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Abstract Nucleophosmin 1 (NPM1) mutations occur in approximately one‐third cases of adult de novo acute myeloid leukemia (AML). Identification of NPM1 mutations is important for classification, risk stratification, tailored therapy, and monitoring minimal residual disease. Mutational analysis is widely used for detecting NPM1 mutations. Immunochemistry assessing abnormal cytoplasmic localization of NPM1 protein has been used as a surrogate marker for NPM1 mutations. We present a case of AML with mutated NPM1 that was missed by sequencing analysis but detected by immunohistochemistry. This case highlights the value of immunohistochemistry in identifying NPM1 mutations in a subset of AML cases.

Not available.

Abstract Acute leukemia with KMT2A rearrangement shows a spectrum of immunophenotypic presentation, but blastic plasmacytoid dendritic cell differentiation is extremely rare. Here we present a case of KMT2A rearranged acute leukemia with a hybrid immunophenotype in which a single blast population showed both blastic plasmacytoid dendritic cell and monocytic differentiation. This unusual case contributes to the diversity of the immunophenotypic spectrum in KMT2A rearranged acute leukemia and also sheds light on the cell of origin of plasmacytoid dendritic cells.

Abstract BACKGROUND Mutations in the RAS‐MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high‐risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results. METHODS We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF‐mutated myeloma, and compare with 79 patients without any mutations. RESULTS We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF‐mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R‐ISS stage. RAS/BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression‐free survival were significantly shorter for RAS/BRAF‐mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R‐ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome. CONCLUSIONS RAS/BRAF mutations occur in 30%–40% of myeloma cases and are associated with higher tumor burden, higher R‐ISS stage, complex karyotype, and shorter overall survival and progression‐free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.

Abstract A wide variety of primary and secondary lymphoma types involves the skin. However, reports with comparisons between both groups are limited in Taiwan. We retrospectively enrolled all cutaneous lymphomas and evaluated their clinicopathologic features. There were 221 cases of lymphoma: 182 (82.3%) primary and 39 (17.7%) secondary. Mycosis fungoides was the most common primary T‐cell lymphoma, 92 (41.7%) cases, followed by CD30‐positive T‐cell lymphoproliferative disorders including lymphomatoid papulosis (n = 33, 14.9%) and cutaneous anaplastic large cell lymphoma (n = 12, 5.4%). The most frequent primary B‐cell lymphomas were marginal zone lymphoma (n = 8, 3.6%) and diffuse large B‐cell lymphoma (DLBCL), leg type (n = 8, 3.6%). DLBCL including variants was the most common secondary lymphoma involving skin. Most primary lymphomas presented at low‐stage (T‐cell, 86%; B‐cell, 75%), whereas the majority of secondary lymphomas presented at high‐stage (T‐cell, 94%; B‐cell, 100%). Patients with secondary lymphomas had an older mean age, more frequent B symptoms, lower serum albumin and hemoglobin, and a higher frequency of atypical lymphocytes in blood than those with primary lymphomas. In primary lymphomas, older age, lymphoma types, decreased lymphocyte counts and atypical lymphocytes in blood were poorer prognostic factors. In secondary lymphoma patients, lymphoma types, high serum lactate dehydrogenase and low hemoglobin levels predicted poorer survival. We found that the distribution of primary cutaneous lymphomas in Taiwan mirrors that of other Asian countries but shows some differences as compared with Western countries. Primary cutaneous lymphomas have a better prognosis than secondary lymphomas. Histologic classification of lymphomas highly correlated with disease presentation and prognosis.

STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low,

Abstract This report highlights the value of flow cytometry analysis, particularly in the setting of myeloproliferative neoplasms showing features of progression, as neoplastic plasmacytoid dendritic cell (PDC) proliferations may be present, representing either a clonal expansion of mature PDCs related to the underlying myeloproliferative neoplasm or transformation to blastic plasmacytoid dendritic cell neoplasm (BPDCN). BPDCN should always be considered in patients with myeloid neoplasms in progression and/or who develop new cutaneous findings, as it may prompt change of management.

