BackgroundFollicular lymphoma (FL) is a common type of non-Hodgkin lymphoma typically characterized by a nodular growth pattern and the t(14;18) translocation. A rare variant, FL with a predominantly diffuse growth pattern (dFL), lacks this translocation, demonstrates diffuse architecture, and is frequently associated with deletion of 1p36.Case presentationWe report the case of a 43-year-old man who presented with an inguinal mass and was diagnosed with follicular lymphoma showing a predominantly diffuse pattern. Fluorescence in situ hybridization (FISH) analysis was negative for both BCL2 rearrangement and TNFRSF14 (1p36) deletion. Chromosomal microarray (CMA) and next-generation sequencing (NGS) were subsequently performed for further molecular characterization.ResultsCMA revealed copy-neutral loss of heterozygosity (cnLOH) at 1p36 and additional abnormalities involving 16p that were not detectable by FISH. NGS identified a TP53 mutation, a finding not previously reported in dFL and typically associated with more aggressive lymphoma behavior. Although dFL is generally considered an indolent and localized disease, the patient developed axillary recurrence within 1 year, requiring radiation therapy. Conclusion: These findings underscore the importance of comprehensive molecular testing, such as NGS and CMA, to refine prognostic assessment and guide personalized treatment strategies for this rare lymphoma variant.

Background: Multiple myeloma (MM) encompasses a broad clinical spectrum from indolent to aggressive disease. Recurrent cytogenetic abnormalities play an important role in biology and prognosis of MM, and accurate detection of those abnormalities defines risk stratification and may guide therapeutic approach. Low proliferative rate of myeloma cells limits utility of conventional karyotyping. Fluorescent in-situ hybridization analysis (FISH) performed on CD138 enriched sample is the current standard for the detection of clinically significant cytogenetic abnormalities, however findings are limited by using a pre-defined set of probes. Cytogenomic microarray (CMA) allows detection of copy number changes and loss of heterozygosity (LOH) (but not balanced translocations) across the entire genome with high resolution, thus potentially allowing to identify novel prognostically significant cytogenetic changes. Aims: To identify cytogenetic abnormalities detected by CMA post-induction that are associated with early post-transplant progression in MM. Methods: We analyzed post-induction bone marrow samples of patients with newly diagnosed MM who underwent autologous SCT at our center. Only patients treated with one line of induction therapy were included. CMA was performed on CD138-enriched samples using ThermoFisher CytoScan HD microarrays for copy number and heterozygosity alterations. Fisher exact test was used to compare frequency of cytogenetic abnormalities between groups. Results: Of 316 pts who met the inclusion criteria, 202 (63.9%) pts were progression free at 18m (late progressors) and 51 pts had progressive disease (PD) before 18 m (early progressors). Patients who were either lost to follow up or started a new line of therapy before 18m without PD were excluded from the analysis. Mean age (62.2y vs 62.7y) and induction regimens (most common RVD in 54.9% vs 54.5%, Dara RVd in 25.5% vs 25.7%, CyBorD in 5.9% vs 7.4%) were very similar between the late and early progressors. Presence of ≥5% plasma cells or presence of abnormal CMA findings in the post-induction bone marrow sample did not differ between the late and early progressors (56.9% vs 47.5%, p 0.273 and 41% vs 37%, p 0.629 respectively). Recurrent abnormalities with frequency cutoff ≥10% in at least one group included 1q+, 8p-, 9+, 13-, 15+, Xq+, and Y-. Comparing the groups of early and late progressors, 8p- was found almost exclusively in early progressors (13.7% vs 0.5%, p 0.0001). Among male patients, Y- was found almost exclusively in early progressors (19.4% vs 2.6%, p 0.003) and was not associated with older age. Other abnormalities significantly more prevalent in early progressors were 13- (21.6% vs 8.4%, p 0.012) and Xq+(11.8% vs 4%, p 0.04). Discussion: Early post-transplant progression in MM patients is associated with inferior survival. While some of those patients have known predictors of inferior PFS at diagnosis, others do not, and fall under the category of functionally high-risk disease. CMA is a sensitive tool that allows detection of chromosomal abnormalities across the entire genome, including ones that are not covered by the standard FISH panels, and therefore may allow detection of additional chromosomal aberrations predictive of high-risk disease. We identified 4 abnormalities that were significantly more prevalent in our cohort of early progressors. One of those, monosomy 13, is a very common abnormality in newly diagnosed MM and is not considered an independent adverse prognostic factor. In our analysis of post-induction marrow samples, detection of monosomy 13 may be associated with early progression by indicating persistence of a resistant clone, or by association with other abnormalities. Strikingly, deletion of 8p was noted almost exclusively in early progressors. It was shown that 8p- may contribute to resistance to bortezomib through loss of TRAIL pathway, but effects of 8p- on transplant outcomes are unknown. Other interesting findings were high incidence of loss of Y in the early progressors, that was independent of age, and gain of Xq, significance of which is unknown. In conclusion, CMA may help to identify novel chromosomal abnormalities associated with high-risk myeloma. Our findings of association of 8p-, Xq+, and Y- with early progression warrant further investigation. Detection of novel predictors of early progression on post-induction assessment may help tailor post-transplant strategies.

