Zhenya Tang

P53 expression correlates with poorer survival and augments the negative prognostic effect of MYC rearrangement, expression or concurrent MYC/BCL2 expression in diffuse large B-cell lymphoma

In patients with diffuse large B-cell lymphoma, MYC rearrangement (MYC-R), MYC expression, or concurrent expression of MYC and BCL2 is associated with a poorer prognosis. P53 expression also has been shown to confer inferior survival in diffuse large B-cell lymphoma patients, but less is known about the role of P53 expression in those with MYC-R, MYC expression (MYC+), or MYC&BCL2 co-expression (MYC+/BCL2+). We studied P53 expression in 201 patients with untreated de novo diffuse large B-cell lymphoma. Sixty-seven (33%) cases were P53 positive, 56 (28%) had MYC-R (including 17 MYC/BCL2 double hit lymphoma), 86 (45%) were MYC+/BCL2+, and 47 (24%) were positive for both MYC and P53. Compared with patients with P53 negative lymphoma, the P53 positive group had a poorer overall survival (P=0.004). In patients with lymphoma harboring MYC-R, MYC expression or MYC+/BCL2+, P53 expression was associated with a significantly worse overall survival (P<0.0001, P=0.01, and P=0.035, respectively). Patients with lymphoma showing concurrent P53 expression and MYC-R had a worse prognosis compared with patients with either P53 expression or MYC-R alone (P<0.0001). Similarly, P53 enhanced the negative prognostic effect of MYC expression in DLBCL patients. In addition, among patients with lymphoma with concurrent MYC and P53 expression, MYC and BCL2 or BCL2 & P53 expression, those patients with tumors with MYC and P53 expression had the worst overall survival (P=0.005), regardless of BCL2 expression status. Multivariate analysis demonstrated that both MYC-R and P53 expression were independent prognostic factors in this patient cohort. In conclusion, our data suggest that P53 expression and MYC -R or MYC expression have an additive negative prognostic effect in diffuse large B-cell lymphoma patients. Assessment of P53 expression adds additional prognostic information in de novo diffuse large B-cell lymphoma patients, especially in subgroups with MYC-R, MYC expression and MYC and BCL2 double expression.

The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia

Chromosome 8q24/MYC rearrangement is associated with Burkitt lymphoma and some aggressive B-cell lymphomas, but is rare in chronic lymphocytic leukemia. We here report a cohort of 20 chronic lymphocytic leukemia patients with 8q24/MYC rearrangement, 3 detected at time of initial diagnosis and 17 acquired after a median interval of 48 months. At the time when 8q24/MYC arrangement was detected, 18 patients had B-symptoms, 17 had lymphadenopathy, and 17 had splenomegaly. Histologically, typical chronic lymphocytic leukemia morphology was seen in six patients, increased prolymphocytes in nine and Richter’s transformation in five patients. Eighteen patients had karyotypic information available that showed t(8;v) in a complex karyotype in 12 patients and in a non-complex karyotype in 6 patients. Fluorescence in situ hybridization confirmed MYC rearrangement in 17/17 patients. All patients required therapy after 8q24/MYC rearrangement was detected. At last follow-up, five of six patients with a non-complex karyotype were alive after a median of 74 months (10~143 months) from the detection of 8q24/MYC rearrangement. In contrast, 10 of 12 patients with a complex karyotype died with a median survival of 5.5 months. We conclude that 8q24/MYC rearrangement in chronic lymphocytic leukemia is rare and often acquired during the course of disease. If it is presented in a complex karyotype, it is often associated with Richter’s transformation, refractory to therapy and an aggressive clinical course; on the other hand, if it is present in a non-complex karyotype, patients often respond to risk-adapted therapies and achieve remission.

Characteristics and clinical significance of cytogenetic abnormalities in polycythemia vera

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.

