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1.  Epstein-Barr Virus-Positivity in Tumor has no Correlation with the Clinical Outcomes of Patients with Angioimmunoblastic T-cell Lymphoma 
Epstein-Barr virus (EBV) is involved in the pathogenesis of angioimmunoblastic T-cell lymphoma (AILT), but its precise role and prognostic impact are not clear. This study aimed to evaluate the incidence of EBV-postitivity in the tumor and bone marrow (BM) samples from AILT patients, and their correlations with the clinical variables and patient survival.
Seventy AILT cases were identified over a period of 8 years. Twenty seven cases were investigated for their EBV tumor status, and 10 BM samples of these patients were investigated for their EBV status with using in situ hybridization (ISH). EBV PCR was performed for the BM mononuclear cells in 8 cases.
Among the 27 tumor specimens, ten (37%) were EBV-positive. Only CD20-negativity in tumor correlated with the EBV-positivity (p=0.035). In 13 (48%) patients, gross tumor involvement was recognized by hematoxylin-eosin staining at the time of diagnosis. Among the 10 patients who had additional BM slides available, there were 3 with BM involvement, and none showed EBV positive results on ISH. EBV PCR of the BM mononuclear cells revealed one-positive case among 8 patients. This patient was negative for both BM involvement and EBV ISH. The median overall survival of the 25 treated patients was 48.9 months (95% CI: 18.6~79.2 months). Neither overall survival nor progression-free survival was related with EBV-positivity of the tumor.
EBV-positivity of tumor had no impact on the prognosis of AILT patients.
PMCID: PMC2686953  PMID: 18363277
Epstein-Barr virus; Angioimmunoblastic T-cell lymphoma; Survival
2.  Extranodal NK/T-cell lymphoma, nasal type extensively involving the bone marrow 
Extranodal NK/T-cell lymphoma, nasal type, is an aggressive EBV-associated lymphoma that mainly involves the nasal cavity but has also been reported to involve other extranodal sites without nasal involvement. In contrast to aggressive NK cell leukemia (a marrow-based aggressive leukemia of NK-cell origin); extensive bone marrow and blood involvement is extremely uncommon by nasal type NK/T lymphoma. We report a patient with extranodal NK/T-cell lymphoma, nasal type that developed extensive bone marrow involvement during the course of her disease with some overlapping features with aggressive NK-cell leukemia.
PMCID: PMC3209612  PMID: 22076172
Nasal NK cell lymphoma; aggressive NK cell leukemia; bone marrow
3.  Persistent Anemia in a Patient with Diffuse Large B Cell Lymphoma: Pure Red Cell Aplasia Associated with Latent Epstein-Barr Virus Infection in Bone Marrow 
Journal of Korean Medical Science  2007;22(Suppl):S167-S170.
We report a case of pure red cell aplasia (PRCA), which was initially suspected as a result of bone marrow involvement of diffuse large B cell lymphoma. Persistent anemia without an obvious cause was observed in a 47-yr-old man diagnosed with relapsed diffuse large B cell lymphoma. The bone marrow study showed only erythroid hypoplasia without the evidence of bone marrow involvement with lymphoma cells, thus PRCA was suggested. However, parvovirus infection was excluded as a potential cause of PRCA because of negative IgM anti-parvovirus B19 antibody and negative parvovirus PCR in the serum. Latent Epstein-Barr virus (EBV) infection of bone marrow was suggested by in situ hybridization with EBV-encoded small RNA (EBER) that showed a strong positive expression in bone marrow cells. Thus, PRCA was thought to be associated with latent EBV infection in bone marrow cells. Although the finding of unexplained anemia is a possible predictor of bone marrow involvement with lymphoma cells, PRCA as a result of a viral infection including EBV should be considered in lymphoma patients. This is the first report of the occurrence of PRCA associated with latent EBV infection in a patient with non-Hodgkin's lymphoma.
