SOX11 is useful in differentiating cyclin D1‐positive diffuse large B‐cell lymphoma from mantle cell lymphoma

Hsiao S‐C, Cortada I R, Colomo L, Ye H, Liu H, Kuo S‐Y, Lin S‐H, Chang S‐T, Kuo T U, Campo E & Chuang S‐S
(2012) Histopathology  61, 685–693 SOX11 is useful in differentiating cyclin D1‐positive diffuse large B‐cell lymphoma from mantle cell lymphoma Aims: To characterize the frequency and clinicopathological features of cyclin D1‐positive diffuse large B‐cell lymphoma (DLBCL) and the usefulness of SOX11 in the differential diagnosis from mantle cell lymphoma (MCL). Methods and results: We retrospectively stained 206 consecutive DLBCLs for cyclin D1, and identified three (1.5%) positive cases, comprising two in the elderly with necrosis, and a third with a starry‐sky pattern. All three cases shared the same non‐germinal centre B‐cell (non‐GCB) phenotype [CD5?/CD10?/bcl‐6+/MUM1+/SOX11?], Epstein–Barr virus (EBV) negativity, and absence of CCND1 aberrations by fluorescence in‐situ hybridization. The third case showed both BCL6 and MYC rearrangements: a double‐hit lymphoma. In the same period there were 22 MCLs, all expressing cyclin D1, with 89% cases expressing SOX11, a frequency that is statistically different from cyclin D1‐positive DLBCL. Notably, we identified a pleomorphic MCL initially misdiagnosed as DLBCL. A separate cohort of 98 DLBCL cases was negative for SOX11, with only one case expressing cyclin D1 with a GCB phenotype (CD10+/bcl‐6+/MUM1?). The two patients with tumour necrosis rapidly died of disease. The other two were in complete remission after immunochemotherapy. Conclusions: Cyclin D1‐positive DLBCLs are rare, and they are negative for SOX11 or CCND1 aberration. SOX11 is useful in differentiating cyclin D1‐positive DLBCL from MCL.     

Clinical features of diffuse large B‐cell lymphoma with polyploidy

Polyploidy, defined as more than two sets of homologous chromosomes, is found in a variety of malignant tumors and is thought to be related to disease pathogenesis. However, there have been no studies that have investigated polyploidy in diffuse large B‐cell lymphoma (DLBCL). Here we reviewed clinicopathological features of 16 cases of DLBCL with polypoidy, which was defined as DLBCL with either near‐tetraploid or greater number of chromosomes as detected by the G‐band method. The frequency of polyploid DLBCL was 2.9 % (16/544), including 15 near‐tetraploid and one near‐pentaploid case. CD5, CD30 and EBER positive cases were 13 % (2/16), 13 % (2/16) and 6 % (1/16), respectively. Bcl2 positive cases were 75 % (12/16). The numbers of huge and multinucleated cells were higher in polyploid than in non‐polyploid DLBCL (P = 0.0029 and P < 0.0001, respectively). Clinical features of polyploid DLBCL included reduced infiltration of extranodal sites (2/15, 13 %) and major lymph node infiltration. Of seven cases that received chemotherapy, six responded to treatment and survived. Our results suggest that polyploid DLBCL represents a clinicopathologically characteristic group of DLBCL. This knowledge can be useful for informing more personalized and targeted management of DLBCL patients.     

At diagnosis,diffuse large B‐cell lymphoma patients show impaired rituximab‐mediated NK‐cell cytotoxicity

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin's lymphoma in adults. It is generally treated by a combination of chemotherapy and CD20‐specific mAbs, such as rituximab, which act, at least partially, by activating antibody‐dependent cell‐mediated cytotoxicity (ADCC). ADCC involves NK cells, particularly the CD56^dim NK‐cell subset expressing CD16, the low affinity Fcγ receptor. Here, we show that CD16 expression levels are decreased in a cohort of 36 newly diagnosed DLBCL patients compared with those in 20 healthy controls (HCs). CD137, a co‐stimulatory molecule expressed on activated NK cells, was also expressed at lower levels in patients compared with controls. Cells sampled from our cohort also showed severely reduced degranulation activity when challenged with rituximab‐coated tumor cells, which could not be corrected by stimulation with high doses of IL‐2. These results suggest that rituximab‐induced NK‐cell ADCC could be defective in some DLBCL patients at diagnosis. These patients should be closely monitored and attempts made to improve their NK‐cell function.     

