Histologic Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Histologic Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma
Rose Lou Marie C. Agbay, MD1, Nitin Jain, MD2, Sanam Loghavi, MD1,
L. Jeffrey Medeiros, MD1, and Joseph D. Khoury, MD1†
Department of Hematopathology1,The University of Texas MD Anderson Cancer
Center, Houston, Texas, USA; Department of Leukemia2,The University of Texas MD
Anderson Cancer Center, Houston, Texas, USA
†
Corresponding author:
Joseph D. Khoury, MD
The University of Texas MD Anderson Cancer Center
Department of Hematopathology
1515 Holcombe Boulevard, MS-072
Houston, Texas 77030
United States of America
E-mail: jkhoury@mdanderson.org
Telephone: (713) 563-9171
Fax: (713) 794-1800
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi: 10.1002/ajh.24473
This article is protected by copyright. All rights reserved.

American Journal of Hematology Page 2 of 41
Agbay et al - 2
Running title: CLL/SLL transformation
Conflict of interest disclosure: None of the authors has declared any competing
financial interests.
Key words: CLL/SLL, lymphoma, leukemia, mutations, genomic, transformation, TP53,
NOTCH1
Manuscript statistics:
Manuscript word count: 3498
Abstract word count: 100
Manuscript pages: 34
Figures: 3
Tables: 3
Supplemental Data: 1
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ABSTRACT
Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo
transformation to a clinically aggressive lymphoma. The most common form of
transformation, to DLBCL, is also known as Richter syndrome. Transformation
determines the course of the disease and is associated with unfavorable patient
outcome. Precise detection of transformation and identification of predictive biomarkers
and specific molecular pathways implicated in the pathobiology of transformation in
CLL/SLL will enable personalized therapeutic approach and provide potential avenues
for improving the clinical outcome of patients. In this review, we present an overview of
the pathologic features, risk factors and pathogenic mechanisms of CLL/SLL
transformation.
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INTRODUCTION
The concept of transformation in patients with chronic lymphocytic leukemia (CLL) was
initially suggested in a case report published in 1928 by Maurice Richter.
(Supplementary figure 1) He described the autopsy findings of a 46-year-old man with
non-tender swelling of the left side of the neck, which gradually increased in size.
Lymphadenopathy was accompanied by occasional pain in the epigastric and
suprapubic regions and weight loss. The laboratory findings included lymphocytosis,
and degenerated white blood cells in the peripheral blood smear. Significant autopsy
findings included generalized lymphadenopathy, hepatosplenomegaly, and a small ulcer
in the ileum. Microscopic examination of the lymph nodes and liver showed two
histologic lesions termed as “leukemic cells” and “tumor cells”. The leukemic cells were
described as small lymphoid cells and the tumor cells as large lymphoma cells. The
bone marrow was comprised mostly of small neoplastic lymphocytes, whereas the ileal
lesion consisted of large lymphoma cells. As such, the simultaneous occurrence of two
lesions of different histologic grades was demonstrated, although their genetic
relationship was not established.[1]
In 1964, Lortholary and colleagues in France coined the term Richter’s syndrome.
(Supplementary figure 2) The authors presented four autopsy reports of patients
presenting initially with CLL. The patients presented with fever, weight loss,
lymphadenopathy, hepatosplenomegaly, and/or lymphocytosis. The CLL was treated
initially with either radiotherapy alone, or radiotherapy and prednisone. All patients
eventually developed a malignant lymphoma such as so-called reticular cell sarcoma
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(most likely diffuse large cell lymphoma) or Hodgkin disease (lymphoma). A mixed
proliferation of small neoplastic lymphoid cells and large lymphoma cells were observed
on histologic sections of the lymph nodes. Fifteen published articles from 1928 until
1963, including the case report by Richter, were reviewed by Lortholary and colleagues
as a part of their manuscript that described cases of concurrent CLL/SLL and a
histologically high-grade malignant lymphoma. The authors proposed that such an
association be known as Richter syndrome and this term remains in current use.[2]
Richter syndrome (RS) refers to a setting in which a patient with CLL/SLL also develops
diffuse large B-cell lymphoma (DLBCL) and, most often, is a manifestation of histologic
transformation. Richter transformation is another term often used as a synonym. Richter
syndrome is also loosely applied to CLL/SLL patients who develop less common
lymphoid neoplasms such as Hodgkin lymphoma (HL), plasmablastic lymphoma or B-
lymphoblastic leukemia/lymphoma. Whereas histologic transformation occurs in patients
with other types of low-grade B-cell neoplasms [3], the term RS is only used in the
context of CLL/SLL.
In this review, we present an overview of the pathologic features, risk factors and
pathogenic mechanisms of Richter syndrome.
CLINICAL FEATURES
Transformation of CLL/SLL into DLBCL or another uncommon type of aggressive
lymphoma is typically suspected when a patient with CLL/SLL develops sudden onset of
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B symptoms, often accompanied by enlarging lymph nodes detected by physical
examination or imaging studies. Commonly, work-up for such a scenario includes 18-
fluorodeoxyglucose-positron emission tomography (18FDG-PET/CT) which detects a
relative increase in metabolic activity, expressed quantitatively as standardized uptake
value (SUV). In a patient with suspected RS, the identification of any lesion (nodal or
