We herein present an overview of the upcoming 5^thedition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4^thedition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5^thedition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied the outcomes of 5876 patients (16-59 years of age) who were classified into 54 cytogenetic subgroups and treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22), and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (P < .001). In patients with t(15;17) treated with extended all-trans retinoic acid and anthracycline-based chemotherapy, additional cytogenetic changes did not have an impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML; whereas in patients with inv(16), the presence of additional changes, particularly +22, predicted a better outcome (P = .004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely abn(3q) (excluding t(3;5)(q25;q34)), inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), −5, −7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11∼13;q23), other t(11q23) (excluding t(9;11)(p21∼22;q23) and t(11;19)(q23;p13)), t(9;22)(q34;q11), −17, and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations but with 4 or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated “complex” karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study is registered at http://www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

Acute myeloid leukemia (AML) in older adults carries a poor prognosis, and the optimum treatment remains to be determined. In younger patients, treatment stratification is frequently based upon diagnostic karyotype, which was the most important prognostic factor in the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of response to induction therapy and overall survival (OS). Those with t(15;17), t(8;21), or inv(16) composed the favorable risk group. Overall, these abnormalities predicted a superior complete remission (CR) rate (72%), reflecting relatively low levels of resistant disease (RD) (8%), and lower relapse risk (RR) (56%) associated with superior OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%; OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR, 85%; OS, 10%) composed the intermediate group; while complex karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%; RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed that the most favorable changes were rarer in older patients (younger than 55 years, 24%; 55 years or older, 7%), while complex abnormalities were more common (6% vs 13%). This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups. Furthermore, it highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML, providing a potential framework for stratified treatment approaches.

Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.

Burkitt's lymphoma is a highly aggressive B-cell non-Hodgkin lymphoma and is the fastest growing human tumour. The disease is associated with Epstein-Barr virus and was one of the first tumours shown to have a chromosomal translocation that activates an oncogene (c-MYC). Burkitt's lymphoma is the most common childhood cancer in areas where malaria is holoendemic. The incidence is very high in immunosuppressed patients in non-endemic areas, especially when associated with HIV infection. Outcome with intensive chemotherapy has improved and is now excellent in children, but the prognosis is poor in elderly adults. The success of intensive treatment relies on good supportive care. The therapy offered in oncology units in low-income countries is not as aggressive as in centres in high-income countries and outcomes are less successful. Adjuvant monoclonal antibody therapy with rituximab shows promise for improved outcomes and reduced toxic effects in the future.

We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.