AJCP / Original Article

Aberrations of MYC Are a Common Event in B-Cell

Prolymphocytic Leukemia
Ellen Flatley, MD,1 Andy I. Chen, MD,2 Xiangrong Zhao, MD, PhD,3 Elaine S. Jaffe, MD,3
Jennifer B. Dunlap, MD,1 Stefania Pittaluga, MD, PhD,3 Shahed Abdullah,3 Susan B. Olson, PhD,4
Stephen E. Spurgeon, MD,2 and Guang Fan, MD, PhD1

From the 1Department of Pathology, Oregon Health & Science University, Portland; 2Department of Hematology-Oncology, Knight Cancer Institute,
Oregon Health & Science University, Portland; 3Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute,
Bethesda, MD; and 4Knight Diagnostic Laboratory, Knight Cancer Institute, Oregon Health & Science University, Portland.

CME/SAM
Key Words: Leukemia; MYC; Prolymphocytic leukemia; Cytogenetics; FISH

Am J Clin Pathol September 2014;142:347-354

DOI: 10.1309/AJCPUBHM8U7ZFLOB

ABSTRACT Upon completion of this activity you will be able to:

• define diagnostic criteria for B-cell prolymphocytic leukemia (B-PLL).
Objectives: B-cell prolymphocytic leukemia (B-PLL) remains • list differential diagnoses for B-PLL.
a controversial entity, and its molecular pathogenesis • discuss the mechanism of MYC deregulation in B-cell lymphoma.
is largely unknown. Patients are older, typically having The ASCP is accredited by the Accreditation Council for Continuing
marked lymphocytosis and splenomegaly in the absence of Medical Education to provide continuing medical education for physicians.
The ASCP designates this journal-based CME activity for a maximum of
lymphadenopathy. It is defined as a mature B-cell leukemia 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only
with more than 55% circulating prolymphocytes. Leukemic the credit commensurate with the extent of their participation in the activ-
ity. This activity qualifies as an American Board of Pathology Maintenance
mantle cell lymphoma and chronic lymphocytic leukemia in of Certification Part II Self-Assessment Module.
prolymphocytic transformation must be excluded. The authors of this article and the planning committee members and staff
have no relevant financial relationships with commercial interests to disclose.
Methods: Case archives were retrospectively reviewed for Questions appear on p 420. Exam is located at www.ascp.org/ajcpcme.
B-PLL in patients without a previous diagnosis of chronic
lymphocytic leukemia or other B-cell neoplasm. B-cell prolymphocytic leukemia (B-PLL) is a rare,
Results: We identified six cases of B-PLL with available aggressive B-cell malignancy, with limited knowledge
cytogenetic data, five of which showed evidence of currently available regarding its molecular pathogenesis. It
aberrations in MYC. Three cases showed additional signals is categorized by the World Health Organization as a mature
for the MYC gene by fluorescence in situ hybridization B-cell neoplasm in which prolymphocytes comprise greater
(FISH), and two cases demonstrated t(8;14)MYC/IGH by than 55% of circulating lymphoid cells.1 Morphologically,
karyotyping or FISH. High levels of MYC protein expression prolymphocytes are medium to large in size with an
were detected in all cases tested with MYC aberrations. ample basophilic cytoplasm and round to oval nuclei
containing clumped chromatin and prominent nucleoli.
Conclusions: These results suggest that deregulation of Chronic lymphocytic leukemia (CLL) in prolymphocytic
MYC plays an important role in the pathogenesis of B-PLL transformation can show similar morphologic features.
and expands the spectrum of B-cell neoplasms associated Mantle cell lymphoma in the leukemic phase can show
with aberrations of MYC. some similar features but is distinguished by the presence
of the t(11;14).2
Patients with B-PLL are typically adults in the
seventh decade who have B symptoms and splenomegaly.
Lymphadenopathy is uncommon. Peripheral blood shows
a markedly increased lymphocyte count, accompanied by
anemia and thrombocytopenia in about 50% of cases.1