KMT2A partial tandem duplication (PTD) is a recurrent genetic alteration in myeloid neoplasms, conferring poor prognosis. KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. There is no universally accepted gold standard for detecting KMT2A-PTDs due to the technical limitations of individual methods and the genomic complexity of PTDs. A retrospective analysis was performed at Fox Chase Cancer Center to compare the utility of chromosomal microarray (CMA; Affymetrix CytoScan HD, 2,696,168 markers) and RNA fusion analysis (Illumina TruSight 523-gene RNA Fusion Panel) in 97 specimens (79 bone marrow, 18 peripheral blood) from 17 patients (12 males, 5 females; median age 68 years) with KMT2A-PTD-positive myeloid neoplasms (11 AML, 4 MDS, 2 MPN), diagnosed between January 2011 and February 2025. A total of 31 specimens were confirmed as KMT2A-PTD-positive by chromosomal microarray (CMA; n = 24) or RNA fusion panel (n = 21). The 73.3% overall concordance (κ = 0.467) between CMA and RNA fusion, with 45.2% KMT2A-PTD-specific concordance, underscores their complementary roles. RNA fusion demonstrated superiority in discordant cases (p = 0.035), reflecting its sensitivity for cryptic PTDs, while CMA identified non-canonical PTDs (e.g., Patient 16) and secondary genomic abnormalities (e.g., trisomy 8, CN-LOH in patient 14 ). The KMT2A-PTD-positive group exhibited greater genomic complexity, with 17 secondary chromosomal abnormality types compared to 6 in the PTD-negative group, reflecting increased clonal heterogeneity. RNA fusion analysis revealed significantly higher median split reads (p = 0.032) and split read-to-coverage (SR/C) ratios (p = 0.046), suggesting elevated KMT2A-PTD transcript expression in CMA KMT2A-PTD(+) patients lacking additional chromosomal abnormalities (vs. CMA KMT2A-PTD(−) patients with abnormalities, p = 0.014-0.020). This may reflect purer PTD clones or fewer competing genomic events. Chromosomal microarray analysis (CMA) identified genomic coverage of KMT2A exons 2-20 (except in patient 16). RNA fusion analysis showed consistent breakpoints between exon 10 and exon 2 (16,200 bp) and between exon 11 and exon 2 (13,720 bp). These disruptions affect critical KMT2A oncogenic domains: CXXC, PHD, and Bromodomain. Targeted 275-gene DNA-sequencing NGS panel analysis (n=60/97 specimens) revealed specific mutational profiles: DNMT3A (51.67%), TET2 (30.00%), ASXL1 (21.67%), RUNX1 (41.67%), GATA2 (15.00%), JAK2 (25.00%), FLT3 (13.33%), NRAS (20.00%), PIK3CA (11.67%), EZH2 (18.33%), and KMT2A (13.33%). RNA fusion analysis revealed significantly higher median split reads and SR/C ratio of KMT2A-PTD in specimens with DNMT3A (p ≈ 0.0423, 0.0387), RUNX1 (p ≈ 0.0198, 0.0234), and FLT3 (p ≈ 0.0087, 0.0123). Similarly, significant correlations with RUNX1T1 gain (p ≈ 0.0345, 0.0412) and cnLOH (p ≈ 0.0214, 0.0178) indicate higher PTD expression with RUNX1T1 gain and lower expression with cnLOH. Kaplan-Meier analysis estimated 41.2% 6-month overall survival (OS). Hematopoietic stem cell transplantation (HSCT) improved outcomes (68.6% vs. 0% OS at 17 months, p = 0.028). Non-transplanted patients (10/17, 8 deceased) had a median survival of 6 months. Abnormal karyotypes and FISH-detected KMT2A gains were associated with high-risk profiles. Concurrent FLT3 mutations correlated with 100% mortality (p=0.0456). CMA and RNA fusion analysis are complementary, with RNA fusion excelling for cryptic PTDs and CMA for genomic alterations. Optimal management of myeloid neoplasms harboring KMT2A-PTD is achieved through the integration of combined testing methodologies, next-generation sequencing, and hematopoietic stem cell transplantation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This retrospective study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The molecular, cytogenetic and clinical data being utilized in the study were collected previously as part of the patient's routine clinical care. No separate specimens were collected for the study. The Institutional Review Board of Fox Chase Cancer Center provided ethical approval for this work. All authors state that the presented material does not include any information, unique characteristics or identifiers that could be used alone or in combination with other information to identify, directly or indirectly, any patients of the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Deidentified raw CMA data (CEL files) and RNA sequencing data supporting the identification of KMT2A-Partial Tandem Duplications, along with a tab-separated values (TSV) file containing breakpoints, read support, and transcript annotations generated using Arriba, are available upon reasonable requests. This data can be obtained by contacting the corresponding author, Reza Nejati (Reza.Nejati{at}fccc.edu), subject to compliance with the Institutional Review Board (IRB) policies of Fox Chase Cancer Center to ensure patient confidentiality and ethical standards.

