Hirokazu Nakamine

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.

Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin‐6 as independent predictors of prognosis in aggressive non‐Hodgkin's lymphoma

Abstract: Therapeutic approaches for non‐Hodgkins lymphoma (NHL) are currently based on the International Prognostic Index (IPI). Research on biological prognostic factors has been actively pursued in recent years, with serum vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) being identified as prognostic factors for NHL. Here, we determined that serum VEGF and IL‐6 levels are independent prognostic factors for aggressive lymphoma. Compared with normal controls, serum VEGF and IL‐6 levels were significantly higher in patients with aggressive lymphoma or adult T‐cell leukemia/lymphoma. Furthermore, overall and disease‐free survival rates for patients with high levels of VEGF or IL‐6 were significantly poorer than for patients with low levels. In addition, the prognosis for patients with high levels of both serum VEGF and IL‐6 was significantly poorer than that for patients with high levels of either VEGF or IL‐6 or with low levels of both VEGF and IL‐6. Multivariate analyses of a variety of prognostic factors, including the five IPI factors, revealed that serum VEGF and IL‐6 were both independent prognostic factors for overall survival of aggressive lymphoma. Therefore, a combination of VEGF and IL‐6 represents a useful prognostic factor for aggressive lymphoma.

Lymphomatoid gastropathy: a distinct clinicopathologic entity of self-limited pseudomalignant NK-cell proliferation

Diagnostic errors in distinguishing between malignant and reactive processes can cause serious clinical consequences. We report 10 cases of unrecognized self-limited natural killer-cell proliferation in the stomach, designated as lymphomatoid gastropathy (LyGa). This study included 5 men and 5 women (age, 46-75 years) without any gastric symptoms. Gastroscopy showed elevated lesion(s) (diameter, ∼ 1 cm). Histologically, medium-sized to large atypical cells diffusely infiltrated the lamina propria and, occasionally, the glandular epithelium. The cells were CD2(+/-), sCD3(-), cCD3(+), CD4(-), CD5(-), CD7(+), CD8(-), CD16(-), CD20(-), CD45(+), CD56(+), CD117(-), CD158a(-), CD161(-), T cell-restricted intracellular antigen-1(+), granzyme B(+), perforin(+), Epstein-Barr early RNA(-), T-cell receptor αβ(-), and T-cell receptor γδ(-). Analysis of the 16 specimens biopsied from 10 patients led to a diagnosis of lymphoma or suspected lymphoma in 11 specimens, gastritis for 1 specimen, adenocarcinoma for 1 specimen, and LyGa or suspected LyGa for 3 specimens. Most lesions underwent self-regression. Three cases relapsed, but none of the patients died. According to conventional histopathologic criteria, LyGa is probably diagnosed as lymphoma, especially as extranodal natural killer/T-cell lymphoma, nasal type. However, LyGa is recognized as a pseudomalignant process because of its clinical characteristics. The concept of LyGa should be well recognized.

Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate

Among methotrexate (MTX)‐related lymphoproliferative disorders (MTX‐LPD), diffuse large B‐cell lymphoma (DLBCL) accounts for about half. We studied the clinicopathological characteristics and prognosis of patients with DLBCL in MTX‐LPD. This study included 29 patients who developed DLBCL after receiving MTX for rheumatoid arthritis. MTX was discontinued in all patients. Their median age was 62u2003years. Elevated lactate dehydrogenase (LDH) level was observed in 97% of the patients, bone marrow involvement in 17%, and involvement of extranodal sites in 41%. As for the cellular immunophenotype, CD20 was positive in 93%, CD5 in 3%, CD10 in 31%, BCL2 in 21%, BCL6 in 69%, and Epstein–Barr virus (EBV)‐encoded small non‐polyadenylated RNA (EBER) in 24%. Chemotherapy was started within 2u2003months after MTX withdrawal in 23 patients, of whom 12 patients received combination with rituximab. Spontaneous remission occurred in the remaining six patients. The EEBV‐positive rate was 67% (4/6), and the four EBV‐positive patients achieved complete response. Among the 23 DLBCL patients treated with chemotherapy, 20 patients achieved complete response. The 5‐year overall survival was 74% and the 5‐year progression‐free survival was 65%. After the development of DLBCL, withdrawal of MTX was the first choice of treatment. Germinal center B‐cell type and EBER‐positive patients tended to show spontaneous remission. The utility of rituximab should be examined in future studies.