extranodal) with increased 18FDG avidity (SUV>5.0) by PET/CT is an indication for
tissue evaluation. Whereas the absence of lesions detectable by 18FDG-PET is highly
sensitive in excluding RS, with a negative predictive value of up to 97%, the positive
predictive value of 18FDG-PET/CT for RS is generally proportional to the SUV; an
SUV>10 is predictive of the presence of aggressive lymphoma with 80% confidence,
and an SUV>13 with >90% confidence.[4-7]
Laboratory studies commonly associated with RS include a substantially elevated
serum lactate dehydrogenase (LDH) level >1.5 times the upper limit of normal and an
elevated serum beta-2 microglobulin (β2M) level >2 mg/L. Hypercalcemia, new onset of
absolute lymphocytosis ≥5.0x109/L, and thrombocytopenia <100x109/L often
accompany RS, but these findings are not by themselves a reliable predictor of RS.[8-
19]
HISTOLOGIC VARIANTS OF RICHTER TRANSFORMATION
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma is the most frequent histologic variant of histologic
transformation in patients with CLL/SLL. The development of DLBCL occurs 1.8 to 4.0
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years from the time of initial CLL/SLL diagnosis and can arise before or subsequent to
CLL/SLL therapy. Among patients with newly diagnosed CLL/SLL, the annual incidence
rate of DLBCL is 0.5 %; whereas among patients who have received treatment for
CLL/SLL the annual incidence rate of DLBCL is ~1%.[15] Up to 10.7% of all CLL/SLL
patients progress to DLBCL (RS-DLBCL).[11, 12, 14, 15, 20-23] (Supplementary table
1) The incidence rate for DLBCL reported in the literature is highly variable, likely
attributable to many factors including the heterogeneity of the patient population
studied, duration of clinical follow-up, and diagnostic criteria used to define development
of DLBCL (clinical/imaging vs. biopsy-proven). DLBCL may arise in any demographic
subset of CLL/SLL patients, but is most common in men over 60 years of age. (Table 1)
Factors associated with RS-DLBCL predisposition
A number of factors are likely involved in predisposing CLL/SLL patients to developing
RS-DLBCL, as are summarized in Table 2. On the basis of stereotyped BCR, CLL/SLL
can be segregated into various subsets. In one study, a subset associated with the
IGHV4-39/IGHD6-13/IGHJ5 stereotype was associated with the highest risk for RS, and
stereotyped BCR as well as IGHV4-39 were independent predictors of RS. Interestingly,
the stereotyped BCR of RS-DLBCL is not observed in de novo DLBCL.[24] Telomeres
play an important role in ensuring genetic stability and regulating critical cellular
functions, including proliferation and replicative senescence.[25] Others have reported
that the 5-year risk of developing RS may be higher in patients with CLL/SLL associated
with shorter (<5000 bp) telomere length (18.9% vs. 6.4%). In the same study, it was
observed that significantly shorter telomeres are present in CLL/SLL with unmutated
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IGVH genes, as well as in CLL/SLL associated with increased telomerase activity.
These findings point to a higher number of antecedent cell replications and thus a
higher chance to acquire additional genetic alterations.[26] Other biological risk factors
of CLL/SLL transformation to RS-DLBCL include expression of CD38[10, 14, 15], ZAP-
70[10, 12-15], and CD49d.[15] Cytogenetic abnormalities, such as del(11q22.3),
del(17p13), del(15q21.3), del(9p21), and/or add(2p25.3), have been also associated
with RS.[10, 15, 27] Heritable germline polymorphisms in BCL2[28], CD38[29] and
LRP4[30] have been reported to impart a higher risk for transformation, although the
functional mechanisms underlying these associations remain to be determined.
Additional factors predictive of the development of RS remain largely unknown.
Konoplev et al[23] showed that CLL/SLL patients with increased serum thymidine
kinase 1 (TK1), a key cellular enzyme involved in DNA synthesis, are at higher risk for
developing RS. Increased serum TK1 level is associated significantly with male sex,
elevated serum β2M level, unmutated IGVH, ZAP-70 expression, and lack of
del(13q14.3). Furthermore, RS patients with a higher serum TK1 level tended to be at a
higher risk of death. These observations were further corroborated by Szantho et al[31]
who showed that increased serum TK1 levels in CLL patients are associated with
advanced Rai stage, CD38 and ZAP-70 expression, and higher levels of absolute
lymphocytosis.
Pathologic features of RS-DLBCL
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Most cases of RS-DLBCL show diffuse effacement of lymph nodes or extranodal sites
by sheets of large cells with centroblastic morphology; a minority of cases have
immunoblastic features. Mitotic figures and apoptotic bodies are usually frequent, and a
starry-sky pattern and tumor necrosis are common.[32] Typically, the neoplastic cells
are positive for the B-cell markers - CD19, CD20, CD22, and PAX5 - as well as
monotypic surface immunoglobulin light chain. CD38, ZAP70, and CD49d are often
positive, whereas CD5 and CD23 expression is retained to a varying extent.[14, 15]
Approximately 80% of RS-DLBCL have a non-germinal center B-cell-like (non-GCB)
immunophenotype (negative for CD10 and positive for MUM1), whereas about 20%
have a GCB immunophenotype (positive for CD10 and/or BCL6+, MUM1-).[10, 33]
Other features often seen in RS-DLBCL include TP53 overexpression and a high
(>70%) Ki-67 proliferation index. (Figure 1) Epstein-Barr virus (EBV)-encoded RNA
transcripts may be detected in some cases.[15, 32]
Clonal relationship
The clonal relationship between CLL/SLL and RS-DLBCL was first established through
primary structural analyses of the IG genes.[34] About 70% to 80% of RS-DLBCL