PMCID: PMC2694371  PMID: 17923747
Red-Cell Aplasia; Epstein-Barr Virus; Lymphoma
4.  Bone marrow involvement by non-Hodgkin's lymphom. 
We retrospectively studied 156 patients with non-Hodgkin's; ymphoma (NHL) in order to evaluate the incidence of bone marrow (BM) involvement at the time of diagnosis. The incidence of marrow involvement in NHL was 35% (55 patients). The most common histologic type of lymphoma was diffuse large cell lymphoma with 30% of the cases having bone marrow involvement. The highest incidence of marrow involvement was seen in immunoblastic lymphoma & the lowest incidence in diffuse mixed cell lymphoma. Bone marrow lymphoma was present in 50% of low-, 34% of intermediate-, and 55% of high-grade lymphomas. B-cell vs T-cell lymphoma in cases of marrow involvement was 56% to 42%. The most frequent pattern of marrow involvement was interstitial & diffuse (56% & 31%). The paratrabecular pattern was rare (4%). Most lymphomas (42%) extensively involved marrow space greater than 76% of the total marrow space. Discordant histology between lymph node and BM was seen in 10 cases (18%). Biopsy was the best method compared to smear & clot section (sensitivity 82% vs 72% vs 69%). In conclusion, our study revealed that the most common histologic type of marrow lymphoma was diffuse large cell type with frequent interstitial and diffuse pattern and extensive involvement of the marrow space. No predilection for a trabecular pattern was found. This result was in contrast to that in the Western literature.
PMCID: PMC3054194  PMID: 7702789
5.  Ocular involvement in nasal natural killer T-cell lymphoma 
International ophthalmology  2008;29(4):275-279.
To describe the clinical, morphologic, and immunohistochemical features of a case of paranasal natural killer/T-cell lymphoma (NKTL) with ocular involvement.
Case report
In March 2005 the patient presented with a maxillary sinusitis and upper nasal obstruction. In July she underwent a nasal computed tomography (CT) scan and multiple biopsies of the granulomatous tissue in the nasal fossae. The diagnosis was NK/T non-Hodgkin's lymphoma nasal type, stage IV A. Afterwards she presented anterior uveitis. In September after the diagnosis of lymphoma the patient underwent a bone marrow biopsy and thoracic and abdominal CT scan. An ophthalmic examination including visual acuity assessment and fundoscopic examination was made. In October she started chemotherapy cycles. Maxillary CT scan and ophthalmic examinations were performed during the cycles. In January 2006 after severe recurrences of panuveitis a diagnostic vitrectomy was performed.
A diagnosis of T-lymphoma cells in the vitreous was made; the tumor was most likely originating from her paranasal NKTL. The condition of the patient deteriorated rapidly and she expired on February 2006.
Nasal and paranasal sinus lymphomas are rare, but aggressive diseases with a tendency to invade tissues and spread to CNS, including the eye. Ocular manifestations prior to systemic ones may be useful to monitor the response to therapy.
PMCID: PMC2714878  PMID: 18438613
Masquerade syndrome; Nasal type lymphoma; Natural killer T-cell lymphoma; Serous retinal detachment
6.  NK cell lymphoma, nasal type, with massive lung involvement: a case report 
Journal of Hematopathology  2010;3(1):19-22.
Extranodal NK/T cell lymphoma, nasal type, is an Epstein–Barr virus-associated lymphoma that most commonly involves the nasal cavity and upper respiratory tract. Lung involvement by NK/T cell lymphoma is rare and seldom reported in the literature. We describe the unusual case of a 41-year-old male with NK cell lymphoma, nasal type, who presented with massive secondary lung involvement 2.5 years after the detection of a retroperitoneal mass. The diagnosis was made by open lung biopsy. Despite aggressive treatment, the patient died shortly after the initiation of therapy. Lung involvement by NK/T cell lymphoma occurs most commonly as part of widely disseminated disease and carries a poor prognosis for the patient. Novel agents and innovative therapies need to be developed for this aggressive lymphoma.
PMCID: PMC2883903  PMID: 21436870
Extranodal NK/T lymphoma; Lung involvement; Epstein–Barr virus
7.  Value of bilateral bone marrow biopsy specimens in non-Hodgkin's lymphoma. 
Journal of Clinical Pathology  1990;43(8):630-632.