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347 DOI: 10.1309/AJCPUBHM8U7ZFLOB 347
Flatley et al / MYC in B-Cell Prolymphocytic Leukemia

Immunohistochemistry Stains
Cytogenetic studies and molecular profiling have failed
to show a single defining genetic aberration, but complex Immunohistochemical staining on paraffin-embedded
karyotypes,3 abnormalities of TP53/p53,4 deletions at tissue sections was performed according to previously
11q23, deletions at 13q14, and trisomy 12 have been published methods.11 Accompanying flow cytometric data
reported.5 A small number of reports have shown MYC were reviewed. For the anti–c-Myc rabbit monoclonal antibody
translocations, including t(8;14), in transformed CLL and (Y69, 1:25 dilution; Abcam, Cambridge, MA), formalin-
B-PLL.6-9 Put et al6 found MYC rearrangement in nine fixed, paraffin-embedded (FFPE) sections were deparaffinized
cases originally reported as B-PLL gathered from multiple in xylene, retrieved for 60 minutes using standard cell
centers; however, four of nine had a CLL-like phenotype conditioning, titrated, and incubated for 120 minutes at 37°C.
(CD5+/ CD23+), favoring transformed CLL rather than de For the SOX11 mouse monoclonal antibody (MRQ-58, 1:50
novo B-PLL. One study used gene expression profiling to dilution; Cell Marque, Rocklin, CA) stains, FFPE sections
compare de novo B-PLL with CLL and found increased were deparaffinized, rehydrated in graded alcohol, placed in hot
expression of MYC to be a distinguishing feature.10 1× low-pH antigen retrieval solution (cat. no. S1699; DAKO,
However, the basis of MYC overexpression has not been Carpinteria, CA), and microwaved for 6 minutes. Sections were
fully explored. Therefore, we undertook a study of cases of blocked with Tris-goat (5%) solution and incubated for 120
B-PLL in which conventional cytogenetic or fluorescence minutes at room temperature. All sections were then detected in
in situ hybridization (FISH) studies had been performed to the BenchMark XT with ultraView Universal DAB Detection
evaluate the status of the MYC gene. We identified three Kit (760-500; Ventana Medical Systems, Tucson, AZ) and
cases with evidence of additional signals for MYC by FISH amplified using the Amplification Kit (760-080; Ventana
and two cases with the t(8;14). To our knowledge, our Medical Systems). MYC was considered positive if more
report is the first to identify B-PLL cases with increased than 40% of tumor cell nuclei were positive, as determined
MYC signals by FISH and provides a new basis for by comparison with CD20.12 SOX11 was scored as positive if
overexpression of MYC in this disease. expressed in most tumor cells (>75%); negative cases did not
show any tumor cell reactivity.13

Cytogenetics
Materials and Methods
Conventional chromosomal analysis was performed on
cultured lymphocytes from peripheral blood or bone marrow
Cases aspirate per standard procedures. For each case, metaphase
We retrospectively searched the case archives of the chromosomes from at least 20 cells were analyzed, and only
Department of Pathology, Oregon Health & Science University clonal aberrations were considered. FISH was performed
(OHSU), and the Hematopathology Section, Laboratory per standard procedures to characterize the aberrations of
of Pathology, National Cancer Institute (NCI), for cases of MYC and, when applicable, its translocation partner.11 FISH
B-PLL without a previous diagnosis of CLL or another B-cell analyses with additional probes were also performed for cases
neoplasm. Six cases, in which the status of the MYC gene 3 and 4 and excluded rearrangements of CCND1 as well as a
had been investigated either by FISH or complete cytogenetic few other relevant gene loci. At least 200 interphase cells and
karyotype, were identified. Five of the six cases had evidence all probed metaphases were evaluated.
of aberrations involving MYC and comprise the subject of
this report. One patient diagnosed with B-PLL had a complex
karyotype lacking MYC abnormalities. This patient presented
Results
to the emergency department with marked leukocytosis (37.9
× 103/µL) and hepatosplenomegaly and died of respiratory All patients demonstrated significant leukocytosis
failure within a few days of diagnosis. Clinical data were ❚Table 1❚, splenomegaly, and bone marrow involvement,
provided by either the Department of Hematology-Oncology, while none presented with lymphadenopathy initially. The
OHSU (cases 1, 2, and 4), or the referring clinicians from morphologic features of the neoplastic cells from all cases
original institutes (cases 3 and 5). Detailed information on were characteristic of B-PLL. The circulating cells were
clinical follow-up was available for four of the five patients. medium to large in size with prominent central nucleoli
Approval was obtained from the institutional review boards at ❚Image 1❚. The chromatin pattern was generally coarsely
OHSU and the NCI. clumped and hyperchromatic. In Wright-Giemsa–stained
H&E-stained slides and Wright-Giemsa–stained smears smears, the cytoplasm appeared basophilic but without
of peripheral blood and bone marrow smears were reviewed cytoplasmic vacuoles. Immunophenotypic analysis by flow
by at least two of the authors for each case. cytometry and/or immunohistochemistry ❚Table 2❚ revealed