Somatic copy number alterations (SCNAs) are frequently observed in high-grade ovarian serous carcinoma (HGOSC). However, their impact on gene expression levels has not been systematically assessed. In this study, we explored the relationship between recurrent SCNA and gene expression using The Cancer Genome Atlas Pan Cancer dataset (OSC, TCGA, PanCancer Atlas) to identify cancer-related genes in HGOSC. We then investigated any association between highly correlated cancer genes and clinicopathological parameters, including age of diagnosis, disease stage, overall survival (OS), and progression-free survival (PFS). A total of 772 genes with recurrent SCNAs were observed. SCNA and mRNA expression levels were highly correlated for 274 genes; 24 genes were classified as a Tier 1 gene in the Cancer Gene Census in the Catalogue of Somatic Mutations in Cancer (CGC-COSMIC). Of these, 11 Tier 1 genes had highly correlated SCNA and mRNA expression levels: TBL1XR1, PIK3CA, UBR5, EIF3E, RAD21, EXT1, RECQL4, KRAS, PRKACA, BRD4, and TPM4. There was no association between gene amplification and disease stage or PFS. EIF3E, RAD21, and EXT1 were more frequently amplified in younger patients, specifically those under the age of 55 years. Patients with tumors carrying PRKACA, BRD4, or TPM4 amplification were associated with a significantly shorter OS. RECQL4 amplification was more frequent in younger patients, and tumors with this amplification were associated with a significantly better OS.

NPM1 mutation, as a founding genetic event, cooperates with other gene mutations, such as DNMT3A and FLT3, to promote the development of acute myeloid leukemia. NPM1 mutation, however, has been reported to be mutually exclusive with RUNX1 mutation in acute myeloid leukemia cases. In this study, we analyzed mutation panel testing data from a relatively large cohort of rare AML cases with both NPM1 and RUNX1 mutations. We describe the dynamic process of the emergence of these mutations, as well as molecular genetic features and clinical outcome of these patients. We show that concurrence of both mutations in acute myeloid leukemia is associated with adverse prognostic factors, such as concurrent karyotypic abnormalities and FLT3 internal tandem duplication mutation, and poorer overall survival.

DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.

Abstract Introduction Earlier studies have shown that lymphomatous effusions in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a very poor prognosis, even worse than for non-effusion-associated patients with stage IV disease. We hypothesized that certain genetic abnormalities were associated with lymphomatous effusions, which would help to identify related pathways, oncogenic mechanisms, and therapeutic targets. Methods We compared whole-exome sequencing on DLBCL samples involving solid organs (n = 22) and involving effusions (n = 9). We designed a mutational accumulation-based approach to score each gene and used mutation interpreters to identify candidate pathogenic genes associated with lymphomatous effusions. Moreover, we performed gene-set enrichment analysis from a microarray comparison of effusion-associated versus non-effusion-associated DLBCL cases to extract the related pathways. Results We found that genes involved in identified pathways or with high accumulation scores in the effusion-based DLBCL cases were associated with migration/invasion. We validated expression of 8 selected genes in DLBCL cell lines and clinical samples: MUC4, SLC35G6, TP53BP2, ARAP3, IL13RA1, PDIA4, HDAC1 and MDM2, and validated expression of 3 proteins (MUC4, HDAC1 and MDM2) in an independent cohort of DLBCL cases with (n = 31) and without (n = 20) lymphomatous effusions. We found that overexpression of HDAC1 and MDM2 correlated with the presence of lymphomatous effusions, and HDAC1 overexpression was associated with the poorest prognosis. Conclusion Our findings suggest that DLBCL associated with lymphomatous effusions may be associated mechanistically with TP53-MDM2 pathway and HDAC-related chromatin remodeling mechanisms.

