Hematopathology / MANTLE CELL LYMPHOMA
Cytogenetic Findings in Mantle Cell Lymphoma
Cases With a High Level of Peripheral Blood Involvement
Have a Distinct Pattern of Abnormalities
Mihaela Onciu, MD,1* Ellen Schlette, MD,1 L. Jeffrey Medeiros, MD,1
Lynne V. Abruzzo, MD, PhD,1 Michael Keating, MD,2 and Raymond Lai, MD, PhD1
Key Words: Mantle cell lymphoma; Leukemia; Lymph node; Conventional cytogenetics
Abstract
We compared conventional cytogenetic findings in
mantle cell lymphomas (MCLs) having an absolute
peripheral lymphocytosis of more than 10,000/µL (>10
× 109/L) at diagnosis (“leukemic”; n = 30) with those
in cases having no or minimal lymphocytosis (“nodal”;
n = 19). Only cases positive for t(11;14) were included
for study. Forty-six cases (94%) had abnormalities in
addition to t(11;14). The most frequent abnormalities
involved chromosome 13 (26 cases [53%]), followed by
chromosomes 1, 3, 7, 8, 9, 10, 12, 15, 17, and 21 (11-18
cases [22%-37%]). There was no difference in the
number of aberrations between the 2 groups.
Abnormalities of chromosomes 17, 21, and 22 were
more frequent, and breakpoints involving 8q24, 9p2224, and 16q24 were found exclusively in leukemic MCL.
Chromosome 17 aberrations involved were structural
(breakpoints involving 17p13, 17p11.2, 17q) in
leukemic MCL but were only numeric in nodal MCL.
Thus, leukemic MCL differs from nodal MCL in their
cytogenetic profiles, which may contribute to the
clinical presentation.
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Am J Clin Pathol 2001;116:886-892
Mantle cell lymphoma (MCL) is a distinct type of nonHodgkin lymphoma that is characterized by the presence of
a balanced chromosomal translocation, the t(11;14)(q13;q32).1
This abnormality juxtaposes the CCND1 gene (11q13) with
the IgH (14q32) gene, resulting in cyclin D1 overexpression.2-4 It has been shown that MCL often carries karyotypic
abnormalities in addition to the t(11;14), as demonstrated by
a variety of techniques. 5-15 In most of these studies,
del(13)(q14) was identified as the most frequent abnormality, found in 30% to 70% of cases. Other common
abnormalities reported involve chromosomes 1, 3, 6, 9, and
17. While it is believed that the t(11;14) is important in upregulating the CCND1 gene, resulting in increased cyclin
D1 protein that promotes cell cycle progression, the significance of other chromosomal abnormalities found in MCL
has not been examined extensively.
Most patients with MCL have nodal-based disease,
although low-level peripheral blood involvement is common. In
1 study, up to 77% (27/35) of cases had morphologic evidence
of MCL involving the peripheral blood, and most of these cases
had a low number of circulating lymphoma cells.16 Less often,
MCL may manifest initially with marked leukemic involvement,
with marked absolute lymphocytosis (ie, >10,000/µL [>10 ×
109/L]) in the peripheral blood.5,17,18 It is possible that leukemic
and nodal MCL are biologically different, and the cytogenetic
profile of these cases may reflect this difference. However, relatively few cases of leukemic MCL analyzed with conventional
cytogenetic methods have been reported.12,19 Furthermore, there
are no studies that have comprehensively correlated cytogenetic
abnormalities with the clinical presentation of MCL.
We describe the results of conventional cytogenetic
studies in 49 well-characterized cases of MCL, 30 that had
© American Society of Clinical Pathologists
Hematopathology / ORIGINAL ARTICLE
marked leukemic involvement (absolute lymphocyte count,
>10,000/µL [>10 × 109/L]) at the time of diagnosis and 19
that manifested as nodal disease and had no or minimal
peripheral lymphocytosis. These results demonstrate that the
cytogenetic profile of MCL is different in patients with
leukemic and nodal tumors.