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348 DOI: 10.1309/AJCPUBHM8U7ZFLOB
 AJCP / Original Article

❚Table 1❚
Patient Clinical and Laboratory Features

    Blood                 Cytogenetics

WBC, Lymph % FISH

Case No. Age, y/Sex × 103/μL in PB Karyotypesa for MYC del(17p)

1 83/F 87 82 47,X,del(X)(q24q28),add(4)(q31), Three signals Yes

der(8)t(8;8)(p21;q24),del(9)(q13q22),
add(10)(q26),del(13)(q14q22),add(13)
(q14),add(14)(p11.2),del(17)(p11.2p13),
+19,add(22)(q13)[cp8]/47,sl,add(19)
(q13.4)[cp3]/47,sdl1,add(2)(p22)
[cp7]/46,XX[2]
2 65/M 262 96 NP More than five signals NP
3 72/M 22.9 64 44,XY,der(1)t(l;9)(p36.3;ql3),der(3)t(3;7) Three signals Yes
(pl3;q22),?del(6),(q21q22),der(7)del(7)
(q22) t(3;7)(pl3;q22),i(8)(ql0),der(9)t(l;9)
(p36.3;q13)t(9;l3)(ql3;qll.2),–13,del(17)
(p11.2),–18[cp12]/46,XY [8]
4 62/F 37.2 81 46,XX,t(8;14)(q24.1;q32)[2]/46,XX[19] MYC/IGH No
5 78/M 27.8 81 45,XY,add(6)(q27),add(7)(q32),del(7) MYC/IGH Yes
(q32),t(8;14)(q24.1;q32),–10,add(11)
(q25),der(12),add(12)(p13), hsr(12)
(p13),–13,add(14)(p10),–17,–18,del(20)
(q11.2), +1-3mar[4]/46,XY[16]

FISH, fluorescence in situ hybridization; NP, not performed; PB, peripheral blood.
a Boldface indicates aberrations of chromosome 8, where MYC is located.