cases are clonally related to the underlying CLL/SLL and can have similar unmutated or
mutated immunoglobulin heavy chain variable region (IGVH) sequences.[33]
Commonly, RS-DLBCL arises from a dominant CLL/SLL clone after having acquired
additional somatic mutations.[10] The molecular characteristics of the B-cell receptor
(BCR) have been suggested to have an impact on the risk for transformation. CLL/SLL
patients with unmutated IGVH genes are at an increased risk for RS compared with
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those with mutated IGVH.[9, 15] A fraction of CLL/SLL cases share common IGVH
complementary determining region 3 motifs (stereotyped BCR) as a result of
nonrandom recombination predispositions involving the V-D-J regions.
Molecular biology of RS-DLBCL
Despite morphologic and immunophenotypic overlap between RS-DLBCL and de novo
DLBCL, these diseases diverge significantly at the molecular level.[10, 27, 35]
The molecular profile of RS-DLBCL is complex. Two major transformation models have
been suggested to lead to development of RS from CLL/SLL.[27] Most RS-DLBCL
cases follow a “linear” model of transformation by which the transformed clone is a
direct progeny of the “parent” CLL/SLL clone; whereas in a minority of cases, a
“branched” model of evolution is implicated in which distinct genetic lesions direct a
common precursor cell to give rise to the CLL and RS clones independently (Figure 2).
Leukemic presentation of RS is associated with the latter model.
The most common chromosomal copy number alteration (CNA) linked to the
development of RS is loss of 17p (~40%) resulting in inactivation of TP53, which in turn
facilitates the development of additional genetic lesions, including additional genome-
wide somatic mutations and chromosomal rearrangements. Biallelic loss of
19p21/CDKN2A/B is frequently observed in RS (~30%) and is associated with the
“branched” model of evolution.[10] Of note, disruptions of TP53 and CDKN2A often
coexist with MYC-activating events. Other recurrent chromosomal CNAs implicated in
the pathogenesis of RS include trisomy 12, del(7q31.31-36.6), del(8p), and del(14q23.2-
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q32.33) as well as high-level amplifications of chromosomes 8, 11, 13, and 18.[10, 27,
36] Absence of del(13q14) also has been associated with an increased risk for
transformation to RS. Rearrangements involving the MYC locus (8q24), very rare in
CLL/SLL, may be gained during the course of disease, and have been suggested as a
secondary event in disease progression, particularly in patients who harbor 8q24/MYC
rearrangement in the context of a complex karyotype[12, 37]. Another possible
mechanism of MYC involvement in CLL/SLL, also associated with a shorter clinical
course, is 8q24/MYC amplification. Brown and colleagues sequenced exon 1 of MYC in
188 CLL/SLL samples and found one case with a MYC p.T58A mutation, and a
heterozygous insertion mutation that duplicates nine amino acids of the N-terminal
interaction and transactivation domain in another sample. Although MYC amplification is
a frequent event, considered to be acquired during transformation, this study showed
that MYC amplification in CLL/SLL without high-grade transformation may occur.[38]
Several genes involved in a host of cellular and biological programs have been
identified to be recurrently mutated in RS. [39-43] Genes involved in proliferation,
apoptosis, and cell cycle regulation seem to stand out. The most commonly mutated
genes implicated in the pathogenesis of RS include TP53 (tumor suppressor), NOTCH1
and MYC (proliferation), and CDKN2A/B (cell cycle regulation), together accounting for
up to 90% of alterations seen in RS-DLBCL.[27] Unlike TP53 and CDKN2A/B,
NOTCH1 mutations and other lesions associated with MYC activation are mutually
exclusive.[40] Notably, TP53 mutations and activating NOTCH1 mutations are less
common in de novo DLBCL. Additional signaling pathways involved in the emergence of
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RS-DLBCL include the MAPK, Wnt, NF-κB, and TGF-β pathways. Cases of de novo
DLBCL and RS-DLBCL share a minor subset of genes as a part of their genetic
signatures - including MYC activation (GCB-derived DLBCL), MYD88 mutations and
CDKN2A/B loss (activated B-cell-derived DLBCL). However, RS-DLBCL lacks other
abnormalities common in de novo DLBCL, such as inactivation of CREBBP/EP300,
β2M, PRDM1/BLIMP1, and TNFAIP3/A20, as well as BCL2 and BCL6
translocations.[27]
Accelerated phase CLL
The term accelerated phase of CLL/SLL has been proposed to describe a biopsy
specimen that shows increased large cells and a high proliferation rate, but without
clear-cut histologic evidence of DLBCL. Patients may or may not have clinical
symptoms of transformation. Patients with CLL/SLL in accelerated phase often,
although not always, have a more aggressive clinical course. In a study by Gine et al,
the authors suggest that the diagnosis of accelerated phase CLL/SLL can be based on
any of three morphologic criteria: (1) expanded proliferation centers (broader than a x20
microscopic field); (2) increased mitotic activity (>2.4 mitotic figures/proliferation center);
or (3) an increased proliferation index within proliferation centers as indicated by high
Ki-67 labeling (>40%). In their study, the median survival of patients with accelerated
phase CLL/SLL was shorter than patients with typical CLL/SLL. In addition, the median
survival from the time of biopsy according to the morphologic patterns of “non-
accelerated” CLL, “accelerated” CLL, and DLBCL transformation was 76 months, 34
months, and 4.3 months, respectively.[44]
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PLASMABLASTIC LYMPHOMA
Plasmablastic lymphoma (PBL) is an aggressive B-cell malignancy, thought to be
related to DLBCL, in which the lymphoma cells exhibit morphologic and