Abstract Diffuse large B-cell lymphoma (DLBCL) may present initially in bone marrow, liver and spleen without any lymphadenopathy (referred to as BLS-type DLBCL), which is aggressive and frequently associated with hemophagocytic syndrome. Its tumorigenesis and molecular mechanisms warrant clarification. By gene microarray profiling with bioinformatics analysis, we found higher expression of the stem cell markers HOXA9 and NANOG, as well as BMP8B, CCR6 and S100A8 in BLS-type than conventional DLBCL. We further validated expression of these markers in a large cohort of DLBCL including BLS-type cases and found that expression of HOXA9 and NANOG correlated with inferior outcome and poor prognostic parameters. Functional studies with gene-overexpressed and gene-silenced DLBCL cell lines showed that expression of NANOG and HOXA9 promoted cell viability and inhibited apoptosis through suppression of G2 arrest in vitro and enhanced tumor formation and hepatosplenic infiltration in a tail-vein-injected mouse model. Additionally, HOXA9-transfected tumor cells showed significantly increased soft-agar clonogenic ability and tumor sphere formation. Interestingly, B cells with higher CCR6 expression revealed a higher chemotactic migration for CCL20. Taken together, our findings support the concept that tumor or precursor cells of BLS-type DLBCL are attracted by chemotaxis and home to the bone marrow, where the microenvironment promotes the expression of stem cell characteristics and aggressiveness of tumor cells.

Abstract Adult T‐cell acute lymphoblastic leukemia (T‐ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)‐negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low‐ vs high‐risk groups in adult T‐ALL patients treated using the Berlin‐Frankfurt‐Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T‐ALL who were uniformly treated with hyper‐CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P = .84) and relapse‐free survival (RFS; P = .18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high‐risk factors and showed that mutations in these genes predicted poorer OS (P = .03) and RFS (P = .04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T‐ALL.

Abstract Background Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification. Methods Mutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma. Results The proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival. Conclusions The mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the patients. PHF6 mutations occurred either concurrently with SF3B1 mutations or in subsequent follow-up samples and are associated with disease progression and impending death in most cases. Most cases had co-mutations, the most common being ASXL1, RUNX1, TET2, and NRAS. With a median follow-up of 39 months (range, 3-155), 17 (81%) patients died, 3 were in complete remission, and 1 had persistent myelodysplastic syndrome. The median overall survival was 51 months. In summary, concurrent mutations in SF3B1 and PHF6 are rare, but they do exist in a variety of myeloid neoplasms, with roles as early initiating events and in disease progression, respectively.

Abstract Hyperdiploidy (chromosomal number 51‐65) is a common cytogenetic abnormality in pediatric patients with B‐lymphoblastic leukemia (B‐ALL) and belongs to the favorable cytogenetic subgroup. Hyperdiploidy in adult B‐ALL is much less common and its clinical significance has not been well studied. Among the 1205 patients with B‐ALL (1018 adults and 187 children) from our institution, 78 had a hyperdiploid karyotype, including 45 (4.4%) adults and 33 (17.6%) children (P

The programmed death-ligands, PD-L1 and PD-L2, reside on tumor cells and can bind with programmed death-1 protein (PD-1) on T-cells, resulting in tumor immune escape. PD-1 ligands are highly expressed in some CD30+ large cell lymphomas, including classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma (PMBL), Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL), and anaplastic large cell lymphoma (ALCL). The genetic alteration of the chromosome 9p24.1 locus, the location of PD-L1, PD-L2, and JAK2 are the main mechanisms leading to PD-L1 and PD-L2 overexpression and are frequently observed in these CD30+ large cell lymphomas. The JAK/STAT pathway is also commonly constitutively activated in these lymphomas, further contributing to the upregulated expression of PD-L1 and PD-L2. Other mechanisms underlying the overexpression of PD-L1 and PD-L2 in some cases include EBV infection and the activation of the mitogen-activated protein kinase (MAPK) pathway. These cellular and molecular mechanisms provide a scientific rationale for PD-1/PD-L1 blockade in treating patients with relapsed/refractory (R/R) disease and, possibly, in newly diagnosed patients. Given the high efficacy of PD-1 inhibitors in patients with R/R CHL and PMBL, these agents have become a standard treatment in these patient subgroups. Preliminary studies of PD-1 inhibitors in patients with R/R EBV+ DLBCL and R/R ALCL have also shown promising results. Future directions for these patients will likely include PD-1/PD-L1 blockade in combination with other therapeutic agents, such as brentuximab or traditional chemotherapy regimens.