Background: Diffuse-Large B-cell Lymphoma (DLBCL) is a heterogeneous disease with outcomes influenced by various clinical and molecular predictors. Our aim for this study was to analyze the RNA Expression data and identify gene signatures associated with overall survival (OS), with the potential to uncover prognostic markers and therapeutic targets. Methods: We analyzed publicly available normalized expression data from NCBI-GEO (GSE181063), encompassing 1,311 DLBCL patients. A custom Python pipeline was developed to analyze the expression data. In preprocessing, we used HumanHT 12 v4.0 Gene Expression BeadChip Median expression of genes was calculated (multiple probes for each gene). Clinical data were integrated with expression data for each patient, followed by statistical tests for OS (Pearson, Spearman, and Linear regression). In addition, we performed the Benjamini–Hochberg false discovery rate (FDR-bh) correction for p-values. Further alignment was done between all the genes and the COSMIC (Catalogue Of Somatic Mutations In Cancer) gene database for cancer, followed by a strict criterion of genes altered in cancer and curated by an expert. Overall survival (median, ± standard deviation, minimum, and maximum) was calculated and/or populated into a table for comparison. The genes were ranked using a composite score base (|r| ≥ 0.13 and FDR-bh < 1×10⁻⁴). Results: That dataset included 1,311 patients with a median OS of 5.3±4.0 years (range: <1 to 14.3 years). Based on the criteria mentioned in the methods section, 41 genes were associated with a significant survival OS association; the genes were ranked using a composite score. Most commonly altered pathways included: PI3K-Akt signaling pathway (genes; n=10), Human T-cell leukemia virus 1 Pathway(n=9), MicroRNAs in cancer (n=7), and Ras signaling pathway (n=7). Favorable prognostic markers included CEBPA (r≈+0.18, FDR≈1×10⁻⁸, ρ≈+0.21), IL7R (r≈+0.13, FDR≈5×10⁻⁵, ρ≈+0.16); other positive predictors (below |r| 0.13 but significant FDR-bh < 0.01) included FGFR1/2, FLT4, GATA3, NTRK3 and, NTRK2. The strongest unfavorable markers included MYC (r≈–0.15, FDR≈6×10⁻⁶, ρ≈–0.16), RECQL4 (r≈–0.14, FDR≈3×10⁻⁵, ρ≈–0.16), and TERT (r≈–0.130, FDR≈8.5×10⁻⁵), while other negative Pearson ranked genes (below |r| 0.13 but significant FDR-bh < 0.01), included BRCA1, BRCA2, DICER1, EZH2, FBXW7, RB1, and SPEN. Discussion: As targeted therapies emerge for DLBCL, identifying patients who are non-responders to standard treatments becomes crucial. This exploratory analysis highlights several genes as potential therapeutic targets for patients with DLBCL who fail standard treatments. Our analysis suggests that four genes displaying high expression are associated with poor OS and that protein products encoded by these genes may serve as viable therapeutic targets. They include MYC (BET-bromodomain inhibitors), RECQL4(ATR or WEE1 inhibitors), TERT (telomerase inhibitors), and RB1(CDK4/6 inhibitors). Conclusions: We identified 41 OS-associated genes across key cancer pathways with CEBPA, IL7R, NTRK3, GATA3, NTRK2, FGFR1/2, and FLT4 as the strongest favorable prognostic markers; and MYC, RECQL4, TERT, RB1, FBXW7, SPEN, EZH2, BRCA1, BRCA2, and DICER1 as the strongest negative predictors. Targeting these genes may benefit patients who do not respond to standard treatment.While the identification of these potential targets is promising, further validation studies are essential to confirm and strengthen these findings.