Materials and Methods
Study Group
The pathology files between 1993 and 2000 at the
University of Texas M.D. Anderson Cancer Center, Houston,
were searched for lymphoma cases that fulfilled the
following criteria: (1) morphologic and immunophenotypic
findings compatible with the diagnosis of MCL and (2)
availability of the results of the conventional cytogenetic
studies that showed the presence of the t(11;14)(q13;q32).
Cases of MCL without the t(11;14)(q13;q32) were excluded,
so that the diagnosis of MCL is well supported in all cases in
this study.
For the purpose of this study, we divided these
patients into 2 groups, leukemic and nodal, based on the
level of absolute lymphocytosis in the peripheral blood.
Patients included in the leukemic group were those with
marked leukemic involvement, which we arbitrarily
defined as an absolute lymphocyte count of more than
10,000/µL (>10 × 109/L) at the time of initial diagnosis.
For the nodal group, all patients had no or minimal peripheral lymphocytosis.
Conventional Cytogenetics
Conventional G-band karyotype analysis was
performed on all cases. Briefly, bone marrow aspirate,
peripheral blood, spleen, or lymph node specimens were
mixed with Ham F10 medium with 20% fetal calf serum for
a total volume of 10 mL and a final concentration of 2 to 4 ×
106 nucleated cells per milliliter. The culture was incubated
overnight at 37°C. Standard harvesting procedures were
used: colcemid (0.1 mL K max Colcemid Solution, GIBCO,
Grand Island, NY) was added to the culture for 20 minutes,
followed by a 0.075-mol/L concentration of potassium chloride for 30 minutes at 37°C. The fixation procedure
consisted of 3 changes of methanol/glacial acetic acid (3:1).
A Thermatron drying chamber (Thermatron Industries,
Holland, MI) was used for slide preparation. Slides were
placed in a 60°C oven overnight, followed by GTG banding.
The karyotype reports were written according to the International System for Human Cytogenetic Nomenclature.20 In
the nodal group, specimens used for cytogenetic studies
were lymph nodes (13 cases) and bone marrow aspirates (6
© American Society of Clinical Pathologists
cases). In the leukemic group, specimens used for cytogenetic studies were bone marrow aspirates (27 cases), lymph
nodes (2 cases), and peripheral blood (1 case). At least 20
metaphases were analyzed in 30 cases, 15 to 19 metaphases
were analyzed in 11 cases, and 3 to 15 metaphases were
analyzed in 8 cases.
Statistical Analysis
Comparisons of the frequency of chromosomal abnormalities between the leukemic and nodal groups were
assessed using the chi-square test. In samples with multiple
clones, only those with 2 or more metaphases were included
in the analysis.
Results
Patient Characteristics
The median age of the 49 patients was 65 years (range,
31-85 years). There were 33 men and 16 women. Nineteen
patients had nodal disease at initial assessment. Of this
group, 18 of 19 patients had no absolute lymphocytosis in
the peripheral blood; 1 patient had mild lymphocytosis
(absolute lymphocyte count, 4,800/µL [4.8 × 109/L]). Thirty
patients had marked leukemic involvement, with an absolute
lymphocyte count ranging from 11,100 to 647,600/µL (11.1647.6 × 109/L; median, 6,600/µL [66 × 109/L]) at the time of
initial assessment. Three of these patients had no specific
diagnosis at the time of referral. The remaining patients had
one of the following diagnoses: chronic lymphocytic
leukemia, 14; chronic lymphocytic leukemia/prolymphocytic
leukemia, 2; prolymphocytic leukemia, 1; splenic lymphoma
with villous lymphocytes, 1; MCL, 7; acute lymphoblastic
leukemia, 1; and small noncleaved cell lymphoma, 1. Fifteen
patients in the leukemic group (50%) received chemotherapy
before referral to our institution. In comparison, 7 (37%)
patients in the nodal group received chemotherapy before
referral to our institution. There was no significant difference
in the frequency of previous chemotherapy between the
leukemic and nodal groups.
