BOB.1, CD79a and cyclin E are the most appropriate markers to discriminate classical Hodgkin’s lymphoma from primary mediastinal large B‐cell lymphoma

Hoeller S, Zihler D, Zlobec I, Obermann EC, Pileri SA, Dirnhofer S & Tzankov A
(2010) Histopathology 56, 217–228 BOB.1, CD79a and cyclin E are the most appropriate markers to discriminate classical Hodgkin’s lymphoma from primary mediastinal large B‐cell lymphoma Aims: To clarify which immunohistochemical markers could be helpful in distinguishing between classical Hodgkin’s lymphoma (cHL) and primary mediastinal B‐cell lymphoma (PMBCL) to more narrowly define ‘B‐cell lymphoma, unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and cHL’. Methods and results: Two hundred and 83 cHLs and 51 PMBCLs were analysed on validated tissue microarray platforms with antibodies to BOB.1, CD15, CD20, CD23, CD30, CD79a, cyclin E, LMP‐1, MUM1p, p63 and Oct2. The marker cut‐off scores were calculated using receiver–operating characteristic curves. Markers with the highest positive predictive value for cHL were: CD15, cyclin E, LMP‐1 (all 100%), MUM1p (93%) and CD30 (83%). High sensitivity was achieved only by CD30 (92%) and cyclin E (79%). Nineteen percent of PMBCLs were also positive for CD30, which led to a lower specificity of CD30 as regards cHL (81%) compared with cyclin E (100%). The antibodies with the highest positive predictive value for PMBCL were: CD23 (98%), p63 (96%), BOB.1 (94%) and CD79a (90%), with high sensitivity for BOB.1 (100%), CD79a (89%) and p63 (82%). Conclusions: The use of at least three of the most accurate immunohistochemical markers, cyclin E, CD79a and BOB.1, may be helpful in the differential diagnosis of cHL and PMBCL.     

Mantle cell lymphoma: recent insights into pathogenesis, clinical variability, and new diagnostic markers

Mantle cell lymphoma (MCL; previously called centrocytic lymphoma or lymphocytic lymphoma of intermediate differentiation) is a distinct subtype of B-cell lymphoma, accounting for approximately 3%-10% of all lymphoma diagnoses. The name refers to the growth pattern in early disease presentation resembling the normal mantle zone that surrounds the germinal center of the B-cell follicle. The hallmark of MCL is the t(11;14)(q13;q32), resulting in aberrant expression of the CCND1 gene and expression of cyclin D1 in the tumor cells. Expression and genomic profiling of MCL have provided new insight into the pathogenesis and will be summarized in this review. Pitfalls in the differential diagnosis versus B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, cyclin D1-positive diffuse large B-cell lymphoma, hairy cell leukemia, and plasma cell tumors will be discussed, including the usefulness new diagnostic markers SOX11 and CD200. In situ MCL, MCL with an indolent clinical course, and cyclin D1-negative MCL are other topics of this review.     

Mantle cell lymphoma with EBV-positive Hodgkin and Reed–Sternberg-like cells in a patient after autologous PBSCT: Phenotypically distinct but genetically related tumors

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed–Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5⁻, CD15⁺, CD20⁻, CD30⁺, PAX5⁺, Bob.1⁻, Oct2⁻ and EBER⁺. The MCL component expressed cyclin D1 and SOX11, whereas cyclin D1 and SOX11 expressions were reduced and lost, respectively, in HRS-like cells. Polymerase chain reaction results showed a single clonal rearrangement of the IGH gene in MCL and cHL-like components. CCND1 break apart fluorescence in situ hybridization showed split signals in both MCL and HRS-like cells, suggesting that MCL and cHL-like components were clonally related. Acquisition of p53 expression and Epstein–Barr virus (EBV)-positivity was seen in HRS-like cells. The patient died of disease progression with elevated hepatobiliary enzymes. The autopsy showed both MCL and cHL-like components around the bile ducts, splenic white pulp and bone marrow. The two components were phenotypically distinct, but genetically related, suggesting that transformation of MCL to HRS-like cells during the course of MCL in association with EBV infection.     