immunophenotypic features of plasma cell differentiation.[45](Supplementary figure 3)
These neoplasms most commonly arise de novo in the setting of immunodeficiency,
however, a few cases of plasmablastic lymphoma (RS-PBL) arising in patients with
CLL/SLL has been reported.[18, 19, 46] Most patients who develop RS-PBL are men,
52 to 77 years of age. A serum or urine paraprotein can be detected in some
patients.[18] In addition to typical plasmablastic features, residual CLL/SLL cells may
be identified in some areas. The neoplastic cells of RS-PBL often express CD38, ZAP-
70, CD138, BLIMP1, IRF4/MUM1, and XBP1. CD5, CD20, PAX5, and IRF8 are
commonly negative. Molecular studies have shown monoclonal IGH[18] and MYC
rearrangement.[46] The prognosis of patients with RS-PBL is grim. The few CLL/SLL
patients with RS-PBL reported in the literature died within 3 to 6 months after
transformation.[18, 19, 46]
B-LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
B-lymphoblastic leukemia/lymphoma (B-LBL) is a neoplasm derived from progenitor B-
lymphoid cells often involving bone marrow, peripheral blood, and less commonly lymph
nodes.[47] Acute lymphoblastic transformation of CLL/SLL (RS-LBL) is rare, although
several cases have been reported. Most patients are men, with a reported age range of
42 to 76 years. The reported interval between CLL/SLL diagnosis and RS-LBL ranges
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from 2 months to 7 years; although simultaneous presentation of CLL/SLL and RS-LBL
may occur.[48-56] RS-LBL is characterized by numerous lymphoblasts in a background
of cells typical of CLL/SLL. The blasts are intermediate size, with indented nuclei, fine
chromatin, one or two small nucleoli, and scant cytoplasm. The neoplastic cells express
HLA-DR, surface Ig, pan-B cell markers and TdT[50, 51, 54-56]; a TdT-negative case
also has been reported.[53] There is variable expression of CD5, CD10, CD22 and
CD23.[50, 51, 53-56]
Early studies supported clonal evolution from CLL/SLL to RS-LBL based on surface
immunoglobulin expression, cytogenetic findings,[50, 54] and molecular analysis of the
IG heavy and light chains.[49, 51, 53, 56] A recent study described an analysis of paired
CLL/SLL and B-LBL specimens from 2 patients with Philadelphia chromosome-positive
B-LL and showed that the CLL/SLL and B-LBL cells used different IGHV families and
were clonally unrelated. In addition, the IGHV gene was unmutated in both CLL/SLL
and B-LBL cells in one of these 2 cases, and IGHV was mutated in CLL/SLL cells but
not in B-LBL cells. These data suggest that B-LBL can occur in patients with CLL/SLL
associated with either mutated or unmutated IGHV. Furthermore, the authors suggested
that B-LBL may represent a secondary neoplasm and not evidence of histologic
transformation in a subset of patients.[55] Cytogenetic studies also have shown the
presence of 8q24 translocation acquired at the time of transformation to B-LBL in some
patients.[50, 51] Some authors use the term Burkitt-like lymphoblastic transformation for
those occurrence.[56] Overall, compared with typical B-LBL, cases of blastic
transformation of CLL/SLL show distinctive clinical features including a poor prognosis,
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and likely a different pathogenesis. In our opinion, classifying these cases as B-ALL or
B-LBL without further comment may be misleading to clinicians and patients and
therefore the pathology report needs to indicate that the neoplasm represents
transformation of CLL/SLL and not de novo disease. We suggest using terms such as
“TdT-positive blastoid lymphoma” or “high-grade TdT-positive blastic B-cell
leukemia/lymphoma” for these tumors.
HODGKIN LYMPHOMA
Less than 1% of patients with CLL/SLL develop Hodgkin lymphoma (RS-HL).[16, 57,
58] Patients with CLL/SLL are typically in the seventh decade of life (range, 30 to 88
years) when they undergo transformation to RS-HL and most are men. The median
interval between CLL/SLL diagnosis and RS-HL is 4 to 6 years (Table 3). Of note,
patients with CLL/SLL who are treated with purine nucleoside analogs (fludarabine,
cladribine) and later on develop RS-HL seem to have worse outcomes compared with
other CLL/SLL patients who develop RS-HL.[59, 60] It has been postulated that
exposure to immunosuppressive chemotherapy in patients with CLL may increase the
risk for HL transformation. The presumed etiologic process is the marked and prolonged
reduction of CD4-positive and CD8-positive T-cells, which likely permits the proliferation
and accumulation of EBV-positive B-cells, eventually resulting in a high-grade
lymphoma.[59, 61]
Hodgkin transformation is characterized by Hodgkin and Reed-Sternberg (HRS) cells in
a polymorphous inflammatory background distinct from the CLL/SLL.[17] (Figure 3) The
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inflammatory background consists of T-cells and histiocytes, with or without abundant
eosinophils. Tumor necrosis is a common finding.[32] Any of the histologic subtypes of
HL can be seen, with the mixed cellularity subtype being most common.[59]
An unusual pattern that raises the possibility of HL transformation is the occurrence of
HRS cells scattered in a monomorphous background of CLL cells. In some patients,
follow-up biopsy specimens show unequivocal CHL as described above, but in other
patients there is no subsequent HL. These lesions have been referred to in the literature
as CLL/SLL with HRS cells.[62-65] A recent study [66] suggests that this pattern can be
considered as an early event in the transformation and appears to have the potential to
progress to the type of RS-HL wherein HRS cells are in a polymorphous inflammatory
background distinct from the CLL/SLL. The same study showed that the overall survival
