RESUMEN
Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Asunto(s)
Fibrosarcoma , Neoplasias de los Tejidos Conjuntivo y Blando , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Niño , Receptor trkA/genética , Proteínas Proto-Oncogénicas B-raf/genética , Recurrencia Local de Neoplasia/genética , Fibrosarcoma/genética , Fibrosarcoma/patología , Neoplasias de los Tejidos Blandos/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Papillary hemangioma (PH) is a recently described vascular tumor with a predilection for the skin of the head and neck. Histopathologically, it is characterized by a bland endothelial proliferation arranged in a papillary configuration, bearing resemblance to glomeruloid hemangioma seen in the context of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome. The largest cutaneous PH reported to date measured 1.5 cm in greatest dimension. Here, we report a case of PH with an alarming size of 10 cm. We present this case to add to the limited literature on this rare tumor, highlight the histopathologic differences between PH and its mimics, and emphasize the variable nature of PH tumor size.
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Hemangioma , Síndrome POEMS , Neoplasias Cutáneas , Neoplasias Vasculares , Humanos , Síndrome POEMS/patología , Hemangioma/patología , Neoplasias Cutáneas/patología , Piel/patologíaRESUMEN
Liquid side-streams from food industries can be processed and used in food applications and contribute to reduce the environmental footprint of industries. The goal of this study was to evaluate the effectiveness and applicability of protein and phosphorus separation processes, namely microfiltration, ultrafiltration and flocculation, using protein-rich process waters with low (LS) and high (HS) salt content from the processing of salted cod (Gadus morhua). The application of different flocculants (chitosan lactate and Levasil RD442) were evaluated at different concentrations and maturation periods (0, 1 or 3 h). The results showed that different flocculation treatments resulted in different recoveries of the nutrients from LS and HS. Proteins in LS could be most efficiently recovered by using Levasil RD442 0.25% and no maturation period (51.4%), while phosphorus was most efficiently recovered when using Levasil RD442 1.23% and a maturation period of 1 h (34.7%). For HS, most of its protein was recovered using Levasil RD442 1.23% and a maturation period of 1 h (51.8%), while phosphorus was recovered the most using Levasil 1.23% and no maturation period (47.1%). The salt contents allowed interactions through intermolecular forces with Levasil RD442. The ultrafiltration method was effective on HS since it recovered higher percentages of nutrients in the retentate phase (57% of the protein and 46% of the phosphorus) compared to LS.
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Quitosano , Ultrafiltración , Animales , Ultrafiltración/métodos , Cloruro de Sodio , Fósforo , NutrientesRESUMEN
Calcified chondroid mesenchymal neoplasm is a term proposed for tumors with a spectrum of morphologic features, including cartilage/chondroid matrix formation, that frequently harbor FN1 gene fusions. We report a series of 33 cases of putative calcified chondroid mesenchymal neoplasms, mostly referred for expert consultation out of concern for malignancy. Patients included 17 males and 16 females, with a mean age of 51.3 years. Anatomic locations include the hands and fingers, feet and toes, head and neck, and temporomandibular joint; 1 patient presented with multifocal disease. Radiologic review showed soft tissue masses with variable internal calcification, which occasionally scalloped bone but in all cases appeared indolent/benign. Tumors had a mean gross size of 2.1 cm and a homogenous rubbery to fibrous/gritty tan-white cut surface. Histology demonstrated multinodular architecture with a prominent chondroid matrix and increased cellularity towards the periphery of the nodules. The tumor cells were polygonal with eccentric nuclei and bland cytologic features and showed a variable amount of increased spindled / fibroblastic forms in the perinodular septa. The majority of cases had notable grungy and/or lacy calcifications. A subset of cases demonstrated at least focal areas of increased cellularity and osteoclast-like giant cells. Herein, we confirm the distinct morphologic and clinicopathologic features associated with this entity with the largest series to date, with a focus on practical diagnostic separation from similar chondroid neoplasms. Awareness of these features is critical in avoiding pitfalls, including a malignant diagnosis of chondrosarcoma.