Clinicopathologic characteristics and treatment outcome of the addition of rituximab to chemotherapy for CD5-positive in comparison with CD5-negative diffuse large B-cell lymphoma

BACKGROUNDnCD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) comprises ∼10% of DLBCLs, and it is associated with poor prognosis. The clinicopathologic characteristics and prognosis of CD5-negative (CD5-) DLBCL and CD5+ DLBCL were compared.nnnPATIENTS AND METHODSnThe subjects were 607 DLBCL patients in whom cell surface markers could be analyzed, among 930 consecutive patients registered in the Adult Lymphoma Treatment Study Group between 1998 and 2008.nnnRESULTSnIn all, 102 patients (16.8%) had CD5+ DLBCL. Compared with CD5- DLBCL, CD5+ DLBCL was more closely associated with elevated serum lactate dehydrogenase level, advanced stage, poor performance status, extranodal sites, CD10-, BCL-2+, MUM1+, and nongerminal center B-cell type. The 5-year overall survival (OS) rates of CD5+ DLBCL (n = 102) and CD5- DLBCL (n = 505) were 55% and 65%, respectively (P = 0.032), with 5-year progression-free survival (PFS) rates of 52% and 61%, respectively (P = 0.041). In the CD5+ DLBCL patients, the addition of rituximab to chemotherapy significantly improved PFS (4-year PFS, 47.4% versus 62.5%), but not OS (4-year OS, 57.8% versus 63.5%).nnnCONCLUSIONSnFor CD5+ DLBCL, the addition of rituximab to chemotherapy significantly improved the PFS, but not OS. Therefore, it is thought that a new treatment strategy is necessary for CD5+ DLBCL.

API2-MALT1 Fusion Gene in Colorectal Lymphoma

The API2-MALT1 fusion gene was originally identified from a t(11;18)(q21;q21) translocation, a specific chromosomal abnormality that is found in mucosa-associated lymphoid tissue (MALT) lymphoma. Gastric MALT lymphomas positive for the API2-MALT1 fusion gene do not respond to Helicobacter pylori–eradication therapy, but otherwise, the incidence and clinicopathological behavior of colorectal MALT lymphoma with this genetic abnormality are unclear. We examined the API2-MALT1 fusion by multiplex RT-PCR method in 47 cases of MALT lymphoma and 13 cases of diffuse large B-cell lymphoma and evaluated the relevance of API2-MALT1 positivity to the clinical and pathological features. The mean ages of MALT lymphoma and diffuse large B-cell lymphoma patients were 65 (range, 37–87 y) and 58 (range, 14–85 y) years, respectively. API2-MALT1 fusion genes were detected in seven cases (15%) of MALT lymphoma and one case (8%) of diffuse large B-cell lymphoma. In MALT lymphomas, the tumor size in API2-MALT1–positive cases was 62 ± 39 mm (mean ± SD), statistically larger than that in API2-MALT1–negative cases (25 ± 19 mm; P < .01). The API2-MALT1–positive cases demonstrated more advanced clinical stages and a male predominance, compared with API2-MALT1–negative cases. Thus, API2-MALT1–positive tumors should be cared for as a more aggressive subgroup and be followed for a longer time.

