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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Second Department of Internal Medicine,
Mie University School of Medicine, Tsu, Japan; Division of Molecular
Medicine, Department of Hematology and Chemotherapy, and Department of
Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya,
Japan; Department of Internal Medicine, Fujita Health University School
of Medicine, Toyoake, Japan; Department of Oral Pathology, Tohoku
University School of Medicine, Sendai, Japan; First Department of
Pathology, Fukushima Medical College, Japan; Department of Pathology,
Okayama University Graduate School of Medicine and Dentistry, Japan;
First Department of Internal Medicine, Fukuoka University School of
Medicine, Japan; Department of Hematology, Nishio Municipal Hospital,
Japan; Third Department of Internal Medicine, Akita University School
of Medicine, Japan; First Division, Department of Internal Medicine,
Faculty of Medicine, Kyoto University, Japan; Department of Pathology,
Saitama Medical Center, Saitama Medical School, Kawagoe, Japan; Second
Department of Internal Medicine, Nagoya City University Medical School,
Japan.
De novo CD5+ diffuse large B-cell lymphoma
(CD5+ DLBCL) is known to have phenotypically and
genotypically different characteristics than CD5 Diffuse large B-cell lymphoma (DLBCL) is the
largest category of aggressive lymphomas; it is regarded as a
heterogeneous group of lymphomas in terms of surface markers,
histology, and clinical features.1 Some patients with
DLBCL can be cured by combination chemotherapy, but more than half of
them die of their disease.2 Therefore, identification of a
high-risk group or a specific subtype of DLBCL is particularly
important and long overdue.
The CD5 molecule is a 67-kd glycoprotein that is expressed by most T
cells and a subset of B cells.3 CD5+ B cells
are the predominant B-cell population in human fetal spleen and cord
blood, but they represent only 10% to 20% of adult peripheral B
cells.3-5 They are distinct from CD5 In mature B-cell neoplasms, CD5 is expressed in most patients
with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL),
but less frequently in patients with DLBCL12 and in only few patients with marginal zone B-cell lymphoma13,14 and
Burkitt lymphoma.15 Of special interest is that
CD5+ DLBCL not preceded by any other lymphoproliferative
disease have been reported,16,17 though they are often
identified as arising secondarily in a CLL (Richter syndrome). Matolcsy
et al16 have highlighted the phenomenon of CD5 expression
in DLBCLs evolving de novo, not as a result of transformation, thus
suggesting that such DLBCL is genotypically distinct from Richter
syndrome-associated DLBCL.
We have also provided evidence that de novo CD5+ DLBCL is
phenotypically and genotypically distinct from MCL.17-22
CD5+ cases account for approximately 10% of DLBCL, which
is usually negative for CD10, CD21, and CD23.17-22
Immunohistochemical examinations have demonstrated that cyclin D1 is
not overexpressed in CD5+ cases18 and that
immunoglobulin heavy chain genes are somatically mutated.19,20,22 These findings support our hypothesis
that de novo CD5+ DLBCL constitutes a distinct subtype, but
previous reports from a single institution include only a small number
of patients.21,23,24 Therefore, the clinicopathologic
features of de novo CD5+ DLBCL remain to be thoroughly
identified. This prompted us to investigate these features in a large
patient population. To further characterize the de novo
CD5+ DLBCL, we performed a collaborative study on 109 patients.
Patient selection
For the control group, 384 patients with CD5 Histopathology
Immunophenotypic study Immunohistochemical and flow cytometric analyses were performed as described previously.18,26 Monoclonal antibodies used were Leu4 (CD3), Leu1 (CD5), and CALLA (CD10) (Becton Dickinson, Mountain View, CA); J5 (CD10) and B1 (CD20) (Coulter, Hialeah, FL); H107 (CD23) (Nichirei, Tokyo, Japan); MHM6 (CD23), UCHL1 (CD45RO), HM57 (CD79a), anti-IgG, anti-IgA, anti-IgM, anti-IgD, anti- , and anti- (DAKO, Carpinteria, CA); 4C7 (CD5) and NCL-CD10 (CD10) (Novocastra, Newcastle, United Kingdom), and cyclin D1 (IBL,
Gunma, Japan). More than 20% positivity of the tumor cells was judged
as indicating positivity for the purposes of this study. In fact, most
neoplastic cells were confirmed to be positive for CD5 in most
patients. In 99 patients with de novo CD5+ DLBCL, CD5
expression was examined by means of flow cytometric analysis or
immunohistochemistry in frozen sections and by immunohistochemically in
paraffin sections in the remaining 10 patients.
Statistical analysis Correlations between the 2 groups were examined by chi-square analysis, the Fisher exact test, the Student t test, and the Mann-Whitney U test. Patient survival data were analyzed by the Kaplan-Meier method and were compared by means of the log-rank test. Univariate and multivariate analyses were performed with the Cox proportional hazard regression model. Data were analyzed with the SAS system (SAS Institute, Cary, NC).