The WHO and ICC classifications lack standardized terminology to define the disease phase of chronic myeloproliferative neoplasms in extramedullary sites, particularly lymph nodes, when infiltrates resemble extramedullary hematopoiesis (EH). We report a lymph node case of extramedullary chronic myelomonocytic leukemia (CMML) in blast phase mimicking EH. Comprehensive genomic profiling, using chromosomal microarray and NGS-based sequencing, identified copy neutral loss of heterozygosity (cn-LOH), previously unreported in extramedullary CMML. We discuss challenges in determining the CMML disease phase in lymph nodes and review the literature to underscore the need for consensus terminology for cases not meeting myeloid sarcoma criteria.

Inflammatory myofibroblastic tumors (IMT) are exceedingly rare, particularly when originating in the bladder. Complete surgical resection is the gold standard treatment for IMTs. We describe a case of IMT of the urinary bladder that achieved complete radiographic and endoscopic resolution after systemic treatment with ipilimumab and nivolumab directed towards metastatic melanoma. This case is noteworthy due to the tumor's serendipitous and remarkable response to immunotherapy.

Background: Diffuse-large B-cell lymphoma (DLBCL) is a heterogeneous disease with outcomes influenced by various clinical and molecular predictors. Our aim for this study was to develop a machine learning based prediction of overall survival using clinical, laboratory, and gene expression data. Methods: We previously analyzed publicly available normalized expression data from NCBI-GEO (GSE181063), encompassing 1,311 DLBCL patients; where we extracted 41 genes that were associated with overall survival using statistical modeling. Here we developed a binary gene matrix that was generated from median expression of all the study population and anything with higher than median expression was considered (high expression) for the differential gene expression of 41 genes and clinical (Age, Gender, first line of treatment, curative intent, ECOG, B symptoms, Stage and IPI score), Imaging (number of lymph nodes), and lab data (LDH, CBC findings) was added to it. Outcomes included time-points (>6 months, >1, >3, >5 and >10 year(s)) and were binarized (alive = 1 and dead = 0). SMOTE (Synthetic Minority Over-sampling Technique) was used because of the imbalanced nature of biological and clinical data. Nine different machine learning models (MLMs) were developed, and the best MLMs were ranked and presented here. MLMs included: RandomForest (RF), Gradient Boosting (GB), XGBoost (XGB), AdaBoost (AB), Logistic Regression (LR), Naïve Bayes (NB), Multi-Layer Perceptron (MLP), Support Vector Machines (SVM), and k-Nearest Neighbors (KNN). The performance of these models was evaluated using true positives (TP), true negatives (TN), false positives (FP), false negative (FN), overall accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), F1-score, and area under the receiver-operator curve (AUROC). Results: That dataset included 1,311 patients with a median OS of 5.3±4.0 years (range: <1 to 14.3 years). Based on the criteria mentioned in the methods section, 41 genes were associated with a significant survival OS association, and clinical factors were included, such as the age of the patient, gender, and others. The best performing modes for each endpoint were as follows: OS >6 months, RF accuracy (87.8%), sensitivity (96.2%), specificity (53.8%), PPV (89.4%), NPV (77.8%), F1-score (0.92), AUROC (0.89). OS >1 year, AB accuracy (79.8%), sensitivity (87.8%), specificity (58.9%), PPV (84.7%), NPV (65.2%), F1-score (0.86), AUROC (0.86). OS >3 years, RF accuracy (79.0%), sensitivity (90.7%), specificity (59.6%), PPV (78.7%), NPV (79.7%), F1-score (0.84), AUROC (0.86). OS >5 years, RF accuracy (78.6%), sensitivity (81.7%), specificity (53.8%), PPV (78.2%), NPV (79.2%), F1-score (0.80), AUROC (0.84). OS >10 years, NB, accuracy (62.6%), sensitivity (78.8%), specificity (60.3%), PPV (22.3%), NPV (95.2%), F1-score (0.35), AUROC (0.76). Discussion: These findings suggest that clinical and gene expression data can be used to predict survival in DLBCL. For each endpoint, a better machine learning algorithm can be developed; however, excessive fine-tuning of the algorithms can lead to over-fitting and can fail external validation. In the current analysis, we did not fine tune any of the algorithms. A deeper analysis all models does show promise in each time point in terms of and each evaluation metric (TP, TN, FP, FN, overall accuracy, sensitivity, specificity, PPV, NPV, F1-score, AUROC). Conclusions: While these machine learning models show promise, further validation studies are essential to developing a robust prediction tool.

BackgroundMultiple Myeloma (MM) is a plasma cell neoplasm encompassing a broad clinical spectrum from more indolent to very aggressive, and characterized by heterogeneous genetic makeup.Certain chromosomal abnormalities are noted to be recurrent in MM and confer prognostic and therapeutic significance. Standard risk stratification models such as R-ISS and mSMART include some of those recurrent abnormalities.CIBMTR forms currently track cytogenetic abnormalities identified at the time of initial diagnosis by conventional karyotyping and FISH only. According to CIBMTR requirements abnormalities identified by any other techniques cannot be reported.Beginning 2015 our program implemented routine testing of all plasma cell disorder(PCD) cases by Chromosome Microarray Analysis (CMA) in addition to conventional karyotyping and FISH testing.CMA is a powerful analytic tool for assessment of chromosomal abnormalities. It evaluates the entire genome with high resolution independently of mitotic activity, unlike conventional G-band karyotyping, which is highly important for PCD due to low proliferative index. In addition to detection of copy number changes it allows detection of copy neutral loss of heterozygosity (cnLOH) that cannot be detected by conventional karyotyping or FISH. CMA cannot detect balanced translocations, therefore, it complements but does not substitute FISH, that is required to detect balanced translocations in myeloma cells.MethodsWe analyzed pathology report of 130 newly diagnosed patients with plasma cells neoplasm, including 82 cases of symptomatic MM and compared results of karyotyping, FISH and CMA tests focusing on identification of high risk abnormalities as defined by mSMART and R-ISS classification.ResultsUsing combination of FISH, karyotyping and CMA we identified significantly higher number of cases with high-risk abnormalities compared to combination of FISH and karyotyping only (Table 1). That indicates that a number of patients with high risk abnormalities were not reported as such to CIBMTR.SummaryOur findings suggest that CMA might detect a greater number of patient with high risk cytogenetic abnormalities compared to current reporting standard. Current practice of CIBMTR not accepting CMA results for reporting of cytogenetic abnormalities could skew the perceived risk profile of transplanted patients with multiple myeloma. This discrepancy may underscore the need to reconsider current data acceptance standards to ensure a comprehensive understanding of myeloma patients profile.