that the neoplastic cells from all cases were positive for one or initial hematologic response but developed refractory disease
more pan–B-cell markers while all were negative for CD23; progression and died 1 month after diagnosis.
three of five cases also exhibited CD5 coexpression. Case
summaries are described below. Case 2, Amplified MYC
A 65-year-old man sought care at an outside hospital
Case 1, Amplified MYC with marked lymphocytosis (WBC count, 262 × 103/mL)
An 83-year-old woman sought treatment for a several- with 96% lymphocytes, extensive bone marrow involvement,
week history of progressive fatigue and had splenomegaly and splenomegaly. The patient was treated initially with
(19 cm) without lymphadenopathy. She had a long-standing rituximab, cyclophosphamide, vincristine, and prednisone
history of monoclonal gammopathy of undetermined signifi- without response and then treated with fludarabine and
cance, and repeat serum protein electrophoresis found an IgM rituximab to a complete response.
l M protein of 0.9 g/dL. She was also anemic (hemoglobin, He developed nodal disease 5 months later. Examination
10 g/dL) with marked leukocytosis (87 × 103/mL) with 82% of an epitrochlear lymph node revealed a diffuse monotonous
lymphocytes. lymphocytic proliferation ❚Image 2C❚ with complete
Peripheral blood smear showed marked lymphocytosis effacement of nodal architecture and extension into perinodal
❚Image 2A❚. A bone marrow aspirate smear and biopsy speci- fat. The lymphoma cells were positive for CD5, CD20, and
men revealed hypercellular marrow with 90% involvement c-Myc protein expression and negative for CD23, CD3,
by intermediate and some large atypical lymphocytes, with CD10, cyclin D1, and SOX11. FISH testing with the MYC
minimal background trilineage hematopoiesis. The leukemia break-apart probe demonstrated additional MYC signals, with
cells were positive for CD5, CD19, CD20, and surface l light approximately 30% of counted cells containing three to four
chain. CD23, cyclin D1, and SOX11 were negative (Table 2). MYC signals and 60% with more than five signals ❚Image 2D❚.
High MYC protein expression was identified by immunohis- All cells had two signals with the CEP8 centromere probe.
tochemistry ❚Image 3❚. He was treated with rituximab weekly for 4 weeks and
Metaphase karyotyping revealed complex cytogenetics then received a reduced-intensity allogeneic transplant from
(Table 1), which included deletion of 17p. FISH analysis an unrelated donor. A posttransplant restaging marrow biopsy
demonstrated the presence of an extra MYC signal in 67% of specimen was negative for malignancy. The patient’s course
cells ❚Image 2B❚ with two signals for the CEP8 centromere was complicated by pulmonary mucormycosis and graft-vs-
probe and confirmed the deletion of the TP53 region. host disease of the gastrointestinal tract. The patient died of
The patient was treated with a combination of these complications 4 months after transplant, 26 months
corticosteroids, rituximab, and alemtuzumab. She had an following his initial diagnosis.

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Flatley et al / MYC in B-Cell Prolymphocytic Leukemia

A B

C D

❚Image 1❚ Morphologic features of B-cell prolymphocytic leukemia. A, Peripheral blood smear shows marked lymphocytosis
(Wright-Giemsa; ×400). B, Circulating cells have features of prolymphocytes, with round to slightly irregular nuclei and prominent
central nucleoli. Cells have a rim of basophilic cytoplasm (Wright-Giemsa, ×1,000). C, Core biopsy specimen shows marked
hypercellularity with replacement of normal hematopoietic elements (H&E, ×400). Inset shows strong positivity for p53 in all
tumor cells (×400). D, Infiltrating prolymphocytes have prominent central nucleoli, and mitotic figures are observed (H&E, ×1,000).

Case 3, Amplified MYC coexpressed CD5, CD11c, and CD43. The cells were
A 72-year-old white man sought treatment in 2012 negative for CD23 and SOX11.
with anemia (hemoglobin, 8 g/dL) and melena. He was Conventional cytogenetic analysis revealed a complex
transfused to stable hemoglobin levels. WBC count was karyotype, including loss of the chromosome 17 short arm.
22.9 × 103/mL with 64% lymphocytes. Further workup FISH analysis demonstrated an extra MYC signal in 44% to
revealed splenomegaly and liver cirrhosis, with no B 46% of the nuclei and also detected the loss of BCL2 and
symptoms or lymphadenopathy per imaging studies. MALT1 signals, with no rearrangement of BCL2, CCND1,
Peripheral blood flow cytometric analysis was consistent IGH, MYC, or MALT1, and normal TP53 signals.
with B-cell leukemia. A subsequent bone marrow biopsy The patient was treated with chemotherapy, with the
specimen yielded a diagnosis of B-PLL. Accompanying WBC levels remaining elevated until 8 months of treatment
flow cytometric analysis of the marrow aspirate revealed (18.9 × 103/mL); the most recent reported WBC level,
that 64% of lymphocytes were k-restricted B cells that however, was within normal range (8 × 103/mL).

