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1.  Two smalls in one: Coincident small cell carcinoma and small lymphocytic lymphoma in a lymph node diagnosed by fine-needle aspiration biopsy 
CytoJournal  2012;9:5.
B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) is one of the most common lymphoproliferative disorders in western countries. Patients with SLL / CLL are at increased risk of site-specific secondary cancers. We present a unique case of a 71-year-old male, with a history of SLL / CLL, who presented with pulmonary symptoms and a mediastinal mass. Fine needle aspiration (FNA) of the mediastinal lymph node revealed synchronous SLL / CLL and small cell carcinoma (SCC).
Materials and Methods:
The patient underwent a computed tomography (CT) scan of the chest and endobronchial ultrasound-guided transbronchial fine needle aspiration of the mediastinal lymph node (4R). The sample was submitted for cytopathology, immunohistochemical stains, and flow cytometry evaluation.
Fine needle aspiration of the mediastinal lymph node revealed neoplastic cells, in clusters and singly, with cytological features suggestive of small cell carcinoma. The immunohistochemistry results confirmed this diagnosis. Small-to-medium, mature-appearing lymphocytes were also present in the background. Flow cytometry analysis revealed that these lymphocytes possessed an immunophenotype consistent with CLL / SLL.
This case illustrates the importance of a pathologist's awareness of the possibility of concurrent lymphoma and metastatic carcinoma in a lymph node. When evaluating lymph nodes, pathologists must strive to identify both foreign cells and subtle lymphoid changes. As demonstrated by our case, ancillary techniques (such as immunohistochemistry and flow cytometry) can be critical to making a complete and accurate diagnosis. The diagnosis of small cell carcinoma in the enlarged lymph node, primarily harboring CLL / SLL, is of critical importance for decision-making and treatment purposes, in addition to having a significant adverse impact on the overall survival.
PMCID: PMC3307210  PMID: 22438859
Small cell carcinoma; lymphoma; FNA
2.  Diffuse large B-cell lymphoma arising in a composite lymphoma with biclonality by flow cytometry and one monoclonal band by PCR 
Composite lymphoma (CL) refers to the presence of two or more distinct types of lymphomas in a single organ or tissue. CL is an infrequent finding and may be due to the existence of two genetically related neoplasms, i.e. transformation of a single lymphoma into another lymphoma, or be due to the presence of two clonally unrelated lymphomas. CL composed of more than two lymphomas is even rare. Herein we describe a case of diffuse large B-cell lymphoma (DLBCL) arising in a CL of follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) in an inguinal lymph node of an 85 year old woman. The three lymphomas were morphologically and immunophenotypically distinct while flow cytometry detected two monoclonal B-cell populations. Karyotyping and Polymerase Chain Reaction (PCR) for B-cell clonality each detected a single monoclonal B-cell population. The morphology findings may suggest DLBCL being transformed from FL while Richter transformation from SLL appears to be less likely in our case. Due to the single clone by chromosome study and PCR study, the precise relationships of the three lymphomas are unknown.
PMCID: PMC3885498  PMID: 24427364
Composite lymphoma; bi-clonality; PCR; diffuse large B-cell lymphoma
3.  Copy neutral loss of heterozygosity in 20q in chronic lymphocytic leukemia/small lymphocytic lymphoma 
Cancer genetics  2014;207(3):98-102.
Single nucleotide polymorphism (SNP)-based chromosome microarray analysis was used to uncover copy neutral loss of heterozygosity (LOH) in the long arm of chromosome 20 in blood or bone marrow specimens from three patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). All three patients presented with lymph node enlargement. While one of the patients has had a complicated clinical course, the other two have a more indolent disease. Sequence analysis of the tumor suppressor gene ASXL1, which is located in 20q and is commonly mutated in malignant myeloid diseases and occasionally in CLL/SLL specimens, revealed no mutations in our three patients with copy neutral LOH in 20q. The possible contribution of other imprinted microRNAs and antisense genes residing in 20q to the pathogenesis of a subset of CLL/SLL patients is discussed. These findings illustrate the value of SNP arrays for the detection of novel recurrent genomic alterations that may contribute to CLL/SLL onset or progression.
PMCID: PMC4010307  PMID: 24704113
Chronic lymphocytic leukemia; copy neutral loss of heterozygosity; chromosome 20; chromosome microarray analysis; imprinting
4.  The value of immunohistochemistry on paraffin wax embedded tissue sections in the differentiation of small lymphocytic and mantle cell lymphomas. 
