Chronic lymphocytic leukaemia/small lymphocytic lymphoma Definition Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is a B-cell lymphoma comprising monomorphic small mature B-cells that frequently co-express CD5 and CD23. A peripheral blood diagnosis of CLL requires a B-cell count >5×109/L, with the characteristic morphology and immunophenotype. A tissue-based diagnosis of SLL requires organ enlargement (e.g., lymphadenopathy >15 mm) and its infiltration by the above neoplastic B-cells. Although CLL and SLL represent the same disease, the name SLL is used for cases with <5×109/L circulating B cells and nodal, splenic, or other extramedullary involvement. 慢性リンパ性白血病／小リンパ球性リンパ腫（CLL/SLL）は、CD5とCD23をしばしば共発現する単形性小型成熟B細胞からなるB細胞性リンパ腫である。CLLの末梢血診断には、B細胞数が5×109/Lを超え、特徴的な形態と免疫表現型を伴うことが必要である。SLLの組織ベースの診断には、臓器腫大（例えば、15mmを超えるリンパ節腫脹）と上記の腫瘍性B細胞による浸潤が必要である。CLLとSLLは同じ疾患であるが、循環B細胞が5×109/L未満で、結節、脾臓、またはその他の髄外病変を有する症例にはSLLという名称が用いられる。 ICD-O coding 9823/3 Chronic lymphocytic leukaemia/small lymphocytic lymphoma ICD-11 coding 2A82.0 Chronic lymphocytic leukaemia or small lymphocytic lymphoma Related terminology Acceptable: B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma Subtype(s) None Localization CLL/SLL involves peripheral blood, bone marrow, and lymphoid tissues such as lymph nodes, spleen, and tonsils. Less frequently, at extranodal sites such as liver, skin, central nervous system, kidney, pleura, and bones may be involved { 24064196 }. In rare cases, CLL/SLL may be detected in the parotid, lacrimal glands, tongue, ocular structures, prostate, lung, pericardium, or intestinal mucosa, and may accompany other pathologies at these sites { 23006943 }. Clinical features Patients may be asymptomatic initially with the diagnosis only being established with a demonstration of lymphocytosis, lymphadenopathy, or splenomegaly. Symptoms related to cytopenia (anaemia, thrombocytopenia, and rarely granulocytopenia, due to bone marrow infiltration or autoimmune mechanisms), recurrent infections (due to hypogammaglobulinemia but also defective cellular immunity), lymphadenopathy, and/or splenomegaly may occur at presentation or subsequently. Constitutional B symptoms (chronic fatigue, unplanned weight loss of >10% of body weight over a period of 6 months, fever of unknown origin and/or night sweats) may occur at any disease stage and can indicate progressive disease or Richter’s transformation (RT) { 21242190 ; 23006943 }. Rapid and asymmetric growth of lymph nodes or extranodal mass(es) is also suggestive of transformation { 29692342 }. About 15% of patients have a small IgM or IgG paraprotein { 32712965 }. Hypogammaglobulinemia may increase over time from 25% at diagnosis, to 50% of patients { 25931291 }. Epidemiology CLL/SLL is most common in fair-skinned populations with an age-adjusted annual incidence of 4.9 per 100,000. It is much less common amongst Asian populations and in Latin Americans with the age-adjusted annual incidence of 0.1-0.5 and 0.5-1.4 per 100,000, respectively. The incidence for Africans is unknown { 30343488 ; 24245986 ; 26133722 ; 29304322 ; 34398558 ; 33884738, 26991956}. Median age at diagnosis in fair-skinned populations (?70 years) is higher than in Asians and Africans (58-62 years). There is a male predominance in Western populations (M:F ratio of 1.5-2.1:1), whilst in Asian and African populations, the ratio is variable { 33077870 }. Etiology Unknown. A family history of CLL is a risk factor for developing CLL and monoclonal B-cell lymphocytosis (MBL) { 29674426 ; 23926461 }. Cancer registry data suggest that family members of patients with CLL or related lymphomas, such as lymphoplasmacytic lymphoma and mantle cell lymphoma (MCL) { 31395603 }, have a 5 to 8-fold increased risk of CLL. These studies support an inherited genetic contribution to CLL aetiology. To date, large genome-wide association studies among European ancestry individuals have identified over 40 single nucleotide polymorphisms (SNPs) associated with the risk of CLL { 18758461 ; 20062064 ; 34285341 ; 29674426 }. The effect of each individual SNP on CLL risk is small (1.1-1.8 fold risk). However, when combining them into a polygenic risk score (PRS), individuals in the top quintile have a 2.5-fold increased risk of CLL compared to individuals