Expression of transmembrane adaptor protein PAG/Cbp in diffuse large B-cell lymphoma: immunohistochemical study of 73 cases

PAG/Cbp is a transmembrane adaptor protein involved in proximal immune signaling. It is expressed in reactive germinal centers (GC) of secondary lymphatic follicles and related malignant lymphomas. We studied PAG/Cbp expression in GC-like and non-GC-like diffuse large B-cell lymphoma (DLBCL) subtypes. Seventy-three cases of DLBCL identified among 155 malignant lymphomas were classified as GC-like DLBCL (CD10+ or CD10-, bcl-6+, and MUM1-) and non-GC-like DLBCL (CD10-, MUM1+ or CD10-, bcl-6+, MUM1+). PAG/Cbp was detected by monoclonal antibody MEM-255 following routine immunohistochemical procedures. Thirty-five of 40 GC-like DLBCLs (88%) and 20 of 33 non-GC-like DLBCL cases (61%) expressed PAG/Cbp. Four of 12 bcl-6-negative non-GC-like DLBCL cases (33%) were PAG/Cbp positive, and only 4 of 20 bcl-6-positive non-GC-like DLBCL cases (25%) were PAG/CBP negative. All 37 FL and all 5 Burkitt's lymphomas (BL) expressed PAG/Cbp, whereas all 6 mantle cell lymphomas (MCL) and 4 of 5 chronic lymphocytic leukemias (CLL/SLL) were PAG/Cbp negative. PAG/Cbp is a reliable GC marker. Its expression correlates with GC-like DLBC phenotype in a significant majority of cases. It is typically absent in MCL and SLL/CLL.     

Lymphomatous polyposis of the gastrointestinal tract, including mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma

AIMS: Lymphomatous polyposis (LP) is considered to represent mantle cell lymphoma (MCL) of the gastrointestinal (GI) tract. However, a few reports have suggested that some are follicular lymphoma (FL) or mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we analysed 35 patients and clarified the clinicopathological features of LP. METHODS AND RESULTS: Paraffin-embedded tissue samples were stained immunohistochemically and analysed by tissue-fluorescence in situ hybridization (T-FISH) for IGH/CCND1 (cyclin D1) and IGH/BCL2. The average age of the patients was 58.3 years. Over half of the cases showed gastric, duodenal, small intestinal, ileocaecal and sigmoid colonic lesions (15, 19, 15, 16 and 16 cases, respectively). Phenotypically, cases were classified into three types of MCL (cyclin D1+ CD5+ CD10-) (n=12), FL (cyclin D1- CD5- CD10+) (n=14) and MALT (cyclin D1- CD5- CD10-) (n=9). T-FISH identified 11 of the 11 examined cases with MCLs to have IGH/CCND1, while seven of 10 cases with FL had IGH/BCL2, and none of the MALT cases were positive for IGH/CCND1 or IGH/BCL2. At the study endpoint, five of 12 patients with MCL were dead, two of 14 with FL and one of nine with MALT were dead of other disease. Event-free survival analysis showed significantly poorest outcome in MCL, followed by FL, while MALT was associated with a favourable outcome (P=0.0040). CONCLUSIONS: Our study emphasizes the importance of differentiating MCL, FL and MALT of LP in evaluating prognosis and hence the most suitable therapeutic regimen.     