A study of 260 patients with non-Hodgkin's lymphoma (NHL) who underwent bilateral bone marrow biopsy at initial diagnosis showed marrow disease in 99 (38%) cases. The highest incidence of disease (83%) was seen in small lymphocytic lymphoma (SLL) and the lowest (19%) in diffuse large cell lymphoma (DLCL). Among cases with positive marrows, disease was bilateral in all 15 cases of SLL but in only 10 of 20 (50%) of the DLCL cases. In 30 of 99 (30%) positive marrows disease was unilateral. Follicular lymphomas were strongly associated with a paratrabecular pattern, with 40 of 45 positive cases showing this. Discordant histology was seen in six of 20 positive cases of DLCL and two of 37 positive cases of follicular small cleaved cell lymphomas (FSCCL). A bone marrow aspirate was positive in only 56 of the 99 (57%) cases. Peripheral blood disease was present in 15% of the bone marrow positive cases and in 6% of the cases overall. The incidence of marrow disease varies with the histological subtype of lymphoma. The paratrabecular pattern is associated with follicular lymphoma, and bilateral biopsy specimens increase the positivity rate in most subtypes of NHL.
PMCID: PMC502641  PMID: 2401730
8.  Identification of genuine primary pulmonary NK cell lymphoma via clinicopathologic observation and clonality assay 
Diagnostic Pathology  2013;8:140.
Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is an uncommon lymphoma associated with the Epstein-Barr virus (EBV). It most commonly involves the nasal cavity and upper respiratory tract. Primary pulmonary NK/T cell lymphoma is extremely rare. If a patient with a NK or T-cell tumor has an unusual reaction to treatment or an unusual prognosis, it is wise to differentiate NK from T-cell tumors. The clinicopathologic characteristics, immunophenotype, EBV in situ hybridization, and T cell receptor (TCR) gene rearrangement of primary pulmonary NK cell lymphoma from a 73-year-old Chinese woman were investigated and the clonal status was determined using female X-chromosomal inactivation mosaicism and polymorphisms at the phosphoglycerate kinase (PGK) gene. The lesion showed the typical histopathologic characteristics and immunohistochemical features of NK/T cell lymphoma. However, the sample was negative for TCR gene rearrangement. A clonality assay demonstrated that the lesion was monoclonal. It is concluded that this is the first recorded case of genuine primary pulmonary NK cell lymphoma. The purpose of the present work is to recommend that pathologists carefully investigate the whole lesion to reduce the likelihood that primary pulmonary NK cell lymphoma will be misdiagnosed as an infectious lesion. In addition, TCR gene rearrangement and clonal analysis, which is based on female X-chromosomal inactivation mosaicism and polymorphisms at PGK and androgen receptor (AR) loci, were found to play important roles in differentiating NK cell lymphoma from T cell lymphoma.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3846405  PMID: 23958352
Extranodal NK/T cell lymphoma; Lung; Immunophenotype; TCR gene rearrangement; Clonality
9.  Human Bone Marrow Mesenchymal Stem Cells Display Anti-Cancer Activity in SCID Mice Bearing Disseminated Non-Hodgkin's Lymphoma Xenografts 
PLoS ONE  2010;5(6):e11140.
Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL.
Methodology/Principal Findings
The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV− Burkitt-type BJAB, median survival = 46 days) and an aggressive (EBV+ B lymphoblastoid SKW6.4, median survival = 27 days) behavior in nude-SCID mice. Intra-peritoneal (i.p.) injection of MSC (4 days after i.p. injection of lymphoma cells) significantly increased the overall survival at an optimal MSC∶lymphoma ratio of 1∶10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days). Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i) MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii) MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures.
Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL.
PMCID: PMC2886845  PMID: 20585401
10.  A probable identical Epstein-Barr virus clone-positive composite lymphoma with aggressive natural killer-cell leukemia and cytotoxic T-cell lymphoma 
The patient was a 52-year old woman with a history of mosquito-bite hypersensitivity since childhood. In July 2011, she developed pyrexia, headaches, and nausea, and Epstein-Barr virus (EBV)-positive aggressive natural killer leukemia (ANKL) was diagnosed on the basis of both a peripheral blood and bone marrow examination. An inguinal lymph node biopsy, on the other hand, revealed EBV-positive cytotoxic T-cell lymphoma plus the presence of a small number of EBV-positive ANKL cells, and a diagnosis of EBV-positive composite lymphoma was made. Both the cytotoxic T-cell lymphoma and ANKL exhibited EBV terminal repeat (Southern blot analysis) monoclonal patterns, and they were almost the same size, approximately 9.0 kb. If it was the identical EBV clone, it is possible that EBV infected progenitor cells common to both NK cells and T cells, that the progenitor cells then differentiated into NK cells and T cells, a chronic active Epstein-Barr virus infection developed, and neoplastic transformation occurred. If it was not the identical EBV clone, fairly similar EBVs must have infected NK cells and T cells separately, and they then underwent neoplastic transformation. Because the mechanism by which EBV infects NK cells or T cells is still unknown, we concluded that this case is also important from the standpoint of elucidating it. We are currently in the process of conducting gene analyses to determine whether the fairly similar EBVs that infected the ANKL and cytotoxic T-cell lymphoma are the identical clone.