in the middle quintile { 29674426 ; 34285341 }. Pathogenesis The cellular origin of CLL/SLL remains unclear; however, transcriptomic and epigenetic analyses suggest that CLL/SLL cells most closely resemble antigen-experienced, memory-like B cells { 33604581 ; 26780610 }. CLL/SLL could derive from normal B-cells differentiating via follicular or extra-follicular maturation pathways, reflected by the presence or absence of somatic hypermutation (SHM) respectively { 34174979 ; 33326765 }. Microenvironment: The centrality of the CLL/SLL microenvironment interactions in CLL/SLL development is highlighted by the therapeutic efficacy of kinase inhibitors targeting the B-cell receptor (BCR)-related kinases: i.e., SYK, BTK, and PI3K. Of these, BTK has emerged as the most effective therapeutic target { 32726532 ; 28138560 }. CLL/SLL-cell growth occurs in proliferation centres (PC) within lymph nodes, where they interact with T-helper cells, mesenchymal stromal cells, and macrophages called ‘nurse-like’ cells, leading to B cell receptor (BCR) signalling { 28074063 ; 20940416 ; 19074730 }. The BCR and its downstream signalling molecules are central drivers of CLL/SLL cell growth. Untreated CLL/SLL lacks activating BCR pathway mutations. Instead, BCR activation follows the principles of normal B lymphocytes, with dependence upon the BCR’s interactions with antigens. The BCR binds microbial and autoantigens or engage each other in homotypic interactions, leading to cell-autonomous BCR signalling { 18812466 ; 15902303 ; 18223168 ; 22885698 ; 28598442 }. Skewed IG gene usage in CLL/SLL culminates in BCR stereotypy, which is the presence of (quasi-)identical BCRs shared by unrelated patients { 9788964 ; 15314077 ; 27811850 }. Different BCR stereotypes are found in up to 41% CLL/SLL patients, supporting the selection and expansion of CLL/SLL cells bearing BCRs specific for discrete antigens { 32992344 }. The relevance of BCR signalling for CLL/SLL-cell proliferation is also underscored by associations between the SHM status of the rearranged immunoglobulin heavy variable (IGHV) gene utilized in clonotypic BCRs and clinical outcomes. CLL/SLL patients with IGHV genes bearing few or no SHM (IGHV-unmutated CLL/SLL) typically experience more aggressive disease compared to those with IGHV genes bearing significant SHM loads (IGHV-mutated CLL/SLL) { 10477712 ; 10477713 ; 12615894 }. Genetics: The genomic landscape of CLL/SLL is very heterogeneous, lacking a unifying genetic lesion. The most frequent chromosomal aberrations are deletions of 13q [del(13q)], 11q [del(11q)], 17p [(del(17p)] and trisomy 12. Occurring in 50-60% of patients, del(13q) removes the DLEU2-mir-15-16 cluster, which regulates expression of anti-apoptotic and cell cycle regulatory proteins { 20060366 ; 16166262 }. del(11q), detected in 10-20% patients, removes ATM, while del(17p) (5-10% of patients) results in loss of TP53. Trisomy 12 occurs in 15-20% of patients, although the genes involved remain unknown { 26466571 ; 28584254 ; 26200345 }. The most frequently mutated genes in CLL/SLL at the time of first treatment are NOTCH1 (10-15%), ATM (10-15%), SF3B1 (10%), TP53 (5-10%), and BIRC3 (5%) { 26466571 ; 26200345 }. Collectively, gene mutations impact diverse pathways and cellular programs. The frequencies and patterns of chromosomal abnormalities and mutations differ according to IGHV gene SHM status and among different subsets of patients with distinct stereotyped BCR (see Table #31699) { 26200345 ; 27198719 }. Cases presenting as SLL more frequently have trisomy 12 than those presenting as CLL (37% vs 15-20%), but show the same distribution of driver gene mutations { 29115891 }. Progressing cases rarely acquire new genetic lesions after ‘watch-and-wait’ management, but large clonal shifts in CLL/SLL can occur following treatment { 31142838 ; 26316624 ; 22915640 }. Chemo-immunotherapy leads to frequent TP53 aberrations (20-30%), MYC gain (15%), and CDKN2A loss (10%) in CLL/SLL cells and are often seen at relapse { 31467127 ; 26466571 ; 23821658 }. The genetics of histologically aggressive CLL/SLL is poorly understood. Trisomy 12 and del(17p) are more frequent in cases with enlarged proliferation centres { 20421272 ; 21941366 }. Diffuse large B-cell lymphoma (DLBCL) transformed