Bcl-2 and BLIMP-1 expression predict worse prognosis in gastric diffuse large B cell lymphoma (DLCBL) while other markers for nodal DLBCL are not useful

Martin‐Arruti M, Vaquero M, Díaz de Otazu R, Zabalza I, Ballesteros J, Roncador G & García‐Orad A
(2012) Histopathology  60, 785–792 Bcl‐2 and BLIMP‐1 expression predict worse prognosis in gastric diffuse large B cell lymphoma (DLCBL) while other markers for nodal DLBCL are not useful Aims: Previous studies have identified clinicopathological and immunohistochemical differences among diffuse large B cell lymphomas (DLBCL) as a function of disease location. Nevertheless, there is a continuing tendency to generalize the prognostic value of various identified markers without taking into account tumour site. Accordingly, we analysed the prognostic value of several of the immunohistochemical markers that have been proposed for nodal DLBCL in a group of patients with gastric DLBCL. Methods and results: Using histochemical methods, CD10, Bcl‐6, Gcet1, MUM‐1, Bcl‐2 and BLIMP‐1 expression was investigated in 43 cases of gastric DBLCL. As in nodal DLBCLs, expression of BLIMP‐1, and of Bcl‐2 in non‐germinal centre B cell‐like (non‐GCB) patients, was associated with a worse prognosis. However, unlike nodal DBLCL, there was no significant association of prognosis with expression of CD10, Bcl‐6, Gcet1 or MUM‐1, or with categorization according to Hans or Muris algorithms. Conclusions: Although most markers of prognosis in nodal DLBCL are not useful indicators for gastric DLBCL, Bcl‐2 or BLIMP‐1 expression does correlate with worse prognosis. These data support the notion that clinicopathological features in DLBCL vary according to the disease location.     

Clinicopathologic significance of immunophenotypic profiles related to germinal center and activation B-cell differentiation in diffuse large B-cell lymphoma from Chinese patients

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into prognostically significant groups with germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 groups. In this study, tissue microarray slides composed of 163 de novo DLBCLs from Chinese patients were immunostained for CD20, CD10, Bcl-6, MUM1, CD138, Bcl-2, Ki-67, cyclin D3, geminin, and P27(Kip1). One hundred forty-nine of 163 DLBCLs could then be classified into GCB group (pattern A), activated GCB group (pattern B) and activated non-GCB group (pattern C) according to the expression of CD10, Bcl-6, MUM1, and CD138. Of the 149 cases, 40 (26%) showed pattern A expression and were grouped as GCB group, lower than reported frequency of the studies involving mostly Western population. Compared with cases with pattern A, those with pattern B (activated GCB group) and C (activated non-GCB group) more often presented with more aggressive tumors and a shorter survival time. These results indicate that most of DLBCLs from Chinese patients can be classified into prognostically different groups based on the antigenic expression models using a panel of GCB- and ABC-associated markers. Polymerase chain reaction analysis of t(14;18) showed that 11 of 64 cases were t(14;18)-positive, and most (10 of 11) of it occurred in the group with pattern A. The translocation was significantly associated with expression of Bcl-2 protein. The group with pattern B demonstrated more frequent expression of Ki-67, cyclin D3, geminin, and showed higher proliferative activity than the group with pattern A. These findings suggest that high proliferative activity of tumors with pattern B may be associated with aggressive tumor behavior and poor clinical outcome in patients with DLBCL.     

Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B-cell lymphoma: a study of six cases concurrently involving the same site

