OBJECTIVE:Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions are rare hematologic malignancies characterized by constitutive kinase activation and sensitivity to tyrosine kinase inhibitors. PDGFRB rearrangements are uncommon, and CCDC6::PDGFRB fusion has been reported only rarely. CASE REPORT:A 44-year-old man presented with leukocytosis, eosinophilia, anemia, splenomegaly, and constitutional symptoms. A bone marrow examination showed granulocytic hyperplasia with marked eosinophilia. Cytogenetic analysis revealed t(5;10)(q32;q21), while optical genome mapping identified a CCDC6::PDGFRB fusion, confirmed by fluorescence in situ hybridization. No additional pathogenic mutations were detected by targeted next-generation sequencing. Treatment with low-dose imatinib achieved rapid hematologic remission, which was maintained at 22 months. CONCLUSIONS:This case highlights the importance of comprehensive genomic testing in patients with eosinophilia-associated myeloid neoplasms for identifying rare and therapeutically actionable PDGFRB rearrangements.

Classification of cases of diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (HGBL) with MYC and BCL6 rearrangements, referred to here as BCL6 double-hit lymphoma (DHL), is controversial. We assessed 60 cases of BCL6-DHL and compared this cohort to 224 cases of DHL with MYC and BCL2 rearrangements (BCL2-DHL) and 217 cases of DLBCL not otherwise specified. Compared with the DLBCL cohort, patients with BCL6-DHL had more aggressive clinical features such as frequent extranodal involvement, high-stage disease, a high International Prognostic Index score, and an elevated serum lactate dehydrogenase level (P < .01 for all). Compared with the BCL2-DHL cohort, patients with BCL6-DHL had similarly aggressive clinical features but a lower frequency of germinal center B-cell (GCB) immunophenotype and MYC and BCL2 double expression. Patients with BCL6-DHL showed overall survival (OS) intermediate between patients with DLBCL and BCL2-DHL. Following induction with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, patients with BCL6-DHL demonstrated poor OS similar to patients with BCL2-DHL and worse OS than that of patients with DLBCL (P = .024). However, among patients who received rituximab, etoposide phosphate, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH), there was no significant difference in OS among the 3 groups (P = .146). Gene expression profiling showed that 60% of BCL6-DHL cases had a double-hit (DH)-like signature compared with 10% of DLBCLGCB and 93% of BCL2-DHL cases. The DH-like signature in BCL6-DHL cases was associated with a GCB immunophenotype. Based on these data, we suggest that BCL6-DHL cases are clinically more aggressive than DLBCL and patients may benefit from a more aggressive therapy than RCHOP. The data also suggest that BCL6-DHL, as currently defined, is heterogeneous and that neoplasms with a GCB immunophenotype are more likely to have a DH-like signature and behave more aggressively. Last, we suggest that BCL6-DHL cases deserve to be recognized separately in a lymphoma classification to facilitate further understanding of these neoplasms and for optimal patient management. (c) 2025 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Background/Objectives: Gene rearrangements involving oncogenes are major drivers in acute leukemia, influencing disease classification, prognosis, and therapeutic decision-making. Targeted RNA sequencing (RNA-Seq) panels capable of detecting intergenic and intragenic fusions across multiple genes are increasingly used in diagnostic settings. However, comparative evaluation with orthogonal technologies remains limited. Material and Methods: We compared the performance of a 108-gene anchored multiplex PCR (AMP)-based RNA-Seq panel with that of Optical Genome Mapping (OGM) in 467 acute leukemia cases. The cohort included 360 cases of acute myeloid leukemia (AML), 89 B-lymphoblastic leukemia (B-ALL), 12 T-lymphoblastic leukemia (T-ALL), and 6 cases of mixed phenotype acute leukemia (MPAL). Results: Results of both methods were concordant in 175 (74.7%) of 234 detected gene/rearrangement fusions. The concordance rate varied significantly across different leukemia types, ranging from 80.2% in B-ALL to 41.7% in T-ALL (p < 0.001) OGM uniquely detected 37 of 234 (15.8%) clinically relevant rearrangements, whereas RNA-Seq exclusively identified 22 of 234 (9.4%). Enhancer-hijacking lesions, including MECOM and BCL11B rearrangements, CDK6::MNX1, and IGH rearrangements, had a markedly lower concordance (20.6%) compared with all other aberrations (93.1%) (p < 0.001). Conversely, some gene fusions arising from intrachromosomal deletions were interpreted by OGM as simple deletions rather than rearrangements or fusions. Conclusions: Targeted RNA-Seq was effective for detecting chimeric fusion transcripts and showed slightly better performance in identifying fusions resulting from deletions. However, OGM was effective for detecting enhancer-hijacking events that do not generate fusion transcripts. Both methods are complementary for the workup of acute leukemia cases.