Patient characteristics for de novo CD5+ DLBCL,
CD5  DLBCL, patients with de novo CD5+ DLBCL
showed a higher age distribution (median, 66 vs 63 years; P = .0083, Student t test) and a female
predominance (female-male ratio, 60:49 vs 159:225;
P = .011). Especially noteworthy is that the patients with
de novo CD5+ DLBCL showed a closer association with the
aggressive clinical features or parameters: 75 patients older than 60 (69%, P = .039), 37 with performance status (PS) greater
than 1 (34%, P = .0016), 75 with serum lactate
dehydrogenase (LDH) level higher than normal (69%,
P < .0001), 68 with stage III/IV disease at diagnosis
(62%, P = .0023), 38 with more than one extranodal site
(35%, P = .023), and 44 with B symptoms (40%,
P = .0031). As a result, the International Prognostic
Index (IPI) score27 for the patients with de novo CD5+ DLBCL was significantly higher than that for patients
with CD5 DLBCL (P = .000 05), with 40 (36%) of the CD5+ group categorized in the IPI
high-risk group.
A comparison with cyclin D1+ MCL (Table 1) showed that the patients with de novo CD5+ DLBCL were characterized by a female predominance (P = .0001), worse PS (P = .020), higher serum LDH level (P < .0001), and lower disease stage (P = .011). The IPI score for the patients with de novo CD5+ DLBCL had the tendency to be higher than that for cyclin D1+ MCL (P = .10). Table 2 summarizes anatomic sites of
extranodal involvement in de novo CD5+ DLBCL. In 31 (28%)
patients of the current series, the disease was limited to extranodal
sites, 25 (23%) had only lymphadenopathies without extranodal
involvement, and the remaining 53 had lymphadenopathies with
extranodal involvement.
The most frequent site of extranodal involvement in de novo
CD5+ DLBCL was bone marrow (n = 31, 28% of patients;
Table 2; Figure 1). Atypical lymphocyte
contents (range, 3%-53%) were noted at presentation in the peripheral
blood smears of 6 patients, whose white blood cell counts ranged from
3700 to 15 100/µL. Twenty-seven (25%) of the patients had
splenomegaly and 20 (18%) had hepatomegaly at presentation (Table 2;
Figure 1). Sites of extranodal involvement in the patients without
lymphadenopathies were relatively limited. Twenty-six of 31 patients
had extranodal involvement in at least one in the following sites: bone
marrow, liver, spleen, lung, skin, stomach, and breast. Nodal and
extranodal disease presented a greater variety of extranodal
involvement when compared to extranodal-only disease.
A comparison with CD5 Four (4%) of our patients had a history of autoimmune disease; 2 with rheumatoid arthritis, and one each had a history of rheumatoid arthritis with Sjögren syndrome and of primary biliary cirrhosis. Three patients had nodal and extranodal involvement (Table 2). Histologic features De novo CD5+ DLBCL showed a diffuse and monomorphic proliferation of large lymphoid cells (Figure 2). These tumor cells were usually morphologically centroblastic and seldom immunoblastic (3 of 109, 3%; Table 3). In many patients, the tumor cells had a moderate rim of pale basophilic or amphophilic cytoplasm. Nuclei were round or sometimes irregular, indented or multilobated, and they contained vesicular chromatin and small distinct nucleoli. In 8 (7%) of the patients, these tumor cells were distributed throughout the interfollicular area while sparing the follicles, which retained their mantle cuffs (Figure 2). Although they were the subject of special attention, the typical mantle zone pattern or naked germinal centers characteristic of MCL were not observed. Moreover, intravascular or intrasinusoidal infiltration was identified in 21 (19%) patients with de novo CD5+ DLBCL. Focal necrosis and infiltration of macrophages were occasionally seen.
Phenotypic features Immunophenotypic features are summarized in Table 4. According to the definition adopted for this study, all patients tested positive for CD5 and B-cell markers (CD19 or CD20) (Figure 3) and negative for cyclin D1. Only 5 (5%) of the patients tested positive for CD10, and even fewer (3 [4%]) tested positive for CD23. This immunophenotype also accentuated the follicular dendritic cells on the paraffin sections and showed that few follicular dendritic cells were interspersed among the tumor cells. The immunoglobulin isotype was most commonly IgM (71 patients, 85%). Fifty-one of the patients examined were also positive for light chain and 25 for light chain. A
comparison with CD5 DLBCL demonstrated that de novo
CD5+ DLBCL was characterized by a
CD5+CD10 CD19+CD20+CD21CD23
phenotype and a predominance of surface IgM (Table 4).
Therapeutic response and prognosis Treatment consisted of chemotherapeutic regimens containing anthracycline for 91 patients and without anthracycline for 4 patients. Eight patients with stage I disease did not undergo chemotherapy but were treated with radiotherapy or surgical resection alone. Finally, the 6 patients who had not received any therapy because of their poor PS died of the disease. In total, 63% (69 of 109) of the patients with de novo CD5+ DLBCL achieved complete remission with the initial therapy. De novo CD5+ DLBCL thus showed a survival curve significantly inferior to that for the CD5 (P = .0026, Figure
4), with a 5-year survival rate of 34%
for the former.