Molecular profiling of lung tumors is crucial for guiding targeted therapeutic strategies and identifying potential resistance mechanisms to specific therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). During this profiling, mutations with uncertain treatment implications can be identified. This case study represents a 69-year-old female with a co-occurring EGFR mutation profile that presents a unique therapeutic challenge. Tumor DNA was used for next-generation sequencing (NGS) of a custom 275 cancer-related QIAseq Human Comprehensive Cancer Panel (Qiagen). Next-generation RNA sequencing was performed using the Illumina TruSight panel. FISH analysis and PD-L1 22C3 immunohistochemical testing were also performed. Microscopic analysis revealed an invasive adenocarcinoma with papillary, acinar, and focal micropapillary features with a 6 mm invasive component. The final pathology stage was determined to be pT1aN0M0. NGS for DNA variant detection identified two mutations in EGFR, an EGFR G719A and EGFR L833_V834delinsFL with a variant allele frequency (VAF) of 22.2% and 21.1%, respectively. Targeted NGS RNA fusion analysis was also performed, which came back negative. PD-L1 22C3 immunohistochemical testing showed only 1% of the tumor cells expression. FISH analysis revealed one copy of MET and D7Z1 in 27% of cells, indicating an aneuploid neoplastic clone with monosomy 7. EGFR TKIs are universally accepted as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation. While mutations such as G719A are sensitive to all generations of EGFR-TKI, the effects are unknown for rare compound mutations in EGFR, such as EGFR L833_V834delinsFL. There are no reports in the literature with any mention of an algorithm of treatment for such a case. The patient had two metachronous lung primary cancers resected in 2022 and 2024. Due to the complete surgical resection, the sensitivity of this mutation of TKIs could not be established. This unique mutation profile still remains of paramount importance to understand if the patient relapses or presents with a new tumor with the same genetic profile.

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.

Metachronous oligometastatic clear cell renal cell carcinoma may take many years before becoming clinically apparent. Herein we report regional lymph node recurrence of clear cell renal cell carcinoma more than two decades following radical nephrectomy. Chromosomal microarray analysis demonstrated multiple chromosomal alterations, including 3pq deletion shared by the original and recurrent tumors, and 17p deletion containing the TP53 gene present only in the latter. Sequencing of 1550 genes revealed mutations of VHL in both the primary and metastasis and BAP1 only in the metastatic lesion. These findings genetically link the original and recurrent tumors and suggest that VHL, TP53, and BAP1 alterations played an evolutionary role in recurrence decades after initial resection.

