Atypical Features Research Articles

Categorization of fibroepithelial breast tumors according to ultrasound BI-RADS classification

Among breast masses, the most common are fibroadenomas (FA), which belongs to the group of a fibroepithelial tumors. Simple pericanalicular FA ordinarily shows the ultrasound signs of a benign mass. Long-standing pericanalicular FA and intracanalicular FA as they grow acquire some ultrasound features uncommon for benign lesions, which requires differential diagnosis with malignant breast masses. The group of fibroepithelial breast tumors also includes phyllodes tumors with frequency of malignant variants of 20–30%. Differential diagnosis of phyllodes tumor and fibroadenomas is difficult, due to the lack of the clear radiologic diagnostic criteria (incl. ultrasound). All breast masses that shows suspicious or atypical features should be selected for biopsy, with the use of BI-RADS classification for the biopsy need indication.Objective: to reveal the rules for fibroepithelial breast tumors categorization according to BI-RADS depending on the ultrasound features.Material and methods. A total of 86 breast masses in 79 women were assessed by ultrasound in B-mode and Color Doppler (CDI). Of these, 22 masses in 15 women showed the typical ultrasound pattern of FA up to 2.0 cm in size with no necessary of morphological evaluation (the average age of the patients was 24.2 ± 5.1 years). Surgery performed for 64 lesions ≥2.0 cm in size, postsurgery morphological examination revealed pericanalicular FA – 38, intracanalicular FA –19 and phyllodes tumors (benign) – 7.Results. The majority of atypical pericanalicular FA (84.2%) were categorized as BI-RADS 4а (a low risk of cancer), 94.7% of intracanalicular fibroadenomas and all phyllodes tumors – as BI-RADS 4b and BI-RADS 4c (а high risk of cancer). The identification of suspicious ultrasound signs led to an increase in the BI-RADS category with indications to the morphological evaluation of the mass.Conclusion. As the suspicious ultrasound signs in B-mode should be considered the irregular shape and borders, vertical orientation and inhomogeneous acoustic shadowing in the absence of macrocalcifications, in Color Doppler – diffuse or focal mass hypervascularity or abnormal vascular pattern. The atypical ultrasound pattern commonly presents in large breast fibroadenomas (>3.0 cm in size), requires differential diagnosis with phyllodes tumors and breast cancer and indicates the need of morphological evaluation and categorizing them as not lower than BI-RADS4.

Nasal and sinonasal tumors formed by atypical adenomatous lesions arising in respiratory epithelial adenomatoid hamartoma/seromucinous hamartoma.

Two benign adenomatous lesions are commonly recognized within the sinonasal tract, namely respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH). We present 10 hitherto unrecognized benign polypoid nasal and sinonasal tumoriform lesions having in average 3.6cm in largest dimension, which are histogenetically related to SH and REAH. In addition to typical structures of REAH and SH, these lesions contained an additional characteristic and slightly atypical adenomatous component, which we termed atypical sinonasal glands arising in SH (ASGSH). ASGSH often produced deep red colored secretion with peripheral clearing similar to that seen in thyroid follicles. In contrast to SH, ASGSH was endowed by both secretory and myoepithelial layers and had mostly angulated shapes with snout-like protrusions into the lumens. Both layers were formed by an irregular, disorganized, and often incomplete cell lining, which had slightly atypical cytological features without mitoses. In 3 cases, ASGSHs revealed sebaceous differentiation, and in 3 cases the stroma produced a well-differentiated cartilage. Neoplastic nature of ASGSH was supported by finding of various mutations as revealed by next generation sequencing in five cases. In two cases each, we found identical mutations in BRAF gene (Val600Glu), and RET gene (Arg912Trp), respectively and in one case FAT1 gene alteration (Pro1665Leu).

Abnormal dopamine transporter imaging in pure autonomic failure: a potential biomarker of central nervous system involvement.