PMCID: PMC3885499  PMID: 24427365
Aggressive NK leukemia; Epstein-Barr virus; cytotoxic T-cell lymphoma; composite lymphoma; large granular lymphocytes
11.  Diagnostic cues for natural killer cell lymphoma: primary nodal presentation and the role of in situ hybridisation for Epstein-Barr virus encoded early small RNA in detecting occult bone marrow involvement 
Journal of Clinical Pathology  2005;58(4):443-445.
Natural killer (NK) cell lymphomas are rare, and atypical features might lead to diagnostic pitfalls. This report describes an unusual patient in whom lymphoma occurred initially as isolated lymph node involvement, an exceptional presentation of an almost exclusively extranodal disease. Furthermore, during the terminal haemophagocytosis in the bone marrow, lymphoma cells lost the expression of the NK cell marker, CD56, making the histopathological diagnosis of bone marrow involvement difficult. This was resolved by in situ hybridisation for Epstein-Barr virus encoded small RNA, which detected occult bone marrow infiltration.
PMCID: PMC1770628  PMID: 15790718
CD56; Epstein-Barr virus encoded early small RNA; natural killer cell lymphoma; nodal
12.  Lymphomatous meningitis in AIDS-related systemic non-Hodgkin's lymphoma: a report of eight cases. 
Meningeal involvement occurred in eight (22%) of 36 adult patients with AIDS-related systemic non-Hodgkin's lymphoma, seen over a 10-year period. Clinical symptoms consisted of cranial nerve palsies, radicular involvement, headache or diffuse encephalopathy. CSF examination established the diagnosis in all cases. Systemic disease had been diagnosed seven to 33 weeks before lymphomatous meningitis in six patients, whereas in the remaining two patients diagnoses of systemic and meningeal disease were made simultaneously. All patients had intermediate or high grade lymphomas and widespread disease. In contrast to non-AIDS related lymphomas, bone marrow involvement at initial staging cannot be used to select patients for prophylactic treatment, as seven of our eight patients had no initial bone marrow involvement. In this retrospective review, prognosis of lymphomatous meningitis was extremely poor, with a mean survival of only five weeks. Survival of patients with systemic lymphoma who eventually developed lymphomatous meningitis was 4.0 months compared with 7.2 months for those who did not. Lymphomatous meningitis appears to have the worst outcome of all AIDS-related neurological complications, regardless of treatment.
PMCID: PMC1072440  PMID: 8126496
13.  Lack of Utility of CD20 Immunohistochemistry in Staging Bone Marrow Biopsies for Diffuse Large B-cell Lymphoma 
The utility of CD20 immunohistochemistry in the evaluation of staging bone marrow biopsies of newly diagnosed diffuse large B-cell lymphomas (DLBCL) patients has not been extensively studied. We used 113 routinely processed bone marrow biopsies to study the extent and pattern of involvement by lymphoma and CD20 staining. Twelve (10.6%) of 113 cases had involvement by morphology, and five (41.7%) of these showed histologic discordance between the primary site and the bone marrow. All cases with morphologic evidence of bone marrow involvement showed staining for CD20. Four (3.5%) of 113 cases had non-neoplastic aggregates that stained for CD20. One case (0.9%) showed a small benign lymphoid aggregate by immunohistochemistry that was not evident by morphology. Our results demonstrate that CD20 staining did not detect any examples of bone marrow involvement by DLBCL that were not evident by morphology. We conclude that immunohistochemistry for CD20 adds no increase in the sensitivity of detection of bone marrow infiltration by DLBCL.