Cotta C V, Coleman J F, Li S & Hsi E D
(2011) Histopathology  59 , 1194–1203
Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B‐cell lymphoma: a study of six cases concurrently involving the same site Aims: Nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is a slowly progressing neoplasm with a favourable prognosis. However, in a minority of cases (3–12%) it progresses to a clonally related diffuse large B‐cell lymphoma (DLBCL), diagnosed between 6 months and 24 years after NLPHL. This study investigated six cases of NLPHL and DLBCL at the same location. Methods and results: The patients were five men and one woman. In four cases, the site was an axillary lymph node, and in two it was inguinal. In all cases, NLPHL areas had typical morphological and immunophenotypic features. DLBCL involvement was multifocal, diffuse, and characterized by large centroblastic and anaplastic cells. Immunohistochemical studies showed DLBCL cells to be positive for CD20, CD45, and BCL6. In one case, DLBCL cells were positive for BCL2, and in two cases they were positive for MUM‐1. There were no networks of follicular dendritic cells (FDC) associated with DLBCL. Rosettes of PD‐1‐positive and CD57‐positive cells surrounding malignant cells in NLPHL were absent in DLBCL. All the cases were negative for Epstein–Barr virus. No translocations involving MYC were identified in DLBCL. Treatment and outcome were known in four cases. All of these patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP), and this was followed by clinical remission (CR). Conclusions: In adequately sampled tumors, DLBCL can be associated with NLPHL at diagnosis. Diffuse architecture, loss of FDC networks, sometimes immunophenotype shift are characteristics of DLBCL associated with NLPHL. Treatment with R‐CHOP usually leads to CR.     

Over‐expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B‐cell lymphoma

The basic region–leucine zipper (bZip) factor BTB, CNC homology 2 (BACH2) is known to have important roles in class switch recombination and somatic hypermutation (SHM) of the immunoglobulin (Ig) gene. In this study, we investigated the relationship between the expression of BACH2 and the status of SHM of the Ig heavy chain gene variable region (IgHV) for SHM in diffuse large B‐cell lymphoma (DLBCL). We examined 20 cases of DLBCL, 13 of which were germinal center B‐cell (GCB) DLBCL and 7 were non‐GCB DLBCL. Seven cases were negative, 6 were positive (cytoplasmic expression) and 7 were strongly positive (both nuclear and cytoplasmic expression) for BACH2. Confirmed mutation (CM) was identified in 8 cases and the CM index (number of confirmed mutations per 10 subclones) was distributed from 0 to 5. A CM index of 7 strongly positive (over‐expression) cases with BACH2 were distributed from 0 to 5, and that of 7 negative and 6 positive cases were distributed from 0 to 1. Over‐expression of BACH2 was statistically related to CM index (P = 0.008). In conclusion, over‐expression of BACH2 is critical for ongoing SHM of IgHV in DLBCL, and our data suggest that BACH2 may play an essential role for SHM of the Ig gene in B‐cell lymphoma.     

146例套细胞淋巴瘤免疫组织化学结果分析

目的：讨论套细胞淋巴瘤的免疫组织化学特征。方法：回顾性分析146例套细胞淋巴瘤的免疫组化结果,并用FISH方法检测1例Cyclin D1阴性病例是否存在t(11;14)易位。结果：套细胞淋巴瘤免疫组化阳性率为CD20：98.6%(144/146);CD79a：100%(146/146);CD5：88.4%(129/146);CyclinD1：99.3%(145/146);PAX-5：100%(122/122);CD43：84%(79/94);Ki67指数：5%~90%,中位数为20%。少部分病例异常表达CD10、Bcl6、CD23、CD56、CD3、CD45RO。FISH检测1例Cyclin D1阴性病例结果为检测到t(11;14)易位形成的IgH/CCND1融合基因。结论：套细胞淋巴瘤存在较为特征性的免疫组化表达模式,并存在异常表达现象。     

Clinicopathological features of double‐hit B‐cell lymphomas with MYC and BCL2, BCL6 or CCND1 rearrangements

Double‐hit (DH) lymphomas are B‐cell lymphomas characterized by chromosomal rearrangements, specifically of MYC and either BCL2, BCL6 or CCND1. We reviewed 22 cases of DH lymphomas. BCL2/MYC DH lymphomas constituted the majority of these DH lymphomas (17 cases; 77%), followed by BCL6/MYC (2 cases; 9%) lymphomas. Assessing morphological features using the 2008 World Health Organization classification system, 15 cases (68%) were determined to be B‐cell lymphoma, unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma (BCLU) (10 cases; 45%), or as DLBCL (5 cases; 23%), and 2 cases (9%) were classified as morphologically untransformed follicular lymphoma. Burkitt lymphoma was rare (1 case; 5%) among DH lymphomas. Nineteen cases were treated with R‐CHOP or a high dose chemotherapy regimen. After a median follow‐up of 11 months, 7 patients had died, and the 1‐year survival rate was 62.5%. High dose chemotherapy did not improve the outcome. We suggest that screening of genetic variations to detect DH lymphomas is required in diagnosing all lymphomas, even those determined morphologically to be follicular lymphoma.     