Journal of Clinical Pathology  1997;50(1):16-21.
AIMS: To determine whether immunohistochemistry applied to paraffin wax embedded biopsy tissue can be used to distinguish between B-small lymphocytic lymphoma (B-SLL) and mantle cell lymphoma (MCL). METHODS: Formalin fixed, paraffin wax embedded tissue blocks of 12 cases of B-SLL and 12 cases of MCL were retrieved from the files of the Department of Pathology, Southampton University Hospitals Trust. Following antigen retrieval, where appropriate, sections were stained for CD3, CD5, CD20, CD23, CD43, Cyclin D, PGP9.5, and MIB1 using a streptavidin-biotin complex technique. RESULTS: CD20 stained the neoplastic cells of B-SLL and MCL, and CD3 labelled the reactive T cells in these tumours. In B-SLL, the T cells were generally dispersed among the tumour cells, whereas in MCL they often formed bands around tumour cell nodules. CD5 could be detected on T cells, following antigen retrieval. The level of expression on B cells of B-SLL and MCL was generally too low to allow detection in paraffin wax embedded tissues. CD23 stained B-SLL but not MCL. However, it could be detected in only five of the 12 cases of B-SLL. CD43 could be detected in most cases of B-SLL and MCL. It is not, therefore, of value in distinguishing between these tumours. It will, however, help in the differentiation of B-SLL and MCL from other low grade B cell lymphomas, such as follicle centre cell and marginal zone lymphomas. Cyclin D was expressed in all of the MCL but in none of the B-SLL. PGP9.5 showed reactivity in most cases of MCL and much weaker reactivity in B-SLL. The proliferation indexes of MCL were generally higher than those of B-SLL, as measured by MIB1 labelling. Both tumours, however, showed a wide range of values and considerable overlap. CONCLUSION: Staining for Cyclin D is the most reliable immunohistochemical mean of differentiating between B-SLL an MCL. High levels of PGP9.5, expressed in MCL, may be related to the degradation of Cyclin D by the ubiquitin pathway.
PMCID: PMC499705  PMID: 9059349
5.  Langerhans Cell Sarcoma Arising from Chronic Lymphocytic Lymphoma/Small Lymphocytic Leukemia: Lineage Analysis and BRAF V600E Mutation Study 
the phenomenon that histiocytic/dendritic cell sarcomas may be transformed from lymphoproliferative diseases is dubbed ‘transdifferentiation’. Langerhans cell sarcoma (LCS) transdifferentiated from chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) is extremely rare. The underlying mechanisms of LCS tumorogenesis and its transdifferentiation from CLL/SLL are largely unknown.
the authors strive to further characterize LCS, to understand the potential molecular changes in LCS and the underlying mechanisms of CLL/SLL transformation to LCS.
Materials and Methods:
a progressively enlarging right inguinal lymph node from a 68-year-old female patient with a history of CLL was biopsied and submitted for flow cytometry analysis, routine hematoxylin, and eosin (H and E) stain and immunohistochemical study. Furthermore, clonality study (fluorescent in situ hybridization (FISH) analysis with a CLL panel probes) and BRAF V600E mutation study (pyrosequencing and immunostain) were performed.
two different neoplasms, LCS and CLL/SLL, were discovered to occur simultaneously in the same lymph node. These two entities were shown to be clonally related. More importantly, for the first time, BRAF V600E mutation was detected in LCS.
LCS can be transdifferentiated from CLL/SLL and BRAF V600E mutation may provide the foundation for alternative therapy of LCS.
PMCID: PMC3731871  PMID: 23923114
BRAF V600E mutation; clonality; Langerhans cell sarcoma; transdifferentiation
6.  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With Cyclin D1 Positive Proliferation Centers Do Not Have CCND1 Translocations or Gains and Lack SOX11 Expression 
Cyclin D1 expression, usually absent in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has been described in the proliferation centers (PC) of some CLL/SLL. The prevalence of this finding is uncertain, as is the explanation for its occurrence and whether these cases have any other unique features. Cyclin D1 immunohistochemical staining was therefore investigated in 57 extramedullary CLL/SLL biopsies. In 6 cases, cyclin D1 immunofluorescence followed by CCND1 fluorescence in situ hybridization (FISH) and PC targeted analysis was performed using a Bioview Duet system. Excluding the prospectively selected cases that had the targeted FISH studies, cyclin D1+ PC were identified in 20% of cases. The cyclin D1+ CLL did not appear pathologically or phenotypically distinctive, though 46% had an interfollicular growth pattern. The cyclin D1+ PCs were SOX11− and lacked CCND1 translocations and gains in 5 of 5 informative cases. The recognition of cyclin D1 expression in PC of a significant minority of CLL/SLL can be a diagnostic aid and should not lead to the diagnosis of focal mantle cell lymphoma.
