Toshiyuki Izumo

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.

Primary non-Hodgkin's lymphoma of the larynx

Three cases of primary non-Hodgkins lymphoma of the larynx are described. Histologically, two tumours belonged to the category of low grade B-cell lymphomas of the small cell type (extranodal marginal zone B-cell lymphoma and lymphoplasmacytoid lymphoma), and the third was classified as a peripheral T-cell lymphoma of unspecified type. The clinical stage was IE in two cases, and IV in another case. In two cases, complete remission was obtained with radical radiotherapy. But in the other case, which was histologically lymphoplasmacytoid lymphoma, the response to radiotherapy was poor, and surgery was required. There was no relapse subsequent to treatment. Primary non-Hodgkins lymphoma of the larynx is rare. Several reported cases have clinical features similar to those of MALT-type lymphomas arising in other extranodal sites. Although most of the reported cases have been cured with radiotherapy, in some cases dissemination to other extranodal sites may occur. Therefore careful periodic evaluation is imperative.

Cardiac involvement by malignant lymphoma: a clinicopathologic study of 25 autopsy cases based on the WHO classification

As cardiac involvement by malignant lymphoma (ML) is relatively uncommon and antemortem diagnosis is difficult, details of this condition remain to be elucidated. To clarify clinicopathologic features of cardiac lymphoma (CL), 25 autopsy cases were studied. Each was rediagnosed according to the World Health Organization (WHO) classification, and clinicopathologic characteristics were investigated by tumor phenotype. The study subjects were 13 males and 12 females with a mean age of 53.4 years. All cases were secondary CL and were not diagnosed as CL before death; 14 cases (56%) were of B-cell and 11 (44%) of T-cell (including natural killer cell) phenotype. Nasal and nasal-type natural killer/T-cell lymphomas (NKTLs) accounted for five (20%). Cardiac manifestation was evident in eight (32%), with hematogenous infiltration as the most common pattern of tumor spread. Some B-cell CLs (n=3) were complicated by cardiac tamponade and heart failure (HF), and T-cell CLs (n=5), including three nasal NKTLs, also featured arrhythmia and sudden death. The incidence of T-cell phenotype was significantly elevated for CLs (p<0.05), especially for CLs with cardiac manifestation (p<0.01), compared with that for MLs in general. Our results indicate that T-cell lymphomas, compared with B-cell lymphomas, invade the heart more frequently and aggressively and are associated with a variety of cardiac manifestations. Where cardiac involvement is suspected, aggressive diagnostic procedures are warranted, especially with MLs having a T-cell phenotype. In cases of nasal NKTL, particular attention is necessary.

AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma

The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase NUAK2 as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify NUAK2 as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan–Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44–10.50; P = 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties.

Stromal Melanocytic Foci (“Blue Nevus”) in Step Sections of the Uterine Cervix

Stromal melanocytic foci (SMF) of the uterine cervix, which are known as extracutaneous blue nevus, were examined in step sections of the cervix. A total of 189 uterine specimens surgically excised for leiomyoma, adenomyosis etc., were studied. The over‐all incidence of SMF of the cervix was 28.6% (54/189 cases). The incidence of these lesions increased with age, and they were most prevalent in the sixth decade of life (12/30 cases, 40%). SMF were presented more often in the anterior wall than in the posterior wall. Most of the lesions were less than 1 mm in size. No case of SMF demonstrated expansive tumorous growth. Six of 54 cases of SMF displayed consecutive spread of SMF in almost all step sections of the cervix. The histological findings confirmed that SMF of the cervix is quite common existence among Japanese women. It is speculated that the mucosal region near the skin and/or cutaneus region near the mucosa may have stromal melanocytosis; malignant melanoma could develop from SMF of the cervix, which did not have junctional activity because of stromal melanocytic origin. Acta Pathol Jpn 41: 751‐756, 1991.