Pure autonomic failure (PAF) is a rare progressive neurodegenerative disease characterized by neurogenic orthostatic hypotension at presentation, without other neurological abnormalities. Some patients may develop other central neurological features indicative of multiple system atrophy or a Lewy body disorder. There are currently no biomarkers to assess possible central nervous system involvement in probable PAF at an early stage. A possibility is to evaluate the nigrostriatal dopaminergic degeneration by imaging of dopamine transporter with DaTscan brain imaging. The objective was to evaluate subclinical central nervous system involvement using DaTscan in PAF. We retreospectively reviewed pure autonomic failure patients who were evaluated at the Autonomic Unit between January 2015 and August 2021 and underwent comprehensive autonomic assessment, neurological examination, brain magnetic resonance imaging and DaTscan imaging. DaTscan imaging was performed if patients presented with atypical features which did not meet the criteria for Parkinson's disease or multiple system atrophy or other atypical parkinsonism. In this cohort, the median age was 49.5 years at disease onset, 57.5 years at presentation, and the median disease duration was 7.5 years. Five of 10 patients had an abnormal DaTscan without neurological features meeting the criteria of an alternative diagnosis. Patients with abnormal DaTscan were predominantly males, had shorter disease duration and had more severe genitourinary symptoms. Degeneration of nigrostriatal dopaminergic neurons measured using DaTscan imaging can present in patients with PAF without concurrent signs indicating progression to widespread α-synucleinopathy. It is advocated that DaTscan imaging should be considered as part of the workup of patients with emerging autonomic failure who are considered to have PAF.

Role of genetic investigation in the diagnosis of short stature in a cohort of Italian children.

Short stature (SS) is defined as height more than 2 standard deviations below the mean for age and sex. Hypothyroidism, celiac disease, growth hormone deficiency, hormonal abnormalities, and genetic conditions are among its causes. A wide range of conditions often due to largely unknown genetic variants can elude conventional diagnostic workup. We used next-generation sequencing (NGS) to better understand the etiology of SS in a cohort of Italian children. The study sample was 125 children with SS of unknown origin referred to our Institute between 2015 and 2021. All had undergone complete auxological and hormonal investigations to exclude common causes of SS. Genetic analysis was performed using a NGS panel of 104 genes. Clinical data were reviewed to clarify the pathogenicity of the variants detected. In this cohort, 43 potentially causing variants were identified in 38 children. A syndromic genetic condition was diagnosed in 7: Noonan syndrome in 3, Leri-Weill syndrome in 3, and hypochondroplasia in 1. Moreover, 8 benign variants and other 37 like benign variants were found. In 88 children, 179 variants of uncertain significance (VUS) were identified. No variant was found in 16 children. Genetic analysis is a useful tool in the diagnostic workup of patients with SS, in adapting management and treatment, and in identifying syndromes with mild atypical clinical features. The role of VUS should not be underestimated, particularly when multiple VUS with possible mutual worsening effects are present in the same child.

Papillon-Lefevre syndrome in twelve Egyptian patients: Five novel CTSC variants and functional characterization of a missense variant and its effect on splicing

Objectivesdescribing the clinical features of twelve Egyptian patients with Papillon-Lefever syndrome (PLS). Five novel mutations in the cathepsin C (CTSC) gene are introduced and the phenotype of the syndrome is expanded by the identification of new clinical features. Designthe clinical, oro-dental data of twelve Egyptian patients from seven unrelated families are described. Sequence analysis of the CTSC gene was performed to identify the causative mutaions. ResultsTypical PLS features were presented in all patints but with variable severity. One patient showed atypical dental features including dental structural defect, minimal periodontitis, severe gingivitis, and delayed closure of root apices. Another patient presented with arachnodactyly, dystrophic nails, and buphthalmos in the right eye secondary to uncontrolled congenital glaucoma. Mutational analysis of CTSC gene revealed seven distinct homozygous variants including five novel ones: c.285_286delGT (p.Leu96GlufsTer2), c .302 G>C (p.Trp101Ser), c.622_628delCACAGTC (p.H208Efs*11), c.1331delinsAAAAA (p.G444Efs*4) and c .1343 G>A (p.Cys448Tyr). The previously reported missense variant c .757 G>A (p.Ala253Thr) was found in one patient. This variant is very close to the splice region and by functional studies, we proved that it results in exon skipping and early protein truncation (p.R214Sfs*46). ConclusionWe report five novel CTSC variants and describe rare and unusual associated clinical and dental findings such as dental structural defects, delayed closure of root apices, and congenital glaucoma. Therefore, our results expand both the phenotypic and mutational spectrum of PLS.