Perforation predicts poor prognosis in patients with primary intestinal diffuse large B-cell lymphoma

Aims:  To elucidate the clinicopathological features and prognostic factors of primary intestinal diffuse large B‐cell lymphoma (PI‐DLBL). Methods and results:  Archival tissues from 30 tumours were used for tissue microarray construction, immunohistochemistry and interphase fluorescence in situ hybridization for chromosomal translocation. The M:F ratio was 1.7:1, with a median age of 60 years. The ileum and ileocaecum were most frequently involved (40% each). Fourteen (47%) were at stage I_E disease, 15 (50%) at stage II_E. Five (17%) tumours were perforated at presentation. The tumours expressed Bcl‐6 (73%), MUM1 (70%), Bcl‐2 (67%) and CD10 (23%). Nine (30%) were classified as germinal centre B‐cell (GCB) phenotype and 21 non‐GCB. Eight of 30 (27%), 7/30 (23%) and 2/29 (7%) cases were positive for rearrangements involving IGH, BCL6, and C‐MYC loci, respectively, whereas all cases were negative for BCL2 and CCND1 translocation. Perforation was a poor prognostic indicator, with a hazard ratio of tumour‐related death at 8.75 (P = 0.001). The differentiation antigens, GCB versus non‐GCB phenotype, or lymphoma‐associated translocations were of no prognostic significance. Conclusions:  We found a higher rate of perforation and lower frequency of GCB phenotype in PI‐DLBL in Taiwan compared with other geographical areas; perforation is a poor prognostic indicator.     

Epstein–Barr virus‐positive diffuse large B cell lymphoma arising from a chronic lymphocytic leukemia: Overlapping features with classical Hodgkin lymphoma

A small proportion of patients with chronic lymphocytic leukemia (CLL) may progress to large cell lymphoma, or Richter syndrome (RS). The large cells of RS may arise through transformation of the original CLL clone (clonally related) or represent a new neoplasm (clonally unrelated), which might be Epstein–Barr virus (EBV)‐associated. We present a 61‐year‐old male with 5‐year history of CLL who developed RS on bilateral adrenal glands. The tumor showed a vague nodular growth pattern separated by thick fibrous bands and the tumor cells were large and pleomorphic, with focal sheet‐like growth pattern, in a background of small B and T‐lymphocytes. The large tumor cells were positive for CD15, CD19, CD20 (intensely and diffusely), CD30, fascin, PAX5, MUM1, OCT2, and LMP‐1 by immunohistochemical stains, and EBV by in situ hybridization. The tumor was diagnosed as EBV‐positive diffuse large B cell lymphoma (DLBCL), with overlapping features of classic Hodgkin lymphoma (CHL). The patient received salvage chemotherapy and was free of disease 2 years after adrenalectomy. We speculated that our case was a clonally unrelated tumor with his underlying CLL and discussed the differential diagnoses between EBV‐positive DLBCL and CHL in the setting of RS.     