We describe a novel pathology finding in a 40-year-old woman without a history of breast carcinoma who presented with axillary swelling. The patient underwent core needle biopsy followed by axillary dissection 6 months later. The core biopsy of the axillary mass was initially considered to be a carcinoma of unknown primary, and as the biopsy specimen showed a pleomorphic malignant neoplasm that was GATA3 positive, the working diagnosis became metastatic breast carcinoma. The patient underwent an axillary dissection and was referred to our center for continuation of care. In addition to being positive for GATA3, the neoplasm was positive for CD21, CD23 and CD35, and negative for keratins, EMA, mammaglobin GCDFP-15, CD138, S-100 protein and other markers. The diagnosis of follicular dendritic cell sarcoma was established. We believe it is important to be aware that follicular dendritic cell sarcoma can be positive for GATA3, to avoid misdiagnosis as a metastatic neoplasm and an exhaustive workup for a primary site.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic neoplasm whose immunophenotype remains incompletely characterized, particularly in terms of distinction from reactive plasmacytoid dendritic cells (PDCs). This limitation complicates detection of low-level involvement by BPDCN as well as minimal residual disease (MRD) assessment following therapy. We conducted the current study to characterize the immunophenotype of BPDCN in a cohort of 39 patients, and compared it to reactive PDCs. We found that, in addition to CD56 expression (97%), BPDCN showed a number of aberrancies, including decreased/negative CD38 (82%), positive CD7 (64%), negative CD2 (81%), negative CD303 (56%), increased HLA-DR (69%) and decreased CD123 (78%). Although BPDCN cells were characterized by CD56 expression, reactive PDCs consistently included a CD56-positive subset, ranging 1.3%-20% (median 4.5%) of total PDCs, challenging MRD detection. These CD56+ reactive PDCs, however, were consistently positive for CD2 and CD303, brightly positive for CD38, and negative for CD7, distinctively different from BPDCN. Based on these findings, we set up a 10-color flow cytometry assay for BPDCN and validated it to a sensitivity of 0.01%. This panel was prospectively tested in 19 bone marrow samples from 7 BPDCN patients, and it effectively distinguished BPDCN cells from background reactive PDCs in all cases. In summary, by understanding the immunophenotype of reactive and neoplastic PDCs, BPDCN can be effectively detected by flow cytometry to a very low level using a panel of markers in addition to CD56, and such assay can be used for initial bone marrow workup as well as MRD detection after therapy.

Mantle cell lymphoma (MCL) with MYC rearrangement (MYC-R) is rare and little is known about the importance of MYC extra copies (EC) in the absence of MYC-R in MCL patients. This study includes 88 MCL patients with MYC tested by fluorescence in situ hybridization and/or conventional cytogenetics, including 27 with MYC-R, 21 with MYC-EC, and 40 with normal (NL) MYC. MCL patients with MYC-R more often had blastoid/pleomorphic morphology; a higher frequency of CD10, MYC, and simultaneous MYC and BCL2 expression; a higher level of MYC; and a higher Ki67 proliferation rate (p

