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Simple Summary: In this study we examined the cytogenetic profile of 1087 patients with plasma cell neoplasms (PCNs) at different stages, including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM), and refractory/relapsed multiple myeloma (RRMM). Our study demonstrated that >95% of patients exhibited at least one cytogenetic abnormality detected by FISH tests and/or chromosomal analysis. The frequency of IGH::CCND1 rearrangement was 26% in this cohort, but with no apparent differences across races, ages, or disease groups. Almost all cases with abnormal karyotypes presented a complex or composite karyotype, with most featuring five or more chromosomal abnormalities, and chromosome 1 structural abnormalities were the most prevalent (65%). The genomic complexity escalated from MGUS to SMM and further to NDMM and RRMM. Elevated frequencies of high-risk cytogenetics (59%) and the presence of subclones (48%) were particularly notable in RRMM cases. The aim of this study was to examine the cytogenetic profiles of plasma cell neoplasms (PCNs) at various disease stages, encompassing 1087 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM), and refractory/relapsed multiple myeloma (RRMM). Fluorescence in situ hybridization (FISH) analyses were conducted on highly purified plasma cell samples, revealing that 96% of patients exhibited at least one cytogenetic abnormality. The genomic complexity escalated from MGUS to SMM and further to NDMM and RRMM, largely driven by 1q gain, del(17p), MYC-rearrangement (MYC-R), del(1p), and tetraploidy. Elevated frequencies of high-risk cytogenetics (59%), 1q gain (44%), and del(17p) (23%), as well as the presence of subclones (48%), were particularly notable in RRMM cases. IGH::CCND1 was observed in 26% of the cases, with no apparent variations across races, ages, or disease groups. Concurrent chromosomal analysis with FISH revealed that the incidence of abnormal karyotypes was strongly correlated with the extent of neoplastic plasma cell infiltration, genomic complexity, and the presence of specific abnormalities like del(17p) and MYC-R. Approximately 98% of the cases with abnormal karyotypes were complex, with most featuring five or more abnormalities. Chromosome 1 structural abnormalities were the most prevalent, found in 65% of cases. The frequent presence of subclones and composite karyotypes underscored the genomic heterogeneity and instability in this cohort. [ABSTRACT FROM AUTHOR]

The article explores A 69-year-old African American woman who had a past medical history of diabetes mellitus, hypertension, and hyperlipidemia presented with bilateral parotid masses with the left side larger than the right side. A left parotidectomy was performed. Histopathologic examination of the left parotidectomy specimen showed a multilocular lymphoepithelial cyst.

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 < 0.0001). Among the patients with hyperdiploid B‐ALL, the adult group had a significantly inferior survival (similar to the patients with a normal karyotype) compared with the pediatric group (median survival: 42 months vs undefined, P = 0.0029). Hyperdiploidy in adults B‐ALL tended to more frequently harbor structural abnormalities (two or more) than children (53% vs 33%). Two or more structural abnormalities in a hyperdiploidy correlated with an adverse survival in adult patients (33 months vs undefined, P = 0.0008), similar to the survival of patients with a complex karyotype. We conclude that hyperdiploidy in adults with B‐ALL is less favorable and more commonly contains structural abnormalities comparing to pediatric patients. We suggest that hyperdiploidy with two or more structural abnormalities are best considered as a complex karyotype in adults with B‐ALL. [ABSTRACT FROM AUTHOR]

Approximately 10% of patients with polycythemia vera (PV) transform to acute leukemia (blast phase) at 10 years after initial diagnosis of PV. The bone marrow pathologic, cytogenetic, and molecular features of blast phase have not been well characterized. In this study, we reviewed 422 PV patients over a period of 11 years and identified 58 patients who developed acute myeloid leukemia (blast phase) during the course of disease. We found that blast phase of PV was characterized by overt myelodysplasia (n = 51, 88%); moderate to severe myelofibrosis (33 of 45, 73%); an abnormal karyotype (n = 51, 88%) that was often complex karyotype (n = 42, 72%); and gene mutations involving TP53 (55%), TET2 (27%), and DNMT3A (25%). Patients with blast phase of PV had an aggressive clinical course, with a median overall survival of 4 months after onset of blast phase. Eleven patients had close follow-up from polycythemic phase to blast phase: Four patients showed dysplastic changes in the polycythemic phase, and three of them transformed to blast phase without a "middle phase" of post-PV myelofibrosis.We conclude that blast phase of PV is characterized by myelodysplasia, moderate to severe fibrosis, a high frequency of an abnormal and often complex karyotype, and frequentTP53mutation. [ABSTRACT FROM AUTHOR]