Abstract Introduction/Objective Among the already described variants of nodal follicular lymphoma (FL), there is a variant with diffuse growth pattern with a predilection to involve the inguinal lymph nodes and peculiar immunohistochemical and molecular characteristics. The diffuse growth pattern is manifested by the complete absence of follicles without a follicular/dendritic meshwork (negative CD21 and CD23). This variant was first described by Katzenberger in 2009. It is distinguished from other variants by CD23 expression, lack of t(14;18)/ IGH::BCL2 rearrangement, and chromosome segment 1p36 deletion or TNFRSF14 mutations. Methods/Case Report A 43-year-old Caucasian male presented with a lump in his left groin, noted by him after exercising and sought surgical opinion to rule out inguinal hernia. CT- scan of abdomen and pelvis showed a well circumscribed 4.3 cm lymph node in the left groin region. Histological analysis of the lesion depicted a lymph node with a predominantly diffuse and focally vaguely nodular proliferation effacing the architecture. Numerous centrocytes admixed with occasional centroblasts averaging <15/HPF. The neoplastic cells are positive for CD20, PAX5, CD10, BCL6, CD23 and BCL2, and are negative for CD5 and cyclin D1. The CD21 highlights few residual germinal centers at the periphery of the lymph node. The proliferative (Ki67+) index is approximately 30-40%. Flow cytometry demonstrates CD10 positive, kappa monoclonal B cell population (20% of total). FISH analysis was negative for both IgH/BCL2 t(14;18) rearrangement and TNFRSF14 (1p36) Deletion. However, cytogenomic microarray analysis (CMA) revealed genomic imbalances and copy neutral Loss of Heterozygosity over 1p36 in a mosaic state representing about 40% of the cells, which notably encompasses PRKC2, SKI, TNFRSF14, PRDM16, TP73 and PRL22 genes. The findings are consistent with a final diagnosis of diffuse follicular lymphoma variant, WHO grade 1-2 of 3. Results (if a Case Study enter NA) N/A Conclusion The copy neutral Loss of Heterozygosity of 1p36 region which contains TNFRSF14 gene was detected by CMA only. Undoubtedly, CMA results can play a pivotal role in identifying copy neutral Loss of Heterozygosity or small regions deletions or gains that can be missed by conventional cytogenetics and FISH studies and subsequently establishing diagnosis and prognostic stratification of hematologic neoplasms.

Background: Multiple myeloma (MM) is a plasma cell neoplasm clinically ranging from indolent to aggressive, and characterized by heterogeneous genetic makeup. Cytogenetic abnormalities play important role in myeloma tumorigenicity, and some recurrent abnormalities are known to have prognostic significance. Low proliferative rate of plasma cells limits the yield of conventional cytogenetics. Fluorescent in situ hybridization (FISH) performed on CD138 enriched sample is current standard for detection of clinically significant cytogenetic abnormalities, however it is limited by use of specific set of probes. Chromosome microarray analysis (CMA) allows detection of copy number changes and copy neutral loss of heterozygosity (cnLOH) across the entire genome with high resolution. Importantly, CMA does not detect balanced translocations, and therefore can supplement, but not replace FISH in MM. We previously reported landscape of CMA detected abnormalities and MRD detection by CMA in post-induction/ pre-transplant bone marrow samples. Here, we characterize cytogenetic abnormalities in patients with untreated symptomatic and smoldering MM using CMA. Methods: We analyzed 78 samples of patients with newly diagnosed, untreated active MM and 22 samples of patients with smoldering MM (sMM), who presented to our program in 2015-2021. CMA was performed on CD138-enriched material using ThermoFisher CytoScan HD microarrays for copy number and heterozygosity alterations. Results: 70 of 78 (89.7%)patients with active MM and 17 of 22 (77.3%) patients with sMM had CMA detected abnormalities. Abnormal findings detected by CMA included copy number changes (additions/ deletions), cnLOH and chromothripsis (CT). Total of 667 abnormalities were detected in 78 active MM samples (including 33 occurrences of cnLOH and 44 CT) and 72 abnormalities in 22 sMM samples (including 3 cnLOH). 53 types of recurrent abnormalities with frequency above 5% of samples were detected in active MM samples and 15 types in sMM samples (Figure 1, panel A: active MM, panel B: sMM). In the samples with active MM, in addition to the commonly tested MM abnormalities (trisomies of odd chromosomes, 1q+, 1p-, 13q-/13-, 17p-), we identified a number of less known recurrent abnormalities, among which 6q-, 6+, 8p-, 11q+, 12p-, 14q-, 16q-, 19p+, Xq+, X- were observed in above 10% samples. Conclusions: Our results demonstrate that CMA is a sensitive technique allowing to identify recurrent cytogenetic abnormalities (excluding balanced translocations) in multiple myeloma that cannot be detected by conventional karyotyping or standard FISH panels. In addition to copy number changes, we also detected multiple occurrences of cnLOH, that may promote tumorigenicity by gene inactivation, and chromothripsis, involving complex genomic abnormalities. Further investigation is required to determine clinical correlation and prognostic significance of those abnormalities. Lastly, our results demonstrate increased cytogenetic complexity of active MM compared to smoldering MM.