Background: For patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL), whole-brain radiation therapy (WBRT) to doses of ≥45 Gy are often given after a partial response (PR) to methotrexate-based induction chemotherapy. We conducted an exploratory analysis to determine whether lower-dose WBRT, given with a boost to sites of persistent disease, might be a reasonable alternative. Methods and materials: We retrospectively reviewed the records of 22 patients with PCNSL who received WBRT, with or without a boost, after methotrexate-based induction chemotherapy. Outcomes were compared among patients according to response to chemotherapy using the Kaplan-Meier method. Results: Median follow-up was 52 months. All patients with a complete response (CR) (n = 5) received WBRT to 23.4 Gy. One CR patient died after an in-field relapse. Patients with partial response (PR) (n = 10) received a median whole-brain dose of 23.4 Gy with (n = 8) or without (n = 2) a boost; there were 2 relapses within the central nervous system (CNS). All PR patients were alive at the time of analysis. The overall survival (P = .127) and freedom from relapse within the CNS (P = .967) were not different for patients with CR versus PR. Baseline and follow-up neurocognitive evaluations were available for 4 PR patients, and there were no significant differences between pre- and post-treatment evaluations (P > .05 for language, memory, visual-spatial, attention, or motor functions). All patients who progressed or did not respond to chemotherapy and then received WBRT had died at a median time of 3.4 months. Patients who progressed or did not respond to chemotherapy had worse overall survival (P = .001) and freedom from CNS relapse (P = .005) compared with CR patients. Conclusions: Among patients with a PR to induction chemotherapy, reduced-dose WBRT with a boost to residual PCNSL may be a viable treatment approach that merits further investigation.

Abstract: The 2017 revision of the World Health Organization (WHO) classification includes substantial changes to the subclassification of chronic myelomonocytic leukemia (CMML): (1) a 3-tiered blast-based scheme including a novel “CMML-0” category replacing a 2-tiered system in place since 2001 and (2) 2 CMML subtypes, myelodysplastic (MDS-CMML) and myeloproliferative (MP-CMML), based on a white blood cell count cutoff of 13 × 109/L. The clinical utility of this subclassification scheme, particularly the expansion of blast-based subgroups, has not been validated. In this study, a large single-institution CMML patient cohort (n = 629) was used to assess the prognostic impact of the newly proposed categories. Patients were risk stratified according to the CMML-specific Prognostic Scoring System (CPSS) and the MD Anderson Prognostic Scoring System. MP-CMML patients had significantly shorter overall survival (OS; P < .0001; hazard ratio: 0.53, 95% confidence interval: 0.42-0.65) and median duration to acute myeloid leukemia (AML) transformation (P < .0001; 15.2 vs 22.0 months) compared with MDS-CMML patients. The CMML-0 group included 36.4% patients with higher risk CPSS categories and 11.2% of patients with high-risk cytogenetics. Among treatment-naïve patients (n = 499), there was a marginal difference in OS between the CMML-0 and CMML-12017 subgroups (P = .0552). The WHO 2017 blast-based categories were not associated with AML-free survival. Incorporation of the WHO 2017 blast-based subgroups in a modified CPSS scheme had a neutral effect and did not improve its prognostic strength. Our data support the inclusion of MP-CMML and MDS-CMML subtypes in the WHO 2017 revision. Although of some utility in MP-CMML, the 3-tiered blast-based system is not well supported in this study.

Abstract: Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [18F]fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning–derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance (P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis (P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression.

PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell–like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation.

Abstract: The high fatality of patients with blast phase (BP) chronic myeloid leukemia (CML) necessitates identification of high-risk (HR) patients to prevent onset of BP. Here, we investigated the risk of BP based on additional chromosomal abnormality (ACA) profiles in a cohort of 2326 CML patients treated with tyrosine kinase inhibitors (TKIs). We examined the time intervals from initial diagnosis to ACA emergence (interval 1), from ACA emergence to onset of BP (interval 2), and survival after onset of BP (interval 3). Based on BP risk associated with each ACA, patients were stratified into intermediate-1, intermediate-2, and HR groups, with a median duration of interval 2 of unreached, 19.2 months, and 1.9 months, respectively. There was no difference in durations of intervals 1 or 3 among 3 groups. Including patients without ACAs who formed the standard-risk group, the overall 5-year cumulative probability of BP was 9.8%, 28.0%, 41.7%, and 67.4% for these 4 groups, respectively. The pre-BP disease course in those who developed BP was similar regardless of cytogenetic alterations, and 84.4% of BP patients developed BP within the first 5 years of diagnosis. In summary, interval 2 is the predominant determinant of BP risk and patient outcome. By prolonging the duration of interval 2, TKI therapy mitigates BP risk associated with low-risk ACAs or no ACAs but does not alter the natural course of CML with HR ACAs. Thus, we have identified a group of patients who have HR of BP and may benefit from timely alternative treatment to prevent onset of BP.