PMCID: PMC3700540  PMID: 22706868
Chronic lymphocytic leukemia; Small lymphocytic lymphoma; Cyclin D1; SOX11; Proliferation centers
7.  Detection of Hodgkin Transformation in a Case of Chronic Lymphocytic Leukemia by PET/CT 
Richter’s transformation (RT) represents the development of high grade lymphoma, most commonly diffuse large B-cell lymphoma, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). CLL/SLL may convert also to Hodgkin’s lymphoma, the so-called Hodgkin’s variant of Richter transformation. Histopathological proof is needed to confirm a definitive diagnosis. Patients with RT generally have a poor prognosis, with prompt recognition optimise clinical management. Whole-body PET scan with 18F-FDG can be used for detection of RT of CLL/SLL. We describe the case of 64-year-old woman with CLL/SLL who developed Hodgkin lymphoma detected with PET/CT.
PMCID: PMC4067880  PMID: 24963449
18F-FDG; Leukemia; lymphocytic; chronic
8.  Small Lymphocytic Lymphoma of the Thyroid Mimicking Plasmacytoma 
European Thyroid Journal  2014;3(3):202-205.
Primary thyroid gland lymphomas (PTLs) typically occur in middle-to older-aged individuals in the setting of lymphocytic thyroiditis with a predilection for females. Diffuse large B-cell lymphoma is the most frequent histologic subtype of thyroid lymphomas. Small lymphocytic lymphoma (SLL) belongs to the least common subtypes of thyroid lymphoma. It is often associated with the involvement of lymph nodes, bone marrow, spleen, liver and, extremely rarely, other organs. PTLs with plasmacytic differentiation or extensive infiltration by plasma cells have been observed in marginal zone B-cell lymphomas in the thyroid but have never been described in a setting of SLL. Here, we present a case of primary SLL of the thyroid mimicking extramedullary plasmacytoma on fine-needle aspiration cytology.
PMCID: PMC4224251  PMID: 25538903
Primary thyroid lymphoma; Small lymphocytic lymphoma; Plasmacytoma; Fine-needle aspiration cytology
9.  Small Lymphocytic Lymphoma Obscuring Microscopic Tonsillar Squamous Cell Carcinoma: an Unknown Occurrence with a Known Primary 
Head and Neck Pathology  2010;6(1):125-129.
Head and neck squamous cell carcinoma (HNSCC) often presents with cervical lymph node metastases and at times the primary tumor cannot be identified despite extensive workup. Lymphoma is the second most common neoplasm in the head and neck region but is seldom synchronous with HNSCC and rarely involves regional mucosal sites. We report herein a rare occurrence of tonsillar involvement by small lymphocytic lymphoma (SLL) incidentally detected during the workup for a cervical lymph node SCC metastasis of a 52-year-old non-smoker male. The microscopic human papillomavirus-positive SCC involving the tonsillar surface and crypts was obscured by SLL leading to the initial designation of ‘unknown primary’. The occult HNSCC are likely explained by small tumor size, quality and quantity of sampling, thoroughness of endoscopic, radiological and pathological assessment or a combination of the above. The coexistence of another tumor such as lymphoma has not yet been reported as a confounding factor in the workup for cervical SCC metastasis. Since oropharyngeal SCC can be very small and Waldeyer’s ring is a common site for lymphoma involvement, identification of such rare collision tumors requires pathologists’ awareness, extensive sampling and occasionally ancillary studies for the accurate diagnosis and staging essential for the correct management.
PMCID: PMC3311942  PMID: 21120710
Head and neck occult carcinoma; Tonsillar carcinoma; Small lymphocytic lymphoma; Collision tumor
10.  Post-GWAS Functional Characterization of Susceptibility Variants for Chronic Lymphocytic Leukemia 
PLoS ONE  2012;7(1):e29632.