Granulomatous inflammation has been reported to be associated with Hodgkin and non-Hodgkin lymphomas. Here, we report a case of recurrent diffuse large B-cell lymphoma (DLBCL) with extensive granulomatous inflammation that was initially misdiagnosed as granulomatous lymphadenitis. In 2019, a 75-year-old Caucasian male presented to our hospital with an enlarged right supraclavicular lymph node. He had a medical history of prostate cancer (in 2004), DLBCL (initially diagnosed in 2009), and rectal adenocarcinoma (in 2017), all of which responded well to treatment. In 2018, the patient had experienced right axillary adenopathy, weight loss, and intermittent night sweats. An excisional biopsy of a right axillary lymph node, performed at another institution, was diagnosed as granulomatous lymphadenitis. In 2019, at our hospital, an excisional biopsy of a right supraclavicular lymph node showed DLBCL in a background of granulomatous inflammation. A review of the prior right axillary lymph node biopsy also showed DLBCL with a background of extensive granulomatous inflammation. Chemotherapy was initiated and the patient's follow-up showed a good response. We report this case to raise awareness that granulomatous inflammation may obscure the diagnosis of some neoplasms, such as DLBCL, which are less commonly known to have granulomatous inflammation. This may result in delayed treatment and may ultimately affect outcomes.

Background: Adenosquamous carcinoma (ASC) of the pancreas is a rare form of malignancy with a poor prognosis. We herein report our case series with review of the contemporary literature. Methods: With institutional review board approval, we identified 23 patients with pancreatic ASC. Results: ASC was more common in women (61%), with a median age of 73 y at presentation. The tumor was in the head of the pancreas in 65% of cases. Six cases (26%) had resectable disease, three (13%) were borderline resectable, and eight (34.7%) were locally advanced or metastatic. First-line treatment included pancreatic resection in eight cases (34.8%), concurrent neoadjuvant chemoradiation in three (13%), and neoadjuvant chemotherapy in two (8.7%). Most resected tumors had pathological T3 stage (80%). Pathological nodal disease was demonstrated in 60%, and margins were positive in three cases. Complete pathological response was not observed, although fibrosis presented in only one case (10%). Eventually, twenty patients developed metastatic disease. Overall survival is 11.5 [95% confidence interval 6, 14.5] months. Conclusions: ASC demonstrates a more aggressive malignant phenotype and carries a worse prognosis. Oncological resection is the mainstay of treatment. Neoadjuvant chemoradiation is an emerging approach in the management of ASC that has been extrapolated from the adenocarcinoma neoadjuvant trials. (C) 2020 Elsevier Inc. All rights reserved.

Acute myeloid leukemia (AML) is defined by the presence of ≥ 20% myeloblasts in the blood or bone marrow. Spontaneous remission (SR) of AML is a rare event, with few cases described in the literature. SR is generally associated with recovery from an infectious or immunologic process, and more recently possibly with clonal hematopoiesis. We review the literature and assess the trends associated with SR, and report a new case of a 58-year-old man with a morphologic diagnosis of AML associated with a severe gastrointestinal (GI) tract infection. The patient had an NF1 variant that was previously unreported in AML as the only clonal abnormality.  After treatment of the infection, the increased blast population subsided with no leukemia-directed therapy, and the patient has remained in a continuous, spontaneous complete remission for > 2 years.