from CLL/SLL (i.e., clonally-related RT) shows greater molecular heterogeneity and complexity than CLL/SLL, a mutation profile different from de novo DLBCL, a lack of specific recurrent genetic alterations causing transformation and either linear or branching evolution { 24127483 ; 24004666 ; 21266718 ; 33206936 }. Genetic aberrations commonly involve TP53 mutations and/or del(17p) (60-70% of cases), NOTCH1 mutations (30%), activation of MYC by translocation, amplification or mutation (30%), and 9p21 deletion affecting CDKN2A (20%). One or more of these abnormalities is present in 90% of RT cases, typically acquired at transformation { 24127483 ; 22077063 ; 21266718 ; 24004666 }. Epigenetics: While the CLL/SLL DNA methylome reflects the cell of origin, it is also characterized by disease-specific changes. Distinct CLL/SLL subtypes bearing distinct DNA methylation signatures have been identified: one similar to germinal-centre (GC) experienced B cells, termed memory-like CLL (m-CLL); and another resembling GC-inexperienced B cells, termed naive-like CLL (n-CLL) { 26053498 ; 26780610 ; 23064414 ; 25151957 ; 22922567 }. m-CLL and n-CLL subsets have prognoses that correspond largely to IGHV-mutated CLL/SLL and IGHV-unmutated CLL/SLL, respectively { 26780610 ; 29427646 }. A third group with an intermediate DNA methylation profile (i-CLL) has an intermediate prognosis { 23064414 ; 26780610 }. Recent studies report that i-CLL is enriched for cases with stereotyped subset #2 (IGHV3-21/IGLV3-21) and IGLV3-21R110 that experience a more aggressive clinical course; the remaining i-CLL cases mostly belong to IGHV-mutated CLL/SLL and follow a more indolent disease course { 33211804 ; 27128508 }. While the DNA methylation profiles remain relatively stable in untreated CLL/SLL patients, those with progressive/relapsing disease display a higher degree of epigenetic changes and evolution, parallel to the genetic evolution { 22922567 ; 31791414 ; 24356097 }. Macroscopic appearance Not relevant Histopathology Peripheral blood & bone marrow aspirate: Bone marrow and peripheral blood smears typically show small lymphoid cells with clumped chromatin, indistinct or absent nucleoli and scant, pale-to-lightly basophilic cytoplasm. Nuclear chromatin can have a “cracked mud” or a “soccer ball” patch-like pattern. Smudge cells are common in blood smears. Bone marrow core biopsy: Marrow involvement may be nodular, interstitial, diffuse, or a combination of the three. Paratrabecular and intrasinusoidal aggregates are not typical; there is usually a spared paratrabecular zone where normal marrow remains, even in heavily involved marrows. Infiltration patterns correlate with prognosis: nodular and interstitial patterns are seen mainly in early CLL/SLL, while a diffuse pattern is seen in advanced disease and is associated with bone marrow failure { 9234573 ; 8611442 ; 23485170 }. Proliferation centres are less common in bone marrow than in lymph nodes but are reported in ~10% of cases { 30086334 }. Immune-related cytopenia is associated with a normal or increased proportion of the affected lineage’s cells without dysplastic features { 28197963 ; 20736453 ; 17986663 }. Pure red cell aplasia (either immune or viral-infection related) is characterized by near-complete absence of erythroid precursors { 28197963 }. Lymph node: Lymph nodes are enlarged with diffuse infiltration of small lymphoid cells, often with variably prominent pale-staining proliferation centres containing larger cells (either prolymphocytes or paraimmunoblasts, which are larger cells with round to oval nuclei, dispersed chromatin, central nucleoli and pale cytoplasm), and may be entirely or partially effaced. Neoplastic B-cells are slightly larger than normal mature B-cells and have clumped chromatin within round, occasionally irregular nuclei. Mitoses are infrequent. PCs contain a spectrum of small lymphoid cells, medium-sized prolymphocytes, and paraimmunoblasts. { 9422315 } [[Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. New York: Springer Verlag.]]