Cytogenetic Findings
The cytogenetic findings are listed in ❚Table 1❚. Only 3
cases (6%) carried the t(11;14)(q13;q32) as a sole cytogenetic
abnormality: 2 were in the nodal group, and 1 was in the
leukemic group. The remaining 46 cases had additional karyotypic abnormalities: 8 cases (16%) had 1 or 2 additional
chromosomal changes, 16 cases (33%) had 3 or 4 additional
chromosomal changes, and 22 cases (45%) had more than 4
additional chromosomal changes. There were no significant
differences in the number of chromosomal abnormalities
Am J Clin Pathol 2001;116:886-892
887
Onciu et al / MANTLE CELL LYMPHOMA
❚Table 1❚
Analysis of 49 Cases of Mantle Cell Lymphoma by Conventional Cytogenetics
Case
No.
Site
Karyotype
Leukemic
1 BM*
2 BM*
BM*
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Nodal
31
32
33
34
35
36
37
38
39
40
41
45,XY,add(10)(p13),t(11;14)(q13;q32),–12,der(13)t(12;13)(q13;q32),add(17)(p13)[9]/44-46,XY,idem,random changes[5]
9/97†: 45,X,–X,t(11;14)(q13;q32),add(17)(p13)[13]/45,X,–X,idem,–9,+r[4]
6/99†: 48,XX,t(1;11)(p36;q13),del(2)(q31q33),del(3)(q23q25),add(8)(q22),–10,t(11;14)(q13;q32),add(12)(q22),+add(12)(q22)x2,
+16,add(17)(p13),+add(17)(p13),–20,+mar[cp20]
BM* 46-48,XX,add(8)(q),add(9)(q),t(11;14)(q13;q32),del(13)(q),del(17)(q),+mar[cp20]
BM
41,X,–Y,der(1)(q32;q21),der(3)t(3;11)(q13;q23),der(3)t(3;21)(q29;q11),–4,der(5)t(5;15)(p15;q11),i(8)(q10),der(11)t(11;14)(q13;q32),
del(12)(p13),t(13;17)(q10;q10),der(14)t(3;11)t(11;14)(q13;q32),–15,–21[15]/46,XY[4]
BM* 73,XXY,+3,i(8)(q10),–9,+11,t(11;14)(q13;q32)X2;del(12)(q12q21),+13,+14,–15,–17,+20,–21,–22,+3mar[11]/73,XXY,idem,dup(1)(q12q21)[2]
BM* 46,XX,t(2;17)(p22;p11),t(11;14)(q13;q32),del(13)(q31)[6]/46,XX[14]
BM* 43-46,XX,–11,t(11;14)(q13;q32),–13,–15,der(17;21)(q10;q10),–17,+5–8mar[20]
BM
47,XX,add(5)(q35),–8,t(11;14)(q13;q32),i(17)(q10),+2mar[5]/46,XX[16]
BM* 46,XX,t(11;14)(q13;q32)[8]/46,XX,idem,+7,+12,+17[5]/46,XX[6]
BM* 46,XX,t(11;14)(q13;q32),–15,add(17)(p11.2),+mar[12]/47,XX,idem,+11[8]
BM* 44,XY,–3,t(3;16)(q23;q24),add(7)(p22),i(8)(q10),add(9)(p22),–10,t(11;14)(q13;q32),add(13)(q22),–17,add(19)(p13.3),add(21)(p13),
–22,+2mar[18]/43-45,XY,idem,random changes[2]
BM