PMCID: PMC2696064  PMID: 19521275
Diffuse large B-cell lymphoma; bone marrow; staging; immunohistochemistry; CD20
14.  Comparative Evaluation of Bone Marrow Aspirate with Trephine Biopsy in Hematological Disorders and Determination of Optimum Trephine Length in Lymphoma Infiltration 
Bone marrow examination is an indispensable diagnostic tool to evaluate neoplastic and non neoplastic hematological diseases.
To compare bone marrow aspirate with trephine biopsy in hematological disorders. To determine the optimum trephine preprocessing length in lymphoma infiltration.
Diagnostic comparison was done between simultaneous bone marrow aspirates and trephine biopsies in 449 patients. Biopsies were fixed in formalin, decalcified in 5.5% EDTA and routinely processed. Concordance rates and validity parameters for aspirate were calculated. Three deeper sections of trephine biopsy, cut at 0.1–0.2 mm intervals, were assessed for lymphoma involvement. Proportion of biopsies showing marrow infiltration by lymphoma cells was plotted against trephine length and correlation was assessed.
Aspirate had a high sensitivity for acute leukemia (89.4%) and multiple myeloma (88.5%), moderate for NHL (67.6%) and nonhematopoietic metastases (58.3%) and low for aplastic anemia (38.5%) and Hodgkin lymphoma (5%). Aspirate has no role in granulomatous myelitis and myelofibrosis. Lymphoma positivity increased with trephine length, with maximum positivity (68.9%) seen in 17–20 mm group and no further gain beyond 20 mm. (lymphoma positivity ≤16mm=40.3% and ≥17mm=66.1%, p=0.0011).
Aspirate has a high specificity; its sensitivity depends upon the type of disease. Apart from few conditions, in which aspirate alone is sufficient, biopsy is mandatory in most. Preprocessing trephine length of 17–20 mm examined at multiple deeper levels was found optimal for assessing lymphoma positivity.
PMCID: PMC3894839  PMID: 24455111
15.  Epstein-Barr Virus-Negative Post-Transplant Lymphoproliferative Diseases: Three Distinct Cases from a Single Center 
Turkish Journal of Hematology  2014;31(1):79-83.
Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa-associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required.
PMCID: PMC3996636  PMID: 24764734
Renal transplantation; Post-transplant lymphoproliferative disease; Lymphoma; Immunosuppression; Rituximab; Abnormal karyotype
16.  Long-Term Remission of Primary Bone Marrow Diffuse Large B-Cell Lymphoma Treated with High-Dose Chemotherapy Rescued by In Vivo Rituximab-Purged Autologous Stem Cells 
Case Reports in Medicine  2012;2012:957063.
Primary bone marrow diffuse large B-cell lymphoma (DLBCL) is a rare type of extranodal lymphoma with poor prognosis. Here, we report a case of primary bone marrow DLBCL successfully treated with high-dose chemotherapy and rescued by in vivo rituximab-purged autologous stem cells. A 39-year-old woman visited our hospital because of anemia. Bone marrow examination revealed a large B-cell lymphoma invasion. An 18F-fluorodeoxyglucose positron emission tomography scan revealed disseminated bone marrow uptake without evidence of dissemination at other sites. These findings led to a diagnosis of primary bone marrow DLBCL. Our patient underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy and achieved complete remission. Subsequently, she received high-dose chemotherapy with an in vivo rituximab-purged autologous stem cell transplant. Seven years have passed since the transplantation, and she remains in remission. This suggests that transplantation of an in vivo rituximab-purged autograft is a promising strategy for primary bone marrow DLBCL.
PMCID: PMC3480674  PMID: 23118770
17.  Routine use of ancillary investigations in staging diffuse large B-cell lymphoma improves the International Prognostic Index (IPI) 
The International Prognostic Index (IPI) is used to determine prognosis in diffuse large B-cell lymphoma (DLBCL). One of the determinants of IPI is the stage of disease with bone marrow involvement being classified as stage IV. For the IPI, involvement on bone marrow is traditionally defined on the basis of histology with ancillary investigations used only in difficult cases to aid histological diagnosis. This study aimed to determine the effect of the routine use of flow cytometry, immunohistochemistry and molecular studies in bone marrow staging upon the IPI.