Posttransplant lymphoproliferative disorder (PTLD) is a rare and life-threatening complication of both solid organ transplantation and hematopoietic stem cell transplantation. In most cases, PTLD develops in Epstein–Barr virus (EBV)-seropositive individuals in the setting of chronic immunosuppression and decreased T-cell surveillance. Clinical manifestations of PTLD may be nonspecific, resembling primary EBV infection (fever, night sweats, malaise, and cervical lymphadenopathy), or it can involve the central nervous system, bone marrow, kidneys, liver, lungs, and gastrointestinal tract. Gastrointestinal symptoms in the posttransplant setting may indicate underlying PTLD, and it is important for physicians to be able to recognize its appearance on endoscopy.

Data in this article presents the results of conventional cytogenetics and fluorescence in situ hybridization (FISH) analyses in 129 patients with confirmed MECOM rearrangement (https://doi.org/10.1016/j.cancergen.2019.03.002) [1]. Generally, the MECOM rearrangement has arisen through translocation, inversion, and insertion and/or unknown mechanism. In addition to the typical chromosomal aberrations, inv(3)(q21q26.2) and t(3; 3)(q21; q26.6) [2–4], over 50% of cases presented here exhibit a wide spectrum of MECOM rearrangement-driven, atypical chromosomal aberrations, including inv(3) with breakpoint other than 3q21; t(1; 3); t(2; 3); t(3; 6); t(3; 8); t(3; 12); t(3; 17); t(3; 21) as well as an insertion of 3q26.2 into different chromosomes. These cases are thoroughly characterized by karyotyping, interphase-, metaphase-, map-back FISH and whole chromosomal painting (WCP) analyses. Keywords: MECOM rearrangement, Inversion, Insertion, Translocation, Fluorescence in situ hybridization (FISH)

The potential of CD123-targeted therapies in acute lymphoblastic leukemia/lymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of patients with acute lymphoblastic leukemia/lymphoma and assessed the in vitro impact of IMGN632, a conjugate of CD123-binding antibody with a novel DNA-alkylating payload. CD123 expression on leukemic blasts was surveyed using multicolor/multiparameter flow cytometry. The in vitro effect of IMGN632 was evaluated on B acute lymphoblastic leukemia/lymphoma cell lines and primary B acute lymphoblastic leukemia/lymphoma blasts. The study cohort (n=213) included 183 patients with B acute lymphoblastic leukemia/lymphoma and 30 with T acute lymphoblastic leukemia/lymphoma. CD123 expression was more prevalent in B acute lymphoblastic leukemia/lymphoma than in T acute lymphoblastic leukemia/lymphoma (164/183, 89.6% versus 13/30, 43.3%; P

Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma worldwide, representing 30–40% of non-Hodgkin lymphomas, and is clinically aggressive. Although more than half of patients with DLBCL are cured by using standard first-line immunochemotherapy, the remaining patients are refractory to the first-line therapy or relapse after complete remission and these patients require novel therapeutic approaches. Understanding the pathogenesis of DLBCL is essential for identifying therapeutic targets to tackle this disease. Cell survival dysregulation, a hallmark of cancer, is a characteristic feature of DLBCL. Intrinsic signaling aberrations, tumor microenvironment dysfunction, and viral factors can all contribute to the cell survival dysregulation in DLBCL. In recent years, several novel drugs that target abnormal cell survival pathways, have been developed and tested in clinical trials of patients with DLBCL. In this review, we discuss cell survival dysregulation, the underlying mechanisms, and how to target abnormal cell survival therapeutically in DLBCL patients.