42-44,–X,Y,add(3)(q29),–5,add(8)(q24),add(9)(q34),add(10)(q26),t(11;14)(q13;q32),add(11)(p15),–13,add(13)(p13),–17,–18,
add(22)(q13),del(22)(q11),+2–6mar[cp13]/46,XY[7]
BM
7/98†: 46,XY,del(1)(q42),+3,t(11;14)(q13;q32),–15,del(17)(q23),+mar[13]/46,XY[6]
LN
8/98†: 46,XY,del(1)(q42),+3,t(11;14)(q13;q32),–15,–17,+mar[13]
BM* 7/99†: 46,XY,del(1)(q42),+3,t(11;14)(q13;q32),–13,–15,del(17)(p11.2),+mar[cp3]/46,XY[9]
BM* 43,X,–X,–4,–9,add(10)(q25),t(11;14)(q13;q32),del(13)(q14q22),del(17)(p11.2),–21,+mar[9]/46,XX[11]
BM* 46,XY,+3,add(5)(p15),t(11;14)(q13;q23),–13[2]/46-48,XY,+3,add(5)(p15),–9,t(11;14)(q13;q32),–15,–17,–18,+19,+21,+1–6mar[cp15]
BM* 45,XY,–1,del(1)(q25),del(4)(q21),i(6)(p10),del(7)(q22q32),–8,add(9)(p24),–10,t(11;14)(q13;q32),add(13)(p13),+mar[14]/46,XY[24]
BM* 5/96†: 46,XY,add(4)(q35),del(7)(q32),t(11;14)(q13;q32),add(16)(q24)[1]/46,XY,idem,i(8)(q10)[10]/46,XY[11]
SPLN* 1/98†: 46,XY,del(7)(q32),t(11;14)(q13;q32),add(16)(q24)[2]/46,XY[17]
BM* 3/98†: 46,XY,del(7)(q32),t(11;14)(q13;q32),add(16)(q24)[11]
BM
11/99†: 40-42,X,–Y,+6,–8,–9,t(11;14)(q13;q32),–18,–19,–20,–21,–22[cp19]/46,XY[1]
BM* 2/00†: 41-42,X,–Y,+6,–8,–9,t(11;14)(q13;q32),–18,–19,–20,–21,–22[cp12]/46,XY[8]
PB
41-44,XY,del(1)(q13),–5,–7,–13,der(14)t(11;14)(q13;q32),+1–5mar[18]/46,XY[2]
LN
46,XY,t(11;14)(q13;32)[7]
BM
46,XY,t(11;14)(q13;q32)[12]/48,XY,idem,t(6;9)(q22;p24),+7,+12[8]
BM
42-44,XY,–3,–8,del(11)(q14),t(11;14)(q13;q32),add(12)(p13),–13,del(13)(q22q32),–21,+1–2mar[11]/46,XY[38]
BM
46,XY,t(11;14)(q13;q32),add(22)(q13)[8]/46,XY[12]
BM
47,XY,t(11;14)(q23;q32),+12[3]/46,XY[16]
BM
45-48,XY,+3,–7,del(10)(q24),t(11;14)(q13;q32),+21,+mar[cp4]/46,XY[16]
BM
46,XX,add(9)(p24),t(11;14)(q13;q32),del(13)(q21),–15,add(16)(q24),+1–3mar[26]
LN
3/97†: 71-74,XXY,+Y,del(1)(p34),–2,del(6)(q21),+del(6)(q21),+10,–11,–13,–14,–15,–17,+18,+20,+21,+22,+4–6mar[20]
PB
3/97†: 73-79,XXY,del(1)(p13p31),–2,del(3)(p24),del(6)(q21),+del(6)(q21),–8,–14,–15,+6–10mar[3]/41-46,XY,random changes[6]
BM* 7/97†: 42-45,XY,del(1)(p13p31),–2,del(3)(p24),add(5)(q35),del(6)(q21),add(9)(p24),t(11:14)(q13;q32),–13,–14,–15,–18,+r,+1–3mar[11]
BM* 46,XY,t(11;14)(q13;q32),add(13)(q34)[17]/44-46,XY,idem[3]
BM