Univariate Cox analysis identified the following prognostic
factors for the 493 patients with CD5+ and
CD5
We also compared the survival of patients with de novo
CD5+ DLBCL with that of patients with cyclin
D1+ MCL (Figure 5). Although
both groups had poor outcomes, several details of the survival curves
were different. The curve for cyclin D1+ MCL gradually but
steadily declined without any plateau, suggesting that MCL is a
generally incurable disease. In contrast, de novo CD5+
DLBCL initially followed a more aggressive clinical course than MCL,
but the survival curve crosses that of MCL 5 years after diagnosis and
shows superior survival thereafter.
An analysis of 109 patients with de novo CD5+ DLBCL
highlighted previously unrecognized features of this disease The prognosis of de novo CD5+ DLBCL was significantly
poorer than that of CD5 De novo CD5+ DLBCL showed a female predominance,
which has also been noted in 3 subtypes of malignant lymphoma,
ie, follicular lymphoma, marginal zone B-cell lymphoma, and primary
mediastinal large B-cell lymphoma; the other types of non-Hodgkin
lymphoma usually tend to show male predominance.2 Indeed,
in our series of DLBCL, the male-to-female ratio was significantly
different for the CD5+ and CD5 Morphologically, 8 patients with de novo CD5+ DLBCL
showed an interfollicular growth pattern not seen in CD5 In conclusion, the current study sheds further light on the clinicopathologic features of de novo CD5+ DLBCL, which may constitute a unique subtype of DLBCL with an aggressive clinical course. Innovative therapeutic strategies must be established by a prospective study.
We thank the members of the research project study group supported by the Ministry of Health, Labour, and Welfare, which is aimed for delineation of molecular biological profile of the refractory lymphoid malignancy and the development of its tumor type-specific management. We also thank the members of the Adult Lymphoma Treatment Study Group. We thank collaborators who provided the patient data and specimens; the names of their institutions are listed in the Appendix.
Submitted May 7, 2001; accepted September 24, 2001.
Supported in part by a Grant-in-Aid for the 2nd-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour, and Welfare, a Grant-in-Aid for Science on Primary Areas (Cancer Research), a Grant-in-Aid for the Encouragement of Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid from the Bristol-Myers Squibb Unrestricted Biomedical Research Grants Program.
M.S. and S.N. share senior authorship and should both be regarded as corresponding authors.
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.
Reprints: Masao Seto, Division of Molecular Medicine, and Shigeo Nakamura, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681; e-mail: mseto{at}aichi-cc.jp and snakamur{at}aichi-cc.jp.
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Patient data and specimens were received from collaborators at the following institutions: Akita University School of Medicine, Akita Kumiai General Hospital, National Miyagi Hospital, Saka General Hospital, Tohoku University School of Medicine, Sendai City Hospital, Furukawa City Hospital, Fukushima Medical College, Iwaki General Hospital, Ohta Nishinouchi General Hospital, Takeda General Hospital, Tokyo Women's Medical University Daini Hospital, Matsudo Municipal Hospital, Higashi Matsudo Hospital, Niigata University, Toyama Prefectural Central Hospital, Kanazawa Medical University, Inazawa Municipal Hospital, Aichi Prefectural Hospital, Toyota Memorial Hospital, Fujita Health University School of Medicine, Okazaki Municipal Hospital, Kasugai Municipal Hospital, Japanese Red Cross Nagoya First Hospital, Nagoya Memorial Hospital, Aichi Cancer Center, Suzuka Chuo General Hospital, Suzuka Kaisei General Hospital, Mie University School of Medicine, Matsusaka Municipal Hospital, Matsusaka Chuo General Hospital, Matsusaka Saiseikai General Hospital, Yamada Red Cross Hospital, Ise City General Hospital, Kyoto University, Kyoto Prefectural University School of Medicine, Okayama University Medical School, Okayama Saiseikai General Hospital, Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Okayama Red Cross General Hospital, Fukuoka University School of Medicine, Kyushu Cancer Center, and Kyusyu University.
© 2002 by The American Society of Hematology.
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  M Roshal, B G Till, J R Fromm, and S Cherian Intravascular large B cell lymphoma presenting in a liver explant J. Clin. Pathol., July 1, 2008; 61(7): 877 - 878. [Full Text] [PDF]
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 D. Ennishi, K. Takeuchi, M. Yokoyama, H. Asai, Y. Mishima, Y. Terui, S. Takahashi, H. Komatsu, K. Ikeda, M. Yamaguchi, et al. CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy Ann. Onc., June 23, 2008; (2008) mdn392v1. |
Top
Abstract
Introduction
), the incidence of bone marrow
involvement was higher than that of CD5
) and
lower than that of cyclin D1+ MCL (
). Hepatomegaly
and splenomegaly occurred more frequently in de novo CD5+
DLBCL than in CD5
high age
at onset, female predominance, frequent association with poor
prognostic components of IPI, and aggressive clinical course. These
features were significantly different from those of CD5