. Plasmacytic differentiation can be seen, but rare { 26454445 }. Spleen: White pulp involvement is usually prominent, but the red pulp can be infiltrated. Diffuse infiltration leads to loss of red and white pulp distinction. Immunophenotype: By flow cytometry, neoplastic cells are typically monotypic surface IgMdim+, IgD+/- (IgG+ in ~10% cases), CD19+, CD5+, CD23+, CD43+, CD200+, CD20dim+, CD11c variable, CD10-, CD79b-, FMC7-, CD25-, CD103-; along with light chain restriction (dim n expression). Atypical immunophenotypes (e.g., CD5-, CD23-, FMC7+, CD79b+ or strongly expressed surface immunoglobulin) are known { 10194119 ; 8603004 ; 20660331 }. In such cases, other small B-cell lymphomas must be carefully excluded. Strong expression of CD200 and ROR1, { 21531460 ; 33344247 } and absence of CD81 expression { 30868852 } characterize CLL. Expression of CD38 and CD49d is associated with a worse prognosis { 11675331 }. A major consensus effort identified CD19, CD5, CD20, CD23, kappa, and lambda as markers essential to be tested for a diagnosis of CLL, and CD43, CD79b, CD81, CD200, CD10, and ROR1 as additional markers useful in differential diagnosis from other small B-cell lymphomas/leukaemias { 29024461 }. Immunohistochemistry: CLL/SLL-cells express pan-B-cell markers (CD19, CD20, CD79a, and PAX5), CD5, and CD23, and are negative for CD10 and other GC markers. Up to 95% of cases express LEF1, which is rarely expressed in other small B-cell lymphomas { 28395058 ; 28395058 ; 25713417 ; 21685909 }. Usually, cyclin D1- and SOX11 are negative. In rare cases, scattered cells in PCs are cyclin D1+, but diffuse expression of cyclin D1 excludes CLL/SLL { 19467018 ; 22706868 }. The cells in the PCs may variably express MYC { 26980727 }. MUM1, CD20, and CD23 expression is usually stronger in PCs than in diffuse areas { 16426914 ; 10872678 ; 10374772 }. The proliferation index is low overall but elevated in PCs. Minimal antibody panels for the diagnosis of B-cell lymphomas have been described { 27247372 }. Accelerated CLL/SLL: histologically aggressive CLL/SLL or prolymphocytic progression Histologically aggressive CLL/SLL: PC size and number of prolymphocytes or paraimmunoblasts vary amongst cases. Those with very large, prominent/confluent PCs (>20x field) or with high proliferation indices (> 2.4 mitoses/PC or >40% Ki67+ in PCs) are designated “histologically aggressive” CLL/SLL. Prolymphocytic progression: If the total numbers of prolymphocytes (medium-sized cells with basophilic cytoplasm and a prominent nucleolus) is >15%, prolymphocytic progression that often shows TP53 disruption should be considered { 420739 ; 3463362 ; 2738163 ; 18216293 } and the blastoid variant of MCL should be excluded. B-cell prolymphocytic leukaemia (B-PLL) is now classified as prolymphocytic progression of CLL/SLL. Cases of histologically aggressive CLL/SLL or prolymphocytic progression have a clinical outcome between that of typical CLL/SLL and RT { 20421272 }, which occurs in ~5% of cases of CLL/SLL { 9482533 }. Richter transformation (RT): The diagnosis of RT is optimally based on lymph node excisional biopsy; on needle biopsy, it may be difficult to distinguish prominent PCs from DLBCL { 29692342 }. Tumour cells in the DLBCL-variant of RT, which are almost always non-GCB immunophenotype, frequently over-express PD1, while background histiocytes express PD-L1 { 30028010 ; 33972504 }. CD5 is occasionally expressed, CD23 is typically negative and EBV is usually absent { 29692342 }. Rare cases of CLL/SLL with progression to lymphoma resembling classic Hodgkin lymphoma (CHL) (‘classic Hodgkin lymphoma-type RT’) also occur (<1%). These cases show both the typical neoplastic cells and the characteristic milieu of CHL, with mixed cellularity CHL being the most common subtype { 22017478 }. Reed-Sternberg cells and variants are usually EBV positive. Survival of CHL-RT is generally better than that of DLBCL-RT possibly because most CHL-RT are clonally unrelated to the original CLL/SLL { 29692342 }. The presence of scattered Reed-Sternberg cells or Reed-Sternberg-like cells (EBV+ or -), without the milieu of CHL, can also be seen in cases of CLL/SLL without transformation { 22017478 ; 35091549 }. In very rare cases, patients with CLL/SLL develop histiocytic/dendritic cell neoplasms, likely representing clonal evolution and trans-differentiation of the original CLL/SLL clone, with loss of characteristic morphology and B-antigen expression { 31317311 ; 21666687 }. Exceptionally