Bone marrow trephines of 156 histologically proven DLBCL cases at initial diagnosis were assessed on routine histology, and immunohistochemistry using two T-cell markers (CD45RO and CD3), two B-cell markers (CD20 and CD79a) and kappa and lambda light chains. Raw flow cytometry data on all samples were reanalysed and reinterpreted blindly. DNA extracted from archived paraffin-embedded trephine biopsy samples was used for immunoglobulin heavy chain and light chain gene rearrangement analysis. Using immunophenotyping (flow cytometry and immunohistochemistry), 30 (19.2%) cases were upstaged to stage IV. A further 8 (5.1%) cases were upstaged using molecular studies. A change in IPI was noted in 18 cases (11.5%) on immunophenotyping alone, and 22 (14.1%) cases on immunophenotyping and molecular testing. Comparison of two revised IPI models, 1) using immunophenotyping alone, and 2) using immunophenotyping with molecular studies, was performed with baseline IPI using a Cox regression model. It showed that the revised IPI model using immunophenotyping provides the best differentiation between the IPI categories.
Improved bone marrow staging using flow cytometry and immunohistochemistry improves the predictive value of the IPI in patients with DLBCL and should be performed routinely in all cases.
PMCID: PMC2786909  PMID: 19930611
18.  Lymphoproliferations in the bone marrow: identification and evolution, classification and staging. 
Journal of Clinical Pathology  1984;37(3):233-254.
Bone marrow biopsies from 3229 patients with lymphoproliferative disorders and 1156 patients with benign or reactive lymphoproliferations were investigated and criteria for distinguishing between them are given. Bone marrow involvement was found in 89% of multiple myeloma, 64% of non-Hodgkin's lymphomas and 8% of Hodgkin's disease. According to the predominant proliferative cell type there were five major entities in multiple myeloma and non-Hodgkin's lymphomas: (1) plasmacytic; (2) lymphocytic; (3) hairy cell; (4) immunocytic; (5) centrocytic. These were further classified into distinct subtypes each of which had independent prognostic significance. The mode of spread of the lymphoproliferative disorders in the bone marrow showed one of six architectural patterns, which together with the quantity of infiltration in the biopsy (reflecting the tumour cell burden) had significant predictive value. These results demonstrate the value of bone marrow biopsies in the identification, classification and staging of lymphoproliferative disorders, as well as in monitoring the course of disease and the response to therapy.
PMCID: PMC498694  PMID: 6699189
19.  EBV in situ hybridization study for non-Hodgkin's lymphomas. 
Epstein-Barr virus(EBV) has been implicated in the pathogenesis of B-lymphoproliferative disorders, T-cell lymphomas and Hodgkin's disease. In this report, we performed an in situ hybridization study on EBV genome in 10 cases of nasal non-Hodgkin's lymphoma(NHL), 20 cases of Waldeyer's ring(WR) NHL, and 20 cases of nodal NHLs to document EBV association with lymphomas in Koreans. For immunophenotyping, monoclonal antibodies for CD 20, MB 2, CD 45Ro & CD 43 were used. For in situ hybridization study, EBV DNA probe for Bam HI 'V' fragment and EBV RNA probe for EBER and BHLF were used. Twenty two cases(44%) of malignant lymphomas were positive for EBV genome. Generally, T-cell lymphomas showed a higher positive rate(61%) than B-cell lymphomas(24%). Among T-cell lymphomas, nasal lymphomas showed a higher positive rate(80%) than WR(50%) or nodal lymphomas(50%). Of 22 EBV genome positive cases, 10 cases were positive for EBER, 10 cases for BHLF, and 2 cases for both EBER and BHLF. The histologic types by Working Formulation(WF) were not correlated with EBV genome positive rate, whereas lymphomas showing the histologic spectrum of polymorphic reticulosis(PR) showed a higher positive rate(65%) than lymphomas without PR-like features(40%). These results indicate that nasal T-cell lymphomas with the histologic spectrum of PR are strongly associated with EBV and that the anatomic site may be an important factor in this association.
PMCID: PMC3054072  PMID: 7993589
20.  Nasal natural killer/T‐cell lymphoma and its association with type “i”/XhoI loss strain Epstein–Barr virus in Chile 
Journal of Clinical Pathology  2006;60(6):656-660.
