Ki-67与Bcl-2在非霍奇金淋巴瘤中的表达及其临床意义

目的：探讨增殖相关抗原Ki-67和抗凋亡蛋白Bcl-2的检测,观察其在非霍奇金淋巴瘤（NHL）中的表达及临床意义。方法：用免疫组织化学染色的方法,对35例NHL外科活检石蜡包埋组织切片进行Ki-67抗原和Bcl-2蛋白的检测。结果：（1）Ki-67在低度恶性NHL组中的表达低于高度恶性组（P＜0．01）,而Bcl-2在低度恶性NHL组中的表达高于高度恶性组（P＜0．01）。（2）B细胞性NHL中Bcl-2的表达高于T细胞性NHL（P＜0．02）,而Ki-67表达差异差异无显著性（P＞0．1）。（3）首次化疗缓解组中的Bcl-2表达低于未缓解组（P＜0．01）,而Ki-67表达差异无显著性。（4）高Ki-67表达组的生存期比低表达组短（P＜0．05）,而Bcl-2的表达在两组之间无差异。结论：增殖相关抗原Ki-67和抗凋亡蛋白Bcl-2的表达与NHL的恶性程度和预后密切相关,是了解肿瘤发生和判断NHL预后的有效指标。     

ZO-1基因甲基化状态在非霍奇金淋巴瘤骨髓检测中的临床意义

目的探讨紧密连接蛋白-1（ZO-1）基因启动子区甲基化状态在非霍奇金淋巴瘤（NHL）检测中的临床意义。方法采用甲基化特异性PCR方法（MS-PCR）分析10例非血液系统肿瘤者骨髓及45例NHL患者骨髓标本的ZO-1基因启动子区甲基化状况。结果ZO-1基因在10例良性血液病及正常人中呈完全非甲基化状态,在39例初治、复发、未完全缓解的淋巴瘤患者中甲基化阳性率53．85％（P〈0．05）。在39例初治或复发或未达到完全缓解的NHL患者中28例Ⅲ、Ⅳ期的NHL患者ZO-1基因甲基化阳性率64．29％,11例Ⅰ、Ⅱ期的NHL患者ZO-1基因甲基化阳性率27．27％（P〈0．05）。初治、复发患者28例中甲基化阳性16例（57．14％）,经治疗达到部分缓解的11例患者中甲基化阳性5例（45．45％）,临床缓解的6例患者均为完全非甲基化。结论ZO-1基因启动子区高甲基化与疾病分期及缓解明显相关,它可以作为判断NHL进展和评价预后的辅助指标,并以此指导临床治疗。     

多种血液肿瘤中NK细胞受体表达差异的临床意义

目的：检测几种血液肿瘤患者中自然杀伤（NK）细胞受体变化，以探究NK细胞功能状态。方法：收集多发性骨髓瘤（MM）患者38例，其中IgG-k型18例、IgG-λ型10例、IgA-k型4例、IgA-λ型6例；非霍奇金淋巴瘤（NHL）患者27例，其中弥漫性大B细胞淋巴瘤18例、边缘区淋巴瘤3例、滤泡性淋巴瘤1例、套细胞淋巴瘤2例、免疫母性T细胞淋巴瘤1例、外周T细胞淋巴瘤2例；慢性髓系细胞白血病（CML）患者10例；30例健康志愿者为正常对照组。通过流式细胞术测定外周血中NK细胞占有核细胞比例，用实时荧光定量聚合酶链反应（RT-qPCR)方法检测NK细胞表面抑制性受体（PD-1）及活化性受体（CD69、NKG2D）的基因表达水平。结果：与正常对照组比较，MM、NHL患者外周血NK细胞占有核细胞比例比较，差异无统计学意义（P均＞0.05）；而CML患者NK细胞占有核细胞数显著减少（P＜0.05）；MM、NHL及CML患者的NK细胞表面活化性受体（CD69、NKG2D）水平较正常对照组明显降低，NK细胞表面抑制性受体（PD-1）表达显著高于正常对照组（P均＜0.05）；MM、NHL及CML患者间受体(PD-1、CD69、NKG2D)表达比较，差异无统计学意义（P均＞0.05）。结论：MM、NHL及CML患者外周血NK细胞表面活化性受体（CD69、NKG2D）水平明显降低，抑制性受体（如PD-1）表达明显增高，提示NK细胞功能耗竭。     