Extranodal diffuse large B cell lymphoma of cutaneous follicle centre lymphoma type: a study of 24 patients with non-cutaneous primary limited stage extranodal diffuse large B cell lymphoma in support of a new concept

Aigner F, Korol D, Schmitt A M & Kurrer M O
(2012) Histopathology  60, 774–784 Extranodal diffuse large B cell lymphoma of cutaneous follicle centre lymphoma type: a study of 24 patients with non‐cutaneous primary limited stage extranodal diffuse large B cell lymphoma in support of a new concept Aims: Follicle centre cell lymphoma of small cell type showing either a follicular or diffuse growth pattern similar to cutaneous follicle centre lymphoma (cFCL) has been recognized in extranodal non‐cutaneous sites. Our aim was (i) to investigate whether diffuse large B cell lymphoma (DLBCL) of cFCL type could be identified in extranodal non‐cutaneous sites and (ii) whether clinical characteristics similar to primary cFCL could be recognized. Methods and results: Of 24 extranodal non‐cutaneous DLBCLs, nine (38%) had large centrocytoid morphology and 15 (62%) were either ‘centrocytoid and centroblastic’ or ‘centroblastic and immunoblastic’. Six centrocytoid cases were Irf‐4 negative, Bcl‐6 positive and at most weakly CD10‐ or Bcl‐2‐positive by immunohistochemistry, consistent with DLBCL of cFCL type. All patients with cFCL type were stage IE and were significantly younger than other patients. Recurrences occurred in two patients and were exclusively extranodal. Conclusion: Our results suggest that DLBCL of cFCL type can be identified in extranodal non‐cutaneous sites and shows clinical characteristics similar to genuine cFCL. We propose to expand the concept of cFCL to encompass large cell lymphomas in extranodal sites.     

Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma

Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell–/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.     

Detection of t(12;14)(p13;q32) in a patient with IGH-CCND1 negative mantle cell lymphoma resembling ultra-high risk chronic lymphocytic leukemia

t(12;14)(p13;q32) is a rare recurrent chromosomal translocation, which has only been identified in a small subgroup of mantle cell lymphoma (MCL) without typical t(11;14)(q13;q32). This rearrangement causes aberrant over-expression of cyclin D2 (CCND2), which disrupts the normal cell cycle. Here we report a subtle case of MCL with t(12;14)(p13;q32) that was initially misdiagnosed as ultra-high risk chronic lymphocytic leukemia (CLL). A 60-year-old male patient presented with obvious leukocytosis and progressive weakness. Morphology of peripheral blood and immunophenotyping by flow cytometry pointed to a diagnosis of chronic lymphocytic leukemia. Fluorescence in situ hybridization (FISH) using IGH-CCND1 probe was negative for CCND1 abnormality, but demonstrated IGH breakapart signals. The initial diagnosis of CLL was established and the patient was treated with six courses of immunochemotherpy with fludarabine, cyclophosphamide and rituximab (FCR). Complete remission (CR) was achieved at the end of treatment, but disease relapsed quickly. The patient was transferred to our hospital, flow cytometry using additional markers showed that the clonal cells were CD200+(dim), CD148+(strong), and chromosome analysis revealed a complex karyotype, 47, XY, t(12;14)(p13;q32), +12, del(9p21), which indicated over-expression of CCND2, and immunostaining showed strong positivity of SOX11 further confirming the characteristics of CCND1-negtive MCL. The final diagnosis was revised to rare subtype of MCL with CCND2 translocation and intensive regimens were employed. This confusable MCL case illustrates the importance of cytogenetic analysis and clinicopathologic diagnosis of this rare category of MCL.     

Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma

Clinical outcome in patients with diffuse large B cell lymphomas (DLBCL) is poorly predictable. Expression of proteins related to germinal centre B (GCB) cell or activated B cells (ABC) and expression of apoptosis-regulating proteins Bcl-2 and XIAP have been found previously to be strongly associated with clinical outcome. In this study we aimed to develop an algorithm based on expression of GCB/ABC-related proteins CD10, Bcl-6 and MUM1 and apoptosis-inhibiting proteins Bcl-2, XIAP and cFLIP for optimal stratification of DLBCL patients into prognostically favourable and unfavourable groups. Expression of CD10 and cFLIP was associated with better overall survival (both p = 0.03), whereas expression of MUM1, Bcl-2 and XIAP was associated with poor clinical outcome (p = 0.01, p = 0.0007 and p = 0.03, respectively). Multivariate analysis revealed that Bcl-2 was the strongest prognostic marker followed by CD10 and MUM1. Stratification of patients according to a new algorithm based on expression of these three markers improved patient risk stratification into low and particularly high clinical risk groups (p = 0.04 and p < 0.0001, respectively). We conclude that, in our group of primary nodal DLBCLs, a new algorithm, based on expression of the apoptosis-inhibiting protein Bcl-2 and the GCB/ABC-related proteins CD10 and MUM1, strongly predicts outcome in International Prognostic Index (IPI)-low and -high patients. Its predictive power is stronger than previously published algorithms based on only GCB/ABC- or apoptosis-regulating proteins.     