Practical Utility of the Revised European‐American Classification of Lymphoid Neoplasms for Japanese Non‐Hodgkin's Lymphomas

A clinicopathological study of 515 non‐Hodgkins lymphoma (NHL) cases was performed using the revised European‐American classification of lymphoid neoplasms (REAL classification) in an HTLV1‐nonendemic area of Japan. The following characteristics were revealed: 1) frequency of extranodal lymphomas was high (59%) with 79% B‐cell lymphomas in this series, while the overall ratio of B:T/NK lineage was 3.7:1; 2) the most common type was the diffuse large B‐cell lymphoma (46%), follicle center lymphomas occurred at an incidence lower (15%) than that in European and American populations, and marginal zone B‐cell lymphomas accounted for as much as 12%; 3) peripheral T‐cell lymphomas were common (19%), with the unspecified type predominant (11%), while adult T‐cell lymphomas were present at a level equivalent to that among European and American patients (1%). Clear segregation of survival curves was rated according to cell lineage and B‐cell lymphomas had a better prognosis than T/NK‐cell lymphomas. Furthermore, new subtypes in the REAL classification, such as marginal zone B‐cell and mantle cell lymphomas, exhibited distinct curves. Taken altogether, the REAL classification demonstrated advantages for assessment of Japanese NHL cases.

Clinical and Genetic Characteristics of Japanese Burkitt Lymphomas with or without Leukemic Presentation

To clarify the clinical and genetic features of Burkitt lymphoma with or without leukemic presentation, we have conducted clinical, cytogenetic, and genetic studies. Of 40 Japanese patients with Burkitt lymphoma examined by cytogenetic and/or fluorescence in situ hybridization analysis or Southern blot analysis usingMYC probes, 35 patients had t(8;14) translocations, and 5 had t(8;22). Breakpoints were located far upstream ofMYC in 4 (12%) of 33 tumors with t(8;14), and Epstein-Barr virus infection was found in 3 (8%) of 40 tumors. These findings are similar to those reported for non-Japanese patients with the sporadic form of Burkitt lymphoma. Clinical and genetic characteristic were compared for 30 patients presenting with lymphoma and 10 presenting with leukemia. The overall survival was shorter in aggressively treated leukemia patients than in aggressively treated lymphoma patients(P =.003); however, the incidence rates ofTP53 mutation,p16INK4a deletion, andp15INK4b deletion that were found in 6 (15%) of 40,3 (9%) of 35, and 2 (6%) of 35 tumors, respectively, were similar between the 2 subtypes. Thus, the present study has shown the different prognoses for the 2 subtypes of Burkitt lymphoma but has failed to clarify the genetic backgrounds that may explain the different outcomes.Int J Hematol. 2003;77:490-498.

Nasal natural killer cell/T-cell lymphoma showing cellular morphology mimicking normal lymphocytes.

We report the autopsy case of a 34-year-old Japanese man with a nasal natural killer (NK)-cell/T-cell lymphoma. The patient developed the disease at 32 years of age, and a biopsy of the nasopharynx revealed pleomorphic lymphoma cell proliferation. Radiotherapy was performed, but the patient eventually died of respiratory failure. After radiotherapy, no histologic evidence of malignancy was obtained with biopsy materials featuring lymphocytic infiltration. Autopsy studies, including in situ hybridization for Epstein-Barr virus-encoded RNA, revealed generalized infiltration of normal lymphocyte-like, UCHL-1-positive, and Epstein-Barr virus-encoded RNA-positive lymphoma cells. Monoclonal proliferation of the Epstein-Barr virus-carrying cells was verified by means of Southern blot analysis. Retrospectively, we concluded that the normal lymphocyte-like presentation of the lymphoma cells, probably influenced by radiotherapy, prevented pathologists from recognizing the lymphoma. The utility of in situ hybridization for Epstein-Barr virus-encoded RNA in identification of tumor cells is emphasized with respect to the present case.