Background/Objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis. Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were missense. Compared with SPEN wild type CLL patients, SPEN mutated patients had a statistically higher frequency of IGHV unmutated status (79.5% vs. 57.8%, p = 0.004), CD38 positivity (73.3% vs. 52.4%, p = 0.01), ZAP70 positivity (77.3% vs. 58.3%, p = 0.01) and trisomy 12 (43.5% vs. 13.7%, p < 0.001). The most common gene mutations co-occurring with SPEN mutations were as follows: NOTCH1 (43.7%), TP53 (22.9%), BIRC3 (12.5%), SF3B1 (10.4%), XPO1 (8.3%), MUC2 (6.2%), ATM (4.2%), FBXW7 (4.2%), and BTK (4.2%). Patients with SPEN mutated CLL had a significantly shorter time-to-first treatment compared to CLL patients with wild type SPEN (2.5 vs. 4.07 years, p = 0.01). The finding of shorter time-to-first treatment in SPEN mutated CLL patients was not maintained in a multivariable analysis. IGHV unmutated status, TP53 disruption, and trisomy 12 remained independently predictive of a shorter time-to-first treatment in a multivariable analysis. Conclusions: These data show that SPEN mutations in CLL are associated with adverse prognostic impact and should be included in sequencing assays performed for the prognostic workup of CLL patients.

Children with HOX-driven AML, including KMT2A or NUP98 rearrangements (KMT2Ar, NUP98r), have poor outcomes, particularly following relapse. Although allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative potential, post-transplant relapse is common. In this high-risk subset, post-transplant complete remission (CR) rates as low as 19% and 0%, respectively, have been reported in large international cooperative group studies. There is a critical need for effective post-transplant maintenance therapy in this population to delay relapse and allow time for the curative graft-vs-leukemia effect. The menin inhibitor revumenib is approved for the treatment of relapsed/refractory KMT2Ar acute leukemia for age >1 year, however, outcomes with maintenance post-HSCT in children with this agent have not been fully characterized. We retrospectively analyzed pediatric patients who received revumenib maintenance following HSCT to assess safety and tolerability of this agent. We identified pediatric AML patients (ages 0–18 years) treated at MD Anderson Cancer Center who underwent HSCT following response to revumenib-based therapies and had resumed revumenib monotherapy as maintenance post-HSCT between June 2022 and June 2025. Toxicities were graded per CTCAE v5.0. Ten pediatric patients received post-HSCT revumenib maintenance. The median follow-up was 15.5 months (range: 1–38). The median age was 10 years (range: 17 months–18 years). Molecular subtypes included KMT2Ar (n=8) and NUP98r (n=2); this was the second or greater transplant for five patients. Before transplant, revumenib was administered either as monotherapy per AUGMENT-101 (NCT04065399) (n=3) or Expanded Access (NCT05918913) (n=2) or in combination with oral decitabine and venetoclax per the SAVE protocol (NCT05360160) (n=5). The median number of revumenib-containing cycles given pre-HCT was 2 (range: 1–4). Donor sources included matched sibling donors (n=2), matched unrelated donors (n=2), haploidentical donors (n=3), and unrelated cord blood units (n=3). Conditioning regimens varied by donor and included combinations of fludarabine, busulfan, thiotepa, total body irradiation (TBI), and post-transplant cyclophosphamide (PTCy). Revumenib maintenance was initiated at a median of 111 days post-HCT (range: 58–175). All patients received concurrent strong CYP3A4 inhibitors. Dosing was weight-based: patients ≥40 kg received 160 mg orally twice daily in 28-day cycles, while those <40 kg received 95 mg/m² twice daily. All patients were in remission at the time of maintenance initiation. One patient had stable grade 2 upper gastrointestinal GVHD at baseline. No new cases of GVHD or GVHD flares were observed during treatment. No bacterial, fungal, or viral infections requiring hospitalization occurred. The most common adverse event was thrombocytopenia, observed in 6 patients; three cases were grade ≥3 (two grade 3, one grade 4), occurring primarily during the first two cycles. Temporary dose reductions or interruptions were required in five patients. Four of these patients were successfully re-escalated to the original dose and continued therapy without further complications. The single patient with baseline GVHD also experienced grade 3 thrombocytopenia and was the only patient who did not undergo dose re-escalation. Treatment was discontinued after cycle 3 due to parental preference for this patient. The median number of maintenance cycles completed was 11 (range: 1–25). At last follow-up, all 10 patients were alive with no relapses, yielding a 1-year event-free survival of 100%. Using revumenib as maintenance post-transplant in children with HOX-driven AML was safe and showed promising early efficacy. Prospective studies are needed to confirm benefit and define optimal use.

Background Children with HOX-driven acute leukemias, including KMT2A and NUP98 rearrangements (r), have dismal outcomes after relapse, with complete remission (CR) rates under 20%. Revumenib, a menin inhibitor approved for relapsed/refractory KMT2Ar leukemia in patients over 1 year, can be associated with QTc prolongation in predominantly adult cohorts, but pediatric data on cardiac safety remain limited. This study focuses on the safety and efficacy of revumenib monotherapy in children with relapsed HOX-driven leukemia, primarily regarding QTc and ventricular function. Methods We identified pediatric patients (ages 0–19 years) treated at our center who received revumenib monotherapy between June 2021 and June 2025. Data on demographics, molecular profile, prior therapies, and adverse events were collected. Toxicities were graded per CTCAE v5.0; responses were assessed by modified IWG criteria. Treatment continued until unacceptable toxicity, disease progression, or lack of response. Cardiac monitoring included serial ECGs and echocardiograms. QTc intervals were calculated using the Fridericia formula, defining prolongation as QTcF ≥450 ms. Echocardiograms assessed biplane ejection fraction (EF) and shortening fraction, with left ventricular dysfunction defined as EF <55% or SF <28%. Pleural effusion, electrolyte abnormalities, and other cardiac events were assessed in the context of prior cardiac history and treatment course. Results A total of 30 pediatric patients received revumenib monotherapy. The median age was 7 years (range, 0.8–19). Baseline diagnoses included AML (90.0%, n=27), acute lymphoblastic leukemia (ALL; 6.7%, n=2), and acute undifferentiated leukemia (AUL; 3.3%, n=1). Molecular alterations included KMT2Ar (83.3%, n=25), NUP98r (10.0%, n=3), NPM1mutations (3.3%, n=1), and UBTF-tandem duplications (3.3%, n=1). Patients had received a median of 3 prior lines of therapy (range, 1–5) and 50% (n=15) had undergone prior allogeneic hematopoietic stem cell transplantation (HSCT). Revumenib was administered either as monotherapy per AUGMENT-101 (NCT04065399) (n=23) or Expanded Access (NCT05918913) (n=7). Revumenib was administered orally at 163 mg every 12 hours (or 95 mg/m² for patients <40 kg), alongside a strong CYP3A4 inhibitor, in continuous 28-day cycles. The median duration of therapy was two cycles (range, 1–8). QTc interval prolongation occurred in 2 patients (6.7%): one grade 2 (3.3%) and one grade 3 (3.3%) event, both during Cycle 1. Both were adolescents (ages 16 and 19); one required a temporary dose interruption. One of the affected patients had a baseline QTc ≥450 ms. No grade 4 events, torsades de pointes, or arrhythmia-related deaths were observed. Scheduled echocardiograms detected transient, asymptomatic declines in EF <50% in 2 patients (6.66%): one after Cycle 3, in the context of septic shock, and one in Cycle 6. An additional patient developed grade 3 symptomatic cardiac dysfunction with pericardial effusion and reduced EF (40%), requiring treatment interruption; this occurred in the setting of progressive disease during Cycle 1. No grade 4 or 5 cardiac events were observed. The composite complete remission (CR/CRi/CRp/CRh/MLFS) rate was 40% (n=12) with 83% (n=10) undetectable MRD by flow cytometry. One patient was non-evaluable due to acellular bone marrow. Five patients had no response, and 12 experienced progressive disease. The median time to response was 28 days (range, 28–168). Nine patients (30%) proceeded to HSCT following revumenib. Conclusion Revumenib was well tolerated in children with relapsed high-risk leukemia. Cardiac events were infrequent in children and rarely required dose interruption, which supports the safety and continued use of revumenib in this population.

Background: Measurable residual disease (MRD) status is a robust indicator of outcomes in patients (pts) with acute myeloid leukemia (AML). Flow cytometric immunophenotyping (FCI) is among the most utilized methods for MRD assessment, particularly in AML without molecular markers of MRD (i.e. FLT3, NPM1, core binding factor fusions). The two main approaches used for MRD assessment by FCI include 1) identifying leukemia-associated immunophenotypes (LAIP); and 2) identifying deviation from normal (DFN). The latter may be confounded by the presence of persistent clonal hematopoiesis (CH) or underlying myelodysplastic (MDS) clones (Loghavi S, Br J Haematol. 2021), leading to non-definitive interpretation of results. Methods: We searched for pts with AML treated at our institution between 2017 and 2022 who achieved CR/CRi and had at least one FCI report interpreted as “indeterminate” or “negative for MRD, but with immunophenotypically atypical myeloid blasts”. These were negative for LAIP but had CD34+ myeloid progenitors with DFN insufficient for a diagnosis of AML MRD, including alterations in intensity of of CD13, CD34, CD38, CD54, CD117, CD123 and HLA-DR; abnormal CD13 vs CD33 pattern; and/or dim/partial expression of CD5, CD7 and/or CD56 herein referred to as “DFN phenotype”. We divided these cases into “persistent” DFN if this phenotype was identified in the first adequate ( >200 CD34+ events) MRD-negative sample and “emergent” if DFN was identified after a previously definitive MRD-negative assessment in an adequate sample. We correlated these findings with baseline and post-remission cytogenetic and molecular features. Routine karyotyping and panel-based next-generation sequencing were performed on all samples at baseline and in the most pts at remission. Results: At least 1 indeterminate MRD assessment was identified in 36/398 pts (9%) treated with intensive therapy (median age: 53 years [range, 25-68]) and in 60/276 pts (20%) treated with lower-intensity therapy (median age: 69.5 years [range, 38-81]). Upon retrospective review, 10 pts had molecular or cytogenetic evidence of AML MRD (e.g. FLT3, NPM1 mutation or CBFB, MECOM or KMT2A rearrangement) and were excluded from the analysis. Baseline AML subtypes for the rest of the cohort (n=86) included myelodysplasia-related (MR) AML (n=30, 35%), AML with NPM1m (n=30, 35%; 8 with MR co-mutations), TP53m (n=8, 9%), KMT2Ar (n=5, 6%), with germline predisposition (n=3, 3%; all with DDX41m), MECOMr (n=1, 1%) and AML, not otherwise specified (n=9, 10%). 