Persistence of IDH1 or IDH2 mutations in remission bone marrow specimens of patients with acute myeloid leukemia has been observed, but the clinical impact of these mutations is not well known. In this study, we evaluated 80 acute myeloid leukemia patients with known IDH1 R132 or IDH2 R140/R172 mutations and assessed their bone marrow at the time of remission to determine the potential impact of persistent IDH1/2 mutations. Approximately 40% of acute myeloid leukemia patients given standard treatment in this cohort had persistent mutations in IDH1/2. Patients with an IDH1/2 mutation had an increased risk of relapse after 1 year of follow-up compared to patients without a detectable IDH1/2 mutation (59% versus 24%; P

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries with an incidence of 3-5 cases per 100,000 persons. Most patients follow an indolent clinical course with eventual progression and need for therapy. In contrast, T-prolymphocytic leukemia (T-PLL) is a rare type of T-cell leukemia with most patients having an aggressive clinical course and a dismal prognosis. Therapies are limited for T-PLL patients and there is a high relapse rate. Morphologically, the cells of CLL and T-PLL can show overlapping features. Here, we report the case of a 61-year-old man who presented with a clinically indolent CLL and T-PLL, initially diagnosed solely and followed as CLL, despite the presence of an associated but unrecognized aberrant T-cell population in blood. After 2 years, the T-PLL component became more apparent with cutaneous and hematologic manifestations and the diagnosis was confirmed by immunophenotypic and cytogenetic analysis. Fluorescence in situ hybridization demonstrated an ATM deletion in both CLL and T-PLL components. Retrospective testing demonstrated that composite CLL and T-PLL were both present in skin and lymph nodes as well as in blood and bone marrow since initial presentation. This case is also unique because it highlights that a subset of T-PLL patients can present with clinically indolent disease. The concomitant detection of ATM mutation in CLL and T-PLL components raises the possibility of a common pathogenic mechanism.

Remarkable progress has been made in the field of cancer immunotherapy in the past few years. Immunotherapy has become a standard treatment option for patients with various cancers, including melanoma, lymphoma, and carcinomas of the lungs, kidneys, bladder, and head and neck. Promising immunotherapy approaches, such as chimeric antigen receptor (CAR) T cell therapy and therapeutic blockade of immune checkpoints, in particular cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 pathway (PD-1/PD-L1), have boosted the development of new therapeutic regimens for patients with cancer. Immunotherapeutic strategies for diffuse large B-cell lymphoma (DLBCL) include monoclonal anti-CD20 antibody (rituximab), monoclonal anti-PD-1 antibodies (nivolumab and pembrolizumab), monoclonal anti-PD-L1 antibodies (avelumab, durvalumab, and atezolizumab) and chimeric antigen receptor (CAR) T cell therapy. In this review, we outline the latest highlights and progress in using immunotherapy to treat patients with DLBCL, with a focus on the therapeutic blockade of PD-1/PD-L1 and CAR T cell therapy in DLBCL. We also discuss current clinical trials of PD-1/PD-L1 and CAR T cell therapy and review the challenges and opportunities of using immunotherapy for the treatment of DLBCL.

Abstract Recognizing Gaucher disease in elderly patients can be challenging. We present a Gaucher disease type 1 case diagnosed in an elderly patient with thrombocytopenia and lung adenocarcinoma. The diagnosis of Gaucher disease was delayed due to lack of familiarity about Gaucher Disease type 1 which can manifest in adulthood.

Key Clinical Message An overlap between human herpesvirus 8 (HHV8) ‐positive diffuse large B‐cell lymphoma and HHV8‐positive germinotropic lymphoproliferative disorder has been proposed. We present a unique Epstein‐Barr virus‐associated case in which features of both conditions were present.