45,X,–X,del(1)(p13p22),–2,der(8)t(2;8)(q13;q24),del(9)(p12),t(11;14)(q13;q32),t(12;18)(q13;q23),–13,add(15)(p15),add(21)(p13),
+2mar[9]/46,XY[11]
BM* 7/97†: 46,XY,del(7)(q22),add(8)(q24),t(11;14)(q13;q32)[4]
BM* 1/98†: 46,XY,del(8)(q22)[2]/46,XY[18]
LN
LN
LN*
LN
LN
42
LN*
LN*
LN*
LN*
BM
BM*
LN*
BM*
43
44
45
46
47
48
49
BM
BM
LN
LN
LN
BM
LN
45,XY,t(11;14)(q13;q32),–13[9]/46,XY[4]
44-46,XY,del(1)(p11p22),del(6)(q21),add(11)(q23),t(11;14)(q13;q32),+mar[cp13]/46,XY[6]
43-44,X,–X,–1,add(1)(p36.3),t(11;14)(q13;q32),–14,–17,+1–3mar[cp12]/46,XX[7]
46,XY,t(11;14)(q13;q32)[18]/47,XY,idem,+5[1]/46,XY,idem,del(1)(p36),+5,t(7;11)(q36;q13)[1]
45,XX,t(1;6)(p22;p21),–6,–10,t(11;14)(q13;q32),–12,add(13)(p12),der(14)add(14)(p11)t(11;14)(q13;q32),+18,del(20)(q13),
+mar[18]/46,XX[2]
43-46,XY,del(6)(q14),del(9)(q13),–9,t(11;14)(q13;q32),–15,+2–3mar[cp6]/46,XY,random changes[2]/46,XY[7]
56-58,XY,+X,+4,+5,t(11;14)(q13;q32),+19,+1–4mar[2]/79,XXY,+8,+11,t(11;14)(q13;q32),+12,+13,–17,+18,–20,+21,+6mar[1]
43-47,XX,t(1;2)(p31.1;p23),+3,del(6)(q21),–10,t(11;14)(q13;q32),+1–2mar[24]/46,XX[1]
89-95,XXXX,add(1)(p11)x2,–3,+5,del(7)(q31)x2,–8,+9,–10,del(11)(p11)x2,t(11;14)(q13;q32)x2,–13,–17x2,+r,+4–6mar[9]/46,XX[8]
46,XY,t(11;14)(q13;q32)[1]/45,X,–Y[4]/46,XY[25]
4/97†: 46,XY,add(3)(q29),t(11;14)(q13;q32)[2]/46,XY[10]
5/97†: 46,XY,add(3)(q29),t(11;14)(q13;q32)[7]
47,XY,t(1;6)(p22;q25),–5,+7,–8,–9,–9,–10,t(11;14)(q13;q32),+12,–13,–13,add(20)(p13),+6mar[5]/47,XY,idem,add(4)(q35),
+6mar[10]/48,XY,idem,add(4)(q35),+18,+6mar[5]
40-43,X,–Y,–5,t(11;14)(q13;q32),–12,add(13)(p11),–15,–16,–18,–19,–20[5]/46,XY[14]
46,X,–X,+2,+3,del(7)(q22),–9,t(11;14)(q13;q32),–13,–14,+1–3mar[cp12]/46,XX[8]
46,XY,t(11;14)(q13;q32),–13,+mar[5]/43-46,XY,idem,add(4)(p16),+mar[3]/46,XY[3]
46,XY,t(11;14)(q13;q32)[5]/46,XY[1]
90-91,t(11;14)(q13;q32)x2[3]/46,XX[9]
45,X,–Y,del(1)(p22),del(6)(q15),t(11;14)(q13;q32)[3]/46,XY,del(1)(p22),del(6)(q15),t(11;14)(q13;q32)[18]
47,XX,der(1)(p22p32)del(1)(q21q25),–2,–4,t(11;14)(q13;q32),+4–5mar[2]/46,XX[1]
BM, bone marrow; LN, lymph node; PB, peripheral blood; SPLN, spleen.
* Following chemotherapy.
† Date (mo/y) when sample was obtained for patients with more than 1 sample.