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❚Table 2❚
Immunophenotype of B-Cell Prolymphocytic Leukemia

CD19/ c-Myc(+)/
Case No. CD20 CD5 CD23 Cyclin D1 SOX11 c-Myc CD20(+), % Ki-67, %

1 + + – – – + >90 70-80
2 + + – – – + >80 >90
3 + + – – – Unsatisfactory NA 40-50
4 + + – – – + >60 <30
5 + – – – – Not performed NA ~20

NA, not applicable due to unsatisfactory c-Myc result; –, negative; +, positive.

Case 4, Positive for t(8;14)(q24.1;q32)(MYC/IGH) subcutaneous nodule. A subsequent positron emission tomog-
A previously healthy 62-year-old woman sought care raphy scan revealed widespread bony lesions. The patient
for weight loss and abdominal pain. She had splenomegaly received radiation therapy and shortly after became paraple-
(26 cm) without lymphadenopathy. The patient was anemic gic. The patient expressed a desire to be on comfort care only,
(hemoglobin, 8.9 g/dL), with marked leukocytosis (37.2 × 103/ and no further therapy for his lymphoma was administered.
mL) with 81% lymphocytes. A bone marrow biopsy specimen
was hypercellular (70%) with nodular and paratrabecular
infiltrates ❚Image 2E❚.
Discussion
The prolymphocytes were positive for CD5, CD20,
Bcl-2, and c-Myc and negative for CD10, CD23, cyclin D1, MYC translocation or mutation is classically associated
CD34, SOX11, and TdT. FISH was positive for a t(8;14) with Burkitt lymphoma, but in recent years, aberrations in
MYC rearrangement ❚Image 2F❚, but no aberrations involving MYC have been associated with an increasing number of
BCL2, BCL6, or CCND1 were identified. Karyotype revealed human malignancies, including other B-cell neoplasms, with
46,XX,t(8;14)(q24.1;q32)[2]/46,XX[19]. the prevalence estimated at 20%.14 Thus far, MYC aberrations
The patient was treated with dose-adjusted rituximab, have been shown to occur as translocations, gene copy
etoposide, prednisone, vincristine (Oncovin), and number increase, and increased messenger RNA (mRNA)
hydroxydaunorubicin hydrochloride with intrathecal accumulation. MYC is considered a global amplifier of the
methotrexate prophylaxis. She entered a complete remission transcriptional output of a particular cell type (lymphocytes,
and was negative for minimal residual disease per flow embryonic stem cells, tumor cells, etc).15 MYC, considered
cytometric analysis. Her blood counts normalized, and she an oncogene, has a far-reaching network of influence; it is
remains in remission at the 2-year follow-up. thought to regulate the expression of more than 15% of all
cellular genes, affecting nearly all aspects of cellular activity.
Case 5, Positive for t(8;14)(q24.1;q32)(MYC/IGH) Among the many genes it influences, most are involved
A 78-year-old man had leukocytosis (27.8 × 103/ in cell growth, cell cycle progression, metabolism, protein
mL), anemia (hemoglobin, 9.1 g/dL), mild splenomegaly, biosynthesis, apoptosis, and cell adhesion. The deregulation
no lymphadenopathy, and a history of idiopathic of MYC therefore serves as a potential basis for tumorigenesis,
thrombocytopenic purpura treated with corticosteroids and since it is involved in a number of proliferative activities.
intravenous immunoglobulin. Flow cytometric analysis of We identified aberrations in MYC in a surprisingly high
peripheral blood showed that 81% of lymphocytes were percentage of cases of B-PLL, five of six cases tested. All five
B cells, l restricted, and expressing CD19 (dim), CD79a patients had marked lymphocytosis, anemia, splenomegaly,
(cytoplasmic), CD10 (dim), FMC7, and HLA-DR. CD5, and marrow involvement, without initial lymphadenopathy or
CD23, and SOX11 were negative. The nuclei showed a clinical history of CLL. CD23 was negative in all five cases,
strong expression of p53 by immunohistochemistry (Image but four of five cases expressed CD5. Two types of MYC gene
1C, inset). Conventional cytogenetic analysis revealed a abnormality were seen, both increased MYC copy number
complex karyotype including t(8;14)(q24.1;q32) and loss and MYC rearrangement. The three cases with increased copy
of chromosome 17 (Table 1). FISH analysis was positive number showed a high Ki-67 expression level (40% to >90%)
for MYC rearrangement. Bone marrow biopsy specimens and exhibited complex cytogenetic abnormalities (cases
confirmed marrow involvement by a B-cell malignancy 1 and 3). Interestingly, both cases with t(8;14)(q24.1;q32)
consistent with B-PLL. translocation showed relatively low expression of Ki-67
The patient was then treated with single-agent rituximab (<30%). However, high MYC protein expression was seen
and returned in 16 months with relapse as a right chest wall in all three evaluable cases, irrespective of the nature of