3q26.2/ EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this study, we aim to explore the clinicopathological features of myelodysplastic/myeloproliferative (MDS/MPN) neoplasms with 3q26.2/ EVI1 rearrangements and determine the potential impact of these cytogenetic abnormalities on treatment response and survival. The study group included 12 cases of MDS/MPN with 3q26.2 rearrangements detected by conventional karyotyping. There were 7 men and 5 women with a median age of 67 years (range, 51–79 years) at time of initial MDS/MPN diagnosis. Ten cases were classified as chronic myelomonocytic leukemia (CMML) and 2 were MDS/MPN, unclassifiable. Among CMML cases, 5 (50%) were proliferative type and 5 (50%) were dysplastic type. Based on blast counts, these 10 CMML were: CMML-0 (n = 2), CMML-1 (n = 3), and CMML-2 (n = 5). Eleven (92%) patients had 3q26 rearrangements at the initial diagnosis. Inv(3)(q21q26.2) was most common, identified in 7(58%) patients, followed by t(3;21)(q26.2;q22) in 2 patients and 1 patient each with t(3;3)(q21;q26.2), t(2;3)(p21;q26-27), and t(3;6)(q26.2;q26). Six (50%) patients had 3q26.2 rearrangements as a sole cytogenetic abnormality and 6 (50%) patients had additional cytogenetic abnormalities. Molecular studies revealed DNMT3A mutations in all 3 patients assessed and RAS mutations in 2 of 8 (25%) patients. No mutations in ASXL1 (n = 3), TET2 (n = 3), FLT3 ITD/D835 (n = 10), and CEBPA (n = 7) were detected. Most patients received hypomethylating agent based chemotherapy. The median follow-up was 11.5 months (range, 1.5–24 months) and at time of last follow-up, 11 (92%) died with a median survival of 13.4 months (range, 1.5–24 months). The only patient alive had a relatively short follow-up of 2.4 months and showed disease progression at the last visit. In conclusion, 3q26.2/ EVI1 rearrangements are a rare event and usually present at time of initial diagnosis in MDS/MPN. The presence of 3q26.2/ EVI1 rearrangements in MDS/MPN is associated with rapid disease progression, poor response to treatment, and a poor prognosis. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the prevalence of constitutional pericentric inversion of chromosome 9 (inv(9)) in patients with chronic myelogenous leukemia (CML). Topics discussed include the evaluation of major molecular response (MMR) and complete cytogenetic response (CCyR), the good response of CML patient with inv(9) to tyrosine kinase inhibitor (TKI) treatment, and the prognostic implications of the presence of inv(9).

• 129 cases with MECOM rearrangement are thoroughly analyzed. • Sophisticated chromosomal aberrations/mechanisms are involved. MECOM rearrangement is associated with rapid disease progression and poor prognosis in myeloid neoplasms. Previous studies were often based on 3q26.2 abnormalities without confirmation of MECOM status. The frequency of MECOM rearrangement and attribution of various chromosomal aberrations remain poorly characterized. This study presented 129 cases with confirmed MECOM rearrangement by karyotyping and multiple FISH methodologies. MECOM rearrangement arose through translocation (49.6%, n = 64), inversion (40.3%, n = 52), insertion (5.4%, n = 7) or unknown mechanism(s) (4.7%, n = 6). The classic inv(3)(q21q26.2) was dominant (n = 50) in inversion-driven MECOM rearrangement; and 3 of them also had double inv(3). For translocation-driven MECOM rearrangement, t(3;21) was most common (n = 15), followed by t (2;3) (n = 13), t(3;12) (n = 10), t(3;3) (n = 9), t(3;8) (n = 6), t(3;6) and t(3;17) (n = 4 each), t(1;3) and t(3;?) (n = 1 each). Cases with t(3;3)-, t(3;12)-, and insertion-driven MECOM rearrangement were prone to exhibit a complex karyotype, while cases with t(2;3)-, t(3;21)- and insertion-driven MECOM rearrangement were prone to have an "unbalanced" MECOM FISH signal pattern, likely caused by uncommon breakpoint(s) within the target of 5'MECOM probe. Therefore, atypical chromosomal aberrations and/or mechanisms are involved in MECOM rearrangement. Confirmation/exclusion of MECOM rearrangement is necessary in all cases with a 3q26.2 abnormality. (Word count: 190) [ABSTRACT FROM AUTHOR]