First case report of partial craniofacial duplication in a Lebanese patient and its functional implications

Craniofacial duplication, a rare congenital anomaly, presents an intricate spectrum of clinical manifestations that can profoundly impact an individual's quality of life. This case report explores the unique presentation of partial craniofacial duplication in a Lebanese patient and sheds light on the associated functional implications. Our patient presented at day of life zero with atypical craniofacial features, including duplication of nasal structures, oral structures including the tongue and the hard palate, and fontanels. Comprehensive clinical and radiological assessments were conducted to ascertain the extent of the craniofacial involvement. The diagnostic workup revealed partial duplication. The baby is still alive with no signs of respiratory distress. The functional implications extend beyond the physical presentation, highlighting the importance of a multidisciplinary healthcare approach to address the complex needs of individuals with craniofacial anomalies. This case contributes to the limited literature on craniofacial duplications and underscores the need for continued research and specialized care in managing such rare and intricate congenital conditions.

In‐vivo and post‐mortem retinal and brain pathological findings in a homozygote for the A431E PSEN1 mutation

AbstractBackgroundThe neuropathology associated with PSEN1 mutations shares many features with late‐onset Alzheimer’s disease although atypical features are also seen. An important question is whether the manifestations of PSEN1 mutations are dose‐dependent. We present the neuropathological findings of a homozygote for the pathogenic A431E mutation in PSEN1 relative to heterozygotes and the finding of retinal Aβ lesions consistent with those that were topographically detected in vivo by retinal fluorescence imaging.MethodsA homozygote for the A431E PSEN1 mutation began having symptoms at age 33 and underwent a comprehensive ophthalmic and neurologic evaluation at age 37 before passing away at age 39. Brain and eyes were collected and brain sections and retinal flatmounts and cross‐sections were processed and immunostained with 4G8 or 12F4 (anti‐Aβ), AT8 or pS396 (anti‐phosphoTau) antibodies. Retinal vascular and astrocytic markers were also assessed.ResultsBrain weight of the homozygote was 1180 grams relative to 840 and 860 grams in two heterozygotes with only mild to moderate gross atrophy appreciable relative to moderate to severe atrophy in the heterozygotes. More abundant 4G8 (Aβ) staining was appreciable in widespread brain areas in the homozygote relative to the heterozygotes with some having a “cotton wool” morphology. Conversely, neurofibrillary tangle density was markedly lower in the homozygote relative to heterozygotes in all areas assessed. Retinal in vivo imaging revealed very small, yellow deposits in the macula in both eyes that were atypical for a 37‐year‐old. These lesions correlated topographically with areas of Aβ deposits stained in post‐mortem flatmounts. In retinal cross‐section, Aβ accumulation, including vascular Aβ40 and Aβ42 deposits, pS396‐positive staining and NFTs are clearly detected, along with enhanced GFAP‐positive gliosis.ConclusionThe neuropathological changes seen in a person homozygous for the A431E PSEN1 mutation showed an increased degree of Aβ pathology and evidence of a lesser degree of downstream pathology, possibly representing a more rapidly evolving disease with progressive disability despite a relative lack of neurodegeneration. We also demonstrated that Aβ and tau pathology occurs in the retina in this form of AD and that it can be visualized on clinical examination during life.Funded by: P30AG066530, U01AG051218, R01AG062007

Atypical presentations of autosomal dominant familial Alzheimer’s disease: insights into genetic, neuropathological and clinical heterogeneity

AbstractBackgroundAutosomal dominant familial Alzheimer’s disease (ADAD), caused by APP, PSEN1 and PSEN2 mutations, is clinically and pathologically similar to sporadic AD, with both typically presenting with memory impairment. However as in sporadic AD, atypical phenotypes and neuropathological heterogeneity occur, including variable vascular Aβ deposition as cerebral amyloid angiopathy (CAA). Investigating relationships between clinical, genetic and neuropathological heterogeneity in ADAD may provide insights into pathophysiological pathways relevant to AD in general.Methods256 symptomatic individuals from ADAD families seen at our Centre were included in a survival analysis, with detailed clinical phenotype data available for 138 (101 PSEN1, 37 APP). 33 of these individuals underwent brain donation (24 PSEN1, 9 APP), all demonstrating end‐stage AD pathology. Frontal and occipital cortex sections were stained immunohistochemically for Aβ and vessel counts used to determine the proportion of cortical and leptomeningeal blood vessels affected by CAA.ResultsAge at onset was, on average, seven years younger for PSEN1 than APP mutations and was influenced by mutation much more than survival was. Atypical (non‐amnestic) cognitive presentations with initial behavioral, language, dyscalculic or dysexecutive symptoms, and atypical clinical features (pyramidal, extrapyramidal and cerebellar signs) were more common in PSEN1 than APP cases, particularly those with post‐codon 200 mutations. Atypical cognitive presentations were associated with longer survival. There was some indication that APOE4 carriers had longer survival and that this effect may be restricted to PSEN1. In the post‐mortem cohort, atypical cognitive presentations occurred in 15%. Additional neurological features comprised myoclonus (45%), seizures (21%), pyramidal signs (21%) and extrapyramidal signs (15%), one individual had cerebellar signs. Increased frontal cortical and leptomeningeal CAA occurred in individuals with pyramidal and extrapyramidal signs, and in PSEN1 post‐codon 200 compared to pre‐codon 200 mutations. Atypical cognitive presentations were associated with increased frontal cortical CAA.ConclusionsPhenotypic heterogeneity in ADAD is influenced by causative gene and mutation type, and atypical clinical presentations are associated with increased CAA. Exploring mechanisms by which certain mutations drive Aβ deposition towards the vasculature, and how these may be impacted by other genetic factors and by therapies targeting Aβ, is an important direction for future research.