72 (84%) pts had persistent and 14 (16%) had emergent DFN. The median time from the start of therapy to the initial identification of DFN was 27 days (range, 14-358 days) in the entire cohort and 148 days for the emergent cohort. The median percentage of aberrant cells was 1% (range, 0.01-3.8%). 79/86 (88%) and 63/86 (73%) pts had repeat cytogenetic/molecular testing at the time of identification of the DFN, respectively. 46/63 samples with DFN phenotype had residual mutations (median= 2; range, 1-6). The most common mutations involved DNMT3A (43%), TET2 (22%), SRSF2 (16%), ZRSR2 (14%), ASXL1 (13%), RUNX1 (10%), IDH1 and IDH2 (10% each), NRAS and U2AF1 (8% each), and TP53 (5%). 17/63 (27%) had no residual mutations; among these, 2 had -Y, and the 15 others had no clonal cytogenetic abnormalities. Among pts with relapsed disease (n=27/86, 31%), 1/17 (6%) in the low-intensity and 2/10 (20%) in the high-intensity group relapsed with the DFN phenotype, suggesting the other DFN phenotypes may represent pre-leukemic or MDS clones. A landmark analysis to compare survival outcomes of the study cohort compared with pts with definitive MRD positive or negative status is underway. Conclusion: Atypical CD34+ myeloid blasts with deviation from normal (DFN) phenotypes are commonly observed in myelodysplasia-related AML and AML with NPM1 (with or without MR gene co-mutations) and are more commonly seen in pts treated with low-intensity regimens. Samples with blasts with DFN phenotypes may represent AML MRD with phenotypic shift or pre-leukemic and myelodysplastic clones. DFN is commonly associated with residual myelodysplasia-related gene mutations (e.g DNMT3A, TET2, ASXL1 (DTA), and IDH1/2). It is important to be aware of these findings to avoid overinterpretation as AML MRD, particularly as more MRD-directed therapies become available in the context of clinical trials for pts with AML.

Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.

OBJECTIVES:Acute myeloid leukemia (AML) with mast cell (MC) differentiation was recently described as an aggressive subgroup of AML cases. The objectives of this study were to assess the flow cytometric immunophenotypic features of AML-MC cases. METHODS:We characterized the immunophenotypic features of 21 AML-MC cases by flow cytometry and compared them to 20 reactive/regenerating bone marrow specimens. RESULTS:The number of MCs detected by flow cytometry in AML-MC cases ranged from 0.4% to 21.1%, with a median of 3.5%, significantly higher than that of normal/reactive bone marrow (BM) (median, 0.01%; range, 0.000%-0.396%; P < .0001). Immunophenotypically, MCs in AML-MC cases demonstrated immaturity, differing from MCs in normal/reactive BMs, including dimmer CD45 (100% vs 0%), lower side scatter (100% vs 0%), more frequent CD34 (81% vs 20%), and CD123 (100% vs 10%) positivity, and more frequent uniform/increased CD38 expression (95% vs 20%) (all P ≤ .0001). CD2 (0/5) and CD25 (2/6, 1 uniform and 1 partial) were assessed in a subset of cases. The myeloblasts in AML-MC were typically CD34+CD117+HLA-DR+ with unusually frequent expression of CD56 (57%, all partial) and CD25 (63%, mostly partial), increased CD117 (62%), and decreased CD38 (86%). The MC percentage determined by flow cytometry correlated well with MCs detected by tryptase immunohistochemistry (r = 0.76, P < .001). CONCLUSIONS:The MCs in AML-MC cases are characterized by dim CD45, low side scatter, CD34 and CD123 positivity, and uniform and increased CD38 expression. Flow cytometry is an excellent tool for identifying AML-MC cases.

