Kayoko Murayama

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

Malignant Lymphoma in Patients with Systemic Rheumatic Disease (Rheumatoid Arthritis, Systemic Lupus Erythematosus, Systemic Sclerosis, and Dermatomyositis): A Clinicopathologic Study of 24 Japanese Cases

We conducted clinicopathologic and immunohistochemical analyses of the prevalence of Epstein-Barr virus (EBV) among 24 patients with malignant lymphoma complicating systemic rheumatic diseases. (SRD) These 24 patients included 17 with rheumatoid arthritis (RA), 3 with systemic lupus erythematosus (SLE), 2 with systemic sclerosis (SS), and 2 with dermatomyositis (DM). There were 2 men and 22 women ranging in age from 30 to 86 years (mean: 64 years). The interval between the onset of rheumatic disease and that of malignant lymphomas ranged from 3 months to 35 years (mean: 142 months). The use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in 15 patients. Among them, 5 patients received methotrexate (MTX) therapy. Malignant lymphomas were found at extranodal sites in 9 patients, and the disease was in the advanced stage in 17 patients. Histologic and immunohistochemical studies demonstrated that 18 cases (75%) were B-cell lymphoma (RA=12, SLE=2, SS=2, DM=2), 3 (12.5%) were peripheral T-cell lymphoma (RA=3), and 3 (12.5%) were classical Hodgkin lymphoma (RA=2, SLE=1). As in previous reports, there was an increased frequency of diffuse large B-cell lymphoma (50%) in the present series. Moreover, a majority of the diffuse large B-cell lymphomas exhibited activated B-cell phenotype. EBV-encoded small RNAs (Epstein-Barr early region [EBER]-) and/or LMP-1+tumor cells were identified in only 3 cases of classical Hodgkin lymphomas. Our findings suggested EBV-associated lymphoma comprised only a small fraction of all non-Hodgkins lymphomas in the general SRD patient population.

Clinical Implication of Idiopathic Plasmacytic Lymphadenopathy with Polyclonal Hypergammaglobulinemia: A Report of 16 Cases

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hyperimmunoglobulinemia is considered identical to multicentric Castlemans disease (MCD) reported in western countries. Clinically, both IPL and MCD are characterized by multicentric lymphadenopathy, prominent polyclonal hypergammaglobulinemia, elevated erythrocyte sedimentation rate, elevated serum interleukin-6 concentration, bone marrow plasmacytosis, and various abnormal laboratory data such as anemia and positive autoantibodies. However, IPL has a significantly better 5-year survival rate than that of MCD. Moreover, none of the present 16 cases developed Kaposis sarcoma or B-cell lymphoma. Histologically, the interfollicular area contains a sheet of polytypic mature plasma cells in both IPL and MCD. In MCD, the majority of lymphoid follicles had hyaline-vascular germinal centers. However, lymphoid follicles of IPL usually exhibit a hyperplastic germinal center. Immunostaining also demonstrated a normal/ reactive follicular dendritic cell network pattern in the germinal center of IPL. Moreover, there were no human herpes virus-8-positive cells detected by immunohistochemistry. The overall clinicopathologic and immunohistochemical findings of our 16 cases suggest that IPL is distinct from MCD reported in Western countries.

PLASMA CELL LEUKAEMIA WITH ALPHA-INTERFERON THERAPY IN MYELOMA

Alpha-interferon (IFN-alpha) is a commonly used therapeutic agent for myeloma. Although its adverse effects are widely recognized, less attention has been given to other possible hazards for myeloma. We report a myeloma patient who developed a plasma cell leukaemia (PCL) apparently triggered by IFN-alpha therapy. A 66-year-old previously untreated Japanese man with IgG kappa type myeloma at clinical stage IIIA was referred to our hospital on 24 March 1992. Investigation revealed: WBC 3.6 x 109/1 with 2.5% plasma cells: serum IgG-kappa Mprotein 71 g/l, lactate dehydrogenase (LDH) 2.49 pkat/l, interleukin 6 (IL-6) 16.2 pg/ml and Bence Jones proteinuria (BJP). Bone marrow aspiration revealed 80% atypical plasma cells. The patient was treated with natural IFN-alpha, sumiferon produced by Sumitomo (Osaka, Japan), along with intermittent melphalan and prednisolone. IFN-alpha was injected intramuscularly at 3 million units daily for 9 d. Treatment was stopped because the number of circulating plasma cells increased, while M-protein and BJP decreased. LDH and IL-6 increased rapidly, showing 12-4 pkat/l and 32.6 pg/ml, respectively. 12 d after starting therapy, the diagnosis of plasma cell leukaemia was established on the basis of a WBC count of 13.1 x 10y/l with 42.5% of circulating plasma cells which were demonstrated by immunohistochemical staining to be monoclonal for cytoplasmic gamma heavy chains and kappa light chains. Chemotherapy with vincristine, adriamycin and dexamethasone (VAD regimen) was begun. However, the patient developed renal failure and died of sepsis and disseminated intravascular coagulation on 22 April 1992. Blade et aZ (1991) described a myeloma patient who had developed PCL triggered by IFN-alpha therapy. IFN-alpha has been shown to stimulate the proliferation of IL-6-dependent myeloma cells by inducing an autocrine IL-6 production (Klein et al, 1990). IL-6 is a growth factor for myeloma (Kawano et a/, 1988; KIein et a!, 1990). In our case, PCL and rise in the serum IL-6 level was recognized during the IFNalpha therapy. Our experience in this case suggests the potential of tumour growth stimulation by IFN-alpha and the need for careful observation of the number of circulating plasma cells and serum IL-6 level under IFN-alpha therapy.