A drive around Pictland

A damaged carving of a two-wheeled horse-drawn vehicle appears on the Pictish cross-slab from Skinnet Chapel, Halkirk, Caithness (Skinnet 1). In this paper the vehicle’s original design is partly re-created, with details of the pair of horses yoked to it. The slab, now in Thurso Museum, was surveyed in 2015 and 2017 by the use of RTI (Reflectance Transformation Imaging), a computer-based enhancement process. Resulting augmentation of surface relief in the processed images allows multiple overlays to be drawn/traced from various light vectors to create a composite final image. The restored components of the vehicle – cart or chariot – are discussed, with relevance to its possible role. Atypical physical features carved on the facing horse of the horse pair may hint at some ceremonial motive for their presence. After a short survey of known evidence for Pictish vehicles, direct derivation of design from antecedent archaeological finds of Iron Age chariots are assessed as unlikely due to the wide time gap. Possible construction influence (in both cultural directions) from wheels found in Scottish Roman sites is noted. The common format of wheels and vehicles on the Skinnet 1 stone and Irish High Cross illustrations of ‘chariots’ are described and mapped, with the appearance of the latter in early medieval times attributed to Pictish traditions of cartwrighting.

Ossifying Fibromyxoid Tumor with Atypical Features: A Case Report and Review of Literature

Abstract Introduction/Objective Ossifying fibromyxoid tumor (OFMT) is a soft tissue neoplasm usually behaving in a benign fashion, however, it can rarely show atypical or malignant features. It most frequently occurs within the extremities and trunk. Although OFMTs are translocation-associated tumors, and very commonly associated with recurrent gene rearrangements involving the PHF1 gene, their morphologic and immunophenotypic profile can overlap with other soft tissue tumors posing a diagnostic challenge. Methods/Case Report Herein we present a case of a 23-year-old woman who had an excision of a subcutaneous shoulder mass. Grossly, the 5.3 cm mass had a thin translucent capsule and a pink, soft-cut surface with scattered calcifications. Microscopic examination revealed a well-circumscribed lesion composed of plump spindle cells with uniform oval nuclei arranged in short fascicles within a mildly collagenous background. There was prominent hemangiopericytoma-like vasculature and foci of ossification. The tumor cells contained moderate cytoplasm and showed a mild degree of nuclear atypia. Mitotic activity was up to 6 per 10 high-power fields. Immunohistochemical stains showed tumor cells are positive for Desmin, SMA, AE1/AE3 (patchy), TLE, and SATB2, while negative for CD31, CD34, S-100, C-kit, DOG-1, CD117, HMB-45, Melan-A, ALK-1, SOX10, Inhibin, and STAT6. Ki-67 proliferation index was low (1-2%). Fluorescence in situ hybridization (FISH) testing was negative for SYT and MDM2 gene amplification. FISH testing for PHF1 gene (using experimental probes) showed a break apart signal in a subset (~ 25%) of tumor cells, which is equivocal but insufficient to establish clonal interchromosomal translocation involving PHF1. Results (if a Case Study enter NA) NA Conclusion There is a histologic spectrum and morphologic overlap of OFMTs with several other soft tissue neoplasms. OFMT with atypical features (increased cellularity and mitotic activity), as in this case, may harbor the unpredictable biologic potential for recurrence and metastasis. Additional studies are required to discover a morphologic, immunohistochemical, and possibly molecular pattern that will help to differentiate OFMT subtypes.