rare cases of mature T-cell lymphoma have arisen in association with CLL/SLL { 15223953 ; 24418862 ; 31433844 ; 33739791 }. Cytology See above Diagnostic molecular pathology In >80% of patients with CLL/SLL, at least one of four recurrent chromosomal alterations can be seen when using fluorescent in situ hybridization (FISH): del(11q), del(13q), del(17p) and trisomy 12 { 11136261 }. Of those with TP53 disruption, ~60% of cases carry both del(17p) and TP53 mutation, roughly 30% display TP53 mutations without del(17p) { 30442727 }. Therefore, prior to therapy, comprehensive assessment of TP53 requires investigation of both deletion of the TP53 locus, and mutations of TP53 by a sufficiently sensitive sequencing method { 29467486 ; 29540348 }. Since TP53 aberrations can emerge during the disease, in particular at the time of progression after chemo-immunotherapy, the TP53 status should be re-assessed at progression in previously TP53-wildtype cases. Unlike other B-cell malignancies, translocations involving the IG gene loci are uncommon in CLL/SLL. Exceptions include t(14;18)(q32;q21)/IGH::BCL2 and its light chain variants (2% of cases) { 34414624 ; 8947590 } and the rare t(14;19)(q32;q13)/IGH::BCL3 { 34414624 ; 18231927 ; 17495977 }. Unlike MCL, CLL/SLL does not harbour t(11;14)(q13;q32) { 34414624 }. The assessment of the SHM status of the clonotypic rearranged IGHV gene is recommended for all patients with CLL/SLL before therapy commencement { 28439111 ; 29540348 }. If the germline identity of the rearranged IGHV gene is below 98%, the patient is considered as IGHV-mutated CLL/SLL, while patients classified as IGHV-unmutated CLL/SLL show a germline identity ?98% { 10477713 ; 10477712 }. As for all cut-offs, there exist ‘borderline’ mutated cases, with a germline identity between 97-97.9%, and these may have diverse clinical outcomes. Caution is warranted in such cases regarding the prognosis { 28439111 }. Subset #2 configuration (IGHV3-21/IGLV3-21) of the IG gene rearrangement, mostly classified as IGHV-mutated CLL/SLL, heralds a poorer prognosis similar to IGHV-unmutated CLL/SLL { 25634617 ; 33131249 }. As the IG gene rearrangement and IGHV gene SHM status do not change over time, the test only needs to be performed once for each patient. In familial cases, germline determination of polygenic risk scores might be considered { 29674426 ; 34285341 }. Essential and desirable diagnostic criteria See Table #31646 Essential: - Classic morphology of CLL cells and absolute B-cell count >5×109/L - Flow cytometry (on peripheral blood and/or bone marrow aspirate samples) showing expression of CD19, CD5, CD20, CD23 (variable) & weakly expressed monotypic light chain. - Histopathology/immunohistochemistry (on bone marrow cell clot/core biopsy, and biopsies of lymph node or other tissue samples) demonstrating CD20+/weak+, CD5+/weak+, CD23 (variable) expression and no expression of cyclin D1- (weak positivity in subset of cells in PCs is allowed) Desirable: -Flow cytometry: Positive for CD200, ROR1, CD43 with absence of FMC7, CD79b (can be weakly positive), CD10, CD81 expression. -Histopathology/immunohistochemistry: Positive for CD23, LEF1, CD43, MUM1 (proliferation centres) with absence of CD10, SOX11 expression. Recommended investigations for prognosis/prediction: See Table #32036>> Essential Evaluation of del(11q), del(13q), del(17p), and trisomy 12 TP53 mutation analysis IGHV gene SHM analysis and subset #2 configuration Desirable Demonstration of complex karyotype BTK, PLCG2, and BCL2 mutation analysis Staging Rai and Binet systems are used. They are based on blood cell counts and physical examination (Table 3 #29086). Stage of SLL is determined with the Lugano modifications to the Ann Arbor system, which is based on CT scan and bone marrow biopsy { 25113753 }. Positron-Emission-Tomography/Computed-Tomography may help differentiate progressive CLL/SLL from RT, and in case of high maximum standardized-uptake-value (SUVmax) of >10, a diagnostic biopsy should be undertaken. Prognosis and prediction Despite significant improvements in clinical outcome since the introduction of targeted therapies, CLL/SLL remains largely incurable. Clinical staging is relevant for prognostication and decision on therapy start. While