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Am J Clin Pathol 2001;116:886-892
© American Society of Clinical Pathologists
Hematopathology / ORIGINAL ARTICLE
❚Table 2❚
Frequent (>20% of Cases) Chromosomal Abnormalities in 49 Cases of Mantle Cell Lymphoma*
Overall
Chromosome Incidence
Trisomy
Monosomy
Specific Additions†
1
17 (35)
0
0
1p31p36 (1)
3
7
13 (27)
11 (22)
6
3
3
2
3q25q29 (2)
8
16 (33)
0
6
9
15 (31)
1
7
10
12 (24)
1
7
12
12 (24)
4
2
8q24
i8q10
9p22-24
9q34
10p11-13
10q24-26
12p13
(3)
(4)
(3)
(2)
(1)
(2)
(1)
Specific Deletions†
1p31p36
1p22
3q25q29
7q22
7q32
(2)
(4)
(1)
(3)
(2)
15
17
21
*
†
26 (53)
1
11 (22)
18 (37)
13
0
1
11 (22)
13q31q34
15q15
17p13
17p11.2
17q
21p13
10
8
3
5
9p12-13 (2)
10q24-26 (1)
12p13 (1)
12q12-13 (1)
13q14 (1)
13q31q34 (2)
17p11.2 (2)
17q (1)
9p22-24 (1)
12q12-13
12q22-24
13q14
13q31q34
(2)
(1)
(1)
(1)
17p11.2 (1)
17q (2)
21q10-11 (2)
Data for incidence are given as number (percentage).
Specific additions, deletions, or translocation of the “hot spots” on specific chromosomes. Numbers in parentheses are the number of additions, deletions, or translocations.
between the leukemic and nodal groups. Both numeric and
recurrent structural abnormalities were identified in both
groups. Only 5 cases showed near-triploid or near-tetraploid
karyotypes. Two cases were leukemic, and 3 cases were
nodal. None of these 5 cases had a blastoid appearance.
The chromosomes that were most frequently abnormal
were chromosome 13 in 26 cases (53%), chromosome 17 in
18 cases (37%), chromosome 8 in 16 cases (33%), and chromosome 1 in 17 cases (35%). Chromosomes 3, 7, 9, 10, 12,
15, and 21 were involved in 11 to 18 cases (22%-37%). The
changes seen in these chromosomes are summarized in
❚Table 2❚.
The frequencies of various cytogenetic abnormalities
differed in leukemic and nodal MCL, as summarized in
❚Table 3❚. Abnormalities involving chromosomes 17, 21, and
22 were significantly associated with leukemic manifestation. Chromosome 17 abnormalities were identified in 16
❚Table 3❚
Differences in Chromosomal Abnormalities Between
the Leukemic and Nodal Cases of Mantle Cell Lymphoma*
Chromosome
Del 8q24
9p22-24
16q24
17
21
22
*
(2)
(1)
(2)
(1)
(1)
(2)
1p31p36 (2)
1p22 (2)
3q25q29 (1)
8q24 (1)
12q22-24 (1)
13
Translocations†
Leukemic (n = 30)
4
4
3
16
11
6
(13)
(13)
(10)
(53)
(37)
(20)
Data are given as number (percentage).
© American Society of Clinical Pathologists
Nodal (n = 19)
0
0
0
2
0
0
(0)
(0)
(0)
(11)
(0)
(0)
P
.1
.1
.15
<.05
<.05
<.05
(53%) of 30 leukemic MCLs, compared with 2 (11%) of 19
nodal MCLs (P < .05). In leukemic MCL, abnormalities of
chromosome 17 involved structural aberrations in 10 (62%)
of 16 cases, including recurrent breakpoints involving 17p13
and 17p11.2. In contrast, both nodal MCLs had monosomy
17. Chromosome 21 abnormalities were observed in 11
(37%) of 30 leukemic MCLs compared with none of the
nodal MCLs (P < .05). Abnormalities of chromosome 22
were present exclusively in 6 leukemic MCLs and were
numeric in 5 (P < .05).
There were 3 other notable differences between the
leukemic and nodal groups. Aberrations involving 8q24 in 4
cases (13%), 9p22-24 in 4 cases (13%), and 16q24 in 3
cases (10%) were found exclusively in leukemic MCL.
Although these differences were not statistically significant,
this is probably due to the relatively low frequency of these
abnormalities.