Expression of nm23-H1 is associated with poor prognosis in peripheral T-cell lymphoma

Summary.u2002 We have reported previously that the serum nm23‐H1 level is a prognostic factor for non‐Hodgkins lymphoma. In this study, we examined nm23‐H1 expression in T‐ and natural killer (NK)‐cell lymphoma in order to evaluate whether lymphoma cells produce the protein. The clinical significance of the cytotoxic molecules, T‐cell intracellular antigen‐1 (TIA‐1) and granzyme B and nm23‐H1 expression were also examined. Expression of nm23‐H1, TIA‐1, or granzyme B was examined by immunohistochemistry in 137 previously untreated lymphoma patients. The relationship between the results and clinical outcome was examined in 81 patients with angioimmunoblastic T‐cell lymphoma, anaplastic large cell lymphoma, or peripheral T‐cell lymphoma, unspecified. The neoplastic cells of some lymphomas produced nm23‐H1 and the expression rates of nm‐23‐H1, TIA‐1 and granzyme B were 36·5%, 78·8% and 32·8% respectively. The nm23‐H1‐positive or TIA‐1‐positive groups had significantly shorter overall and disease‐free survivals. Multivariate analysis confirmed nm23‐H1 expression to be an independent prognostic factor. The nm23‐H1 protein can be an important prognostic factor in the lymphomas studied here. New treatments that target nm23 overexpression could be developed as a result of nm23‐HI production by lymphoma cells.

Spontaneous Complete Regression of High Grade Non-Hodgkin's Lymphoma Morphologic, Immunohistochemical, and Gene Amplification Analyses

Background. Spontaneous regression of non‐Hodgkins lymphoma, occasionally reported in low grade groups, is a rare phenomenon in high grade groups. Clonal proliferation has not been confirmed in the majority of reported cases. In this woman, age 58 years, who had been diagnosed as having high grade immunoblastic lymphoma after excision of a single cervical lymph node, the remaining bilateral cervical, inguinal, and axillary adenopathy regressed completely without any cytotoxic treatments 22 days after biopsy. At the time of this writing, the patient has been free of disease for 24 months.

A clinicopathological study of nm23-H1 expression in classical Hodgkin’s lymphoma

BACKGROUNDnWe carried out immunohistochemistry to examine the expression of nm23-H1 in Hodgkin and Reed-Sternberg cells in patients with classical Hodgkins lymphoma (CHL).nnnPATIENTS AND METHODSnWe evaluated 128 patients with CHL [87 patients with nodular sclerosis (NS) and 41 patients with mixed cellularity (MC)] for CD15, CD20, Ki-67, EBER, TIA-1, and nm23-H1 by immunohistochemistry.nnnRESULTSnCD15 was expressed in 79%, CD20 in 11%, Ki-67 in 93%, EBER in 34%, TIA-1 in 11%, and nm23-H1 in 60% of the CHL patients. NS patients showed a significantly higher rate of nm23-H1 expression than MC patients (P < 0.001). The serum nm23-H1 level was significantly higher in patients with positive nm23 expression. Univariate analysis showed that stage IV, poor performance status, low hemoglobin level, low serum albumin level, age of 45 years or older, TIA-1-positive status, and nm23-H1-positive status were associated with significantly shorter progression-free survival. Multivariate analysis with these factors showed TIA-1 and cytoplasmic nm23-H1 expression to be significant and independent prognostic factors.nnnCONCLUSIONSnOur results indicate that nm23-H1 expression is a prognostic factor for CHL and that it is as important as serum nm23-H1, both of which are useful for planning the treatment strategy.

Renal Collecting Duct Carcinoma

BACKGROUND Collecting duct carcinoma (CDC) of the kidney is a rare type of renal cell carcinoma (RCC) of collecting duct origin. Cytologic differentiation of CDC from conventional RCC is important because CDC has a poorer prognosis than the latter. CASE A 60-year-old male incidentally demonstrated a left renal mass that was hypovascular by angiography. Fine needle aspiration (FNA) revealed numerous clusters of cells arranged in a tubular structure. The cells consisted of highly atypical cells having large nuclei with coarse or vesicular chromatin, prominent nucleoli and lacy or granular cytoplasm. Based on these findings, which were indicative of high grade RCC, he underwent left radical nephrectomy and lymphadenectomy. Histologic and immunohistochemical findings, including anti-high-molecular-weight cytokeratin (HMCK) antibody, confirmed the diagnosis of CDC. CONCLUSION CDC should be added to the differential diagnosis when the result of cytologic examination of a renal mass is suggestive of high grade RCC. These features of FNA smears, together with HMCK immunohistochemistry, can be useful for the cytologic differential diagnosis of renal tumors.