Epstein‐Barr virus‐positive diffuse large B‐cell primary central nervous system lymphoma associated with organized chronic subdural hematoma: A case report and review of the literature

We here report on a rare case of Epstein‐Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) detected in both brain parenchyma and in an organized chronic subdural hematoma (OCSH). A 96‐year‐old man diagnosed with asymptomatic OCSH in the left frontal convexity was referred to our hospital because of a de novo mass lesion just beneath the OCSH on contrast‐enhanced magnetic resonance imaging. The size of the OCSH remained stable. We diagnosed the lesion as a malignant tumor. At surgery, the organized hematoma and the soft fragile tumor were removed. Histological examinations revealed pleomorphic lymphoid cells not only in the brain tissue but also in the OCSH component with tumor necrosis, and these were immunopositive for B‐cell markers. In situ hybridization revealed positive signals for EBV‐encoded small RNAs, consistent with EBV‐positive DLBCL. Since the membranes of the subdural hematoma were fibrous and the tumor progression resulted in necrosis of the tumor, the DLBCL may have originally developed in the OCSH and infiltrated into the brain parenchyma. We believe that this rare case provides crucial information for the understanding of DLBCLs associated with OCSH.     

FOXP1 protein overexpression is associated with inferior outcome in nodal diffuse large B‐cell lymphomas with non‐germinal centre phenotype,independent of gains and structural aberrations at 3p14.1

Hoeller S, Schneider A, Haralambieva E, Dirnhofer S & Tzankov A
(2010) Histopathology 57, 73–80
FOXP1 protein overexpression is associated with inferior outcome in nodal diffuse large B‐cell lymphomas with non‐germinal centre phenotype, independent of gains and structural aberrations at 3p14.1 Aims: To determine the molecular epidemiology and prognostic importance of structural and numeric FOXP1 gene aberrations with respect to BCL‐6 gene and to FOXP1 protein expression in 389 diffuse large B‐cell lymphomas (DLBCL) from the pre‐rituximab era on tissue microarrays. Methods and results: By interphase fluorescence in situ hybridization with colour‐labelled bacterial artificial chromosome clones, 12% (27/223) analysable cases showed FOXP1 gains and 1% (2/210) FOXP1 breaks. Seven percent of cases with known BCL‐6 and FOXP1 gene status (n = 159) showed an isolated FOXP1 gain, 19% an isolated BCL‐6 gain and 18% a trisomy 3. FOXP1 gains (isolated and due to trisomy 3) were more frequent in nodal than extranodal DLBCL and in non‐germinal centre B‐cell‐like (non‐GCB) DLBCL than in GCB DLBCL. By immunohistochemistry, FOXP1 protein was more often overexpressed in non‐GCB than in GCB cases. FOXP1 overexpression was associated with poor disease‐specific survival in all DLBCL, particularly in nodal and non‐GCB cases. There was no correlation between FOXP1 gene aberrations and either FOXP1 protein expression or survival. Conclusions: FOXP1 is recurrently targeted by numeric, and rarely by structural, genetic aberrations in DLBCL. Only the presence of FOXP1 protein, irrespective of its gene status, is decisive for prognosis in DLBCL.