Recent genome-wide association studies (GWAS) have identified several gene variants associated with sporadic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Many of these CLL/SLL susceptibility loci are located in non-coding or intergenic regions, posing a significant challenge to determine their potential functional relevance. Here, we review the literature of all CLL/SLL GWAS and validation studies, and apply eQTL analysis to identify putatively functional SNPs that affect gene expression that may be causal in the pathogenesis of CLL/SLL. We tested 12 independent risk loci for their potential to alter gene expression through cis-acting mechanisms, using publicly available gene expression profiles with matching genotype information. Sixteen SNPs were identified that are linked to differential expression of SP140, a putative tumor suppressor gene previously associated with CLL/SLL. Three additional SNPs were associated with differential expression of DACT3 and GNG8, which are involved in the WNT/β-catenin- and G protein-coupled receptor signaling pathways, respectively, that have been previously implicated in CLL/SLL pathogenesis. Using in silico functional prediction tools, we found that 14 of the 19 significant eQTL SNPs lie in multiple putative regulatory elements, several of which have prior implications in CLL/SLL or other hematological malignancies. Although experimental validation is needed, our study shows that the use of existing GWAS data in combination with eQTL analysis and in silico methods represents a useful starting point to screen for putatively causal SNPs that may be involved in the etiology of CLL/SLL.
PMCID: PMC3250464  PMID: 22235315
11.  Clonally related Histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: A study of 7 cases 
Histiocytic and interdigitating dendritic cell sarcomas are rare tumors originating from bone marrow derived myeloid stem cells. Recent studies have shown evidence of cross-lineage transdifferentiation of B-cells in follicular lymphoma to histiocytic and dendritic cell sarcomas. In this study, we report the morphologic, molecular and cytogenetic analysis of 7 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age, 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in 6 of 7 patients, and one patient had both tumors diagnosed at the same time. The tumors included 4 interdigitating dendritic cell sarcomas; 1 Langerhans cell sarcoma, 1 histiocytic sarcoma, and 1 immature neoplasm with evidence of histiocytic origin. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. There was a preferential usage of IGHV4-39 by the V-D-J gene rearrangement. By FISH analysis two cases showed deletion 17p in both components, while 4 cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors. Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in 5 of 6 cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBPβ. Our study provides evidence for transdifferentiation of CLL/SLL B-cells to tumors of dendritic and less often histiocytic lineage, and suggests that secondary genetic events may play a role in this phenomenon.
PMCID: PMC3175277  PMID: 21666687
CLL; SLL; histiocytic sarcoma; interdigitating dendritic cell sarcoma; clonal; transformation; transdifferentiation
12.  Possible role of CD22, CD79b and CD20 expression in distinguishing small lymphocytic lymphoma from chronic lymphocytic leukemia 
Contemporary Oncology  2014;18(1):29-33.
Aim of the study
Flow cytometry has an important role in diagnosis and classification of B-cell lymphoproliferative disorders (BCLPDs). However, in distinguishing chronic lymphocytic leukemia (CLL) from small lymphocytic lymphoma (SLL) only clinical criteria are available so far. Aim of the study was to determine differences in the expression of common B cell markers (CD22, CD79b and CD20) on the malignant lymphocytes in the peripheral blood samples of CLL and SLL patients.
Material and methods
Peripheral blood samples of 56 CLL and 11 SLL patients were analyzed by 5-color flow cytometry on the CD45/CD19/CD5 gate for CD22, CD79b and CD20.
In the samples collected from the CLL patients, CD22 expression was detected in only 20% of patients in the low pattern, while in SLL patients the expression was medium and present in 90.9% of patients (p < 0.0001). For CD79b expression, statistical significance is reached both in the expression pattern, which was low/medium for CLL and high for SLL, and expression level (p = 0.006). The expression of CD20 was counted as the CD20/CD19 ratio. The average ratio was 0.512 in the CLL patients vs. 0.931 in the SLL patients (p = 0.0001).
The pattern of expression and expression level of CD22, CD79b and CD20 in peripheral blood could be used for distinguishing SLL from CLL patients.
PMCID: PMC4037993  PMID: 24876818
CD20; CD79b; CD22; CLL; SLL
13.  Racial Differences in Three Major NHL Subtypes: Descriptive Epidemiology 
Cancer epidemiology  2015;39(1):8-13.
NHL (non-Hodgkin lymphoma) consists of over 60 subtypes, ranging from slow-growing to very aggressive. The three largest subtypes are DLBCL (diffuse large B-cell lymphoma), FL (follicular lymphoma), and CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma). For each subtype, different racial groups have different presentations, etiologies, and prognosis patterns.