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Neoplasias Óseas , Condrosarcoma , Neoplasias de los Tejidos Conjuntivo y Blando , Masculino , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de los Tejidos Conjuntivo y Blando/diagnóstico por imagen , Neoplasias de los Tejidos Conjuntivo y Blando/genética , Condrosarcoma/patología , Cartílago/patología , Dedos del Pie/patología , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/genética , Neoplasias Óseas/patologíaRESUMEN
We report a case of a 67-year-old male patient with a sinonasal tumor that showed areas of classic biphenotypic sinonasal sarcoma (BSNS) which in some sections sharply transitioned into high-grade rhabdomyosarcoma. Immunohistochemically, the conventional BSNS parts showed S100 protein, SMA, PAX7, and focal MyoD1 expression, whereas desmin and myogenin were negative. In contrast, the cells in high-grade areas expressed desmin, MyoD1, myogenin, and PAX7, while being negative for S100 protein and SMA. Using the Archer FusionPlex assay, the classical PAX3::MAML3 gene fusion was detected. FISH for PAX3 and MAML3 confirmed a break of these genes in both components. Despite aggressive therapy, the tumor progression resulted in the patient's death. The herein presented case, together with 2 previously published cases of BSNS with high-grade transformation, helps to better understand this novel phenomenon. Although the risk for such transformation appears low, it has important clinical and diagnostic implications which are discussed.
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Neoplasias de los Senos Paranasales , Rabdomiosarcoma Alveolar , Rabdomiosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Masculino , Biomarcadores de Tumor/genética , Desmina , Inmunohistoquímica , Miogenina , Neoplasias de los Senos Paranasales/patología , Factor de Transcripción PAX3/genética , Rabdomiosarcoma/genética , Proteínas S100 , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Transactivadores , Persona de Mediana EdadRESUMEN
This study aims to develop a comprehensive and easily executable histopathologic grading scheme for murine knee osteoarthritis (OA) using specific scoring criteria for both cartilage and periarticular changes, which may overcome important limitations of the existing grading systems. The new grading scheme was developed based on mouse knee OA models with observation periods up to 24 months of age (spontaneous OA) or 24-week post-injury (posttraumatic OA). Semi-quantitative assessments of the histopathologic OA changes were applied to all four quadrants per femorotibial joint for 50 joints (200 quadrants) using specific scoring criteria rather than mild to severe grades. Scoring elements per quadrant were as follows: cartilage lesion (0-7), osteophyte (0-3), subchondral bone change (0-3), synovitis (0-3), and ectopic periarticular soft-tissue chondrogenesis and ossification (0-3). The new histopathologic grading scheme had high intra- and interobserver reproducibility (correlation coefficients r > 0.95) across experienced and novice observers. Sensitivity and reliability analyses confirmed the ability of the new scheme to detect minimal but significant OA progression (p < 0.01) within a 2-week interval and to accurately identify tissue- and quadrant-specific OA severity within the joints. In conclusion, this study presents the first whole-joint histopathologic grading scheme for murine knee OA that covers all-stage osteoarthritic changes in all major joint tissues, including periarticular soft-tissue ossification that is not included in any of the existing OA grading systems. This reproducible scheme is easy to execute and sensitive to minimal OA progression without using computer software, suitable for quick OA severity assessments of the entire femorotibial joint.
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Cartílago Articular , Osteoartritis de la Rodilla , Osteofito , Ratones , Animales , Osteoartritis de la Rodilla/patología , Reproducibilidad de los Resultados , Articulación de la Rodilla/patología , Cartílago/patología , Osteofito/patología , Cartílago Articular/patologíaRESUMEN
BACKGROUND: Methods for identifying gene fusion events, such as fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and transcriptome analysis, are either single gene approaches or require bioinformatics expertise not generally available in clinical laboratories. We analytically validated a customized next-generation sequencing (NGS) panel targeting fusion events in 34 genes involving soft-tissue sarcomas. METHODS: Specimens included 87 formalin-fixed paraffin-embedded (FFPE) tissues with known gene fusion status. Isolated total nucleic acid was used to identify fusion events at the RNA level. The potential fusions were targeted by gene-specific primers, followed by primer extension and nested PCR to enrich for fusion candidates with subsequent bioinformatics analysis. RESULTS: The study generated results using the following quality metrics for fusion detection: (a) ≥100 ng total nucleic acid, (b) RNA average unique start sites per gene-specific primer control ≥10, (c) quantitative PCR assessing input RNA quality had a crossing point <30, (d) total RNA percentage ≥30%, and (e) total sequencing fragments ≥500 000. CONCLUSIONS: The test validation study demonstrated analytical sensitivity of 98.7% and analytical specificity of 90.0%. The NGS-based panel generated highly concordant results compared to alternative testing methods.