非霍奇金淋巴瘤p53蛋白表达与临床疗效及预后的相关性研究

目的研究p53蛋白表达在非霍奇金淋巴瘤（NHL）临床治疗疗效判断及预后评估中的意义。方法采用免疫组织化学染色法（LSAB法）检测128例NHL患者活检石蜡组织中p53蛋白的表达,同时予CHOP方案4个或以上疗程的化疗,观察p53与化疗疗效及预后的关系。结果 p53蛋白表达阳性率为39.8%。p53蛋白阳性表达和阴性表达病例的总生存期、无瘤生存期均有统计学差异。而p53蛋白的表达对不同国际预后指数（IPI）评分患者总生存期和无瘤生存期的影响无统计学差异。结论 p53蛋白作为进展型NHL临床近期疗效的有效预测指标,对NHL预后预测意义不大。     

B细胞非霍奇金淋巴瘤患者FHIT与Bcl-2关系的初步探讨

目的初步探讨B细胞非霍奇金淋巴瘤（NHL）组织中脆性组氨酸三联体（FHIT）、Bcl-2蛋白表达及意义。方法应用免疫组化EnVision法检测52例B细胞NHL组织（NHL组）和10例坏死增生性淋巴结炎组织（对照组）中FHIT、Bcl-2蛋白的表达情况。结果与对照组比较,NHL组FHIT蛋白表达降低,Bcl-2表达升高;NHL组中FHIT蛋白与Bcl-2蛋白表达呈负相关（P〈0.05）。结论 B细胞NHL发生可能与FHIT蛋白缺失、Bcl-2蛋白介导的凋亡受阻有关。     

PCNA在非霍奇金淋巴瘤中的表达及意义

目的探讨增殖细胞核抗原（PCNA）在非霍奇金淋巴瘤中（NHL）的表达及临床意义。方法采用免疫组化SP方法检测52例NHL及12例淋巴结反应性增生（RH）患者PCNA的表达情况。结果PCNA在RH患者中的阳性表达率明显低于NHL患者；侵袭性NHL患者表达水平明显高于惰性NHL患者。乳酸脱氢酶（LDH）〈250U／L的NHL患者PCNA阳性表达率明显低于LDH〉250U／L者。PCNA阳性表达率〉25％NHL患者平均生存期较阳性表达率〈25％者短。结论PCNA与NHL的发生发展有关，并可对预后判断提供参考依据。     

真核细胞翻译起始因子4E在非霍奇金淋巴瘤组织中的表达和意义

目的检测非霍奇金淋巴瘤（NHL）淋巴组织中真核细胞翻译起始因子4E（EIF4E）的表达。方法对134例NHL和30例反应性增生淋巴结石蜡包埋病理切片标本用免疫组织化学方法检测EIF4E的表达，同时对134例NHL患者进行临床资料分析。结果（1）反应性增生淋巴结中的EIF4E表达主要见于生发中心内活化的淋巴细胞：而NHL淋巴组织中肿瘤细胞均有EIF4E的表达。（2）NHL淋巴组织中EIF4E的表达率明显高于反应性增生淋巴结（P〈0．01），且高、中度恶性淋巴瘤EIF4E的表达强度明显高于低度恶性组（P〈0．05）。（3）NHL淋巴组织中不同性别、年龄、B症状、临床分期水平间EIF4E的表达率均无显著性差异（P〉0．05），而LDH增高组NHL患者EIF4E表达率明显高于LDH正常组（P〈0．05）。结论EIF4E一定程度上反映NHL细胞的恶性程度，并对NHL的病理分级和临床预后具有一定的意义。     