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A B

C D

❚Image 2❚ A, Peripheral blood smear from case 1 showing prolymphocytes (Wright-Giemsa, ×630). B, Fluorescence in situ
hybridization (FISH) for case 1 with MYC break-apart probe showing three intact signals consistent with a single increase in
copy number. C, Lymph node from case 2 showing cells with prominent nucleoli. D, FISH for case 2 on formalin-fixed, paraffin-
embedded tissue demonstrating at least four intact MYC signals in the plane of section.

the MYC aberration (Table 2). Interestingly, there was no immunophenotype in four of nine cases and concluded that
direct correlation between MYC expression and proliferative they were more likely transformed CLL than de novo B-PLL.
activity, although the number of cases analyzed is small. None of our cases had clinical evidence of underlying CLL,
MYC abnormalities were often associated with TP53 although CD5 was commonly expressed. B-PLL is a rare form
deletion (del(17p)) in our series (three of four cases tested). of B-cell malignancy, and in the past, some cases have been
Recurrence as nodal disease was seen in one patient (case proven to be examples of mantle cell lymphoma presenting
2) with MYC amplification (more than five signals), and in the leukemic phase.2 We ruled out mantle cell lymphoma,
recurrence as a subcutaneous mass was seen in another patient both by negative testing for cyclin D1 and negative staining for
(case 5) with MYC rearrangement. SOX11. Furthermore, the hairy cell variant would be positive
A few case reports and small case series have found MYC for CD103 and usually positive for SOX11. Three of five cases
activating translocations in B-PLL, including de novo B-PLL in this study were tested for CD103 by flow cytometry and
and CLL in prolymphocytoid transformation. Put et al6 reported showed negativity, and all five were negative for SOX11 by
MYC rearrangement in nine cases originally diagnosed as B-PLL immunohistochemistry stain, as stated above. Thus, we think
from multiple institutions. However, they found a “CLL-like” the diagnosis of hairy cell variant is unlikely.

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352 DOI: 10.1309/AJCPUBHM8U7ZFLOB
 AJCP / Original Article

E F

❚Image 2❚ (cont) E, Bone marrow aspirate from case 4 with prolymphocytic infiltrate (Wright-Giemsa, ×630). F, FISH for case 4
with tricolor dual-fusion probe demonstrating translocation of MYC and IGH by the presence of two fusion (yellow) signals in the
background of one IgH (green), one MYC (red), and two centromeres of chromosomes 8 (aqua) signals.

