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Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2253-2261
CLINICALOBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Pathology and Clinical
Laboratories, Laboratory of Chemotherapy, and
the Department of Hematology and Chemotherapy, Aichi Cancer
Center, Nagoya; the Departments of Medical Oncology
and Pathology, National Cancer Center, Tokyo;
the Department of Pathology, Tohoku University School of Medicine,
Sendai; the Department of Internal Medicine, Fujita Health
University School of Medicine, Nagoya; the Second
Department of Internal Medicine, Mie University School of Medicine,
Tsu; the First Department of Pathology, Chiba University
School of Medicine, Chiba; the Department of
Hematology, National Kyushu Cancer Center, Fukuoka; and the
First Department of Pathology, Fukushima Medical College,
Fukushima, Japan.
Mantle cell lymphoma (MCL) is a distinct clinicopathologic entity of
non-Hodgkin's lymphoma, characterized by a monotonous proliferation of
small to medium-sized lymphocytes with co-expression of CD5 and CD20,
an aggressive and incurable clinical course, and frequent
t(11;14)(q13;q32) translocation. We examined 151 cases of lymphoma with
MCL morphology from a viewpoint of cyclin D1 overexpression, which is
now easily detectable by immunohistochemistry. 128 cases (85%) showed
positive nuclear staining for cyclin D1, while the remaining 23 (15%)
were negative. Except for cyclin D1 immunohistochemistry, current
diagnostic methods, including morphological and phenotypical
examinations, could not make this distinction. Although both the cyclin
D1-positive and -negative groups were characterized by male
predominance, advanced stages of the disease, frequent extranodal
involvement, and low CD23 reactivity, the cyclin D1-positive group
showed a higher age distribution (P = .04), larger cell
size (P = .02), higher mitotic index (P = .01),
more frequent gastrointestinal involvement (P = .05), higher international prognostic index score (P = .05), and
lower p27KIP1 expression (P < .0001). Of
particular interest is that cyclin D1-positive MCL showed significantly
worse survival than cyclin D1-negative lymphoma (5-year survival: 30%
versus 86%, P = .0002), which was confirmed by
multivariate analysis to be independent of other risk factors. These
data suggest that cyclin D1-positive and -negative groups may represent
different entities and that the former closely fits the characteristics
of classical, typical MCL. We therefore propose that cyclin
D1-positivity should be included as one of the standard criteria for
MCL, and that innovative therapies for this incurable disease should be
explored on the basis of the new criteria. (Blood.
2000;95:2253-2261
(Blood. 2000;95:2253-2261)
Mantle cell lymphoma (MCL) is a malignant proliferation
of B cells in the mantle zone of lymphoid follicles.1 Since
its initial recognition in the mid-1970s, this distinct entity has been
described with various diagnostic terms, ie, lymphocytic lymphoma of
intermediate differentiation by Berard,2 centrocytic lymphoma by Lennert,3 and mantle zone lymphoma by
Weisenburger.4 This history reflects the process of
identifying the relatively divergent histologic patterns (diffuse,
nodular, and mantle zone patterns) of this entity, which may sometimes
create diagnostic pitfalls even for expert pathologists. In 1992, Banks
et al5 showed that these differently named lymphomas fell
within the same entity and named it mantle cell lymphoma.
MCL is mostly characterized by a monotonous proliferation of small to
medium-to-large lymphocytes with scant cytoplasm and slightly irregular
contoured nuclei. Immunophenotypically, co-expression of CD5 and pan
B-cell antigens (CD19, CD20, CD22, and CD24) are characteristic of MCL,
though this feature is also observed in chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL). CD23, which is positive
for CLL and generally negative for MCL, is a
distinguishing feature, but some contradictory findings
have been reported.6 The intensity of CD20 and
immunoglobulin light chain expression, which is bright in MCL and dim
in B-CLL/SLL, has also been shown to be useful for distinguishing MCL
from B-CLL/SLL,7 but some exceptional cases have been
identified.8 Clinically, patients with MCL are
characterized by advanced age and male predominance, presentation at
advanced stages (III and IV), and frequent involvement of bone marrow
(BM), peripheral blood, and other extranodal sites.9-16 Despite the use of combination chemotherapy for aggressive lymphoma, the median survival of patients has been only 3 to 4 years in most
large-scale series. Thus, MCL is regarded as an incurable lymphoma.