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Secuenciación de Nucleótidos de Alto Rendimiento , Reacción en Cadena de la Polimerasa Multiplex , Fusión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in SituRESUMEN
CONTEXT.: Bone and soft tissue tumors are heterogeneous, diagnostically challenging, and often defined by gene fusions. OBJECTIVE.: To present our experience using a custom 34-gene targeted sequencing fusion panel. DESIGN.: Total nucleic acid extracted from formalin-fixed, paraffin-embedded (FFPE) tumor specimens was subjected to open-ended, nested anchored multiplex polymerase chain reaction and enrichment of 34 gene targets, thus enabling detection of known and novel fusion partners. RESULTS.: During a 12-month period, 147 patients were tested as part of routine clinical care. Tumor percentage ranged from 10% to 100% and turnaround time ranged from 3 to 15 (median, 7.9) days. The most common diagnostic groups were small round blue cell tumors, tumors of uncertain differentiation, fibroblastic/myofibroblastic tumors, and adipocytic tumors. In-frame fusion transcripts were identified in 64 of 142 cases sequenced (45%): in 62 cases, the detection of a disease-defining fusion confirmed the morphologic impression; in 2 cases, a germline TFG-GPR128 polymorphic fusion variant was detected. Several genes in the panel partnered with multiple fusion partners specific for different diagnoses, for example, EWSR1, NR4A3, FUS, NCOA2, and TFE3. Interesting examples are presented to highlight how fusion detection or lack thereof was instrumental in establishing accurate diagnoses. Novel fusion partners were detected for 2 cases of solid aneurysmal bone cysts (PTBP1-USP6, SLC38A2-USP6). CONCLUSIONS.: Multiplex detection of fusions in total nucleic acid purified from FFPE specimens facilitates diagnosis of bone and soft tissue tumors. This technology is particularly useful for morphologically challenging entities and in the absence of prior knowledge of fusion partners, and has the potential to discover novel fusion partners.
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Biomarcadores de Tumor/genética , Quistes Óseos Aneurismáticos/genética , Neoplasias Óseas/genética , Perfilación de la Expresión Génica , Fusión Génica , Reacción en Cadena de la Polimerasa Multiplex , Neoplasias de los Tejidos Blandos/genética , Transcriptoma , Ubiquitina Tiolesterasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quistes Óseos Aneurismáticos/patología , Neoplasias Óseas/patología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Neoplasias de los Tejidos Blandos/patología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Although tumors with nerve sheath differentiation are vast, the main clinically significant problems faced by the pathologist are the separation of malignant peripheral nerve sheath tumors (MPNSTs) from histologic mimics, the diagnosis of neurofibromatous neoplasms with atypical features, and the separation of cutaneous neurofibromatous neoplasms from melanoma. This review briefly discusses a variety of common nerve sheath tumors and summarizes recent advances on these diagnostic fronts. RECENT FINDINGS: Much of recent work has focused on abnormalities in polycomb repressive complex 2, and the ways in which these abnormalities may be exploited in the diagnosis of MPNSTs. Progress has been made in the diagnostic and clinical understanding of atypical neurofibromatous neoplasms and low-grade MPNSTs. A number of reports have explored the diagnostic distinction between cutaneous neurofibroma and melanoma. SUMMARY: New discoveries show promise in the diagnosis of peripheral nerve sheath tumors, but challenges - old and new - remain.