for these two types of morphology is similar.
By immunohistochemistry, HRS cells express CD30, CD15, and PAX5 (dim), and these
cells are commonly positive for EBV (Table 4).[33] HRS cells may be positive for CD20,
usually with variable intensity, in 20% to 30%of cases.[59]
In about 80% of patients with RS-HL, the CLL/SLL cells have mutated IGVH. This is a
much higher frequency than that observed among patients who develop RS-DLBCL or
have no transformation.[33] In addition, it has been demonstrated that similar VH gene
rearrangements can be seen in HRS and CLL/SLL cells, implying that the two
populations of cells were derived from a common precursor B-cell.[67, 68] A recent
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study showed that most of the CLL/SLL that is ZAP-70 positive is IGHV unmutated,
whereas ZAP-70 negative cases are IGHV mutated. HRS cells from all IGHV unmutated
(ZAP-70 positive) CLL/SLL cases were clonally unrelated, while HRS cells from IGHV
mutated (ZAP-70 negative) CLL/SLL cases frequently share clonal origin with the
associated CLL.[66]
T-CELL LYMPHOMAS
Rarely patients with CLL/SLL develop T-cell lymphomas. In general, the relationship
between CLL/SLL and these neoplasms is poorly understood.[69, 70] These rare
patients are usually not included under the umbrella term of RS in the literature. A few
relevant papers are cited, but these patients are not the focus of this review.
Treatment
Patients with RS generally have a poor prognosis. Most data for treatment for RS is
derived from single-arm phase I-II studies, and retrospective analyses.[13, 71-78] The
standard therapy for RS is chemoimmunotherapy with a median survival after therapy
of less than 1 year.[79] MD Anderson Cancer Center has used oxaliplatin-based
regimen (OFAR: oxaliplatin, fludarabine, Ara-c [cytarabine], rituximab) for patients with
RS.[13, 71] OFAR regimen led to an overall response rate (ORR) of 50% with a 20%
CR rate.[71] However, the median progression-free survival (PFS) was only 4 months,
and the median OS was 8 months. Langerbeins and colleagues reported outcomes in
15 patients with RS who received rituximab, cyclophosphamide, doxorubicin, vincristine,
prednisone (R-CHOP).[74] Two-thirds of the patients responded, with a median PFS of
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10 months and a median OS of 21 months. Ibrutinib, a BTK inhibitor, is approved for
patients with CLL.[80, 81] Anecdotal reports have suggested the activity of ibrutinib in
patients with RS.[82-84] Pembrolizumab, a PD-1 monoclonal antibody, has also been
reported to have encouraging activity in patients with RS.[85] Several other targeted
agents such as PI3K inhibitors, antibody-drug conjugates, or bi-specific antibodies may
have a role in patients with RS, and need further evaluation. Allogeneic stem cell
transplantation (allo-SCT) remains an important therapeutic modality for patients with
RS.[86, 87] Although allo-SCT is indicated for treating RS patients who undergo
remission, and is the only modality that offers a potential for cure, many patients do not
qualify because of their older age or inadequate response to induction therapy. For
Hodgkin’s transformation, treatment is with multidrug chemotherapy such as
doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD).[88]
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Figure Legends
Figure 1. Diffuse large B cell lymphoma transformation of CLL/SLL. (A, B) CLL
involving the bone marrow. (A) CLL with cytologically atypical morphology in a bone
marrow aspirate smear with a population of small and medium-sized cells. (B) Bone
marrow space replaced by sheets of small lymphocytes. A proliferation center is
present. (C to F) Concurrent nasal mass biopsy involved by DLBCL. (C) Diffuse
growth of large neoplastic lymphoid cells and a conspicuous starry sky pattern. (D)
Neoplastic cells with immunoblast-like and centroblast-like morphology. (E) The
neoplastic cells are positive for PAX5 and negative for CD5. (F) Ki-67
immunohistochemistry demonstrates a high proliferation rate. (A, wright-giemsa stain; B
to D, hematoxylin-eosin; E and F, IHC with hematoxylin counterstain)
Figure 2. Patterns of clonal evolution in CLL/SLL transformation. In the linear
model (A) of transformation, more common among patients with RS-DLBCL, DLBCL
originates directly from the major CLL/SLL clone following the acquisition of additional
genetic alterations. In this model, the DLBCL and CLL/SLL clones show similar IGVH
mutation profiles. In the branched model (B), clones derive directly from a common
precursor cell (CPC) by way of acquiring distinct genetic lesions. Note that both clones
share a subset of alterations with the CPC and with each other in addition to harboring
distinct genetic lesions. In both models, a minor subclone arising from the CPC and
already equipped with transformation-specific gene signatures may be present at the
time of diagnosis and may later declare itself as bona fide transformation.
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Agbay et al - 34
Figure 3. Hodgkin lymphoma transformation of CLL/SLL. (A and B) Lymph node
involved by CLL/SLL (dark areas) and Hodgkin lymphoma (light/pale areas) indicating
transformation. (C) Low-grade component composed of small lymphocytes (D) with
CD5 expression. (E) Hodgkin and Reed-Sternberg (HRS) cells in a polymorphous
inflammatory background composed of T cells, histiocytes and eosinophils. (F) HRS
cells are CD30+. (A to C, E, hematoxylin-eosin; D and F, IHC with hematoxylin
counterstain)
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Agbay et al - 35
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Tables
Table 1: Summary of current studies on clinical features of CLL patients with Richter syndrome
Study Age Gender LDH β2M TK1 Absolute Platelets

