Naoko Asano

Age-Related EBV-Associated B-Cell Lymphoproliferative Disorders Constitute a Distinct Clinicopathologic Group: A Study of 96 Patients

Purpose: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs. To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Experimental Design: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected. We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Results: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). Conclusions: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.

Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients.

Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder (aEBVLPD) is a disease group characterized by EBV-associated large B-cell lymphoma in elderly without predisposing immunodeficiency. In nearly one- third of cases, aEBVLPD occurs as a polymorphous subtype with reactive cell-rich components, bearing a morphologic similarity to classic Hodgkin lymphoma (cHL). The aim of this study was to clarify clinicopathologic differences between the polymorphic subtype of aEBVLPD (n = 34) and EBV(+) cHL (n = 108) in patients aged 50 years or older. Results showed that aEBVLPD was more closely associated with aggressive clinical parameters than cHL, with a higher age at onset (71 vs 63 years); lower male predominance (male-female ratio, 1.4 vs 3.3); and a higher rate of involvement of the skin (18% vs 2%), gastrointestinal tract (15% vs 4%), and lung (12% vs 2%). aEBVLPD was histopathologically characterized by a higher ratio of geographic necrosis, greater increase (> 30%) in cytotoxic T cells among background lymphocytes, higher positivity for CD20 and EBNA2, and absence of CD15 expression. As predicted by the clinical profile, aEBVLPD had a significantly poorer prognosis than EBV(+) cHL (P < .001). The polymorphous subtype of aEBVLPD constitutes an aggressive group with an immune response distinct from EBV(+) cHL, and requires the development of innovative therapeutic strategies.

Clinicopathologic and prognostic significance of cytotoxic molecule expression in nodal peripheral T-cell lymphoma, unspecified

Cytotoxic molecules (CMs) are apoptosis-inducing molecules that are present in azurophilic cytoplasmic granules of T lymphocytes. Expression of TIA-1 and granzyme B was examined for 100 cases of nodal peripheral T-cell lymphoma, unspecified (PTCL-U) to assess clinicopathologic significance of CM. Forty-one were positive for at least one CM. Patients with CM-positive PTCL-U showed younger onset (median, 55 years vs. 64 years, P = 0.01) and less male predominance (male:female ratio, 21:20 vs. 44:15, P = 0.02). CM-positive PTCL-U was significantly associated with several clinical factors to indicate poor prognosis, in comparison with CM-negative PTCL-U, such as poorer performance status (P = 0.006), more frequent B-symptoms (68% vs. 35%, P = 0.002), higher serum lactate dehydrogenase levels (P = 0.003), and more frequent extranodal involvement, particularly bone marrow involvement (33% vs. 9%, P = 0.004). Epstein-Barr virus was mostly found in CM-positive PTCL-U (51% vs. 2%, P < 0.0001). The CM-positive group showed higher distribution of the International Prognostic Index (P = 0.009) and the Prognostic Index for T-cell lymphoma (P = 0.004) scores than CM-negative group. Complete remission rate was 30% for the former but 63% for the latter. Overall survival of CM-positive PTCL-U was significantly lower than that of CM-negative patients (P = 0.004). Multivariate analyses confirmed that CM expression is a significant prognostic factor, independent from other clinical factors or prognostic index scores. These findings suggest that nodal CM-positive PTCL-U show distinct clinicopathologic characteristics among the current category of PTCL-U.

Age‐related Epstein–Barr virus‐associated B‐cell lymphoproliferative disorders: Special references to lymphomas surrounding this newly recognized clinicopathologic disease

Epstein–Barr virus (EBV) is associated with some disease entities of malignant lymphomas, including Burkitt lymphoma, Hodgkin lymphoma, immunodeficiency‐associated lymphoproliferative disorders (LPD), and a part of diffuse large B‐cell lymphoma. We have recently identified a series of elderly patients with EBV‐associated (or EBV+) B‐cell LPD (B‐LPD) showing similarities in many respects to immunodeficiency‐associated LPD, although no evidence of underlying immunodeficiency was found. Therefore, the nosological category of senile or age‐related EBV+ B‐LPD has been proposed for those patients. A larger series of patients with this disease revealed that the relative ratios of such EBV+ B‐LPD to all diffuse large B‐cell lymphoma cases were higher with increasing with age, reaching a peak (20–30%) at ≥90 years of age, with a median of 71 years, providing additional evidence for our assertion that this disease may be related to immunological deterioration as a result of the aging process. This new disease entity is characterized pathologically by centroblasts, immunoblasts, and Hodgkin and Reed–Sternberg‐like giant cells with a varying degree of reactive components, often posing therapeutic and diagnostic problems for hematologists and pathologists, respectively. The aim of the present review is to briefly summarize the overall clinicopathological profile of this newly recognized age‐related (also called ‘senile’) EBV+ B‐LPD and EBV+ Hodgkin lymphoma for a practical diagnostic approach. (Cancer Sci 2008; 99: 1085–1091)

