologies are excluded. Integration of clinical, radiological, and laboratory findings can facilitate a timely diagnosis.

Peripheral ameloblastic fibro-odontoma-Report of 2 cases of a very rare entity.

Ameloblastic fibro-odontoma (AFO) is a rare benign mixed odontogenic tumor that affects children and young adults. AFO occurs mainly intraosseous. Extraosseous AFO is extremely rare. We report 2 cases of rare peripheral ameloblastic fibro-odontoma in 2- and 12-year-old female patients. Microscopic examination revealed a benign proliferation of odontogenic epithelium associated with a dentinoid material distributed within a cell-rich mesenchymal stroma resembling dental papilla. Simple surgical excision of the lesion is usually curative. There was no recurrence after a short period of follow-up. Clinicians should be cognizant of this rare entity, which can be considered in a differential diagnosis of gingival growths that are noted in early childhood.

Enterobius vermicularis-associated appendicitis: A 22-year case series and comprehensive review of the literature.

INTRODUCTION: Enterobius vermicularis is known to be associated with appendicitis, however a causal relationship between Enterobius and appendicitis has not been established. The aim of this study was to explore the relationship between appendiceal Enterobius and histologic appendicitis. METHODS: A retrospective review was performed of all pediatric appendectomies between 1997 and 2019. Patients with diagnosed with Enterobius were included for analysis. Patient demographics, operative findings, and pathologic reports were queried. Data were entered into an encrypted database and subsequently analyzed. A comprehensive review of the literature was also conducted. RESULTS: Thirty-eight cases of Enterobius-associated appendicitis were identified out of 3541 (1.07%). Grossly normal appendices at operation were seen in 27% of patients. Inflammatory infiltrate was noted on histopathology in 78.3%, and Enterobius was considered to be the cause of that inflammation in 68.4%. The comprehensive literature review revealed 19 articles (1.87% incidence) that noted 35% of patients with appendiceal Enterobius had appendicitis on either histopathology or gross evaluation. CONCLUSION: The high rate of inflammation on pathology found among our patients with pinworm appendicitis suggests an association with presentation as acute appendicitis. Our comprehensive review revealed a higher proportion of Enterobius appendicitis. Treatment with antihelminthic therapy is recommended. LEVEL OF EVIDENCE (LOE): Level IV(4)-case series and comprehensive review.

Prospective Comparative Evaluation of Post-extraction Bleeding in Cardiovascular-Compromised Patients with and without Antiplatelet Medications.

BACKGROUND AND OBJECTIVE: A considerable number of patients consulting a dental surgeon are on antiplatelet therapy, and an interruption of these agents for 3 to 7 days has been practised by majority of them prior to dental surgical intervention fearing excessive bleeding, risking the patient for the occurrence of adverse thrombotic events. The dental and medical literature shows a very low risk of excessive bleeding associated on the continuation of antiplatelet therapy. The objective of this study is to compare the bleeding following single-firm molar tooth extraction in patients who interrupt and those who continue antiplatelet therapy perioperatively. METHODOLOGY: This is a prospective descriptive study on 170 patients on long-term low-dose antiplatelet therapy with 2 groups, each containing 85 patients-Group 1 with patients who interrupted antiplatelet therapy for 5 days before extraction and Group 2, patients who continued it perioperatively. A single molar tooth extraction was done under local anaesthesia with a vasoconstrictor. Gauze pressure pack was placed for 60 min. Socket was observed every 15 min for 1 h to look for excessive post-extraction bleeding. RESULTS: No statistically significant differences were found in post-extraction bleeding between the patients who stopped antiplatelet therapy and those who continued it. CONCLUSION: The bleeding risk when continuing long-term low-dose antiplatelet therapy following a single molar tooth extraction is minimal. Bleeding, if excessive, can be easily controlled by gauze pressure pack or other local haemostatic agents. Thus, dental extractions can be performed on these patients without interrupting the antiplatelet drug pre-operatively provided a thorough medical history, physician's consent and coagulation profile have been obtained prior to the procedure.

Wrong Tissue in Block.

OBJECTIVES: Maintaining specimen identity during surgical pathology tissue processing is critical. Epic Beaker Laboratory Information System requires sequential scanning of specimen label and grossed blocks (block confirmation) to ensure specimen identity. We report our institution's experience with wrong tissue in block (WTIB) grossing errors before and after adopting block confirmation. METHODS: During the first 18 months of Beaker implementation, block confirmation was not required. We then mandated block confirmation for a 3-month period. To ensure compliance, we then built a "hard stop" feature that prevents scanning any unconfirmed blocks onto a packing list. We reviewed WTIB incidents pre- and postimplementation of these solutions. RESULTS: Before using block confirmation, we had WTIB incidents involving 17 (0.043%) of 38,848 cases. When we mandated block confirmation use, we had WTIB involving 2 (0.043%) of 4,646 cases. After implementing the hard stop feature, we had WTIB incidents involving 2 (0.005%) of 42,411 cases. Overall, there was an 88.4% (0.043% vs 0.005%; P < .001) reduction in WTIB incidents using block confirmation with a hard stop. CONCLUSIONS: Beaker is a customizable platform that can be tailored to a laboratory's workflow. By using barcoding, implementing custom-built features, and improving workflow protocols, we significantly reduced WTIB errors.