Male Female (>1.5 times lymphocyte <100x109/L
% % the upper count >
limit) 5.0x109/L
Tsimberidou 53% NR NR 47% 40% NR 37% 57%
et al (87) (>60 years) (>3 x UNL) (> 5x109/L) (<100x109/L)
Rossi et al 70 years 64.7 35.3 35% 3 mg/L NR NR 204
(12) (64-73) (2.3-3.7) (150-232)
Tsimberidou 66 50 50 55% 55% NR 20% NR
et al (13) (34-77) (>2 x ULN) (>30x109/L)
Rossi et al 65% 62.7 NR 45% NR NR 51.2% 30.5%
(9) (>60 years) (> 5x109/L) (<100x109/L)
Fan et al 37.5% 62.5 37.5 31% 4.35 mg/L 37.5% 18.75% NR
(14) (>60 years) ( 2.0-16.7) (> 2.0 pmol/L) (> 5x109/L)
Chingrinova 70% 56 NR 50% NR NR 44% 24%
et al (10) (>60 years) (> 5x109/L) (<100x109/L)
Parikh et al 61 78 NR NR 3.1 mg/L NR 9.1x109/L 190
(15) years (1.2-13.1) (0.7 to 415.5) (71-493)
(21-85)
NR: not reported; UNL: upper normal limit; LDH: Lactate dehydrogenase; β2M: Beta 2 microglobulin; TK1: Thymidine
kinase 1
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Table 2: Summary of factors reported to be associated with risk for RS in patients with CLL/SLL
Frequency in RS patients (%) References
Biological characteristics Unmutated IGVH 89 Tsimberidou et al (13)
66.7 Fan et al (14)
76 Parikh et al (15)
Stereotyped B-cell receptors 49.3 Rossi et al (24)
Short telomere length (≤5000 bp) 47 (90/191) Rossi et al (26)
ZAP-70+* 89 Tsimberidou et al (13)
66.7 Fan et al (14)
61 Chigrinova et al (10)
CD38+* 93 Fan et al (14)
46 Chigrinova et al (10)
CD49d+* 77 Parikh et al (15)
Genetic characteristics del(11q) 20 Tsimberidou et al (13)
26.7 Fan et al (14)
del(17p) 33 Tsimberidou et al (13)
26.7 Fan et al (14)
40 Fabbri et al (27)
del (9p21) ~30 Fabbri et al (27)
add(2p25.3) 14 Chigrinova et al (10)
TP53** disruption*** 60 (12/20) Chigrinova et al (10)
47 Rossi et al (9)
36 Fabbri et al (27)
MYC** aberrations 18 Chigrinova et al (10)
26 Rossi et al (9)
CDKN2A disruption ~30 Fabbri et al (27)
Trisomy 12** 40 Tsimberidou et al (13)
26.7 Fan et al (14)
~30 Fabbri et al (27)
NOTCH1** Fabbri et al (27)