Highlights • Cryptic ETV6 deletion in BPDCN. • Common in skin lesions. • Clinical course related. Abstract Background Chromosomal aberrations at the ETV6 gene locus on 12p13.2 are common in bone marrow samples involved by blastic plasmacytoid dendritic cell neoplasm (BPDCN). However, their pathogenic role, incidence in cutaneous BPDCN lesions, and clinical significance have not been assessed systematically. Results The study group included 30 BPDCN patients, 25 men and 5 women, with a median age of 64 years. Conventional cytogenetic analysis demonstrated karyotypic aberrancies in 15 cases, of which 8 had chromosomal lesions involving 12p. In addition, 2 cases with normal diploid karyotype had cryptic 12p/ ETV6 deletion by ETV6 FISH test. Notably, 2 bone marrow samples with ETV6 rearrangement had no detectable BPDCN involvement, but otherwise dynamic changes in the detection of 12p/ ETV6 aberrations correlated with the presence of morphologically and/or immunophenotypically detectable disease. Tissue specimens from 6 patients with cutaneous BPDCN all tested positive for homozygous or heterozygous ETV6 deletions. Conclusion We demonstrate that monoallelic and biallelic 12p/ ETV6 deletions are highly prevalent in BPDCN, and their detection is enhanced by the use of FISH and aCGH. In addition, 12p/ ETV6 may be present in the bone marrow of BPDCN patients in the absence of detectable disease suggesting that such alterations might represent an early pathogenic event. [ABSTRACT FROM AUTHOR]

8q24 /MYC rearrangements resulting in MYC overexpression occur most frequently in lymphoid neoplasms. MYC rearrangements rarely have been described in blastic plasmacytoid dendritic cell neoplasm (BPDCN). Over an 8-year period in our hospital, 5 of 41 (12%) patients with BPDCN were shown 8q24/ MYC rearrangements, including 2 with t(6;8)(p21;q24), 1 with t(8;14)(q24;q32), 1 with t(X;8)(q24;q24), and 1 with t(3;8)(p25;q24). 8q24/ MYC rearrangement was present in the stemline in 4 patients and in the sideline in one; the latter was a patient with primary myelofibrosis who then developed BPDCN. MYC overexpression by immunohistochemistry was variable, but largely correlated with the percentage of blasts. Four patients were treated with acute lymphoblastic leukemia-type chemotherapy regimens and 3 had a good response; 1 patient was treated with acute myeloid leukemia-type regimens and was refractory to therapy. By the end of the follow-up, 3 patients died and 2 were alive in complete remission. We conclude that 8q24/ MYC rearrangements occur in 10–15% of BPDCN, often partnered with non-immunoglobulin chromosomal loci, and may play a role in BPDCN pathogenesis. In this small patient sample, patients with BPDCN and MYC rearrangement often responded to therapy with acute lymphoblastic leukemia-type chemotherapy regimens. [ABSTRACT FROM AUTHOR]

A tetraploid/near tetraploid (T/NT) karyotype is a rare finding in acute myeloid leukemia (AML). Here we report 38 AML patients with a T/NT karyotype, including 26 men and 12 women with a median age of 65 years. T/NT karyotype was detected at initial diagnosis of AML in 16 patients, and acquired during the course of disease in 22 patients. All patients showed large blasts with frequent prominent nucleoli, cytoplasmic vacuoles and/or inclusions, nuclear irregularity and/or budding. Eleven patients had a non-complex and 27 had a complex T/NT karyotype; 21 patients also had pseudodiploid and/or triploid clones. After T/NT karyotype detection, 32 patients received chemotherapy and 10 also received stem cell transplant. After a median of 6.2 months follow-up, 32 patients died of disease or complications, 5 were alive with complete remission, and 1 alive with persistent AML. Median overall survival (OS) was 5 months. Patients with a non-complex T/NT karyotype had a significantly superior OS compared to those with a complex T/NT karyotype (10.7 vs. 3.4 months, p = 0.0280). We conclude that T/NT karyotype in AML is often associated with distinctive morphologic features and conveys generally poor outcomes. Distinction of complex versus non-complex T/NT karyotype provides further prognostic information. [ABSTRACT FROM AUTHOR]

It has been controversial if trisomy 15 (+15) as an isolated clonal cytogenetic abnormality in bone marrow (BM) is disease-associated or a benign finding. To answer this question, we retrospectively reviewed our cytogenetic archives and identified 31 patients with isolated +15. Four patients presented with acute myeloid leukemia (AML), +15 was the major clone (56–95% of interphases) in BM and the clonal size of +15 was correlated with blast burden and disease status. For the remaining 27 patients, +15 was a minor clone (3–24% of interphases) in BM. Eighteen patients had a history of cytotoxic therapies and developed +15 after a median latency interval of 34 months. Six patients had BM involvement by lymphoma or myeloma, and +15 was exclusively detected in myeloid and erythroid cells, not in lymphoma or myeloma cells. With a median follow-up of 28 months, none of these 27 patients had clinical or morphological evidence of myelodysplastic syndromes. We conclude that +15 can be associated with AML, but more often isolated +15 presents as a minor clone in BM, and may not be disease associated. Clinical follow-up rather than an immediate therapeutic intervention seems most appropriate for non-leukemic patients with isolated +15. [ABSTRACT FROM AUTHOR]