Masafumi Abe

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.

Study Protocol for the Fukushima Health Management Survey

Background The accidents that occurred at the Fukushima Daiichi Nuclear Power Plant after the Great East Japan Earthquake on 11 March 2011 have resulted in long-term, ongoing anxiety among the residents of Fukushima, Japan. Soon after the disaster, Fukushima Prefecture launched the Fukushima Health Management Survey to investigate long-term low-dose radiation exposure caused by the accident. Fukushima Medical University took the lead in planning and implementing this survey. The primary purposes of this survey are to monitor the long-term health of residents, promote their future well-being, and confirm whether long-term low-dose radiation exposure has health effects. This report describes the rationale and implementation of the Fukushima Health Management Survey. Methods This cohort study enrolled all people living in Fukushima Prefecture after the earthquake and comprises a basic survey and 4 detailed surveys. The basic survey is to estimate levels of external radiation exposure among all 2.05 million residents. It should be noted that internal radiation levels were estimated by Fukushima Prefecture using whole-body counters. The detailed surveys comprise a thyroid ultrasound examination for all Fukushima children aged 18 years or younger, a comprehensive health check for all residents from the evacuation zones, an assessment of mental health and lifestyles of all residents from the evacuation zones, and recording of all pregnancies and births among all women in the prefecture who were pregnant on 11 March. All data have been entered into a database and will be used to support the residents and analyze the health effects of radiation. Conclusions The low response rate (<30%) to the basic survey complicates the estimation of health effects. There have been no cases of malignancy to date among 38 114 children who received thyroid ultrasound examinations. The importance of mental health care was revealed by the mental health and lifestyle survey and the pregnancy and birth survey. This long-term large-scale epidemiologic study is expected to provide valuable data in the investigation of the health effects of low-dose radiation and disaster-related stress.

Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma, nasal type

BACKGROUND Patients with natural killer (NK) cell neoplasms, aggressive NK cell leukemia (ANKL) and extranodal NK cell lymphoma, nasal type (ENKL), have poor outcome. Both diseases show a spectrum and the boundary of them remains unclear. The purpose of this study is to draw a prognostic model of total NK cell neoplasms. PATIENTS AND METHODS We retrospectively analyzed 172 patients (22 with ANKL and 150 with ENKL). The ENKLs consisted of 123 nasal and 27 extranasal (16 cutaneous, 9 hepatosplenic, 1 intestinal and 1 nodal) lymphomas. RESULTS Complete remission rate for ENKL was 73% in stage I, but 15% in stage IV, which was consistent with that for ANKL (18%). The prognosis of ENKL was better than that of ANKL (median survival 10 versus 1.9 months, P < 0.0001) but was comparable when restricted to stage IV cases (4.0 months, P = 0.16). Multivariate analysis showed that four factors (non-nasal type, stage, performance status and numbers of extranodal involvement) were significant prognostic factors. Using these four variables, an NK prognostic index was successfully constructed. Four-year overall survival of patients with zero, one, two and three or four adverse factors were 55%, 33%, 15% and 6%, respectively. CONCLUSION The current prognostic model successfully stratified patients with NK cell neoplasms with different outcomes.

The Characteristics of Epstein-Barr Virus (EBV)-positive Diffuse Large B-Cell Lymphoma: Comparison between EBV^+ and EBV^- Cases in Japanese Population

We have investigated 114 cases with diffuse large B‐cell lymphoma (DLBCL) to clarify the characteristics of DLBCL with Epstein‐Barr virus (EBV) infection. Thirteen cases (11.4%) showed EBVencoded RNA 1 (EBER1) signals by RNA in situ hybridization. EBV‐encoded latent membrane protein 1 (LMP1) and EBV‐encoded nuclear antigen 2 (EBNA2) were expressed in 11 and 4 cases, respectively. Expression of CD30, Bcl‐6 and immunoglobulin (Ig) was found in 92%, 31% and 23% with EBV+ DLBCL, and in 15%, 79% and 82% with EBV‐ DLBCL, respectively. The sequence of rearranged Ig heavy chain (IgH) variable (V) region gene was analyzed in 5 cases with EBV+ DLBCL and 61 cases with EBV‐ DLBCL. Somatic mutation was found in all cases except one with EBV‐ DLBCL. Average mutation frequency was 9.6% in EBV+ DLBCL vs. 11.5% in EBV‐ DLBCL. The rates of replacement mutation vs. silent mutation (R/S values) in complementarity determining region II and framework region III were 2.7 and 1.5 in EBV+ DLBCL, 2.6 and 1.4 in EBV‐ DLBCL. Crippling mutation generating a stop codon was found in 2 of 5 cases (40%) with EBV+ DLBCL, but none of 61 cases (0%) with EBV‐ DLBCL. These findings suggest that EBV+ DLBCL and EBV‐ DLBCL were both derived from germinal center (GC) or post‐GCB cells, and EBV+ DLBCL frequently have a non‐functional IgH gene owing to crippling mutation.