We compared the frequency of chromosomal changes
in patients who had or had not received previous treatment,
and chromosome 17 and Y abnormalities correlated with
therapy. Fourteen (64%) of 22 cases of treated MCL had
chromosome 17 abnormalities compared with 5 (19%) of 27
cases of untreated MCL (P < .05). No cases of treated MCL
had chromosome Y abnormalities, compared with 5 (19%)
of 27 cases of untreated MCL (P < .05). There was no
significant difference in the distribution of specific breakpoints involving chromosome 17 between the 2 groups.
None of the 7 cases with follow-up cytogenetics data (cases
2, 13, 17, 18, 27, 30, and 41) developed abnormalities of
Am J Clin Pathol 2001;116:886-892
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Onciu et al / MANTLE CELL LYMPHOMA
chromosome 17 after chemotherapy administered at our
institution. No other chromosomal abnormalities correlated
with a history of chemotherapy.
Of the 49 cases in this study, only 3 cases (6%) had
high-grade morphologic features. Owing to their small
number, no further statistical analysis was performed.
Discussion
There are relatively few studies reported in the literature
that have extensively assessed cytogenetic abnormalities in
MCL.7,13,21,22 These studies have been performed using a
variety of techniques, including conventional cytogenetics,
fluorescence in situ hybridization, and comparative genomic
hybridization; thus, it is difficult to discern a comprehensive
view of these findings. Most of these studies also are limited
by a lack of clinical information, and, thus, the relative
frequencies of each chromosomal abnormality may be
biased, depending on the stage or clinical manifestation of
disease. Also, some MCL cases reported in previous studies
were diagnosed morphologically, with no documentation of
cyclin D1 overexpression or the presence of the
t(11;14)(q13;q32).
We hypothesized that leukemic and nodal MCLs are
biologically different, and the cytogenetic profile of these
cases may reflect this difference. Thus, we comprehensively
examined chromosomal abnormalities in 49 well-characterized cases of MCL as determined by conventional cytogenetics. Thirty patients had marked leukemic involvement at
the time of initial diagnosis, which we arbitrarily defined as
an absolute lymphocyte count of more than 10,000/µL (>10
× 109/L), and 19 patients had nodal disease. Each case of
MCL carried the t(11;14) and had compatible morphologic
and immunophenotypic features.
Forty-six cases (94%) in this series had karyotypic
abnormalities in addition to the t(11;14), in agreement with
the results of 1 previous study of MCL using conventional
cytogenetics.13 The frequent presence of these karyotypic
abnormalities suggests their importance in the pathogenesis
of MCL, consistent with findings in previous studies of
transgenic mice that have shown that cyclin D1 overexpression, by itself, is insufficient for tumorigenesis.23,24 As indicated in Table 2, karyotypic abnormalities often are close to
or overlap with the loci of known or putative oncogenes or
tumor suppressor genes, such as the p16INK4a at 9p22-24,
p53 at 17p13, erbB-2 at 17p11.2, cyclin D2 at 12q12-13,
and ING1 at 13q34. Some of these genes have been shown
previously to be important in MCL, including p16 and p53,
both of which are more likely to be inactivated in highgrade MCL cases that are associated with a worse prognosis.21,25-27 Other genes, such as cyclin D2, ING1, and
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Am J Clin Pathol 2001;116:886-892
erbB-2, have not been examined in MCL. ING1 is a putative
tumor suppressor gene.28
We identified a significant correlation between specific
chromosomal changes and clinical presentation. As shown in
Table 3, abnormalities involving chromosomes 17, 21, and
22 were more common in leukemic than in nodal MCL. In
addition, abnormalities involving 8q24, 9p22-24, and 16q24,
although present at low frequency, were found exclusively in
leukemic MCL. Another interesting finding is that the types
of chromosome 17 abnormalities were different between
these 2 groups. Only monosomy 17 was observed in nodal
MCL. In contrast, leukemic MCL cases had breakpoints
involving chromosome 17, including 17p13 and 17q, the loci
harboring the p53 and the erb-B2 genes, respectively. These
findings suggest that both genes may be involved in the
pathogenesis of leukemic MCL.