del(13q), presenting as sole aberration, is associated with indolent disease, TP53 deletion and/or mutation is a biomarker that predicts resistance to chemoimmunotherapy. { 30442727 ; 29467486 ; 29540348 }. An unmutated IGHV gene is predictive of shorter progression-free survival if patients are treated with chemoimmunotherapy { 26486789 ; 31628428 ; 32206772 }. Prognostic markers with the highest impact on outcome should be evaluated at the time of therapy, to aid therapeutic strategy decision-making. Markers that may develop later during the disease, due to clonal evolution, should be tested repeatedly { 26466571 }. Among the chromosomal and molecular genetic aberrations, del(17p) and/or TP53 mutation have the strongest impact on prognosis and prediction of therapeutic outcome (Table 4 #32036), even with the use of targeted agents { 20697090 ; 33026937 }. Furthermore, IGHV mutated and unmutated CLL/SLL show different kinetics with respect to proliferation and, therefore, have different time-to-therapy and time-to-relapse with time-limited chemotherapy-based regimens { 10477712 ; 10477713 }. Stereotyped subset #2, independent of its IGHV gene SHM status, is associated with poor responses to chemoimmunotherapy { 33131249 }. IGHV mutational status and presence of TP53 aberrations are both included in the CLL-international prognostic index (CLL-IPI) { 27185642 }, along with age, stage and beta2-microglobulin level. The international prognostic score for early-stage CLL/SLL (IPS-E) includes IGHV mutational status, absolute lymphocyte count >15 × 109/L, and presence of palpable lymph nodes { 32267500 }. Cases progressing under treatment with BTK-inhibitors often (60-80% of cases) show mutations of BTK (mostly in the kinase domain), PLCG2 and others. Further, BTK and PLCG2 mutations may occur in RT patients on BTK-inhibitor therapy. Genetic aberrations associated with RT following novel agents are like those observed following chemoimmunotherapy { 24869598 ; 25189416 ; 31243043 ; 28049639 ; 28418267 ; 28366935 ; 29259203 ; 29296715 ; 26182309 ; 30508305 ; 29463802 ; 28473407 }. In ~50% of cases progressing on treatment with BCL2-inhibitors, the CLL/SLL-cells acquire mutations in BCL2 (disrupting drug-binding site) or amplification of 1q (involving MCL1) { 30514704 ; 31004028 ; 32232486 ; 31951646 ; 31543463 }. Complex karyotype and genomic complexity can be identified by a variety of different methods including chromosome banding analysis, microarrays or whole genome sequencing { 30602617 ; 31974198 , 29808933}. The precise definition of complex karyotype depends on the technology used and is predictive of resistance to chemoimmunotherapy, in TP53-wild-type patients { 30602617 ; 32777106 ; 34314481 ; 31974198 }. Overexpression of ZAP70 (intracellular), CD38 and CD49d (membrane-associated) reflects activation and proliferation of CLL/SLL and tends to correlate with unfavourable genetic markers, such as unmutated IGHV genes { 21765022 ; 28935990 }. Similarly, the presence of PCs in marrow biopsies is often associated with TP53 abnormalities and complex karyotype { 30086334 }. The presence of either >15% prolymphocytes in peripheral blood (prolymphocytic progression) or of large confluent PCs in lymph nodes (histologically aggressive CLL/SLL) is associated with disease evolution and with poorer outcomes (i.e., accelerated CLL/SLL) { 420739 ; 3463362 ; 2738163 ; 18216293 ; 20421272 }. Amongst the serum parameters, beta2-microglobulin is an independent prognostic marker in early and advanced CLL/SLL. Elevated lactate dehydrogenase (LDH) appears to reflect inferior prognosis in relapsed CLL/SLL { 27185642 ; 33026937 ; 32562875 }. Responsible editor(s) Anna Schuh Co-editor(s) Sarah E. Coupland William Arthur Sewell Responsible Author Kikkeri N. Naresh Co-author(s) Judith A. Ferry Davide Rossi William Robert Geddie Catherine J. Wu Andy C. Rawstron Barbara Eichhorst Norah Olubunmi Akinola Shenmiao Yang Carlos Chiattone Jan Andreas Burger Nicholas Chiorazzi Kostas Stamatopoulos Richard Rosenquist Kanti Rai Stephan Stilgenbauer Abraham Varghese Susan Slager Individual entity section ¬e{:Naresh KN, Ferry JA, Rossi D, et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2023 Jun 28]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63/116.};