Bcl-2、P53、CyclinD1在B细胞淋巴瘤中的表达及意义

目的探讨Bc l-2、P53和细胞周期蛋白D1（CyclinD1）在B细胞淋巴瘤发生发展中的作用。方法采用组织芯片技术制备高通量的样本,采用免疫组织化学SP法检测Bc l-2、P53、Cyc linD1在B细胞淋巴瘤中的表达。结果 Bc l-2和P53主要表达于弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、黏膜相关淋巴组织结外边缘淋巴瘤、套细胞淋巴瘤和小淋巴细胞淋巴瘤;而CyclinD1只在套细胞淋巴瘤和弥漫性大B细胞淋巴瘤中表达。结论由Bc l-2和P53协同表达途径以及CyclinD1异常表达途径是弥漫性大B细胞淋巴瘤发生的重要机制。     

非霍奇金淋巴瘤骨髓侵犯细胞形态分析

目的：对骨髓侵犯非霍奇金淋巴瘤患者的淋巴瘤细胞形态进行分析。方法：对243例病理上确诊的非霍奇金淋巴瘤患者进行骨髓涂片,分析其形态学改变。结果：243例中发生侵犯40例,侵犯率为16.5%,其中淋巴瘤细胞骨髓浸润27例（67.5%）;淋巴瘤细胞白血病13例（32.5%）。总体上瘤细胞异形性明显,胞体大小不等,核明显畸形,易见到双核或多核,核染色质较粗而密,核仁可见或不见,胞质量少,染色偏碱性。结论：骨髓涂片观察瘤细胞形态,不仅可确定瘤细胞浸润程度,而且可分辨淋巴瘤细胞类型。     

BRCA1在弥漫性大B细胞淋巴瘤中的表达及意义

目的 探讨BRCA1在弥漫性大B细胞淋巴瘤的表达及与疾病预后的关系.方法 收集50例弥漫性大B细胞淋巴瘤标本和20例瘤周正常组织标本,采用免疫组化方法检测BRCA1在弥漫性大B细胞淋巴瘤和瘤周正常组织的表达,分析BRCA1表达与患者临床特点以及疾病预后的关系.结果 不同性别、年龄、发病部位、临床分期弥漫性大B细胞淋巴瘤患者BRCA1表达差异均无统计学意义（P均＞0.05）;弥漫性大B细胞淋巴瘤组织BRCA1表达的阳性率明显低于瘤周正常组织（x2=4.047,P＜0.05）;BRCA1表达阴性组的2年生存率高于阳性组（P＜0.05）.病变部位、临床分期、BRCA1表达、国际预后指数是影响弥漫性大B细胞淋巴瘤患者预后的独立变量.结论 BRCA1表达降低与弥漫性大B细胞淋巴瘤的发生有关,BRCA1可作为判断弥漫性大B细胞淋巴瘤预后的分子标志物.     

Cyclin Dl expression in B-cell non Hodgkin lymphoma

Disorders of the cell cycle regulatory machinery play a key role in the pathogenesis of cancer. Over-expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the effect of its expression on clinical behavior and outcome in B-cell Non-Hodgkin lymphoma (NHL). In this study, we investigated the expression of cyclin Dl in group of patients with NHL and correlated the results with the clinical and laboratory data. The degree of expression of cyclin Dl protein was evaluated by flow cytometry in a group of NHL patients (n = 46) and in normal control group (n = 10). Cyclin Dl over expression was detected in 10 out of 46 (21.7%) patients; they were 5/5-mantle cell lymphoma (MCL) (100%) and 5/28 large B-cell lymphoma (17.8%). All other NHL subtypes showed normal cyclin D1 expression. The clinical signs (hepatomegaly, splenomegaly and B-symptoms, clinical staging) and laboratory data (hemoglobin, white cell count (WBCs), platelet count, and bone marrow infiltration) were not significantly different between NHL subgroup with cyclin Dl over expression and that with normal cyclin Dl expression. Serum lactic dehydrogenase (LDH) levels and lymphadenopathy were significantly higher in NHL group with cyclin D1 over expression as compared to those without. Also, cyclin D1 over expression is associated with poor outcome of NHL patients. Cyclin Dl over expression was evident among all cases of MCL and few cases of large B-cell lymphoma. Cyclin Dl over expression might be used as adjuvant tool for diagnosis of MCL; has role in NHL biology and is bad prognostic index in NHL.     