The Distinction between Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma with c- myc Rearrangement

To compare immunophenotypic and molecular features between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with c-myc rearrangements (c-mycR DLBCL), we analyzed 18 cases of B-cell non-Hodgkins lymphoma with c-mycR that were confirmed by chromosomal and/or Southern blotting analyses. The cases were histologically classified into 10 BLs and five DLBCLs. The remaining three cases could not be classified because of suboptimal quality of the surgical materials. BLs were from five adults and five children, whereas all DLBCLs were from adults. BLs were positive for CD20 (10/10 cases examined), CD10 (9/10), Bcl-2 (1/9), and Bcl-6 (10/10), whereas they were negative for CD3 (0/10) and EBV (0/8), by Epstein-Barr virus (EBV) EBER-1 RNA in situ hybridization. c-MycR DLBCLs were positive for CD20 (5/5), CD10 (2/5), Bcl-2 (3/4), and Bcl-6 (4/4), whereas none of them were positive for CD3 and EBV. A mean of MIB-1 index (MIB-1+ cells/neoplastic cells, %) of BLs (98.1%) was higher than that of c-mycR DLBCLs (66.3%; P < .0001). Somatic mutation of immunoglobulin heavy-chain gene variable region (VH gene) in BLs (four cases) ranged from 0.7 to 4.9% with an average value of 2.3%, whereas those in DLBCLs (three cases) from 8.2 to 32.0% with an average value of 17.0%. It is, therefore, concluded that a growth fraction of nearly 100%, as well as a monotonous proliferation of medium-sized cells and c-mycR, should be of value in the diagnosis of BL, which is probably different from c-mycR DLBCL. In addition, CD10+, Bcl-2−, and low frequency of mutation of the VH gene could be helpful for the histologic distinction of BL from (c-mycR) DLBCL.

Primary breast diffuse large B-cell lymphoma shows a non-germinal center B-cell phenotype

Primary breast diffuse large B-cell lymphoma has a poor prognosis relative to other extranodal diffuse large B-cell lymphoma. Recently, diffuse large B-cell lymphoma has been subclassified as germinal center B-cell-like and nongerminal center B-cell types using tissue microarrays. The 5-year overall survival rate of the germinal center B-cell group is better than that of the nongerminal center B-cell group. To elucidate the reason for which primary breast diffuse large B-cell lymphoma has a poor clinical outcome, we investigated 15 patients with primary breast diffuse large B-cell lymphoma (stage IE; 13 cases, stage IIE; two cases) by immunohistochemistry using various markers including CD10, Bcl-6, MUM1 and MIB-1 and by molecular analysis of the immunoglobulin heavy chain gene variable region. Immunohistochemistry showed 0/15 (positive cases/examined cases) for CD10, 5/15 for Bcl-6, 15/15 for MUM1, 10/15 for Bcl-2, 2/15 for CD5 and 4/15 for CD40. The expression pattern of CD10(−) MUM1(+) in primary breast diffuse large B-cell lymphoma corresponded to the nongerminal center B-cell group. Moreover, the MIB-1 index was distributed from 60 to 95% with a mean of 79%, indicating a high proliferation of the lymphoma cells. The immunoglobulin heavy chain gene variable region of primary breast diffuse large B-cell lymphoma had a mutation frequency of 1–10% (seven cases) and 0–1 additional mutations in ongoing mutation analysis (five cases). Primary breast diffuse large B-cell lymphoma had characteristics of the nongerminal center B-cell group. In conclusion, primary breast diffuse large B-cell lymphoma has a nongerminal center B-cell phenotype and has a high MIB-1 index. These features might therefore be associated with poor prognosis.

Psychological distress and the perception of radiation risks: the Fukushima health management survey.

Abstract Objective To assess relationships between the perception of radiation risks and psychological distress among evacuees from the Fukushima nuclear power plant disaster. Methods We analysed cross-sectional data from a survey of evacuees conducted in 2012. Psychological distress was classified as present or absent based on the K6 scale. Respondents recorded their views about the health risks of exposure to ionizing radiation, including immediate, delayed and genetic (inherited) health effects, on a four-point Likert scale. We examined associations between psychological distress and risk perception in logistic regression models. Age, gender, educational attainment, history of mental illness and the consequences of the disaster for employment and living conditions were potential confounders. Findings Out of the 180 604 people who received the questionnaire, we included 59 807 responses in our sample. There were 8717 respondents reporting psychological distress. Respondents who believed that radiation exposure was very likely to cause health effects were significantly more likely to be psychologically distressed than other respondents: odds ratio (OR) 1.64 (99.9% confidence interval, CI: 1.42–1.89) for immediate effects; OR: 1.48 (99.9% CI: 1.32–1.67) for delayed effects and OR: 2.17 (99.9% CI: 1.94–2.42) for genetic (inherited) effects. Similar results were obtained after controlling for individual characteristics and disaster-related stressors. Conclusion Among evacuees of the Fukushima nuclear disaster, concern about radiation risks was associated with psychological distress.