Clinical significance of acquired loss of the X chromosome in bone marrow

Acquired loss of the X chromosome (-X) as a sole abnormality is detected rarely in bone marrow (BM) and its clinical importance remains largely unknown. We studied 38 patients with isolated -X in BM. All patients were women, with a median age of 71 years. At the time of -X detection, BM was positive for myeloid neoplasm in 14 patients, lymphoma/myeloma in 10 patients, and was normal in 14 patients. -X was detected as a major clone in 15 patients (11 of them had myeloid neoplasm) and a minor clone in 23 patients. Combined morphologic and FISH analysis was performed in 16 cases, -X was detected in myeloid/erythroid cells in all 16 patients and in lymphocytes in 15 patients. With a median of 23 months follow-up, none of the patients with a negative BM or BM with involvement by lymphoid neoplasms developed a secondary myeloid neoplasm. We conclude that isolated -X is a rare finding in BM. In majority of patients, -X presents as a minor clone and is likely to be an aging effect or a benign finding; whereas when -X presents as a major clone in BM, it is often disease associated.

Prognostic significance of cytogenetic abnormalities in T‐cell prolymphocytic leukemia

T‐cell prolymphocytic leukemia (T‐PLL) is an aggressive mature T‐cell neoplasm. The most common cytogenetic abnormality associated with T‐PLL is inv(14)(q11.2q32) involving TCL1, but other abnormalities also have been reported. In this study, we correlated cytogenetic abnormalities with clinical outcome in 97 T‐PLL patients, including 66 men and 31 women with a median age of 63 years (range, 34‐81). Twenty‐seven patients had a normal karyotype (NK), one had two chromosomal aberrations, and 69 had a complex karyotype (CK). Patients with a CK had poorer overall survival (OS) than patients with a NK (P = .0016). In the CK group, the most common aberrations involved 14q (n = 45) and 8q (n = 38). Additional deletions of chromosomes 17p, 11q, 6q, 12p, 13q were observed frequently. No individual cytogenetic abnormality impacted OS. Patients with ≥5 aberrations had an OS of 11 months versus 22 months in patients with <5 aberrations (P = 0.0132). Fluorescence in situ hybridization for TCL1 successfully performed in 27 cases showed rearrangement in 8/10 (80%) NK versus 16/17 (94%) CK cases. OS of patients with TCL1 rearrangement and/or 14q aberrations was not significantly different from patients without TCL1 rearrangement and 14q aberrations (P = .3467). Patients with refractory disease showed worse OS in both the NK and CK groups (P = .0014 and P < .0001, respectively), compared with patients who achieved remission but then relapsed. Stem cell transplantation did not appear to improve OS regardless of karyotype complexity. In conclusion, patients with T‐PLL often have a CK which is a poor prognostic factor, particularly in patients with ≥5 cytogenetic aberrations.

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4–190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median follow-up of 21 months (range, 1–135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding.

8q24/MYC rearrangement is a recurrent cytogenetic abnormality in blastic plasmacytoid dendritic cell neoplasms

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.

Clinical significance of isolated del(7p) in myeloid neoplasms

Sole del(7p) is a rare finding in myeloid neoplasms and its clinical significance is largely unknown. Here we report 10 patients with isolated del(7p), 4 had acute myeloid leukemia (AML), 2 myelodysplastic syndromes (MDS), 1 chronic myelomonocytic leukemia (CMML), 1 primary myelofibrosis (PMF), and 2 AML in remission. Seven patients had large and 3 had small del(7p) clone. For patients with AML, 3 acquired del(7p) either at disease relapse or disease progression, then became refractory to therapy and died shortly thereafter (median 5 months). Detection of del(7p) in patients with MDS, CMML, or PMF appeared to predict poorer prognosis as all 4 patients experienced disease progression or transformation to AML after 5-24 months. In the remaining 3 patients (1 AML and 2 AML in remission), del(7p) was only detected in 10% to 30% of metaphases and was a transient finding that did not appear to have any clinical impact. We conclude that detection of del(7p) in myeloid neoplasms, when presents as a major clone, often poses a high risk for disease progression and refractoriness to therapy; whereas when del(7p) presents as a small clone, it may not carry any clinical significance.