Cyclin D1 expression in B-cell non Hodgkin lymphoma

Disorders of the cell cycle regulatory machinery playa key role in the pathogenesis of cancer. Over-expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the effect of its expression on clinical behavior and outcome in B-cell Non-Hodgkin lymphoma (NHL).

In this study, we investigated the expression of cyclin D1 in group of patients with NHL and correlated the results with the clinical and laboratory data. The degree of expression of cyclin D1 protein was evaluated by flow cytometry in a group of NHL patients (n = 46) and in normal control group (n = 10). Cyclin D1 over expression was detected in 10 out of 46 (21.7%) patients; they were 5/5-mantle cell lymphoma (MCL) (100%) and 5/28 large B-cell lymphoma (17.8%). All other NHL subtypes showed normal cyclin D1 expression. The clinical signs (hepatomegaly, splenomegaly and B-symptoms, clinical staging) and laboratory data (hemoglobin, white cell count (WBCs), platelet count, and bone marrow infiltration) were not significantly different between NHL subgroup with cyclin D1 over expression and that with normal cyclin D1 expression. Serum lactic dehydrogenase (LDH) levels and lymphadenopathy were significantly higher in NHL group with cyclin D1 over expression as compared to those without. Also, cyclin Dl over expression is associated with poor outcome of NHL patients.

Cyclin D1 over expression was evident among all cases of MCL and few cases of large B-cell lymphoma. Cyclin D1 over expression might be used as adjuvant tool for diagnosis of MCL; has role in NHL biology and is bad prognostic index in NHL.     

Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin- embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.     

BCL6 rearrangement in a patient with mantle cell lymphoma

 We describe a patient with mantle cell lymphoma (MCL) associated with BCL6 gene rearrangement. MCL is a distinct subtype of non-Hodgkin's lymphoma characterized by CD5+, CD10–, CD20+, t(11;14)(q13;q32) and PRAD1/cyclin D1 overexpression. Although rearrangement of the BCL6 gene is the most frequent genetic change among diffuse lymphomas and some follicular lymphomas this is the first report of a patient with MCL associated with BCL6 rearrangement. Received: 6 January 1997 / Accepted: 17 February 1997     

Characteristics and prognosis of KI-1 positive anaplastic large cell lymphoma in Asians

Background : Ki-1 positive anaplastic large cell lymphoma is a rare type of non-Hodgkin's lymphoma (NHL), and has not been extensively described in Asian patients.
Aim : To evaluate the clinical characteristics, prognostic factors and treatment outcome of Ki-1 positive lymphoma in an Asian community.
Methods : A retrospective analysis of all patients with CD30 antigen positive anaplastic large cell lymphoma from 1987 to 1996 in a single institution.
Results : Of 218 patients with NHL, ten (5%) were identified with Ki-1 positive anaplastic large cell lymphoma. Eight were Chinese, two Indians. The male: female ratio was 1.5:1, and the median age was 32 years. Seven patients presented with B-symptoms, and five had stage III/IV disease. The majority (seven of ten) was low-or low-intermediate risk according to the International Prognostic Index (IPI). Four out of five cases immunophenotyped showed a T-cell origin. Five out of eight patients who received first-line combination chemotherapy achieved a complete remission. Two relapsed, with one being re-induced into a durable second remission. One patient with recurrent cutaneous lymphoma received solely radiotherapy and was disease-free at 20+ years from diagnosis. At analysis, two patients had died, five were disease-free at four, 27, 78, 89 months and 20 years respectively, and three were alive with disease. The IPI appears to have prognostic significance.
Conclusion : Incidence and clinical characteristics in our Asian patients were similar to those described in Western populations. The IPI appears to have prognostic relevance. In approximately one-third of patients, long term survival can be achieved with standard treatment.     

Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management

DISEASE OVERVIEW: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with a short remission duration to standard therapies and a median overall survival of 4-5 years. DIAGNOSIS: Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t(11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION: The mantle cell lymphoma international prognostic index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median overall survival (OS) for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 and 29 months for the high-risk group. RISK-ADAPTED THERAPY: For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytarabine containing regimen ± autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), BTK inhibitors or CAL-101 (B-cell receptor inhibitors) or lenalidamide (antiangiogenesis) have clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients.     

Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells

Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma subtype, characterized by overexpression of cyclin D1 as a consequence of the chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed. The present study investigated the effect of a specific proteasome inhibitor, lactacystin, on cell cycle progression and apoptosis in two lymphoma cell lines harbouring the t(11;14)(q13;q32) and additional cytogenetic alterations, including p53 mutation (NCEB) and p16 deletion (Granta 519). Granta cells were more susceptible to inhibition of the proteasome with respect to inhibition of proliferation and apoptosis induction. No changes were observed in the expression levels of the G1 regulatory molecules cyclin D1 and cdk4, but cell cycle arrest and apoptosis induction was accompanied by accumulation of the cdk inhibitor p21 in both cell lines. Increased p53 expression was only observed in Granta cells with wild-type p53. Cleavage of procaspase-3 and -9 was observed but cleavage of procaspase-8 was not involved in apoptosis induction. The proapoptotic effect of lactacystin was reversed by pretreatment with the pancaspase inhibitor zVAD.fmk. Lactacystin was also effective in inducing apoptosis in lymphoma cells from MCL patients. We conclude that inhibition of the proteasome might be a promising therapeutic approach for this incurable disease.     

The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9

Mantle cell lymphoma (MCL), a distinct type of non-Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17-allylamino-17-demethoxy-geldanamycin (17-AAG), a HSP90 small molecule inhibitor, induced G(0/1) cell cycle arrest and cell death in a dose- and time-dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17-AAG may have a potential therapeutic value in patients with MCL.     

B-prolymphocytic leukaemia with t(11;14) revisited: a splenomegalic form of mantle cell lymphoma evolving with leukaemia

We reviewed eight cases that were diagnosed before 1995 with B-prolymphocytic leukaemia (B-PLL) harbouring t(11;14)(q13;q32) and/or cyclin D1 staining. Thirteen B-PLL patients without t(11;14) were selected as controls. Peripheral blood, bone marrow and histological sections were re-examined without cytogenetic information. Final diagnosis was made using morphology, cytogenetics, immunophenotype and immunohistochemistry. Clinical characteristics were similar for both groups except for younger age, male predominance and extranodal involvement in cases with t(11;14). CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)- group (31%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but only 45% of t(11;14)- cases. Histopathological and cytological review of cases with t(11;14) showed an infiltrate with a mixture of cells, some resembling prolymphocytes and others with mantle cell lymphoma (MCL) morphology. Blood films of cases with t(11;14) showed features suggestive of B-PLL in three, and in others, a mixture of cells resembling MCL and nucleolated ones; none corresponded to the blastoid form of MCL. We suggest that 'B-PLL' with t(11;14) may represent a splenomegalic form of MCL evolving with leukaemia. These cases illustrate the importance of tissue diagnosis with cyclin D1 staining and fluorescence in situ hybridization analysis in B-cell leukaemia with prolymphocytic features.     

Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma

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 p27(KIP1) 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.