SEER (Surveillance, Epidemiology, and End Results) data on DLBCL, FL, and CLL/SLL patients diagnosed between 1992 and 2010 were analyzed. Racial groups studied included NHW (non-Hispanic whites), HW (Hispanic whites), blacks, and API (Asians and Pacific Islanders). Patient characteristics, age-adjusted incidence rate, and survival were compared across races. Stratification and multivariate analysis were conducted.
There are significant racial differences for patients’ characteristics, including gender, age at diagnosis, stage, lymph site, and age, and the patterns vary across subtypes. NHWs have the highest incidence rates for all three subtypes, followed by HWs (DLBCL and FL) and blacks (CLL/SLL). The dependence of the incidence rate on age and gender varies across subtypes. For all three subtypes, NHWs have the highest five-year relative survival rates, followed by HWs. When stratified by stage, racial difference is significant in multiple multivariate Cox regression analyses.
Racial differences exist among DLBCL, FL, and CLL/SLL patients in the U.S. in terms of characteristics, incidence, and survival. The patterns vary across subtypes. More data collection and analysis are needed to more comprehensively describe and interpret the across-race and subtype differences.
PMCID: PMC4323749  PMID: 25560974
non-Hodgkin lymphoma; racial differences; subtype; SEER
14.  Initial diagnosis of small lymphocytic lymphoma in parotidectomy for Warthin tumour, a rare collision tumour 
Journal of Clinical Pathology  2005;58(3):331-333.
Warthin tumours (WT) and malignant lymphomas are only rarely associated, and most are examples of involvement of the lymphoid stroma of WT by a disseminated lymphoma. This report describes a case where excision of a parotid mass led to the initial diagnosis of WT and small lymphocytic lymphoma (SLL). The diagnosis of SLL was confirmed by immunohistochemistry and molecular studies. The patient had stage IV A disease and is currently in chemotherapy induced complete remission. This case highlights the extremely rare association of SLL with WT and the importance of evaluation of the WT stroma, where the pale proliferation centres of SLL may mimic germinal centres of reactive lymphoid nodules.
PMCID: PMC1770608  PMID: 15735173
small lymphocytic lymphoma; Warthin tumour; collision tumour
15.  The Spectrum of Kidney Pathology in B-Cell Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma: A 25-Year Multicenter Experience 
PLoS ONE  2015;10(3):e0119156.
Chronic lymphocytic leukemia and small lymphocytic lymphoma are 2 different presentations of the most common B-cell neoplasm in western countries (CLL/SLL). In this disease, kidney involvement is usually silent, and is rarely reported in the literature. This study provides a clinicopathological analysis of all-cause kidney disease in CLL/SLL patients.
Fifteen CLL/SLL patients with kidney biopsy were identified retrospectively. Demographic, clinical, pathological and laboratory data were assessed at biopsy, and during follow-up.
At biopsy 11 patients presented impaired renal function, 7 patients nephrotic syndrome, 6 patients dysproteinemia, and 3 patients cryoglobulinemia. Kidney pathology revealed CLL/SLL-specific monoclonal infiltrate in 10 biopsies, glomerulopathy in 9 biopsies (5 membranoproliferative glomerulonephritis, 2 minimal change disease, 1 glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits, 1 AHL amyloidosis). Five patients presented interstitial granulomas attributed to CLL/SLL. After treatment of the hematological disease, improvement of renal function was observed in 7/11 patients, and remission of nephrotic syndrome in 5/7 patients. During follow-up, aggravation of the kidney disease systematically occurred in the absence of favorable response to hematological treatment.
A broad spectrum of kidney diseases is associated with CLL/SLL. In this setting, kidney biopsy can provide important information for diagnosis and therapeutic guidance.
PMCID: PMC4374947  PMID: 25811382
16.  The Feature of Distribution and Clonality of TCR γ/δ Subfamilies T Cells in Patients with B-Cell Non-Hodgkin Lymphoma 
Journal of Immunology Research  2014;2014:241246.