Nasal T/natural killer (NK)‐cell lymphoma is an aggressive type of non‐Hodking's lymphoma associated with Epstein–Barr virus (EBV) and striking geographical variations worldwide.
To characterise nasal NK/T‐cell lymphoma associated with genotypes of EBV in Chile, a Latin American country, where multiple strains of EBV, including two new recombinant strains, in healthy individuals were recently found.
Cases with diagnosis of primary nasal lymphoma were selected for histological and immunohistochemical analysis (CD3, CD3e, CD4, CD8, CD79a, CD56, CD57 and TIA‐1) and in‐situ hybridisation, serology and genotyping analysis for EBV.
Out of 22 cases, 9 (41%) cases fulfilled the World Health Organization criteria for nasal NK/T‐cell lymphoma; of these 7 (78%) cases were positive for EBV. Genotyping analysis revealed 6 cases of type 1 EBV and wildtype F at the BamHI‐F region, 4 cases type “i” EBV at the BamHI‐W1/I1 region; XhoI wild type was found in 2 and XhoI loss in 4 cases, respectively. Cosegregation analysis of the BamHI‐W1/I1 region and XhoI restriction site showed the new recombinant strain type “i”/XhoI loss in 3 cases and type “i”/XhoI wild‐type strain in 1 case. Most patients were treated with combined anthracycline‐containing regimens. Half of the cases attained complete remission.
Although nasal NK/T‐cell lymphomas from Chile share similar clinicopathological features, high association with EBV and unfavourable prognosis with those described elsewhere, genotype analysis shows that the new recombinant type “i”/XhoI loss strain might contribute to explain the intermediate incidence of nasal NK/T‐cell lymphomas in Latin America.
PMCID: PMC1955082  PMID: 16775124
21.  Primary cutaneous diffuse large B-cell lymphoma, leg type, with multiple local relapses: case presentation and brief review of literature 
Hippokratia  2013;17(2):174-176.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBL-LT) is a primary cutaneous B-cell lymphoma of intermediate behavior. The disease predominantly affects elderly patients. A 76-year old man presented with red to violaceous nodules in the anterior aspect of both tibias. Histology confirmed the diagnosis of PCDLBL-LT. A thorough clinical and laboratory investigation was negative for any systemic involvement. However, computed tomography of the thorax showed mediastinal lymphadenopathy. Both bone marrow aspiration and trephine did not show any evidence of bone marrow infiltration. Initially R-CHOP regimen (rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone) achieved a total clearance of the lesions. Nevertheless, five months later patient presented with a relapse and was managed with palliative radiotherapy. The same treatment modality was applied for the second recurrence, as well. PCDLBL-LT affects mostly elderly patients. The consequent age related comorbidities and the frequent relapses require a strict follow up of the patients.
PMCID: PMC3743626  PMID: 24376327
B-cell cutaneous lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg type (PCDLBL-LT); R-CHOP regimen
22.  Extra Nodal NK/T-Cell Lymphoma Nasal Type: Efficacy of Pegaspargase Report of Two Patients from the United Sates and Review of Literature 
Leukemia research  2009;34(1):e50.
Extranodal NK/T cell lymphoma nasal type is an EBV driven non-Hodgkin lymphoma, rare in the United States, with no known satisfactory treatment. Two patients with this entity refractory to CHOP chemotherapy responded to single agent pegaspargase (pegylated L-asparaginase). A 64-year-old Caucasian woman presented with extranodal NK/T lymphoma nasal type on her left buttocks. After initial treatment with loco-regional irradiation and CHOP, she developed extensive lower extremity lesions, and subsequent paranasal sinus involvement. With pegaspargase, she had a dramatic improvement of her skin lesions and proceeded to autologous stem cell transplant. A 48 year old Asian man presented with nasal cavity extranodal NK/T lymphoma which resolved with radiation therapy. Multiple liver lesions which developed while receiving CHOP completely resolved on pegaspargase. L- Asparaginase and its pegylated form have activity in this disease and further exploration alone or in combination is warranted.