Typical MCL contains a cytogenetic abnormality with t(11;14)(q13;q32)
translocation, less commonly with t(11;22)(q13;q11),17 which involves a rearrangement of the BCL-1 locus. The putative oncogene deregulated by this alteration has subsequently been identified as cyclin D1.18-21 Cyclin D1 belongs to the G1
cyclins and plays a key role in cell cycle regulation during the G1/S transition by cooperating with cyclin-dependent kinases
(CDKs).22,23 Further evidence suggests that cyclin D1 can
function as an oncogene, the overexpression of which may lead to growth
advantage for tumor cells by way of cell cycle progression. Indeed, its
overexpression has also been reported in various other human cancers,
eg, esophageal, breast, and bladder carcinomas. Among hematolymphoid
malignancies, cyclin D1 overexpression resulting from translocational
activation has also been recognized in a subset of B-chronic
lymphocytic leukemia (B-CLL), multiple myeloma, splenic marginal zone
lymphoma, and hairy cell leukemia, though the relationship between them remains to be clarified. Because the breakpoint on chromosome 11q13
covers a wide range between 15 kb and more than 400 kb distance from
the cyclin D1 gene, Southern blotting or polymerase chain reaction
(PCR) analysis cannot detect all of t(11;14). Immunohistochemical detection of the cyclin D1 protein has been reported to correlate with
overexpression of cyclin D1 mRNA.24 A previous preliminary study of ours demonstrated that the cyclin D1-positive MCL group, which
comprises the majority of MCLs and pursues an aggressive clinical
course, should be demarcated from the cyclin D1-negative group, which
has a remarkably favorable prognosis.12 For the current
study, we collected data on 151 patients with lymphomas with
morphological features of MCL and retrospectively investigated incidence, clinicopathologic features and prognosis to clarify the
significance of cyclin D1 overexpression for the diagnosis of MCL.
Patients
Histopathology
Immunophenotyping Immunohistochemical13 and flow-cytometric26 analyses were performed as described previously. The monoclonal antibodies used were OKT11 (CD2), OKB7 (CD21), OKB22 (CD22), and OKT10 (CD38) (Ortho Diagnostics, Raritan, NJ); Leu4 (CD3), Leu3a (CD4), Leu1 (CD5), Leu2 (CD8), CALLA (CD10), LeuM1 (CD15), Leu12 (CD19), Leu16 (CD20), TCR1 (TCR  ), and TCR 1 (TCR ) (Becton Dickinson,
Mountain View, CA); Tp120 (CD6) and Tp40 (CD7) (established in our
laboratory); J5 (CD10), B4 (CD19), B1 (CD20), B2 (CD22), My9 (CD33),
and NKH-1 (CD56) (Coulter, Hialeah, FL); MCS-2 (CD13) and H107 (CD23)
(Nichirei, Tokyo, Japan); L26 (CD20), Tac (CD25), Ber-H2 (CD30), UCHL1
(CD45RO), anti-HLA-DR, anti-IgA, anti-IgG, anti-IgM, anti-IgD,
anti- , and anti- (DAKO, Carpinteria, CA); and MT1/CD43
(Bio-Science Products, Emmenbrucke, Switzerland). Intensity of antigen
expression by flow cytometry was defined as the ratio of the linearized
peak fluorescence of the positive distribution to that of the
isotype-matched control. The expression intensity of CD20 and
immunoglobulin light chain (IgL) was compared with that of CD19 with
the same fluorescein, and a higher intensity than that of CD19 was
defined as "bright" and a lower intensity as "dim" as
previously described. 7,8
Immunohistochemistry for cyclin D1 and cell cycle regulators Formalin-fixed, paraffin-embedded 5-µm thick sections were stained with standard ABC methods, using diamino-bentizine as the visualizing substrate.27,28 Antigen retrieval for the staining of cyclin D1 and p27KIP1 was performed with microwave treatment in 0.01 mol/L citrate buffer (pH 6.8). The following antibodies were used: cyclin D1 (IBL, Gunma, Japan),27 p27KIP1 (Transudation Laboratories, Lexington, KY), and the phosphorylated form of pRb (ppRb) at serine 780 (MBL, Nagoya, Japan).29 For the analysis of pRb, frozen sections of 35 available patients were fixed with paraformaldehyde for 15 minutes, followed by immunohistochemical staining as described above.Statistical analysis The chi-square test, the Fisher exact test, and Student t test were used to examine the relation between any 2 factors. The Mann-Whitney U test was performed to compare graded factors. Actuarial survival curves were estimated with the Kaplan-Meier method and compared by means of the log-rank test. A Cox proportional hazard regression model was used to identify factors with a significant influence on survival. Data were analyzed with the SAS system (SAS Institute, Cary, NC).
