Citations

Over the last decade, there have been widespread efforts to reduce non-evidence-based therapies for viral bronchiolitis. We question whether this change in practice has inadvertently impacted the diagnosis and management of other pediatric lower-respiratory-tract illnesses. We used the Pediatric Health Information System (PHIS) and logistic regression to describe trends in relative diagnosis frequency of bronchiolitis, viral pneumonia, and reactive airway disease (RAD)/asthma as well as systemic corticosteroid use among children of the age range 1 to 4 years over a 10-year period. Among 169,207 children, the relative frequency of asthma/RAD diagnoses declined over a 10-year period, while bronchiolitis and viral pneumonia diagnoses increased among children of the age range 1 to 3 years and 2 to 4 years, respectively. Frequency of systemic corticosteroid use declined. We question whether the observed shift in diagnosis from asthma/RAD to bronchiolitis or viral pneumonia is reflective of true disease pathophysiology or if it represents an unintended consequence of campaigns surrounding bronchiolitis.

Hepatocellular carcinoma (HCC), constituting the predominant manifestation of liver cancer, stands as a formidable medical challenge. The prognosis subsequent to surgical intervention, particularly for individuals presenting with a solitary tumor, relies heavily on the degree of invasiveness. The decision-making process surrounding therapeutic modalities in such cases assumes paramount importance. This case report illuminates a rather unusual clinical scenario. Here, we encounter a patient who, following a disease-free interval, manifested an atypical presentation of HCC, specifically, a solitary cardiac metastasis. The temporal interval of remission adds an additional layer of complexity to the case. Through a multidisciplinary planning process, the decision was made for surgical removal of the metastatic tumor.

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin–positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

Introduction The discovery of MAPK/ERK pathway mutations has revolutionized the care for patients with histiocytic neoplasms. However, mutational analysis on biopsy specimens is often limited by low tumor cellularity leading to testing failure or disease involvement of difficult-to-reach sites (e.g., central nervous system). Recently, molecular analysis of cell-free DNA (cfDNA) has shown promise as a viable tool for discovering driver mutations in multiple cancers. A recent study of mainly BRAF-mutated non-Langerhans cell histiocytosis (LCH) showed 50% concordance between tumor and plasma cfDNA analysis for BRAF-V600E. However, it is unknown whether cfDNA has a role in the evaluation of cases that harbor mutations beyond BRAF-V600E. We conducted this study to address this unanswered question using a large cohort of individuals with diverse histiocytic neoplasms from a tertiary-care institution. Methods We included 40 cases with histiocytic neoplasms with stored plasma and germline DNA in this study. Tissue molecular analysis was conducted using a targeted next generation sequencing (NGS) using commercial assays or whole exome sequencing (WES) using an in-house assay. A custom panel of 226 genes, including exonic and intronic regions, was used for the cfDNA assay in this study. To avoid cfDNA false positives, germline mutations identified from normal DNA sequencing were filtered using a BostonGene ®-developed error reduction algorithm.The total length of the analyzed genomic regions was 1.56 MB. For samples with an input greater than 30 ng, a 0.2% variant allele frequency (VAF) limit of detection (LOD) was used; a 0.4% VAF LOD was used for samples less than 30 ng. Results The final analysis cohort included 38 patients with histiocytic neoplasms after exclusion of 2 cases (failure of germline DNA library preparation and mismatch of germline and somatic DNA, respectively). Disease types included Erdheim-Chester disease (ECD; n=13, 34%), Langerhans cell histiocytosis (LCH; n=13, 34%), and Rosai-Dorfman disease (RDD; n=12, 32%). 24 cases were multisystem (63%), and the remaining were single-system. Commonly involved organs included bone (n=25, 66%), kidney (n=12, 32%), skin (n=8, 21%), central nervous system (n=7, 18%), and pituitary (n=7, 18%). Most cases (n=31, 82%) underwent plasma collection pre-treatment, 5 cases underwent collection after histiocytosis-directed therapy, and 2 while on treatment. Tissue NGS/WES data were available for 28 (74%) cases; 5 cases (13%) had insufficient tissue cellularity, and 5 (13%) did not undergo any tissue sequencing. Among those who underwent successful tissue sequencing assays, the most common common driver alterations was BRAF V600E (n=5, 26%). Other alterations included those in MAP2K1 (n=4, 21%), BRAF-fusions (n=3, 10%; partners UBDT2, RNF11, and LMTK2, respectively), and single cases of KRAS, NRAS and BRAF indel, respectively. cfDNA analysis showed at least one variant in 23 cases (60%). Correlation between tissue and cfDNA for known driver mutations was poor and concordant findings were only seen in one case with ECD harboring BRAF V600E in tissue as well as plasma (VAF 0.5%). Among the 5 cases where tissue mutational analysis had failed, cfDNA showed mutations in MUTYH, PTCH2, NOTCH3 SDHD, and TMEM127, respectively (Figure 1). Among the 5 cases where tissue molecular assessment could not be undertaken due to various reasons, cfDNA showed alterations in 4 cases, encompassing NOTCH1, TET2, BRCA1, MSH6, PIK3CD, and FUS genes. Conclusions In a large cohort of adults with diverse histiocytic neoplasms, we found poor correlation between tumor and plasma cfDNA molecular findings. The reason for the lack of correlation may be related to low tumor shedding especially among non- BRAF V600E cases. cfDNA analysis may have a role to identify potential drivers of pathogenesis among cases that are unable to successfully undergo tissue molecular analysis. Further studies are underway to characterize other novel alterations that were discovered in the cfDNA analysis.