*By immunohistochemistry or flow cytometry.
**Among the 4 most commonly altered aberrations ~90% of RS cases.
***Includes deletion and/or mutation.
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Agbay et al - 3
Table 3: Summary of major studies of Hodgkin transformation in patients with CLL
Study Study Type of study Age, years Gender Median time to Frequency of EBV
period (range) Male Female development Hodgkin positive
% % of Hodgkin transformation RS
transformation, cells
years (range)
Bockorny 1975- Meta-analysis 65.7 76.5 23.5 4.3 86 cases in 36 70.6%
et al (60) 2011 (34-85) (0-26) years
Parikh et 1995- Cohort 68 81 NR 6.2 0.05%/year 67%
al (58) 2011 (45-88) (0-24.5)
Tadmor et 1996- Retrospective 58 75 25 5.9 13% 50%
al (16) 2010 (30-77) (0.8-11.9) (16 of 119)
NR: Not reported
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Figure 1. Diffuse large B cell lymphoma transformation of CLL/SLL
194x156mm (300 x 300 DPI)
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Figure 2. Patterns of clonal evolution in CLL/SLL transformation.
193x116mm (300 x 300 DPI)
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Figure 3. Hodgkin lymphoma transformation of CLL/SLL.
195x157mm (300 x 300 DPI)
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Histologic Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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Histologic Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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Histologic Transformation of Chronic Lymphocytic Leukemia/Small Lymphocytic