Role of complexity of variant Philadelphia chromosome in chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

Dear Editor, Chronic myeloid leukemia (CML) is a type of myeloproliferat ive neoplasm characterized by the presence of der(22)t(9;22)(q34;q11.2), or Philadelphia chromosome (Ph), resulting in the fusion gene BCR-ABL1, which encodes a constitutionally active tyrosine kinase. Variation of the standard Ph translocation occurs in about 5–10% of CML patients, in which BCR-ABL1 is generated by a variant rearrangement [1–3]. A variant can be formed by multiple mechanisms: (1) three-way or more complicated reciprocal translocations, with the formation of 22q11.2::9q34 fusion; (2) BCR-ABL1 fusion gene formation from a microinsertion of 9q34 to the 22q11.2 locus, or vice versa, followed by a rearrangement between the distal segment 9q34->9qter or 22q11.2->22qter and a third chromosome; (3) standard Ph rearrangement followed by an additional translocation involving the 22q11.2 or 9q34 locus, resulting in the BCR or ABL1 gene segment translocating to a third chromosome. The most common type of variant rearrangement is a three-way reciprocal translocation. Other complex processes, like four-way, five-way, or even more complex translocations, are much less frequent. Rarely, BCRABL1 can be generated by a simple aberration that involves 22q11.2 but does not appear to involve 9q34, such as t(17;22)(p13;q11.2) or even del(22)(q11.2) [3]. These simple variants are indeed masked complex ones undetectable by karyotyping analyses. Additional chromosomal abnormality (ACA) is defined as chromosomal changes other than BCR-ABL1 in a Ph+ cell. The incidence of ACAs is low in chronic myeloid leukemia (CML), chronic phase (CP). About 5% of CML patients have ACAs at the time of the initial diagnosis of CP. However, as the disease progresses, ACAs emerge, and nearly 70–80% of patients have ACAs at diagnosis of CML, blast phase (BP) [4–6]. The emergence of ACAs is considered as cytogenetic evidence of clonal evolution, which is an indicator of disease progression. The prognostic impact of ACAs in CML has been extensively studied. In recent studies, we have demonstrated that ACAs can be stratified into two different risk groups: i(17)(q10), 3q26.2 rearrangement, and −7/del(7q) belonging to the high-risk group, and +8, +Ph, and –Y, belonging to the low-risk group [7–9]. In contrast to the “real” ACAs, the prognostic impact of variant Ph translocations is still controversial. Variant Ph translocations were associated with more frequent deletions on der(9) and were considered an adverse prognostic factor in pre-tyrosine kinase inhibitor (TKI) era [10–12]. However, most studies performed in the era of TKI therapy suggest that patients with variant translocations have a similar prognosis to those with the standard Ph [1, 13, 14]. Based on these findings, variant translocations are generally not considered as ACAs in the TKI era. However, this conclusion might be confounded by several factors. First, the majority of these studies were performed in a relatively small number of patients. Secondly, all types of variant translocations were analyzed as one group regardless of the complexity or the emerging time of variant translocations: at the initial diagnosis of CML or acquired later during therapy, with the latter indicating clonal evolution. To address the prognostic relevance of variant translocations in the era of TKI therapy, we focused on Electronic supplementary material The online version of this article (doi:10.1007/s00277-016-2892-7) contains supplementary material, which is available to authorized users.

Coexistent genetic alterations involving ALK , RET , ROS1 or MET in 15 cases of lung adenocarcinoma

In lung cancer, targetable activating alterations in cancer genes, such as EGFR, ALK, RET, ROS1 and MET, are usually mutually exclusive. Rare lung cancer cases with coexistent alterations of EGFR and ALK or EGFR mutations with RET or ROS1 rearrangements have been reported. In this study, we report 15 patients (3 men and 12 women; 14 Caucasians and 1 African American) with ages ranging from 43 to 81 years (median 60 years) with lung adenocarcinoma in which coexistent alterations of two cancer-associated genes, including ALK, ROS1, or RET rearrangement or MET amplification were present. The combination of alterations detected by fluorescence in situ hybridization included ALK combined with ROS1 (n=4), ALK with MET (n=3), ALK with RET (n=1); RET with MET (n=4), RET with ROS1 (n=2), and ROS1 combined with MET (n=1). The frequencies of involvement were similar for all 4 genes, 53% for both ALK and MET (n=8), 47% for both RET and ROS1 (n=7). Activating gene mutations were also detected by next-generation sequencing for TP53 (n=6), EGFR (n=5), KRAS (n=3) and STK11 (n=2). Nine patients reported a smoking history (8 heavy and 1 light) and 6 patients were non-smokers. These findings suggest the need for assessing a panel of genes in lung cancer. Since targetable agents are available for each of these activating alterations, treatment with more than one targeted agent may be beneficial for this rare group of patients.