Similar to our cases, most of the B-PLL cases (six of nine)

evaluated in this analysis also harbored TP53 abnormalities
(del(17p)). However, an increase in MYC copy number by
FISH, Ki-67, and clinical outcomes were not reported.
Another mechanism for MYC deregulation is an increase
in MYC copy number, including MYC amplification. MYC
amplification has been reported in cases of diffuse large B-cell
lymphoma, using FISH probes to demonstrate an increase in
MYC signals in comparison to the signals from centromeric
probes for chromosome 8. Furthermore, increased MYC
mRNA levels have been correlated with a copy number
increase, suggesting that increased copy number also may
portend an adverse prognosis.18
Here we report three B-PLL cases with increased MYC
copy numbers detected by FISH, varying from three to more
than five copies per cell. Two patients had a progressive
clinical course, and one patient had a 9-month follow-up.
❚Image 3❚ B-cell prolymphocytic leukemia stained for MYC
While the exact prognostic value of the MYC copy number
protein (case 1) (×400). More than 90% of tumor cells
increase in B-PLL is currently unclear, our small case series
showed nuclear reactivity.
suggests that an increase in MYC copy number on FISH
may be associated with poor clinical outcome, with similar
Reported translocations in B-PLL include t(8;14)MYC/ implications as the MYC translocation.
IGH, t(2;8)IGK/MYC, and t(8;22)MYC/IGL.8,9,16,17 MYC To our knowledge, there is no published association
translocations have occurred either as the sole cytogenetic between Ki-67 activity and MYC abnormality in B-PLL.
abnormality or in a background of complex karyotypes. In a study of diffuse large B-cell lymphoma, there was no
Activating translocations involve the juxtaposition of MYC association found between MYC copy number and Ki-67
with constitutively active B-cell genes, most commonly IGH expression level.19 In our five cases, both cases with t(8;14)
on chromosome 14. (q24.1;q32) demonstrated a low Ki-67 (<30%), and following
Gene expression profiling of B-PLL has shown treatment, one patient (case 4) remained disease free at a 2-year
significant increases in MYC expression compared with follow-up, while another patient (case 5) went 16 months
CLL. Specifically, Del Giudice et al10 subjected nine B-PLL before his disease recurred. Two of our three patients with
samples and 10 CLL samples to gene expression profiling. increased MYC signal showed high Ki-67 activity (70% to

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353 DOI: 10.1309/AJCPUBHM8U7ZFLOB 353
Flatley et al / MYC in B-Cell Prolymphocytic Leukemia