Cyclin D1 overexpression in MCL Among the 151 patients with MCL morphology, cyclin D1 overexpression was detected in 128 (85%). Representative morphology and immunohistochemical profiles of both cyclin D1-positive and -negative groups are shown in Figure 1.
Patient characteristics for cyclin D1-positive and -negative The clinical features of the cyclin D1-postive and -negative groups were analyzed for comparison (Table 1). Those of the cyclin D1-negative patients are summarized in Table 2 to facilitate evaluation. The patients of both groups showed male predominance, whereas the cyclin D1-positive group showed a higher age distribution (median age, 65 and 60 years, respectively; P = .04, Student t test). The majority of both groups presented with advanced stages (III or IV) of the disease (85% and 69%, respectively). Primary sites of involvement of stage I cases were Waldeyer ring (n = 2), stomach (n = 1), and lymph nodes (n = 3; neck, inguinal, and abdominal) for the cyclin D1-positive group, whereas they were orbit (n = 2), Waldeyer ring (n = 1), and subcutis (n = 1) for the cyclin D1-negative group. Extranodal involvement was frequently recognized in both groups (71% and 74%, respectively). BM and peripheral blood were the most frequent sites of extranodal involvement in both groups. The cyclin D1-positive group exhibited a significant preponderance of gastrointestinal tract involvement compared with the cyclin D1-negative group (27% versus 9%; P = .05), and the cyclin D1-negative group showed more frequent presentation or involvement of the orbit (2% versus 13%; P = .05). Serum LDH level and performance status tended to be higher for the cyclin D1-positive group, though the difference was not statistically significant. IPI score was higher for the cyclin D1-positive group (P = .04; Mann-Whitney U test).
Histologic features In histologic terms, both cell size and mitotic index of the 2 groups were different (Table 3). In the cyclin D1-positive group, the majority (107 patients, 84%) featured a monotonous population of atypical small to medium-sized lymphoid cells with irregular and indented nuclei, whereas pleomorphic and blastic/blastoid variants were encountered in 10 (8%) and 11 patients (9%), respectively. Consequently, cyclin D1-positive MCL showed a larger cell size (P = .006) and higher mitotic index (P = .003). However, the distribution of growth patterns (mantle zone, nodal, or diffuse) revealed no remarkable differences between the 2 groups. The characteristic mantle zone pattern was also seen in cyclin D1-negative patients without identification of a proliferation center.
Phenotypic features Immunophenotypically, most of the cyclin D1-positive and -negative patients showed similar profiles of CD5+, CD10 , CD19+, CD20+, and
CD23 phenotypes, though 10 of the cyclin D1-positive
patients (11%) and 4 of the cyclin D1-negative patients (27%) showed
CD23 expression (Table 4). With the aid of
flow cytometry, the intensity of CD20 and IgL expression was compared
with that of CD19 in 40 of the cyclin D1-positive and 7 of the cyclin
D1-negative patients. Bright expression of CD20 and IgL was recognized
in most of the patients in both groups (Table 4), but 1 patient showed
a dim expression of both CD20 and IgL, and 2 other patients in the
cyclin D1-positive group showed bright CD20 and dim IgL expression. In
the cyclin D1-negative group, 1 patient also displayed a dim expression
of both antigens, and another patient displayed dim CD20 but bright IgL
expression. Five other patients exhibited a bright expression of both
CD20 and IgL.
Cytogenetic and genetic studies Cytogenetic profiles are summarized in Table 4. Exactly half of the cyclin D1-positive MCLs showed t(11;14)(q13;q32), and none of the cyclin D1-negative group did, though the number of informative patients was limited. Southern blotting identified the rearrangement of the BCL-1 locus in 8 of 15 cyclin D1-positive patients (2 with t(11;14) and 6 with no cytogenetic data), and Northern blotting detected cyclin D1 mRNA in 14 of 15 cyclin D1-positive patients (3 with t(11;14), 1 with normal karyotype, and 10 with no cytogenetic data) as described previously.24 In contrast, none of the 3 cyclin D1-negative patients (1 without t(11;14) and 2 with no cytogenetic data) showed any evidence of either rearrangement of BCL-1 or cyclin D1 mRNA.Expression of cell cycle regulators In both the cyclin D1-positive and -negative groups, the expression of ppRb was low throughout (Figures 2A, 2B), and no difference in expression was found between the 2 groups. Less than 20% of the tumor cells were positive for ppRb in all patients. However, the labeling index for p27KIP1 expression (Figures 2C, 2D) showed a sharp division into 2 categories, very low (less than 10% positivity), and high (more than 60%). Twenty of the 23 cyclin D1-positive MCL patients exhibited no or a low expression of p27KIP1, and 10 of the 12 cyclin D1-negative patients exhibited a high expression of p27, thus showing a marked difference in expression (Table 5, P < .0001).