Distribution of Epstein-Barr Virus in Systemic Rheumatic Disease (Rheumatoid Arthritis, Systemic Lupus Erythematosus, Dermatomyositis) With Associated Lymphadenopathy: A Study of 49 Cases

Among systemic rheumatic diseases (SRDs), lymphadenopathy is frequently found in patients with rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) may occur in patients following methotrexate therapy for RA and dermatomyositis (DM). However, little is known about the distribution of EBV in reactive LPDs in patients with SRDs who had no history of methotrexate therapy. We analyzed 49 such patients (SLE=25, RA=23, DM=1) for the presence and distribution of EBV+ cells using Epstein-Barr virus (EBV)-encoded small RNA (EBER) specific in situ hybridization. A positive signal for EBERs was identified in 9 (SLE=5, RA=4) (18%) of 49 cases, and 3 main distribution patterns of EBER+ cells could be delineated: pattern A, more than 500 EBER-positive cells were located in the germinal centers as well as interfollicular area (SLE=2); pattern B, EBER + cells were located in a few germinal centers (RA=2); and pattern C, up to 100 EBER+ cells were located in the interfollicular area (SLE=3, RA=2). Recent EBV infection may be a cause of lymph node lesion in only 2 cases of patients with pattern A. However, the pathognomonic significance of pattern B and pattern C EBER+ cell distribution patterns still remains unclear. Our study indicates that the underlying immune deficits of patients with SRDs may also play an important role in the development of EBV-associated LPDs in SRDs, as previously suggested by several authors.

Histological variety of floral variant of follicular lymphoma.

To further clarify the histopathological findings of the floral variant of follicular lymphoma (FVFL), we studied 13 Japanese cases. Two histological subtypes of neoplastic follicles of FVFL have been described: (i) A macrogerminal center pattern where the mantle zone lymphocytes were invaginated into the neoplastic germinal center, often reminiscent of a floral design. (ii) A microgerminal center pattern where the massive invasion of mantle zone lymphocytes resulted in almost complete breakage of the neoplastic follicles. In the former pattern, the neoplastic germinal center usually contained large clusters of tumor cells, whereas in the latter, small clusters of up to 20 tumor cells or isolated tumor cells were observed in the neoplastic germinal centers. Moreover, occasional tumor cells showed a lymphocytic and/or histiocytic Reed‐Sternberg cell (L&H cells)‐like morphology. Both types of neoplastic follicles were observed to a varying degree in most cases. The macrogerminal center pattern was predominant in nine cases (70%), whilst the microgerminal center pattern was predominant in only four cases (30%). Three lesions (23%) had a marginal zone component. Immunohistochemistry showed that atypical follicular center cells, including L&H cells, were CD3−, CD5−, CD10+, CD20+, CD43−, bcl‐2+, cyclinD1−. The overall histological findings of the macrogerminal center are similar to those of florid progressive transformation of germinal center (PTGC), whilst the microgerminal center pattern is similar to that of nodular lymphocyte‐predominant Hodgkin lymphoma. Initially, the differential diagnosis between FVFL and florid PTGC was emphasized. However, the present study indicates that nodal marginal zone B‐cell lymphoma possessing floral follicles and nodular lymphocyte‐predominant Hodgkin lymphoma should be added to the differential diagnosis of FVFL. The germinal center B‐cell nature of FVFL is most clearly recognizable by immunohistochemistry, though histological appearance alone may cause some diagnostic problems.

Reactive Lymphoid Hyperplasia of the Lymph Nodes with Giant Follicles: A Clinicopathologic Study of 14 Japanese Cases, with Special Reference to Epstein-Barr Virus Infection

To clarify the clinicopathologic and immunohistochemical features of reactive lymphoid hyperplasia with giant follicles (RHGF) among Japanese, 14 patients were studied. The subjects consisted of 9 males and 5 females, ranging in age from 9 to 61 years, with a mean age of 30 years and a median age of 24 years. None of the patients exhibited systemic symptoms. The affected lymph nodes were located in the head and neck area except in 1 case. At the time of lymph node biopsy, 1 patient was diagnosed as having acute infectious mononucleosis (IM) and 2 patients had a recent history of acute IM. One each with myelogenous leukemia or diffuse large B-cell lymphoma had a history of peripheral blood stem cell transplantation. There were no recurrences during follow-up periods ranging from 3 to 50 months. Histologically, 14 lesions were characterized by numerous enlarged, coalescing lymphoid follicles with distortion rather than effacement of the lymph node architecture. By in situ hybridization, Epstein-Barr virus (EBV) genomes were demonstrated in 5 (36%) of 14 cases. The present study indicates that a portion of RHGF appears to represent a histologic finding of acute IM. Moreover, as previously stated, RHGF should be differentiated from follicular lymphoma, particularly the floral variant.