7. Huh YO, Lin KI, Vega F, et al. MYC translocation in

>90%) and had an aggressive course, with one patient (case 1) chronic lymphocytic leukaemia is associated with increased
dying 1 month following diagnosis and another patient (case 2) prolymphocytes and a poor prognosis. Br J Haematol.
surviving only 26 months. Follow-up could not be obtained on 2008;142:36-44.
the third patient (case 3). 8. Merchant S, Schlette E, Sanger W, et al. Mature B-cell
leukemias with more than 55% prolymphocytes: report
The treatment approach in CLL has been based on the of 2 cases with Burkitt lymphoma–type chromosomal
status of TP53 abnormalities. Published data have shown translocations involving c-myc. Arch Pathol Lab Med.
that the use of fludarabine, cyclophosphamide, and rituximab 2003;127:305-309.
in patients without TP53 abnormalities induced complete 9. Lens D, Coignet LJ, Brito-Babapulle V, et al. B cell
prolymphocytic leukaemia (B-PLL) with complex karyotype
remissions that held for greater than 5 years but not in the and concurrent abnormalities of the p53 and c-MYC gene.
patients with the TP53 mutation.20 Patients with abnormal Leukemia. 1999;13:873-876.
TP53 need to receive alemtuzumab in addition to standard 10. Del Giudice I, Osuji N, Dexter T, et al. B-cell prolymphocytic
chemotherapy, because TP53-positive tumors have been leukemia and chronic lymphocytic leukemia have distinctive
gene expression signatures. Leukemia. 2009;23:2160-2167.
shown to have primary resistance to purine analogue-based
11. Kelemen K, Braziel RM, Gatter K, et al. Immunophenotypic
therapy. Currently, the treatment approach for B-PLL is variations of Burkitt lymphoma. Am J Clin Pathol.
similar to that of CLL, despite differences in the underlying 2010;134:127-138.
biology of the two diseases; resistance to therapy is common in 12. Johnson NA, Slack GW, Savage KJ, et al. Concurrent
B-PLL.21 MYC abnormalities may contribute to the aggressive expression of MYC and BCL2 in diffuse large B-cell
lymphoma treated with rituximab plus cyclophosphamide,
course of B-PLL in certain patients. Accordingly, identifying doxorubicin, vincristine, and prednisone. J Clin Oncol.
MYC abnormalities may allow for the development of altered 2012;30:3452-3459.
therapeutic regimens for this subset of patients. 13. Soldini D, Valera A, Sole C, et al. Assessment of
SOX11 expression in routine lymphoma tissue sections:
Address reprint requests to Dr Fan: Dept of Pathology, Oregon characterization of new monoclonal antibodies for diagnosis
Health & Science University, 3181 SW Sam Jackson Park Rd, of mantle cell lymphoma. Am J Surg Pathol. 2014;38:86-93.
Mail Code L471, Portland, OR; [email protected]. 14. Dang CV, O’Donnell KA, Zeller KI, et al. The c-Myc target
gene network. Semin Cancer Biol. 2006;16:253-264.
  This work was supported by the intramural research program, 15. Klapproth K, Wirth T. Advances in the understanding
Department of Pathology, Oregon Health and Science University, of MYC-induced lymphomagenesis. Br J Haematol.
Portland, Oregon, and the intramural research program of 2010;149:484-497.
the Center for Cancer Research, National Cancer Institute, 16. Crisostomo RH, Fernandez JA, Caceres W. Complex
Bethesda, Maryland. karyotype including chromosomal translocation (8;14)
(q24;q32) in one case with B-cell prolymphocytic leukemia.
Leuk Res. 2007;31:699-701.
17. Kuriakose P, Perveen N, Maeda K, et al. Translocation
(8;14)(q24;q32) as the sole cytogenetic abnormality in
References B-cell prolymphocytic leukemia. Cancer Genet Cytogenet.
1. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO 2004;150:156-158.
Classification of Tumours of Haematopoietic and Lymphoid 18. Stasik CJ, Nitta H, Zhang W, et al. Increased MYC gene copy
Tissues. 4th ed. Lyon, France: IARC; 2008. number correlates with increased mRNA levels in diffuse
2. Schlette E, Lai R, Onciu M, et al. Leukemic mantle cell large B-cell lymphoma. Haematologica. 2010;95:597-603.
lymphoma: clinical and pathologic spectrum of twenty-three 19. Yoon SO, Jeon YK, Paik JH, et al. MYC translocation and an
cases. Mod Pathol. 2001;14:1133-1140. increased copy number predict poor prognosis in adult diffuse
3. Sole F, Woessner S, Espinet B, et al. Cytogenetic large B-cell lymphoma (DLBCL), especially in germinal
abnormalities in three patients with B-cell prolymphocytic centre-like B cell (GCB) type. Histopathology. 2008;53:205-
leukemia. Cancer Genet Cytogenet. 1998;103:43-45. 217.
4. Lens D, De Schouwer PJ, Hamoudi RA, et al. p53 20. Stilgenbauer S, Zenz T. Understanding and managing ultra
abnormalities in B-cell prolymphocytic leukemia. Blood. high-risk chronic lymphocytic leukemia. Hematology Am Soc
1997;89:2015-2023. Hematol Educ Program. 2010;2010:481-488.
5. Lens D, Matutes E, Catovsky D, et al. Frequent deletions at 21. Dearden C. How I treat prolymphocytic leukemia. Blood.
11q23 and 13q14 in B cell prolymphocytic leukemia (B-PLL). 2012;120:538-551.
Leukemia. 2000;14:427-430.
6. Put N, Van Roosbroeck K, Konings P, et al. Chronic
lymphocytic leukemia and prolymphocytic leukemia with
MYC translocations: a subgroup with an aggressive disease
course. Ann Hematol. 2012;91:863-873.

354 Am J Clin Pathol 2014;142:347-354 © American Society for Clinical Pathology

354 DOI: 10.1309/AJCPUBHM8U7ZFLOB
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