Therapeutic response and prognosis Of the patients with cyclin D1-positive MCL, 78% received chemotherapy containing doxorubicin, whereas 73% of the cyclin D1-negative group did. Other patients were treated with radiation or chemotherapy without doxorubicin. In both groups, approximately 40% (44% of cyclin D1-positive and 42% of cyclin D1-negative) attained complete remission. However, survival showed a significant difference between the 2 groups (Figure 3, P = .0002): the 5-year survival rate for the cyclin D1-positive group was only 30%, whereas that for the cyclin D1-negative group was 86% (Figure 3). Analysis after exclusion of patients with CD23+ phenotype or those with orbital involvement also resulted in a statistically significant difference in survival (P = .001). The survival rates were not different, however, for subgroups divided according to the choice of initial treatment, that is, chemotherapy with or without doxorubicin, or radiation (data not shown). Univariate analysis showed that patient's age, serum LDH level, stage, PS, and IPI at diagnosis were significant risk factors for survival (Table 6). Multivariate analysis confirmed that cyclin D1 status (positive or negative) was an independent factor for survival when compared with each of the risk factors and with the IPI risk category (Table 6); both types of analysis determined that cyclin D1 positivity was the highest risk factor (respective relative risks, 8.5 and 7.5). Analysis after the exclusion of patients with CD23+ phenotype or with orbital involvement also showed the statistical significance of cyclin D1 (respective relative risks, 6.5 [1.5-28.0, P = .01] and 7.4 [1.8-30.8, P = .005]).
In this study, we examined 151 patients of lymphomas with the
morphologic features of MCL. Because of the clinicopathologic and
significant prognostic differences between the cyclin D1-positive and
-negative groups indicated by our results, the determination of cyclin
D1 status is thought to be essential for the diagnosis of MCL. For the
cyclin D1-positive group, the median survival period was 3.5 years,
which was consistent with that for intermediate grade lymphomas as
determined by the Working Formulation. However, there was no plateau in
the survival curve, in clear contrast with that for other intermediate
grade lymphomas. The incurable clinical course of the patients with
cyclin D1-positive, but not cyclin D1-negative, lymphomas corroborated
the characteristic behavior of the former type of lymphoma, which was
almost the same as the reported prognosis for a smaller series of
MCL.9-16 Those studies emphasized the overall poor outcome
for MCL because of the predominance of cyclin D1-positive patients and
overlooked the favorable clinical course of the cyclin D1-negative
patients because there were so few.
We thank the collaborators from the following institutions for
providing the patients' data and specimens: Third Department of
Internal Medicine, Akita University School of Medicine; Japanese Red
Cross Nagoya First Hospital; Aichi Prefectural Hospital, Okazaki Municipal Hospital; First Department of Internal Medicine,
Nagoya University School of Medicine; Atomic Disease Institute,
Nagasaki University School of Medicine; Research Institute for
Radiation Biology and Medicine, Hiroshima University School of
Medicine; Second Department of Internal Medicine, Kyoto Prefectural
University School of Medicine; Asahikawa Kosei Hospital; First
Department of Internal Medicine, Saitama Medical School; Niigata Cancer
Center Hospital; National Minami-Okayama Hospital; Departments of
Hematology and Pathology, Kawasaki University School of Medicine; Tenri
Hospital; Hamamatsu Medical Center; Miyagi Medical Cancer; Sapporo
National Hospital; Ichinomiya Municipal Hospital.
Submitted April 19, 1999; accepted December 8, 1999.
Y.Y. and R.S. contributed equally to this study and should both be
regarded as first authors.
Reprints: Shigeo Nakamura, Department of Pathology
and Clinical Laboratories,
Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
e-mail: snakamur{at}aichi-cc.pref.aichi.jp.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
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Abstract
Introduction
that cyclin D1 overexpression is a strong, independent, and
significant prognostic factor for lymphoma with MCL morphology.