Atypical Facial Chondroid Syringoma of Medial Canthus, A rare clinical entity

Abstract Introduction/Objective Chondroid syringoma (CS) is an uncommon, benign mixed tumor originating from the sweat gland. Its incidence rate is extremely low, estimated to be less than 0.01%. CS predominantly affects adult males and shows a preference for the head and neck region. Typically, the size of the lesion is smaller than 1.0 cm, and it presents as a solitary, painless, subcutaneous nodule that is soft to firm, non-ulcerative, and gradually progressive. Histologically, CS is characterized by a neoplasm composed of epithelial and myoepithelial cells, which are surrounded by a myxomatous, pseudochondromatous, or hyaline stroma containing mucous secretions. Although atypia is rare in CS, there is a potential for it to undergo malignant transformation. Methods/Case Report A 49-year-old man presented with a slowly growing mass on the medial canthus that had been present for 6 months. Examination revealed a tender, mobile nodule measuring 1.1 cm. An MRI of the head confirmed a subcutaneous lesion without involvement of deeper structures. Excisional biopsy of the lesion suggested adnexal carcinoma with involvement of the margins. The patient underwent Mohs surgery.Histopathology revealed localized basaloid epithelial proliferation forming solid sheets, trabecular, ductal structures with, chondroid myxoid stroma. Immunohistochemically, the tumor cells of solid sheets and trabeculae were positive for CK5/6, P63, and Vimentin, whereas the cells were focally positive for S100, Calponin, alpha Actin, and SOX10. Also, ductal epithelial cells were highlighted with CK7, Cam5.2, EMA, and CEA. Ki-67 showed 1–5% reactivity. A few satellite nodules with infiltrative margins were seen. The atypical features, including cell atypia and a focal infiltrating border, suggest atypical chondroid syringoma. This tumor is considered a low-grade lesion, and no unequivocal evidence of malignancy has been identified. Results (if a Case Study enter NA) NA Conclusion Awareness of chondroid syringoma as a rare cause of eyelid lesions is important because although it is a benign neoplasm, incomplete excision can lead to recurrence or malignant transformation. Chondroid syringoma rarely exhibits atypia but can convert to the malignant spectrum. When malignant, it has a significant potential for recurrence, metastasis, and even death. Due to the tumor's rarity, making an accurate preoperative diagnosis can be challenging. Therefore, the possibility of chondroid syringoma should be kept in mind when dealing with a gradually progressive, soft to firm subcutaneous swelling.

Identification of potential diagnostic biomarkers for tenosynovial giant cell tumour by integrating microarray and single-cell RNA sequencing data

PurposeTenosynovial giant cell tumour (TGCT) is a benign hyperplastic and inflammatory disease of the joint synovium or tendon sheaths, which may be misdiagnosed due to its atypical symptoms and imaging features. We aimed to identify biomarkers with high sensitivity and specificity to aid in diagnosing TGCT.MethodsTwo scRNA-seq datasets (GSE210750 and GSE152805) and two microarray datasets (GSE3698 and GSE175626) were downloaded from the Gene Expression Omnibus (GEO) database. By integrating the scRNA-seq datasets, we discovered that the osteoclasts are abundant in TGCT in contrast to the control. The single-sample gene set enrichment analysis (ssGSEA) further validated this discovery. Differentially expressed genes (DEGs) of the GSE3698 dataset were screened and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were conducted. Osteoclast-specific up-regulated genes (OCSURGs) were identified by intersecting the osteoclast marker genes in the scRNA-seq and the up-regulated DEGs in the microarray and by the least absolute shrinkage and selection operator (LASSO) regression algorithm. The expression levels of OCSURGs were validated by an external dataset GSE175626. Then, single gene GSEA, protein–protein interaction (PPI) network, and gene-drug network of OCSURGs were performed.Result22 seurat clusters were acquired and annotated into 10 cell types based on the scRNA-seq data. TGCT had a larger population of osteoclasts compared to the control. A total of 159 osteoclast marker genes and 104 DEGs (including 61 up-regulated genes and 43 down-regulated genes) were screened from the scRNA-seq analysis and the microarray analysis. Three OCSURGs (MMP9, SPP1, and TYROBP) were finally identified. The AUC of the ROC curve in the training and testing datasets suggested a favourable diagnostic capability. The PPI network results illustrated the protein–protein interaction of each OCSURG. Drugs that potentially target the OCSURGs were predicted by the DGIdb database.ConclusionMMP9, SPP1, and TYROBP were identified as osteoclast-specific up-regulated genes of the tenosynovial giant cell tumour via bioinformatic analysis, which had a reasonable diagnostic efficiency and served as potential drug targets.