Restricted T-cell receptor (TCR) Vα/Vβ repertoire expression and clonal expansion of αβ T cells especially for putative tumor-associated antigens were observed in patients with hematological malignancies. To further characterize the γδ T-cell immune status in B-cell non-Hodgkin lymphoma (B-NHL), we investigated the distribution and clonality of TCR Vγ/Vδ repertoire in peripheral blood (PB), bone marrow (BM), and lymph node (LN) from patients with B-NHL. Four newly diagnosed B-NHL cases, including three with diffuse large B-cell lymphoma (DLBCL) and one with small lymphocytic lymphoma (SLL), were enrolled. The restrictive expression of TCR Vγ/Vδ subfamilies with different distribution patterns could be detected in PB, BM, or LN from all of four patients, and partial subfamily T cells showed clonal proliferation. At least one clonally expanded Vδ subfamily member was found in PB from each patient. However, the expression pattern and clonality of TCR Vγ/Vδ changed in different immune organs and showed individual feature in different patients. The clonally expanded Vδ5, Vδ6, and Vδ8 were detected only in PB but neither in BM nor LN while clonally expanded Vδ2 and Vδ3 could be detected in both PB and BM/LN. In conclusion, the results provide a preliminary profile of distribution and clonality of TCR γ/δ subfamilies T cells in PB, BM, and LN from B-NHL; similar clonally expanded Vδ subfamily T cells in PB and BM may be related to the same B-cell lymphoma-associated antigens, while the different reactive clonally expanded Vγ/Vδ T cells may be due to local immune response.
PMCID: PMC4055414  PMID: 24963496
17.  Combined applications of fine needle aspiration cytology and Flow cytometric immunphenotyping for diagnosis and classification of non Hodgkin Lymphoma 
CytoJournal  2006;3:24.
Aims and objectives
In this present study we have evaluated the feasibility of sub-classification of non-Hodgkin's lymphoma (NHL) cases according to World Health Organization's (WHO) classification on fine needle aspiration cytology (FNAC) material along with flow cytometric immunotyping (FCI) as an adjunct.
Materials and methods
In this five years study, only cases suggested or confirmed as NHL by FNAC were selected and FCI was performed with a complete panel of antibodies (CD3, CD2, CD 4, CD5, CD8, CD7, CD10, CD19, CD20, CD23, CD45, κ and λ) by dual color flow cytometry. Both cytologic findings and FCI data were interpreted together to diagnose and sub-classify NHL according to WHO classification. Wherever possible the diagnoses were compared with cytology.
There were total 48 cases included in this study. The cases were classified on FNAC as predominant small cells (12), mixed small and large cells (5) and large cells (26). In five cases a suggestion of NHL was offered on FNAC material and these cases were labeled as NHL not otherwise specified (NHL-NOS). Flow cytometry could be performed in 45 cases (93.8%) and in rest of the three cases the material was inadequate because of scanty blood mixed aspirate. Light chain restriction was demonstrated in 30 cases out of 40 cases of B-NHL (75%). There were 15 cases each of κ and λ light chain restriction in these 30 cases. With the help of combined FCI and FNAC, it was possible to sub-classify 38 cases of NHL (79%) according to WHO classification. Combined FNAC and FCI data helped to diagnose 9 cases of small lymphocytic lymphoma (SLL), 2 cases of mantle cell lymphoma (MCL), 4 cases of follicular lymphoma (FL), 17 cases of diffuse large B lymphoma (DLBL) and 6 cases of lymphoblastic lymphoma. Histopathology diagnosis was available in 31 cases of NHL out of which there were 14 recurrent and 17 cases of primary NHL. Out of 15 DLBL cases diagnosed on FCI and FNAC, histology confirmed 14 cases and one of these cases was diagnosed as Burkitt's lymphoma on histology. Cases of FL (4), SLL (3) and MCL (2) were well correlated with histopathology. Out of the five cases suggestive of NHL on cytology, histopathology was available in four cases. Histology diagnosis was given as DLBL (1), SLL (1), anaplastic large cell lymphoma (1) and FL transformed into large cell NHL (1). Considering histopathology as gold standard, diagnostic specificity of combined FNAC and FCI was 100% (31/31) and sensitivity in sub-classification was 83.8% (26/31).
FNAC combined with FCI may be helpful in accurately sub-classifying NHL according to WHO classification. Many of the subtypes of NHL such as FL and MCL which were previously recognized as a pure morphologic entity can be diagnosed by combined use of FNAC and FCI. Other ancillary investigations such as chromosomal changes, cell proliferation markers etc. may be helpful in this aspect.
PMCID: PMC1634871  PMID: 17069647
18.  Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma 
BMC Cancer  2012;12:478.
Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR) and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma (MZL) patients.
Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR), CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling.
Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p)-SFKs, p-PLCγ, p-ERK, p-p38, p-p65 (NF-κB), p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCγ levels. Impaired anti-BCR-induced p-PLCγ was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-κB) was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells.
BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation-induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.
PMCID: PMC3519597  PMID: 23072591
B-cell lymphoma; B-cell receptor; CD40; Phospho-flow cytometry; Cell signaling
19.  The spectrum of coincident entities with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) diagnosed by cytology 
CytoJournal  2010;7:20.