A subset of patients with familial platelet disorder with propensity to myeloid malignancy and germline RUNX1 mutation develops hematological malignancies, often myelodysplastic syndrome/acute myeloid leukemia, currently recognized in the 2016 WHO classification. Patients who develop hematologic malignancies are typically young, respond poorly to conventional therapy, and need allogeneic stem cell transplant from non-familial donors. Understanding the spectrum of bone marrow morphologic and genetic findings in these patients is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of hematologic malignancies, particularly myelodysplastic syndrome. However, bone marrow features remain poorly characterized. To address this knowledge gap, we analyzed the clinicopathologic and genetic findings of 11 patients from 7 pedigrees. Of these, 6 patients did not develop hematologic malignancies over a 22-month follow-up period; 5 patients developed hematologic malignancies (3 acute myeloid leukemia; 2 myelodysplastic syndrome). All patients had thrombocytopenia at initial presentation. All 6 patients who did not develop hematologic malignancies showed baseline bone marrow abnormalities: low-for-age cellularity (n=4), dysmegakaryopoiesis (n=5), megakaryocytic hypoplasia/hyperplasia (n=5), and eosinophilia (n=4). Two patients had multiple immunophenotypic alterations in CD34-positive myeloblasts; 1 patient had clonal hematopoiesis. In contrast, patients who developed hematologic malignancies had additional cytopenia(s) (n=4), abnormal platelet granulation (n=5), bone marrow hypercellularity (n=4), dysplasia in ≥2 lineages including megakaryocytes (n=3) and acquired clonal genetic aberrations (n=5). In conclusion, our study demonstrated that specific bone marrow abnormalities and acquired genetic alterations may be harbingers of progression to hematological malignancies in patients with familial platelet disorder with germline RUNX1 mutation.

Up to 20% of patients with polycythemia vera have karyotypic abnormalities at the time of the initial diagnosis. However, the cytogenetic abnormalities in polycythemia vera have not been well characterized and their prognostic impact is largely unknown. In this study, we aimed to address these issues using a large cohort of polycythemia vera patients with cytogenetic information available. The study included 422 patients, 271 in polycythemic phase, 112 with post-polycythemic myelofibrosis, 11 in accelerated phase, and 28 in blast phase. Abnormal karyotypes were detected in 139 (33%) patients, ranging from 20% in those in the polycythemic phase to 90% among patients in accelerated/blast phase. Different phases harbored different abnormalities: isolated del(20q), +8 and +9 were the most common abnormalities in the polycythemic phase; del(20q) and +1q were the most common abnormalities in post-polycythemic myelofibrosis; and complex karyotypes were the most common karyotypes in accelerated and blast phases. Patients with an abnormal karyotype showed a higher frequency of disease progression, a shorter transformation-free survival and an inferior overall survival compared with patients with a normal karyotype in the same disease phase. Cytogenetics could be effectively stratified into three risk groups, low- (normal karyotype, sole +8, +9 and other single abnormality), intermediate- (sole del20q, +1q and other two abnormalities), and high-risk (complex karyotype) groups. We conclude that cytogenetic changes in polycythemia vera vary in different phases of disease, and carry different prognostic impacts.

In 2011, the Vysis Break Apart ALK fluorescence in situ hybridization (FISH) assay was approved by the United States Food and Drug Administration as a companion diagnostic for detecting ALK rearrangement in lung cancer patients who may benefit from treatment of tyrosine kinase inhibitor therapy. This assay is the current “gold standard”. According to updated ALK testing guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology published in 2018, ALK immunohistochemistry is formally an alternative to ALK FISH, and simultaneous detection of multiple hot spots, including, at least, ALK, ROS1, RET, MET, ERBB2, BRAF and KRAS genes is also recommended while performing next generation sequencing (NGS)-based testing. Therefore, ALK status in a specimen can be tested by different methods and platforms, even in the same institution or laboratory. In this review, we discuss several clinically relevant technical aspects of ALK FISH, including pros and cons of the unique two-step (50- to 100-cell) analysis approach employed in the Vysis Break Apart ALK FISH assay, including: the preset cutoff value of ≥15% for a positive result; technical aspects and biology of discordant results obtained by different methods; and incidental findings, such as ALK copy number gain or amplification and co-existent driver mutations. These issues have practical implications for ALK testing in the clinical laboratory following the updated guidelines.