Morphologic and Genetic Features of Unclassifiable Chronic Myeloid Neoplasms: Five-Year Experience of a Canadian Provincial Referral Center

Introduction: The challenge of diagnosing and definitively classifying myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) remains a conundrum in the field of hematology. While the World Health Organization has outlined diagnostic criteria for various categories, there remain cases that elude specific classification, falling under the umbrella of MPN, unclassifiable (MPN-U) and MDS/MPN, unclassifiable (MDS/MPN-U). In this study, we aimed to compare the morphological and genetic profiles of cases classified as MPN-U or MDS/MPN-U against more definitively classified cases (including chronic myelomonocytic leukemia (CMML), essential thrombocythemia (ET), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and primary myelofibrosis (PMF), including prefibrotic PMF (pre-PMF)). Methods: Morphologically unclassifiable myeloid neoplasm cases referred for pathologist review to our laboratory in the largest tertiary care center in British Columbia, Canada were identified through pathology database query over a five-year period. Bone marrow materials were reviewed and reanalyzed with standardized collection of qualitative and semiquantitative data by two hematopathologists. Morphological parameters studied included the myeloid to erythroid ratio, bone marrow cellularity, lineage dysplasia, megakaryocyte histotopography, bone marrow blast frequency, fibrotic changes, and bone marrow vascularity, among others. Clinical data, cytogenetic findings, and results of a targeted sequencing panel assessing a set of approximately 50 genes recurrently mutated in myeloid malignancies were collected by electronic medical record review. A cohort of contemporarily collected myeloid neoplasms with definitive pathologic diagnoses was reviewed for comparison. Statistical analyses were performed using python3. Results: The cohort comprised 29 cases classified as MPN-U, 12 cases of MDS/MPN-U, and 5 cases each of ET, PMF, pre-PMF, CMML, and MDS/MPN-RS-T. MPN-U cases were further subcategorized based on the apparent reason for difficulty in classification, including: overlapping features with another MPN; late stage/overt fibrosis; early stage without fully-developed morphologic features; and coexisting atypical morphologic findings. MPN-U with overlapping features had highly variable reticulin fibrosis, while, as expected, late stage entities had a high degree of reticulin fibrosis and early stage entities showed less overt fibrosis (Figure, Left, demonstrating select morphologic features of evaluated chronic myeloid neoplasms). MPN-U as a whole appeared to show less prominent fibrosis-associated findings than MDS/MPN-U and to, in general, show a greater degree of neovascularization, similar to changes observed in cases with PMF. Splicing factor and epigenetic modifier mutations appeared to be overrepresented in MDS/MPN-U relative to MPN-U, notably excluding MPN-U with atypical morphologic features (Figure, Right, demonstrating the distribution of pathogenic variants identified in evaluated myeloid neoplasms; results are indicated as presence (1) or absence (0) of a variant for each gene). Notably, no CALR mutations were identified in the MDS/MPN-U category or early stage / atypical morphology MPN-U, though they were enriched in overtly fibrotic MPN-U entities. Discussion/Conclusion: In this cohort we observed, as expected, significant overlap in cases classified as MPN-U and MDS/MPN-U with better delineated entities, though patterns of morphologic change and mutational spectra suggest potential directions for further investigation of additional criteria that may guide accurate classification of these neoplasms. These findings reflect the heterogeneity of MPNs described in the literature and the complexity of their genetic underpinnings, particularly in the context of concurrent dyshematopoiesis; suggest enhanced bone marrow vascularization may be an informative differential diagnostic criterion in evaluation of these neoplasms, though further study is required; and emphasize the need for broader genetic testing and perhaps further subtyping of MPN-U cases for a more nuanced analytical approaches for these disorders.