The biologic significance of these karyotypic differences between the nodal and leukemic groups needs to be
studied further. Nevertheless, the differences may reflect
genetic abnormalities that are associated with disease
progression. Thus, nodal MCL cases acquire additional cytogenetic abnormalities as they progress to the leukemic phase
of the disease. In support of this concept, there are more
similarities than differences in the complexity and overall
pattern of the karyotypic abnormalities between the nodal
and leukemic groups. We also considered the possibility that
karyotypic differences between the nodal and leukemic cases
may be attributed to the use of specimens from different
anatomic sites, as most of the specimens in the leukemic
group were from the bone marrow, whereas most of the
specimens in the nodal group were from the lymph nodes.
However, we consider this possibility unlikely, because karyotypic results from multiple specimens of different anatomic
sites were available in 4 cases (Table 1, cases 13, 17, 27, 41),
and the results were consistent from site to site.
We included only unequivocal cases of MCL that have
t(11;14) detectable by conventional cytogenetics. This selection criterion is rigorous and may have excluded a proportion
of MCL cases that did not grow well in culture and/or did
not have the t(11;14) detectable by conventional cytogenetics. Nevertheless, this selection criterion carries an important advantage—the diagnosis of MCL in our study cases
was well supported. In addition, our study is relatively reproducible owing to this simple but objective selection criterion.
Excluding the t(11;14), chromosome 13 abnormalities
have been reported most frequently in MCL. Of these,
del(13)(q14) has been reported commonly.8,29 This deletion
has been found in cases of leukemic follicular lymphoma30
and some aggressive cases of multiple myeloma.31 In our
series, only 2 cases had this abnormality. In the present study,
we observed that monosomy 13 was most common and that
13q31-34 was the most frequently involved breakpoint.
© American Society of Clinical Pathologists
Hematopathology / ORIGINAL ARTICLE
13q31-34 is known to harbor a candidate tumor suppressor
gene, ING1, which is frequently rearranged in head and neck
squamous cell carcinoma.32
We did not observe any significant difference in the
overall frequency of chromosomal aberrations in MCL
between patients who had or had not received previous
chemotherapy. Nevertheless, we found that abnormalities of
chromosome 17 were more frequent in the tumors of previously treated patients, and it is possible that chromosome 17
abnormalities are therapy induced. However, we believe that
this possibility is unlikely. Seven patients had sequential
cytogenetic studies, before and after chemotherapy, and in
no case were chromosome 17 abnormalities found in MCL
after treatment. Thus, we believe that the chromosome 17
abnormalities detected in this study are most likely intrinsic
to MCL. The association between loss of chromosome Y
and the untreated group is difficult to explain. Loss of chromosome Y is known to occur in the bone marrow of elderly
patients with or without evidence of malignancy, most likely
as an age-related nondisjunctional phenomenon.33,34 The
occurrence of chromosome Y loss in hematologic disease,
including B-cell lymphoma, is related directly to patient age,
does not seem to correlate with disease progression or prognosis, and may be a secondary event.34,35
We confirm the observations of others that most cases of
MCL have nonrandom chromosomal abnormalities in addition to the t(11:14)(q13;q32). Our findings also support the
concept that aberrations of these specific chromosomal
regions are important in the pathogenesis of these
neoplasms. The differences between the cytogenetic profiles
of leukemic and nodal MCL suggest that these karyotypic
abnormalities contribute to the clinical and biologic behavior
of MCL. Further characterization of known or putative oncogenes and tumor suppressor genes at the sites of recurrent
breakpoints will be useful in further delineating the pathogenesis of these neoplasms.
From the Departments of 1Hematopathology and 2Leukemia,
University of Texas M.D. Anderson Cancer Center, Houston.
Address reprint requests to Dr Lai: Dept of
Hematopathology, University of Texas M.D. Anderson Cancer
Center, Box 72, 1515 Holcombe Blvd, Houston, TX 77030.
* Dr Onciu is now with the Department of Hematopathology,
St Jude Children’s Research Hospital, Memphis, TN.
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