Anaplastic variant of diffuse large B‐cell lymphoma: Reappraisal as a nodal disease with sinusoidal involvement

Anaplastic variant (av) of diffuse large B‐cell lymphoma (DLBCL) is morphologically defined in the 2017 World Health Organization classification, but still an enigmatic disease in its clinicopathologic distinctiveness, posing the differential diagnostic problem from gray zone lymphoma (GZL) and classic Hodgkin lymphoma (cHL). Thirty‐one cases previously diagnosed as avDLBCL were reassessed. Of these, 27 (87%) and 4 (13%) were node‐based and extranodal diseases, respectively. They were further reclassified into nodal avDLBCL (n = 18), nodal CD30+ DLBCL with T‐cell/histiocyte‐rich large B‐cell lymphoma‐like features (CD30+ DLBCL‐THRLBCL) (n = 6), GZL with features intermediate between DLBCL and cHL (n = 3) and CD30+ extranodal DLBCL, NOS (n = 4). The nodal avDLBCL cases had a sheet‐like proliferation of large cells and/or Hodgkin/Reed‐Sternberg (HRS)‐like cells in 12 (67%) notably with a sinusoidal pattern in 16 (89%). They showed an expression of CD20 and/or CD79a in all and CD30 in 15 of 18. All of them were negative for PD‐L1 on tumor cells, although HRS‐like cells showed negativity or partial loss of other B‐cell markers to varying degrees. The present study highlighted the distinctiveness of the nodal avDLBCL with sinusoidal pattern, but without neoplastic PD‐L1 expression, which provide refined diagnostic criteria for a more precise pathologic and clinical characterization of this disease.     

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.     

Variability in immunophenotype in diffuse large B-cell lymphoma and its clinical relevance

Diffuse large B-cell lymphoma (DLBCL), the single largest category of lymphoma, is a clinically and biologically heterogeneous disease entity. Clinically, patients differ in their mode of presentation and respond variably to therapy. A combination of clinical parameters can be used to predict the patient's response to therapy and survival. The pathological variability of DLBCL is expressed in morphology, immunophenotype, cytogenetic and molecular genetic features. Numerous markers detectable by immunohistochemistry and linked to different aspects of tumour biology have been studied in DLBCL, including lineage-associated and immune markers, proliferation and apoptosis markers, cell adhesion molecules, and more recently stage-specific markers of B-cell differentiation. This review summarizes these studies in regard to their clinical significance and in the light of recent advances in our understanding of the molecular pathology and histogenesis of DLBCL.     

Primary pancreatic diffuse large B‐cell lymphoma diagnosed by endoscopic ultrasound guided FNAC: A rare entity

Primary pancreatic lymphoma (PPL) is an uncommon neoplasm which can clinico‐radiologically mimic carcinoma. But the management of these patients differs from that of a carcinoma. Endoscopic ultrasound (EUS) guided fine‐needle aspiration (FNA) serves as a potential tool to identify pancreatic lymphomas and thus prevent an invasive diagnostic test. This case report describes the presentation and diagnosis of primary pancreatic lymphoma. A 37‐year‐old female presented with nausea, vomiting with signs of icterus and elevated liver function test and Bilirubin. Abdominal computed tomography (CT) revealed a hypodense lesion in the head of the pancreas. EUS guided FNA was performed and cytological material was collected. The lesion was diagnosed as Non‐Hodgkin Lymphoma (NHL) and subtyped as diffuse large B‐cell lymphoma‐germinal centre (DLBCL‐GCB) base on immunohistochemistry on cell block. The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) regimen. EUS guided FNA along with ROSE, cell bock, and immunocytochemistry helps in the diagnosis of primary pancreatic lymphoma.     

De novo CD5‐positive primary cardiac diffuse large B‐cell lymphoma diagnosed by pleural fluid cytology

Primary cardiac lymphomas are exceedingly rare. The presence and extent of the intracardiac mass is determined by echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI); however, the diagnosis is established by endomyocardial biopsy or by pericardial or pleural effusion cytology. We describe the pleural effusion cytologic features of a primary cardiac lymphoma in a 55‐year‐old woman who presented with progressive shortness of breath, fatigue, mild dizziness, dull chest ache, and lower extremity edema. Transthoracic echocardiography, CT, and MRI showed a large mass centered in the right atrium and extending into the right ventricle, associated with pericardial effusion and bilateral pleural effusions. Cytologic examination of the pleural fluid showed very large pleomorphic malignant cell, some of which were binucleated and multinucleated and had anaplastic features. Flow cytometry showed a kappa monotypic population of large cells coexpressing CD5, CD19, and CD20; and immunoperoxidase stains performed on the cell block sections showed that the large neoplastic cells were positive for CD20, PAX5, CD5, and MUM1 and showed a very high proliferation rate (over 90%) by Ki67 staining. The cytologic, flow cytometry, and immunohistochemistry findings established the diagnosis of de novo CD5‐positive primary cardiac diffuse large B‐cell lymphoma (DLBCL), anaplastic variant, which was confirmed by the subsequent endomyocardial biopsy. This is, to the best of our knowledge, the first report of de novo CD5‐positive primary cardiac diffuse large B‐cell lymphoma, and the first report of the anaplastic variant of DLBCL diagnosed by effusion cytology. Diagn. Cytopathol. 2014;42:259–267. © 2012 Wiley Periodicals, Inc.     