Multiple lymphomatous polyposis of the gastrointestinal tract is a heterogenous group that includes mantle cell lymphoma and follicular lymphoma: Analysis of somatic mutation of immunoglobulin heavy chain gene variable region

Multiple lymphomatous polyposis (MLP) is characterized by multiple polyps involving long segments of the gastrointestinal (GI) tract. MLP is thought to represent mantle cell lymphoma (MCL) of the GI tract; however, some cases of follicular lymphoma (FL) of the GI tract are found with a multiple polypoid appearance. In the present study, to clarify the cellular origin of MLP, clonal immunoglobulin heavy chain (IgH) gene rearrangement of four cases with MLP was amplified by polymerase chain reaction (PCR) and analyzed for the presence of somatic mutation. The IgH variable (VH) region sequences of three cases (CD5+ CD10- cyclin D1+) showed a little somatic mutation compared with the closest published germline. The other case (CD10+ CD5- cyclin D1-) was highly mutated and showed intraclonal heterogeneity (ongoing somatic hypermutation). These data indicate that three of the cases with MLP are derived from pregerminal center B cells (mantle zone B cells) and one case with MLP from germinal center B cells. Our study suggests that MLP is a heterogenous group that includes MCL and FL.

Tumor-associated macrophages correlate with vascular space invasion and myometrial invasion in endometrial carcinoma.

OBJECTIVE This study was conducted to determine whether tumor-associated macrophages (TAMs) correlate with clinicopathological features in endometrioid adenocarcinoma. METHODS 76 cases of endometrioid adenocarcinoma treated initially by hysterectomy with pelvic lymphadenectomy were retrospectively retrieved, and their histological features were evaluated. Immunohistochemical staining for CD68, CD34, and Ki-67 was performed on paraffin-embedded sections. TAMs were counted in two areas: in the invasive margin (margin TAMs) and in the tumor (intratumor TAMs). RESULTS Margin TAMs were significantly associated with FIGO stage (P=0.033), histological grade (P=0.008), myometrial invasion (P=0.0001), pelvic lymph node metastasis (P=0.027), and vascular space invasion (P=0.0001). Intratumor TAMs were significantly associated with intratumor Ki-67 (P=0.006) and microvessel density (P=0.020). Patients with high margin TAMs (> or = 20) had significantly worse progression-free survival (PS) and overall survival (OS) than those with low margin TAMs (< 20) (log rank test, P=0.0031 and P=0.0085, respectively). On multivariate analysis, high margin TAMs were significantly associated with vascular space invasion (P=0.013; HR, 6.05; 95% confidence interval [CI], 1.468-24.938) and myometrial invasion (P=0.041; HR, 4.03; 95% CI, 1.06-14.71). Vascular space invasion was only associated with PFS. CONCLUSION Although on univariate analysis TAMs are associated with other poor prognosticators, on a multivariate analysis, TAMs appear only to be associated with MI and VI. TAMs may play a significant role in the biology of tumor progression of endometrial adenocarcinoma, but do not appear to be independent prognostic indicators of patients survival.

Rhabdoid papillary meningioma

We have studied an uncommon case of rhabdoid papillary meningioma in a 15-year-old boy with a dura-based mass arising in the left posterior fossa. The patient exhibited prominent extracranial extension during the past 6 years, consisting of a mixture of both perivascular pseudopapillary growth and rhabdoid cytologic features of neoplastic meningothelial cells. The meningothelial features were evidenced by the focal whorl formation of tumor cells, coexpression of epithelial membrane antigen and vimentin, and ultrastructural findings of interdigitated cytoplasmic process and intercellular junction. However, the regional and histologic resemblances to ependymoma were further complicated by unexpected focal expression of glial fibrillary acidic protein, neurofilament, and &agr;-smooth muscle actin of the tumor cells. The rhabdoid morphology was characterized by sheets of tumor cells with eccentric nuclei and abundant eosinophilic cytoplasm with often recognizable intracytoplasmic hyaline inclusions. These inclusions revealed ultrastructural paranuclear whorls of intermediate filaments, ruling out the other forms of intracytoplasmic eosinophilic inclusions resembling rhabdoid morphology. Diagnosis of an unusual rhabdoid papillary meningioma with aggressive behavior is resoluble by immunohistochemical and ultrastructural analyses.