Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.     

Targeting protein kinase C in mantle cell lymphoma

Although targeting the Bruton tyrosine kinase (BTK) with ibrutinib has changed lymphoma treatment, patients with mantle cell lymphoma (MCL) remain incurable. In this study, we characterized a broad range of MCL cell lines and primary MCL cells with respect to the response to the BTK inhibitor, ibrutinib, and compared it with the response to the protein kinase C (PKC) inhibitor, sotrastaurin. At clinically relevant concentrations, each drug induced potent cell death only in the REC‐1 cell line, which was accompanied by robust inhibition of AKT and ERK1/ERK2 (ERK1/2, also termed MAPK3/MAPK1) phosphorylation. In sensitive REC‐1 cells, the drug‐mediated impaired phosphorylation was obvious on the levels of B‐cell receptor‐induced and basal phosphorylation. Similar results were obtained in primary MCL cells with ibrutinib and in a subset with sotrastaurin. The various drug‐resistant MCL cell lines showed very distinct responses in terms of basal AKT and ERK1/2 phosphorylation. Interestingly, targeting PKC and BTK at the same time led to ibrutinib‐mediated rescue of a weak sotrastaurin‐induced apoptosis in MINO cells. Additional targeting of AKT sensitized MINO cells to inhibitor‐mediated cytotoxicity. In summary, MCL cells are heterogeneous in their response to BTK or PKC inhibition, indicating the need for even more individualized targeted treatment approaches in subsets of MCL patients.     

以淋巴增殖性疾病为表现的套细胞淋巴瘤的临床与诊断分析

目的：研究以慢性B淋巴细胞增殖性疾病（B-LPD）为表现的套细胞淋巴瘤（MCL）的临床特点与诊断。方法：对过去7年间以LPD为主要表现并可诊断为MCL的15例患者的临床特点和诊断进行回顾性分析。结果：①15例MCI。中,依靠病理及CyclinD1诊断6例,依靠典型的免疫表型特征诊断9例;②部分以LPD表现的MCL患者临床表现、瘤细胞形态与慢性淋巴细胞白血病（CLL）难以区别,而免疫表型分析不符合CLL特点;③淋巴结或脾脏病理检查结合免疫组织化学是诊断MCL的主要依据,典型的免疫表型对MCL的诊断价值值得探讨。结论：部分MCL患者以广泛侵犯骨髓的LPD发病,对不典型LPD应进行病理检查明确诊断,而不能按CLL处理,以免贻误治疗。     

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.     

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.     

套细胞淋巴瘤21例临床分析

目的探讨套细胞淋巴瘤（MCL）的临床特点,并对合并骨髓侵犯患者临床资料进行分析。方法回顾性分析我院21例套细胞淋巴瘤的临床特点,比较有骨髓侵犯者的发病年龄、乳酸脱氢酶（LDH）、β2-微球蛋白、白细胞数及生存时间与无骨髓侵犯者有无差异。结果21例患者中男15例,女6例,中位年龄55岁,Ⅲ～Ⅳ期者17例,其中有骨髓侵犯者10例。有骨髓侵犯者的发病年龄、LDH、β2-微球蛋白、白细胞数等指标与无骨髓侵犯者比较均无统计学差异（P均〉0．05）。总体生存时间,两者分别为（23．4±4．2）月和（72．6±15．4）月,差异有统计学意义（P=0．035）。结论MCL有骨髓侵犯患者生存期短。     

Properties of the mantle cell and mantle cell lymphoma.

The major lymphoid inhabitant of the follicular mantle is the mantle cell, an immunologically na?ve B cell. It is the putative cell of origin of mantle cell lymphoma (MCL), the cells of which have similar morphologic, immunophenotypic, and molecular characteristics to the normal B lymphocytes of the mantle zone. In the past year a number of advances have been made in the biology of the normal mantle cell, its interactions with the other constituents of the follicular and mantle zone microenvironments, and the development of neoplasia in this cell population. In addition, new developments in diagnostic molecular pathology have been used to more readily identify cases of MCL. The authors summarize these new advances in the understanding of the biology of the mantle cell and newer ancillary techniques in the diagnosis of lymphomas arising from this cell type.     

Histopathology of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a relatively rare lymphoma, accounting for less than 10% only of all lymphomas. Its morphology is quite homogeneous, but it varies strikingly in about 10% of the cases, making the diagnosis of MCL challenging for histopathologists. The definition of the disease was greatly influenced by the discovery of the translocation t(11;14)(q13,q32), which juxtaposes the cyclin D1 and the immunoglobulin heavy chain genes and is present in the vast majority of MCL cases. The introduction of monoclonal antibodies for the detection of cyclin D1 expression into the diagnostic procedure substantially improved the reproducibility and reliability of the pathological diagnosis. However, new challenges for histopathologists have arisen over the last years, among which are the detection of cyclin D1-negative MCL cases and clinically relevant prognostic subgroups.     

Advances in the understanding of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 that may show a spectrum of morphological and phenotypic features broader than initially described. Although some patients may follow an indolent clinical evolution, in most of them the tumour has an aggressive behaviour with poor response to conventional chemotherapy. The genetic hallmark is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which is considered the initial oncogenic event. In addition to this translocation, MCL may carry a high number of secondary chromosomal and molecular alterations that target regulatory elements of the cell cycle machinery and senescence (BMI1/INK4/ARF/CDK4/RB1), DNA damage response pathways (ATM/CHK2/p53), and cell survival signals. The knowledge of these mechanisms and their influence on the behaviour of the tumour are facilitating the development of prognostic models with a more precise prediction of the clinical evolution of the patients. This information coupled with the availability of a new generation of innovative drugs targeting basic molecular process of the tumour cells, should facilitate the design of new therapeutic protocols able to overcome the resistance of this aggressive lymphoma to conventional treatments and improve the life expectancy of the patients.