PMCID: PMC2813903  PMID: 19786301
L-Asparaginase; aspargase; NK/T-Cell Lymphoma; natural killer lymphoma
23.  Bifocal Presentation of Primary Testicular Extranasal NK/T-Cell Lymphoma: A Case Report and Review of the Literature 
Introduction. Testicular lymphoma is an aggressive disease with a very poor prognosis. Nasal-type natural killer/T-cell lymphoma (NKTCL-N) in particular is very uncommon and has a rapidly progressive, fatal course. Case Report. We report a case of primary NKTCL-N of the testis in a 38-years-old Middle Eastern man. The patient had a history of primary right testicular tumor diagnosed at an outside institution as a seminoma and treated with orchiectomy followed by chemo/radiation. On admission, the patient had an enormous nasal granuloma with blood workup showing pancytopenia and elevated liver function tests due to active hepatitis B infection. CT scan of the sinuses showed a very large soft tissue mass, and PET scan showed splenomegaly with multiple lymph node masses in the pelvis and the chest areas. Bone marrow and nasal tumor biopsies as well as review of the slides from the initial orchiectomy were all in favor of NKTCL-N lymphoma. The patient was treated with CHOD based combination chemotherapy and responded dramatically to the first two cycles but passed away from fulminant hepatitis B infection. Conclusion. Despite all known treatments of NKTCL-N lymphoma of the testes, this disease has a very poor prognosis and invariably follows an aggressive clinical course.
PMCID: PMC3753765  PMID: 23997969
24.  Primary sacral non-germinal center type diffuse large B-cell lymphoma with MYC translocation: a case report and a review of the literature 
An 85-year-old man presented with pain and numbness in the left buttock, and physical examination revealed an approximately 7 cm mass extending from the first to the third sacral vertebrae; biopsy of the mass led to the diagnosis of CD10-negative, BCL6-weakly positive, MUM1-positive, non-germinal center (non-GC) type diffuse large B-cell lymphoma (DLBCL). Furthermore, serological testing showed negative results for Epstein-Barr virus (EBV) infection, and fluorescence in situ hybridization (FISH) revealed a MYC translocation. Radiographs showed no remarkable osteolytic bone destruction, and the patient was staged with Stage IAE. After 8 cycles of rituximab therapy and 6 cycles of CHOP therapy, complete remission has been maintained until now, approximately 1 year after the treatment. Primary sacral lymphoma is very rare, with only 6 reported cases, including the present one. A review of the reported cases revealed that the disease predominantly affects elderly men, is usually non-GC-type DLBCL and stage IAE, measures approximately 2-7 cm in diameter in general, and does not show early recurrence after chemotherapy or chemoradiotherapy. There is no report in the literature yet of primary sacral DLBCL with MYC translocation, and this is the first case report. On the other hand, 35 cases of CD10-negative DLBCL with MYC translocation, including the present one, have been reported, and a review of the reported cases showed that the disease predominantly affects Asians, middle-aged or elderly men, shows positivity for either BCL6 or MUM1 and negativity for EBV, and has a high international prognostic index and poor prognosis.
PMCID: PMC3759501  PMID: 24040459
Primary sacral lymphoma; non-germinal center DLBCL; CD10-negative; MYC; paraffin-embedded tissue section-fluorescence in-situ hybridization
25.  Bone biopsy in haematological disorders. 
Journal of Clinical Pathology  1982;35(3):257-284.
Bone marrow biopsies are now widely used in the investigation and follow-up of many diseases. Semi-thin sections of 8216 undecalcified biopsies of patients with haematological disorders were studied. Observations were made on the cytopenias and the myelodysplastic syndromes, the acute leukaemias the myeloproliferative disorders, Hodgkin's disease and the malignant lymphomas including multiple myeloma, hairy cell leukaemia and angioimmunoblastic lymphadenopathy. Bone marrow biopsies are essential for the differential diagnosis of most cytopenias and for the early recognition of fibrosis which most frequently occurred as a consequence of megakaryocytic proliferation in the myeloproliferative disorders. Different patterns of bone marrow involvement were found in the lymphoproliferative disorders and both their type and extent constituted factors of prognostic significance. A survey of the literature is given and the conclusion is drawn that bone marrow biopsies provide indispensible information for the diagnostic evaluation and the follow-up of patients with haematological disorders.
PMCID: PMC497529  PMID: 7040489

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