Serous Cystadenoma: A Review on Diagnosis and Management

Incidental pancreatic cysts are highly prevalent, with management dependent on the risk of malignant progression. Serous cystadenomas (SCAs) are the most common benign pancreatic cysts seen on imaging. They have typical morphological patterns but may also show atypical features that mimic precancerous and cancerous cysts. If a confident diagnosis of SCA is made, no further follow-up is warranted. Therefore, a preoperative distinction between SCA and precancerous or cancerous lesions is critically essential. Distinguishing an SCA from other types of pancreatic cysts on imaging remains a challenge, thus leading to misdiagnosis and ramifications. This review summarizes the current evidence on diagnosing and managing SCA.

Optical Coherence Tomography in the Evaluation of Suspected Carotid Webs

BackgroundCarotid web (CaW) is a subtype of fibromuscular dysplasia that predominantly involves the intimal layer of the arterial wall and is commonly overlooked as a separate causative entity for recurrent...

Combined WNT-activated deep-penetrating/plexiform melanocytoma: insights into clinicopathological andmolecular characterization.

A combined deep-penetrating tumour redefined as WNT-activated deep-penetrating/plexiform melanocytoma (DPM), may pose challenging clinical and histological diagnoses. To review the clinicopathological characteristics of combined DPMs and characterize the molecular profile of atypical and malignant forms. The study included 51 patients with combined DPMs diagnosed at the Hospital Clinic of Barcelona and the University of Florence between 2012 and 2020. Clinical data, dermoscopy images (when available) and histological characteristics were reviewed. Immunohistochemistry for β-catenin, LEF1, HMB45, Ki67, p16 and PRAME (preferentially expressed antigen in melanoma) was performed. Atypical forms underwent next-generation sequencing (NGS) panel analysis, including driver genes implicated in DPMs, TERT-promoter (p) mutations and the investigation of the 9p21 locus via fluorescence in situ hybridization. Among the 51 patients (32 females and 19 males, age range 4-74 years), 68% with available clinical data (15/22) were initially suspected of having melanoma. Except for one patient, complete excision resulted in no recurrences or metastases. One patient who had an incompletely excised combined DPM developed a lymph node melanoma metastasis 10 years later. In the 51 patients, 10 samples (20%) showed atypical histological features; 7 (14%) exhibited a significant loss of p16 expression; and 2 (4%) showed a high-proliferative index (Ki67 over 5%). NGS analysis in 11 patients revealed a double mutation BRAFV600E and exon 3 CTNNB1; no TERTp mutations were detected. Clinical suspicion of melanoma is common in combined DPMs, but malignant progression is infrequent in tumours lacking high-grade atypia or proliferation. These findings are congruent with the consideration of these lesions as intermediate-grade tumours or melanocytomas.

Pneumomediastinum complicating acute asthma.

A 19 year old female with a history of asthma presented with an acute life-threatening asthma exacerbation. Atypical features, particularly a persistent oxygen requirement promted further investigation with a subsequent CT Thorax confirming pneumomediastinum. Her case was managed conservatively as per our treatment proctocol for asthma. Pneumomediastinum can present during an acute asthma exacerbation. Although it is benign and spontaneous recovery is to be expected, due to the risk of respiratory comprimise and profound hypoxia a high level of clinical suspicion and close monitoring is advised.

PATH-33. MORPHOLOGY, MOLECULAR FEATURES, AND CLINICAL BEHAVIOR OF METHYLATION CLASS PLEOMORPHIC XANTHOASTROCYTOMA

Abstract Methylation profiling has revealed unexpected relationships between traditional histopathology-based versus biologically-based classifications of brain tumors. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the same methylation signature as classical PXA but with additional morphologic patterns, including overlap with glioblastoma (GBM). To characterize mcPXA, we examined epidemiologic, histologic, and molecular features as well as clinical behavior of a cohort (n=313) of tumors matching to mcPXA by the DKFZ classifier (v12 score >= 0.85). Patient median age was 19 (range 1-73) with a female predominance (178 female/135 male). CDKN2A/B homozygous deletion was observed in 273 (87%) cases. In the subset of cases tested for BRAF p.V600E (n=120), 111 (93%) harbored the mutation. Concomitant chr7+/chr10- was observed in 66 (21%) cases. In the subset of cases tested for TERT promoter mutations (n=50), 11 (22%) harbored the mutation, always with co-occurrence of BRAF p.V600E (11/11) and infrequently with chr7+/chr10- (3/11). MGMT promoter methylation was observed in 40 (13%) cases. Overall and progression-free survival (OS, PFS) in mcPXA were similar to grade 2-3 IDH-mutant astrocytoma (A-IDH). Prognostic factors in mcPXA included GBM-like histopathology (defined as cases diagnosed as GBM prior to methylation profiling), concomitant chr7+/chr10-, and MGMT promoter methylation. GBM-like histopathology was associated with shorter OS (p=0.02) and PFS (p< 0.01) compared to cases without GBM-like histopathology. Concomitant chr7+/chr10- was associated with shorter PFS (p=0.02), and MGMT promoter methylation was associated with shorter OS (p=0.03). Our findings demonstrate that mcPXA tumors affect adolescents and young adults, share molecular features of classical PXA, and manifest clinical behavior similar to classical PXA, but subsets of tumors with atypical features (chr7+/chr10-, MGMT promoter methylation, and/or GBM-like histopathology) are more aggressive. The use of a molecular definition of PXA reveals that this tumor type is more common than previously appreciated and warrants in-depth study for therapeutic options.