The cytologic diagnosis of Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) often relies on finding a small lymphoid population with the characteristic immunoprofile by ancillary testing. There are only a few reports of other processes identified with SLL/CLL. The aim of this study was to review the fine needle aspiration (FNA) and touch prep (TP) diagnoses of SLL/CLL in order to identify any coincident entities.
Materials and Methods:
We retrospectively reviewed all FNA and TP cytology cases between January 2005 and May 2009 with a diagnosis of SLL/CLL to determine the presence of any coincident process.
We identified 29 cases, including 23 FNAs and six TPs, from 23 patients. Ancillary studies were utilized in 97% of the cases, including flow cytometry (FC, 79%), immunohistochemistry (IHC, 55%), fluorescent in situ hybridization studies (24%) and special stains (7%). Coincident entities were identified in nine cases (31%) and included seven (28%) neoplastic entities (Hodgkin lymphoma [HL], adenocarcinoma, squamous cell carcinoma, seminoma) and two (7%) non-neoplastic entities (infection and immunoglobulin containing cells). Six cases (21%) suspicious for large cell transformation were also identified.
In our review of SLL/CLL, coincident entities were present in 31% of the cases and included a spectrum of non-neoplastic and neoplastic processes. FC was the most frequently utilized ancillary test, but IHC provided important information by excluding a mantle cell lymphoma or confirming a coincident process. Thus, cytomorphologic evaluation in these patients is important due to the high risk of a coincident process that may not be apparent by FC alone and may require clinical management.
PMCID: PMC2955352  PMID: 20976208
Chronic lymphocytic leukemia; cytopathology; SLL/CLL; small lymphocytic lymphoma
20.  Hodgkin lymphoma transformation of chronic lymphocytic leukemia: cases report and discussion 
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common form of leukemia affecting adults in Europe and North America. Large B-cell lymphoma known as Richter’s syndrome (RS) may develop approximately in 3–15 % patients. Furthermore, other hematological malignancies may also occur as RS variants, among them—Hodgkin lymphoma (HL). CLL/SLL transformation into HL is observed in about 0.5 % of patients, and till now, fewer than 100 cases have been reported in the medical literature. We present two cases of HL transformation of CLL/SLL and review the previously published literature.
PMCID: PMC3890034  PMID: 24338339
Hodgkin lymphoma; Chronic lymphocytic leukemia; Histological transformation; Trephine biopsy
21.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two subtypes of non-Hodgkin lymphoma. A number of studies have evaluated associations between risk factors and CLL/SLL risk. However, these associations remain inconsistent or lacked confirmation. This may be due, in part, to the inadequate sample size of CLL/SLL cases.
We performed a pooled analysis of 2440 CLL/SLL cases and 15186 controls from 13 case-control studies from Europe, North America, and Australia. We evaluated associations of medical history, family history, lifestyle, and occupational risk factors with CLL/SLL risk. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
We confirmed prior inverse associations with any atopic condition and recreational sun exposure. We also confirmed prior elevated associations with usual adult height, hepatitis C virus seropositivity, living or working on a farm, and family history of any hematological malignancy. Novel associations were identified with hairdresser occupation (OR = 1.77, 95% CI = 1.05 to 2.98) and blood transfusion history (OR = 0.79, 95% CI = 0.66 to 0.94). We also found smoking to have modest protective effect (OR = 0.9, 95% CI = 0.81 to 0.99). All exposures showed evidence of independent effects.
We have identified or confirmed several independent risk factors for CLL/SLL supporting a role for genetics (through family history), immune function (through allergy and sun), infection (through hepatitis C virus), and height, and other pathways of immune response. Given that CLL/SLL has more than 30 susceptibility loci identified to date, studies evaluating the interaction among genetic and nongenetic factors are warranted.
PMCID: PMC4155456  PMID: 25174025
22.  Automated analysis of multidimensional flow cytometry data improves diagnostic accuracy between mantle cell lymphoma and small lymphocytic lymphoma 
Mantle cell lymphoma (MCL) and small lymphocytic lymphoma (SLL) exhibit similar, but distinct immunophenotypic profiles. While many cases can be diagnosed with high confidence based on flow cytometry (FCM) results alone, ambiguous cases are frequently encountered and necessitate additional studies including immunohistochemistry for cyclinD1 and fluorescence in-situ hybridization (FISH) analysis for t(11;14) translocation.