L. Jeffrey Medeiros, MD1, and Joseph D. Khoury, MD1†

Department of Hematopathology1,The University of Texas MD Anderson Cancer

Center, Houston, Texas, USA; Department of Leukemia2,The University of Texas MD

Anderson Cancer Center, Houston, Texas, USA

The University of Texas MD Anderson Cancer Center

1515 Holcombe Boulevard, MS-072

Houston, Texas 77030

United States of America

Telephone: (713) 563-9171

Fax: (713) 794-1800

This article is protected by copyright. All rights reserved.

Running title: CLL/SLL transformation

Key words: CLL/SLL, lymphoma, leukemia, mutations, genomic, transformation, TP53,

Manuscript word count: 3498

Abstract word count: 100

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Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo

transformation to a clinically aggressive lymphoma. The most common form of

transformation, to DLBCL, is also known as Richter syndrome. Transformation

outcome. Precise detection of transformation and identification of predictive biomarkers

and specific molecular pathways implicated in the pathobiology of transformation in

the pathologic features, risk factors and pathogenic mechanisms of CLL/SLL

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initially suggested in a case report published in 1928 by Maurice Richter.

(Supplementary figure 1) He described the autopsy findings of a 46-year-old man with

Lymphadenopathy was accompanied by occasional pain in the epigastric and

findings included generalized lymphadenopathy, hepatosplenomegaly, and a small ulcer

lesions of different histologic grades was demonstrated, although their genetic

relationship was not established.[1]

(Supplementary figure 2) The authors presented four autopsy reports of patients

lymphadenopathy, hepatosplenomegaly, and/or lymphocytosis. The CLL was treated

eventually developed a malignant lymphoma such as so-called reticular cell sarcoma

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as a part of their manuscript that described cases of concurrent CLL/SLL and a

histologically high-grade malignant lymphoma. The authors proposed that such an

transformation. Richter transformation is another term often used as a synonym. Richter

lymphoid neoplasms such as Hodgkin lymphoma (HL), plasmablastic lymphoma or B-

lymphoblastic leukemia/lymphoma. Whereas histologic transformation occurs in patients

pathogenic mechanisms of Richter syndrome.

Transformation of CLL/SLL into DLBCL or another uncommon type of aggressive

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B symptoms, often accompanied by enlarging lymph nodes detected by physical

fluorodeoxyglucose-positron emission tomography (18FDG-PET/CT) which detects a

relative increase in metabolic activity, expressed quantitatively as standardized uptake

extranodal) with increased 18FDG avidity (SUV>5.0) by PET/CT is an indication for

tissue evaluation. Whereas the absence of lesions detectable by 18FDG-PET is highly

predictive value of 18FDG-PET/CT for RS is generally proportional to the SUV; an

SUV>10 is predictive of the presence of aggressive lymphoma with 80% confidence,

and an SUV>13 with >90% confidence.[4-7]

Laboratory studies commonly associated with RS include a substantially elevated

absolute lymphocytosis ≥5.0x109/L, and thrombocytopenia <100x109/L often

HISTOLOGIC VARIANTS OF RICHTER TRANSFORMATION

DIFFUSE LARGE B-CELL LYMPHOMA

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attributable to many factors including the heterogeneity of the patient population

of DLBCL (clinical/imaging vs. biopsy-proven). DLBCL may arise in any demographic

Factors associated with RS-DLBCL predisposition

A number of factors are likely involved in predisposing CLL/SLL patients to developing

RS-DLBCL, as are summarized in Table 2. On the basis of stereotyped BCR, CLL/SLL

stereotyped BCR as well as IGHV4-39 were independent predictors of RS. Interestingly,

the stereotyped BCR of RS-DLBCL is not observed in de novo DLBCL.[24] Telomeres

functions, including proliferation and replicative senescence.[25] Others have reported