Age‐related EBV‐associated B‐cell lymphoproliferative disorders: Diagnostic approach to a newly recognized clinicopathological entity

EBV is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age‐related EBV‐associated B‐cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency‐associated ones, which may be associated with immune senescence in the elderly and which are now incorporated into the 2008 World Health Organization lymphoma classification as EBV‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly. This newly described disease is pathologically characterized by a proliferation of atypical large B cells including Reed–Sternberg‐like cells with reactive components, which pose a diagnostic problem for pathologists. Clinically, this disease may present with lymphadenopathy, and is often extranodal, frequently involving the skin, gastrointestinal tract, or lung. Onset is usually after the age of 50; the median patient age is 70–79 years, and incidence continues to increase with age, providing additional support to the nosological term of EBV+ DLBCL of the elderly. These patients have a worse prognosis than those with EBV‐negative DLBCL or EBV+ classical Hodgkin lymphoma (CHL). The aim of the present review was to summarize the clinicopathological profile of age‐related EBV+ LPD and EBV+ Hodgkin lymphoma to facilitate diagnostic approach.

Clinicopathological features of neuropathy associated with lymphoma

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkins lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.

Prognostic Significance of T-Cell or Cytotoxic Molecules Phenotype in Classical Hodgkin’s Lymphoma: A Clinicopathologic Study

PURPOSE Classical Hodgkins lymphoma (CHL) is characterized by Hodgkins and Reed-Sternberg (H-RS) cells, most of which are derived from germinal-center B cells. Nevertheless, one or more markers for T cells and follicular dendritic cells (FDC) may be expressed in a minority of H-RS cells in some CHL patients, although the clinical significance of this remains controversial. The aim of this study was to clarify the association between phenotypic expression and clinical outcome in CHL. PATIENTS AND METHODS Participants were 324 consecutive CHL patients, comprising 132 patients with nodular sclerosis (NS), 35 patients with NS grade 2 (NS2), and 157 patients with mixed cellularity (MC). We evaluated the presenting features and prognosis of patients on categorization into four phenotypically defined groups: B-cell (CD20+ and/or CD79a+; n = 63), T-cell and/or cytotoxic molecules (CD3+, CD4+, CD8+, CD45RO+, TIA-1+, and/or granzyme B+; n = 27), FDC (CD21+ without B-cell marker; n = 22), and null-cell types (n = 212). Other potential prognostic factors were examined. RESULTS The T-cell and/or cytotoxic molecules group showed a significantly poorer prognosis than the other three groups (P < .0001). This finding was seen consistently in multivariate analyses. Morphologic subtyping (NS/NS2/MC) and Epstein-Barr virus positivity were not identified as independent prognostic factors. CONCLUSION The presence of T-cell and/or cytotoxic antigens in H-RS cells may represent a poor prognostic factor in CHL, even if their expression is not regarded as lineage specific. Examination of T-cell and/or cytotoxic molecules phenotype in CHL patients is recommended as a routine pathologic practice.

Clinicopathologic analysis of IgG4-related skin disease

IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4+ cells in affected tissues and elevation of serum IgG4 levels. In 2009, we were the first to report skin lesions in patients with IgG4-related disease, but no large case series has been reported and clinicopathological findings remain unclear. To clarify these features, we herein report 10 patients (9 men and 1 woman; median age, 64 years; age range, 46–81 years) with IgG4-related skin disease. All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek, and mandible regions, except for one patient, whose forearm and waist skin were affected. In addition, eight patients had extracutaneous lesions: these were found on the lymph nodes in six patients, the lacrimal glands in three patients, the parotid glands in three patients, and the kidney in one patient. Histologically examined extracutaneous lesions were consistent with IgG4-related disease; five of six lymph node lesions showed progressively transformed germinal centers-type IgG4-related lymphadenopathy. Cases of IgG4-related skin disease were classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes, and eosinophils; the majority of the plasma cells were IgG4+. The IgG4+ cell count was 49–396 per high-power field (mean±s.d., 172±129), with an IgG4+/IgG+ cell ratio ranging from 62 to 92%. Serum IgG4 levels were elevated in all examined patients. In conclusion, patients with IgG4-related skin disease had uniform clinicopathology. Lesions were frequently present on the skin of the periauricular, cheek, and mandible regions, and were frequently accompanied by IgG4-related lymphadenopathy.

Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4+ progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4+ plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4+ progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

Significance of chemokine receptor expression in aggressive NK cell leukemia

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.