A case of composite classical and nodular lymphocyte predominant Hodgkin lymphoma with progression to diffuse large B‐cell non‐Hodgkin lymphoma: Diagnostic difficulty in fine‐needle aspiration cytology

A small percentage of nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) progresses to diffuse large B‐cell lymphoma (DLBCL). There have also been rare reports of gray zone lymphoma with features intermediate between classical Hodgkin lymphoma (CHL) and DLBCL. We report a very rare case of composite lymphoma (CHL and NLPHL) progressing to DLBCL, and highlight the diagnostic difficulty faced during its fine‐needle aspiration (FNA) cytology diagnosis. A 65‐year‐old woman presented with a right axillary swelling which was subjected to FNA cytology. The routine FNA cytology diagnosis was anaplastic large cell lymphoma (ALCL) but immunocytochemistry did not support this diagnosis completely. The histopathological diagnosis of the excised lymph node was NLPHL with progression to DLBCL in our hospital but in a hospital abroad where the patient was treated, the reviewed diagnosis was CHL. The patient had a rapid downhill course with development of terminal pleural effusion and died approximately one year from initial diagnosis.The review of the cyto‐histologic material along with additional immunocyto/histochemical studies and the clinical course of the disease support the diagnosis of a composite lymphoma (CHL and NLPHL) with progression to DLBCL. It is suggested that all the three lesions were clonally related. Diagn. Cytopathol. 2017;45:262–266. © 2016 Wiley Periodicals, Inc.     

Array‐based profiling of the lymphoma cell DNA methylome does not unequivocally distinguish primary lymphomas of the central nervous system from non‐CNS diffuse large B‐cell lymphomas

Primary lymphomas of the central nervous system (PCNSL) are diffuse large B‐cell lymphomas (DLBCLs) confined to the central nervous system (CNS). We here performed array‐based DNA methylation analyses of 26 PCNSL and 78 DLBCL and validated our findings in an independent dataset. We identified 2847 CpGs differentially methylated between PCNSL and non‐CNS‐DLBCL. Neither a supervised analysis using these CpGs nor application of 3 CpG classifiers selected for class separation unambiguously separated PCNSL from non‐CNS‐DLBCL. Remarkably, 6/78 non‐CNS‐DLBCL consistently segregated with PCNSL, which displayed molecular features typical for PCNSL. Our findings suggest that a subset of non‐CNS‐DLBCL exists which molecularly resembles PCNSL.     

Clinicopathological features of 49 primary gastrointestinal diffuse large B‐cell lymphoma cases; comparison with location,cell‐of‐origin,and frequency of MYD88 L265P

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B‐cell lymphoma (DLBCL), with approximately one‐third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically‐assessed cell‐of‐origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC‐like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin‐2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC‐like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC‐like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.     

Prognostic significance of immunophenotypes and a nodular pattern in primary mediastinal large B‐cell lymphoma

To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B‐cell lymphoma (PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4‐year progression free survival (PFS) rate was 78%, and the 4‐year overall survival (OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6⁺ (P = 0.013), MUM1⁺ (P = 0.091), and pale cytoplasm (P = 0.064) were favorable prognostic indicators of PFS, and Bcl6⁺ (P = 0.051) and MUM1⁺ (P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity (n = 11) had 4‐year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma (CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6⁺, MUM1⁺, Bcl2^‐, and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL.     

B cell lymphoma,unclassifiable, with features intermediate between diffuse large B cell lymphoma and classical hodgkin lymphoma: Diagnosis by fine‐needle aspiration cytology

A 58‐year‐old lady presented with mediastinal lymphadenopathy. A thoracoscopic ultrasound‐guided fine‐needle aspiration showed large atypical epithelioid cells arranged in cohesive sheets and dispersed as single cells with intact cytoplasm amid a background of lymphocytes and histiocytes. A cytological diagnosis of “a malignant neoplasm” was made, raising a broad list of differential diagnoses. A broad panel of immunocytochemical stains performed on the cell block was indicative of a lymphoproliferative disorder, but the immunophenotype was intermediate between diffuse large B cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). Diffuse and strong reactivity to CD20, CD79a, and PAX‐5, and weak reactivity to CD30, was in favor of a DLBCL, or more precisely mediastinal (thymic) large B cell lymphoma (MLBL). However, there were negative staining for LCA, OCT‐2, and BOB‐1 as well as positive staining for EBV‐encoded RNA, which were against a diagnosis of MLBL and raised the possibility of cHL. The absence of RS cells and the typical mileu, the negativity for CD15 and the strong positivity of CD20 and PAX‐5 were against a diagnosis of cHL. On this basis, the diagnosis of “B‐cell lymphoproliferative disorder with features intermediate between DLBCL and cHL” was rendered. The diagnosis was subsequently confirmed on excisional biopsy. This case report demonstrates broad differential diagnoses raised by this diagnostic entity and the importance of an adequate cell block for accurate designation. Diagn. Cytopathol. 2014;42:690–693. © 2013 Wiley Periodicals, Inc.