Design and Methods
In order to determine if greater diagnostic accuracy could be achieved from flow cytometry data alone, we developed an unbiased, machine-based algorithm and used it to automatically identify those features within the multidimensional space that best distinguish between the two disease types.
Data from 44 MCL cases and 70 SLL cases were analyzed. Using conventional diagnostic criteria, we were able to accurately assign only 64% of MCL and 69% of SLL cases. Using features identified by our automated approach, we were able to assign 100% of MCL and 97% of SLL cases correctly. The most discriminating feature was the ratio of mean fluorescence intensities (MFI) between CD20 and CD23. Unexpectedly, we also observed that inclusion of FMC7 expression in the diagnostic algorithm reduced its accuracy.
Computational methods allow objective assessment of the relative contribution of component data features to overall diagnostic accuracy, and reveal some conventional criteria can actually compromise this accuracy. Furthermore, computational approaches enable exploiting the full dimensionality of FCM data and can potentially lead to discovery of novel biomarkers relevant for clinical outcome.
PMCID: PMC4090220  PMID: 22180480
23.  Hodgkin lymphoma transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma 
Transformation to a large cell lymphoma may occur during the course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in approximately 5% of the cases. This is known as Richter's transformation. A much less frequent transformation to Hodgkin lymphoma may occur. We report a case of CLL/SLL in which a transformation to Hodgkin lymphoma occurred, and we review previously published reports of this transformation. Transformation to Hodgkin lymphoma in CLL/SLL has a poor outcome compared to de novo cases of Hodgkin lymphoma.
PMCID: PMC3523758  PMID: 23382602
24.  Dietary factors and risk of chronic lymphocytic leukemia and small lymphocytic lymphoma: a pooled analysis of two prospective studies 
Other than male sex, family history, advanced age, and race, risk factors for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are unknown. Very few studies have investigated diet in relation to these leukemias, and no consistent associations are known.
Using two large prospective population-based studies, we evaluated the relationship between diet and CLL/SLL risk. Among 525,982 men and women free of cancer at enrollment, we identified 1,129 incident CLL/SLL cases during 11.2 years of follow-up.
We found no associations between total fat, saturated fat, fiber, red meat, processed meat, fruit or vegetable intake and risk of CLL/SLL. We noted a suggestive positive association between body mass index (BMI) and CLL/SLL (hazard ratio =1.30; 95% confidence interval= 0.99-1.36).
We did not find any associations between foods or nutrients and CLL/SLL.
Our large prospective study indicates that diet may not play a role in CLL/SLL development.
PMCID: PMC3501724  PMID: 20929883
diet; chronic lymphocytic leukemia; body mass index; cohort study
25.  Second Malignancy Risks After Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: Differences by Lymphoma Subtype 
Journal of Clinical Oncology  2010;28(33):4935-4944.
Previous studies have shown increased risks of second malignancies after non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, no earlier investigation has quantified differences in risk of new malignancy by lymphoma subtype.
Patients and Methods
We evaluated second cancer and leukemia risks among 43,145 1-year survivors of CLL/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL) from 11 Surveillance, Epidemiology, and End Results (SEER) population-based registries during 1992 to 2006.
Among patients without HIV/AIDS–related lymphoma, lung cancer risks were significantly elevated after CLL/SLL and FL but not after DLBCL (standardized incidence ratio [SIR], CLL/SLL = 1.42, FL = 1.28, DLBCL = 1.00; Poisson regression P for difference among subtypes, PDiff = .001). A similar pattern was observed for risk of cutaneous melanoma (SIR: CLL/SLL = 1.92, FL = 1.60, DLBCL = 1.06; PDiff = .004). Acute nonlymphocytic leukemia risks were significantly elevated after FL and DLBCL, particularly among patients receiving initial chemotherapy, but not after CLL/SLL (SIR: CLL/SLL = 1.13, FL = 5.96, DLBCL = 4.96; PDiff < .001). Patients with HIV/AIDS–related lymphoma (n = 932) were predominantly diagnosed with DLBCL and had significantly and substantially elevated risks for second anal cancer (SIR = 120.50) and Kaposi's sarcoma (SIR = 138.90).
Our findings suggest that differing immunologic alterations, treatments (eg, alkylating agent chemotherapy), genetic susceptibilities, and other risk factors (eg, viral infections, tobacco use) among lymphoma subtypes contribute to the patterns of second malignancy risk. Elucidating these patterns may provide etiologic clues to lymphoma as well as to the second malignancies.
PMCID: PMC3020697  PMID: 20940199

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