Background: Cladribine-based combination chemotherapy has demonstrated promising efficacy in patients with relapsed/refractory adult acute myeloid leukemia (AML), prompting its increased utilization in the frontline; in pediatrics, it has been typically reserved for relapsed or refractory cases. While fludarabine has been used more commonly as a purine analog in intensive regimens, cladribine may be an important alternative. Methods: We performed a retrospective study at MD Anderson Cancer Center from January 2015 to July 2023, which included patients aged 1-21 years with refractory or relapsed AML who received cladribine outside of a transplant conditioning. Results: A total of 30 patients were included, with a median age of 20 years (range, 2-21), and 55% being male. Similar to adults, cladribine exhibited good tolerability in pediatric and adolescent patients, with the most common adverse events being febrile neutropenia and myelosuppression. The most common grade 3 or 4 adverse events included febrile neutropenia (55%) and sepsis (26%), and there were no treatment discontinuations due to adverse events. Among patients with a median number of 2 (0-7) prior treatments, the overall response rate (CR/CRi) was 45%, and median event-free and overall survival were 6 and 12 months, respectively. Disease progression resulted in 4 deaths within 30 days of treatment. Conclusions: Cladribine was tolerated in pediatrics. No new safety signals were seen with cladribine regimens in this cohort. Response assessment is limited due to the heavily pretreated cohort. Further prospective studies are warranted on the safety and efficacy of cladribine and establish its role in pediatric, adolescent, and early young adult patients with AML.

Breast implant-associated anaplastic large cell lymphoma has been recognized as a distinct entity in the World Health Organization classification of hematolymphoid neoplasms. These neoplasms are causally related to textured implants that were used worldwide until recently. Consequently, there is an increased demand for processing periprosthetic capsules, adding new challenges for surgeons, clinicians, and pathologists. In the literature, the focus has been on breast implant-associated anaplastic large cell lymphoma; however, benign complications related to the placement of breast implants occur in up to 20% to 30% of patients. Imaging studies are helpful in assessing patients with breast implants for evidence of implant rupture, changes in tissues surrounding the implants, or regional lymphadenopathy related to breast implants, but pathologic examination is often required. In this review, we couple our experience with a review of the literature to describe a range of benign lesions associated with breast implants that can be associated with different clinical presentations or pathogenesis and that may require different diagnostic approaches. We illustrate the spectrum of the most common of these benign disorders, highlighting their clinical, imaging, gross, and microscopic features. Finally, we propose a systematic approach for the diagnosis and handling of breast implant specimens in general.

A small subset of high-grade B-cell lymphoma (HGBL) with blastoid morphology remains poorly understood. We assessed 55 cases of blastoid HGBL, not otherwise specified (NOS) and compared their clinicopathologic characteristics with those of 81 non-blastoid HGBL-NOS and 62 blastoid HGBL with MYC and BCL2, with or without BCL6 rearrangements (double/triple-hit lymphoma [D/ THL]). Patients with blastoid HGBL-NOS showed similar clinicopathologic features to patients with blastoid D/THLs and non-blastoid HGBL-NOS, except more frequently with a history of low-grade B -cell lymphoma, bone marrow involvement, and BCL2 rearrangement (P <.05) compared to the latter. MYC rearrangement (MYC-R), detected in 40% of blastoid HGBL-NOS, was associated with aggressive clinicopathologic features and poorer overall survival, even worse than that of blastoid D/THL (P < .05). Transcriptome profiling revealed a distinct gene expression pattern with differentially expressed genes enriched in MYC and P53-targeted genes in MYC-R blastoid HGBL-NOS. Fifty-two percent of blastoid HGBL-NOS had a double hitelike signature, similar to non-blastoid HGBL-NOS (P = .73). The overall survival of the blastoid HGBL-NOS group was similar to that of the blastoid D/THL group but appeared poorer than that of its non-blastoid counterparts (P = .07). Taken together, blastoid HGBL-NOS is an aggressive B-cell lymphoma that shares overlapping clinico-pathologic and genetic features with non-blastoid HGBL-NOS. MYC-R in patients with blastoid HGBL-NOS identifies a highly aggressive subgroup with distinct aggressive clinicopathologic fea-tures, unique molecular signatures, and a dismal clinical outcome.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.