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Melanoma/diagnóstico , Neoplasias de la Vaina del Nervio/diagnóstico , Neurilemoma/diagnóstico , Neurofibroma/diagnóstico , Diagnóstico Diferencial , Humanos , Melanoma/patología , Neoplasias de la Vaina del Nervio/patología , Neurilemoma/patología , Neurofibroma/patologíaRESUMEN
Peripheral nerve sheath tumors are commonly encountered and frequently pose challenges to the pathologist and the clinician. This review discusses the wide range of entities with an emphasis on new discoveries in the past decade. Clinical, histologic, immunohistochemical, and pathogenetic findings are discussed with an emphasis on clinical implications and differential diagnosis.
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Neoplasias de la Vaina del Nervio/patología , Transformación Celular Neoplásica , Diagnóstico Diferencial , Tumor de Células Granulares/diagnóstico , Tumor de Células Granulares/etiología , Tumor de Células Granulares/patología , Humanos , Neoplasias de la Vaina del Nervio/diagnóstico , Neoplasias de la Vaina del Nervio/etiología , Neurilemoma/diagnóstico , Neurilemoma/etiología , Neurilemoma/patología , Neurofibroma/diagnóstico , Neurofibroma/etiología , Neurofibroma/patologíaRESUMEN
We report 2 continuous flow HeartWareTM left ventricular assist devices successfully used in a patient with advanced heart failure of giant cell myocarditis origin in a biventricular configuration. Despite technical challenges of adapting a left ventricular assist device engineered for systemic pressure to function as a right ventricular assist device, the addition of dynamic banding on the right ventricular assist device outflow graft allowed successful adaptation of afterload. This patient has now been on biventricular configuration support for 9 years, and remains stable to this day.
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Arteritis de Células Gigantes/complicaciones , Insuficiencia Cardíaca/terapia , Ventrículos Cardíacos/fisiopatología , Corazón Auxiliar , Miocarditis/complicaciones , Función Ventricular Izquierda/fisiología , Femenino , Estudios de Seguimiento , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Persona de Mediana Edad , Miocarditis/diagnóstico , Miocarditis/fisiopatología , Factores de Tiempo , Resultado del TratamientoRESUMEN
One caveat of next-generation sequencing (NGS)-based clinical oncology testing is the high amount of input DNA required. We sought to develop a focused NGS panel that could capture hotspot regions in relevant genes requiring 0.5-10â¯ng input DNA. The resulting Penn Precision Panel (PPP) targeted 20 genes containing clinically significant variants relevant to many cancers. One hundred twenty-three samples were analyzed, including 83 solid tumor specimens derived from FFPE. Various input quantities of DNA (0.5-10â¯ng) were amplified with content-specific PCR primer pools, then sequenced on a MiSeq instrument (Illumina, Inc.) via paired-end, 2â¯×â¯186 base pair reads to an average read depth of greater than 6500x. Variants were detected using an in-house analysis pipeline. Clinical sensitivity and specificity were assessed using results from our previously validated solid tumor NGS panel; sensitivity of the PPP is 96.75% (387/400 variants) and specificity is 99.9% (8427/8428 base pairs). Variant allele frequencies (VAFs) are highly concordant across both assays (râ¯=â¯0.98 pâ¯<â¯0.0001). The PPP is a robust, clinically validated test optimized for low-yield solid tumor specimens, capturing a high percentage of clinically relevant variants found by larger commercially available NGS panels while using only 0.5-10â¯ng of input DNA.
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ADN de Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , ADN de Neoplasias/análisis , Humanos , Límite de DetecciónRESUMEN
Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
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Lamina Tipo A/genética , Lipodistrofia Generalizada Congénita/genética , Mutación , Progeria/genética , Absorciometría de Fotón/métodos , Adolescente , Adulto , Antropometría/métodos , Niño , Femenino , Humanos , Lipodistrofia Generalizada Congénita/metabolismo , Lipodistrofia Generalizada Congénita/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Miocardio/patología , Fenotipo , Progeria/metabolismo , Progeria/patologíaRESUMEN
Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNγ in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with αPD-1 mAbs, with or without αCTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist αCD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to αPD-1 and αCTLA-4. The combination of αCD40/chemotherapy plus αPD-1 and/or αCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with αCD40/chemotherapy.