Follicular Colonization of Nodal Marginal-Zone B-Cell Lymphoma Resembling Follicular Lymphoma: Report of 6 Cases

The formation of neoplastic B-cell follicles is accepted as a diagnostic criterion of follicular lymphoma. However, extranodal marginal-zone B-cell lymphomas (MZBLs) of mucosa-associated lymphoid tissue (MALT) type also sometimes contain numerous lymphoid follicles and may even have a predominantly follicular growth pattern. However, morphologic, immunohistochemical, and genotypic findings suggest that lymphoid follicles in extranodal MZBLs are neoplastic follicles formed as the result of colonization of previously reactive follicles by tumor cells (centrocyte-like cells). We present here 6 cases of nodal MZBL demonstrating a follicular growth pattern. Immunohistochemical study demonstrated that the tumor cells were CD10-, CD20+, CD79a+,CD 138-, Bcl-2+, Bcl-6and IRF4+. Residual nonneoplastic follicular center cells were CD1O+, CD20+, CD79a+, Bcl-2-, and Bcl-6+. CD21/CD23 immunostain demonstrated a disrupted follicular dendritic cell pattern characteristic of follicular colonization in extranodal MZBL of MALT type. Taken in conjunction with the morphologic findings, nodal MZBL may also show a follicular growth pattern similar to extranodal MZBL of MALT type. The marginal-zone nature is most recognizable on immunohistochemistry, although the histologic appearance alone may cause some diagnostic problems. It is important for pathologists to consider this type of lesion in diagnostic practice.

Primary Plasma Cell Leukemia in the Era of Novel Agents: A Multicenter Study of the Japanese Society of Myeloma

We investigated the treatment and outcome of Japanese patients with primary plasma cell leukemia (pPCL) in the era of novel agents and analyzed the risk factors affecting survival. Among 3,318 patients with symptomatic multiple myeloma (MM), 38 patients were diagnosed with pPCL. The median overall survival (OS) of the pPCL patients was 2.85 years, which was significantly extended compared with that in previous reports. The proportion of patients treated with novel agents was 61%. The OS of the patients treated with novel agents was significantly extended compared with that of patients treated without novel agents according to the generalized Wilcoxon test (2.85 vs. 1.16 years, p = 0.049). This statistical finding suggests that treatment with novel agents could have prevented early death in the patients with pPCL. Age was the only statistically significant prognostic factor associated with an inferior OS (hazard ratio 4.57). Five patients received maintenance therapy with novel agents, and their OS tended to be longer than that of the other patients without maintenance (4.45 vs. 2.85 years). Unlike MM, OS for pPCL has not been improved significantly over the last decade, especially in elderly patients. Therefore, it is important to establish the treatment strategy, particularly after induction treatment.

Plasmacytic hyperplasia in age-related Epstein–Barr virus-associated lymphoproliferative disorders: A report of two cases

Age-related Epstein-Barr virus (EBV)+B-cell lymphoproliferative disorder (LPD) is a recently recognized entity that occurs in patients over 40 years of age without any known immunodeficiency. However, this entity is thought to be related to the immunological deterioration that is part of the aging process. Histologically, age-related EBV+B-cell LPDs are classified into the polymorphous subtype and large B-cell lymphoma subtypes. However, plasmacytic hyperplasia, which is thought to be the earliest recognizable EBV+PT-LPD, has not been reported among EBV+B-cell LPDs. We report here two cases of age-related EBV-associated LPD and demonstrate the histological evolution. Pathologically, the initial lymph node biopsy specimens from both cases showed the classical Hodgkin lymphoma-like polymorphous subtype. Hodgkin (H) and Reed-Sternberg (RS) cells were CD3-, CD20+, CD15-. CD30+, CD45RB+, and latent membrane antigen-1+. In-situ hybridization (ISH) study demonstrated that numerous H and RS cells contained EBV-encoded small RNA (EBER)+. Repeated lymph node biopsy specimens from each case contained a mixture of lymphoid cells with prominent plasma cell differentiation, including immunoblasts without atypia. A portion of B-immunoblasts were CD30+ and EBER+. As assessed by polymerase chain reaction (PCR) assay, only the initial biopsy specimen in Case 1 displayed a solitary faint immunoglobulin heavy chain (IgH) gene rearrangement, consistent with the presence of a small clonal B-cell population. However, PCR analyses for EBV-genomes demonstrated the same single clonal infection of EBV in the initial and recurrent lymph node lesions in the present two cases. These two cases demonstrated the presence of plasmacytic hyperplasia in age-related EBV+B-cell LPDs, and plasmacytic hyperplasia also appears to be the earliest lesion of age-related EBV+B-cell LPDs.