Abstract 14735: Fabry's Disease as a Potential Overlapping Diagnosis in Progressive Hypertrophic Cardiomyopathy

Background: Fabry's disease (FD), an X-linked lysosomal storage disorder, can present with cardiac manifestations similar to HCM. We aim to emphasize considering FD as a differential diagnosis in patients with HCM while highlighting the role of genetic testing in evaluating left ventricular hypertrophy (LVH). Cases Presentation: We present a case series of 3 patients with LVH. Despite initial clinical suspicion of primary HCM, genetic testing confirmed the diagnosis of FD. Patient 1: A 38-year-old male with no prior medical history presented with presyncope, lightheadedness, and chest tightness. EKG, Echo, and cardiac MRI suggested apical HCM. Genetic testing indicated FD. Patient 2: A 62-year-old male sought a second opinion regarding his diffuse HCM. EKG suggested RBBB. Echo showed a binary appearance of the myocardium, concentric LVH. Genetic testing confirmed FD. Patient 3: A 64-year-old male with a history of hypertension and renal disease underwent evaluation for kidney transplantation. Echo showed severely increased concentric LVH and Valsalva-induced intracavitary gradient/obstruction. Alpha-galactosidase level returned very low, suggesting FD, which was confirmed by genetic testing. Discussion: FD can be challenging to diagnose due to overlapping clinical and imaging features with HCM, leading to misdiagnosis and delayed management. Therefore, Genetic testing should be offered to all patients with suspected HCM to exclude phenocopies. Particularly, those with progressive HCM and atypical clinical features (renal disease and family history predominantly in males) and imaging features (conduction abnormalities on EKG, binary appearance on Echo). Early identification of FD enables appropriate management, including enzyme replacement therapy, potentially improving clinical outcomes. Conclusions: FD should be considered as a differential diagnosis in patients with HCM. Genetic testing plays a vital role in evaluating patients with HCM.

Autoimmune Heparin-Induced Thrombocytopenia.

Autoimmune thrombocytopenia (aHIT) is a severe subtype of heparin-induced thrombocytopenia (HIT) with atypical clinical features caused by highly pathological IgG antibodies ("aHIT antibodies") that activate platelets even in the absence of heparin. The clinical features of aHIT include: the onset or worsening of thrombocytopenia despite stopping heparin ("delayed-onset HIT"), thrombocytopenia persistence despite stopping heparin ("persisting" or "refractory HIT"), or triggered by small amounts of heparin (heparin "flush" HIT), most cases of fondaparinux-induced HIT, and patients with unusually severe HIT (e.g., multi-site or microvascular thrombosis, overt disseminated intravascular coagulation [DIC]). Special treatment approaches are required. For example, unlike classic HIT, heparin cessation does not result in de-escalation of antibody-induced hemostasis activation, and thus high-dose intravenous immunoglobulin (IVIG) may be indicated to interrupt aHIT-induced platelet activation; therapeutic plasma exchange may be required if high-dose IVIG is ineffective. Also, aHIT patients are at risk for treatment failure with (activated partial thromboplastin time [APTT]-adjusted) direct thrombin inhibitor (DTI) therapy (argatroban, bivalirudin), either because of APTT confounding (where aHIT-associated DIC and resulting APTT prolongation lead to systematic underdosing/interruption of DTI therapy) or because DTI inhibits thrombin-induced protein C activation. Most HIT laboratories do not test for aHIT antibodies, contributing to aHIT under-recognition.