Vascular endothelial growth factors C and D and lymphangiogenesis at the early stage of esophageal squamous cell carcinoma progression.

We conducted a detailed study of lymphangiogenesis and subsequent lymph node metastasis in early-stage esophageal squamous cell carcinoma (ESCC) using immunostaining for D2-40 and vascular endothelial growth factor (VEGF)-C and D. The study materials included 13 samples of normal squamous epithelium, 6 samples of low-grade intraepithelial neoplasia (LGIN), and 60 samples of superficial ESCC (M1 and M2 cancer 24; M3 or deeper cancer 36). We assessed lymphatic vessel density (LVD) using D2-40 and immunoreactivity for VEGF-C and D in relation to histological type, lymphatic invasion, and lymph node metastasis. LVD in M1 and M2 lesions and M3 or deeper lesions was significantly higher than in normal squamous epithelium (P < 0.001). High expression of VEGF-C and D was observed in M1 and M2 cancer and in M3 or deeper cancer, but not in normal squamous epithelium or LGIN. LVD in VEGF-C- and D-positive cases was significantly higher than in negative cases (P < 0.001). In M3 or deeper cancer, the correlation between VEGF-C or D status and lymphatic invasion or lymph node metastasis was not significant. LVD in cases with positive lymphatic invasion and those with lymph node metastasis was significantly higher than in cases lacking either (P = 0.02 and 0.03, respectively). ESCC cells produce VEGF-C and D from the very early stage of progression. VEGF-C and D activate lymphangiogenesis, and this increase of lymphatic vessels leads to lymphatic invasion and subsequent lymph node metastasis.

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab.

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

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.

BACKGROUND: CD5-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. PATIENTS AND METHODS: The 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. RESULTS: In 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%). CONCLUSIONS: For 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.

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

BACKGROUND: We carried out immunohistochemistry to examine the expression of nm23-H1 in Hodgkin and Reed-Sternberg cells in patients with classical Hodgkin's lymphoma (CHL). PATIENTS AND METHODS: We 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. RESULTS: CD15 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. CONCLUSIONS: Our 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.

Acquired C1-esterase inhibitor deficiency and positive lupus anticoagulant accompanied by splenic marginal zone B-cell lymphoma.

A 70-year-old woman complained of mild shortness of breath. Laboratory findings revealed pancytopenia, positive lupus anticoagulant and severe hypocomplementemia without anti-nuclear or anti-DNA antibodies. After the failure of prednisolone treatment, an acquired C1-esterase inhibitor (C1-INH) deficiency was diagnosed. There were no episodes of angioedema or deep vein thrombosis. Three months later, extreme splenomegaly was detected. Lymph node biopsy suggested splenic marginal zone B-cell lymphoma. Acquired C1-INH deficiency due to a lymphoproliferative disorder should be considered as a possible diagnosis for patients with severe hypocomplementemia.

Cytotoxic molecule expression is predictive of prognosis in Hodgkin's-like anaplastic large cell lymphoma.

AIMS: The Revised European American Lymphoma classification uses the term Hodgkin's-like anaplastic large cell lymphoma (HD-like ALCL) for borderline cases with features of both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (HL). The aim of this study was to clarify the association between cytotoxic molecule (CM) expression and clinical outcome in HD-like ALCL. METHODS AND RESULTS: Subjects were 59 patients with HD-like ALCL, defined by nodal presentation without mediastinal bulky lesions, T- or null-cell phenotype, CD30+ anaplastic lymphoma kinase (ALK)- phenotype and by confluent sheets or nodules of large cells mimicking classic Hodgkin and Reed-Sternberg cells. We evaluated the presenting features and prognosis of subjects on categorization into two defined groups, namely CM (TIA1 and/or granzyme B)-positive (n = 21) and CM-negative (n = 38). The series consisted of 18 women and 41 men ranging from 16 to 88 years of age (median 59 years). The CM+ group had poorer disease-specific survival than the CM- group (P = 0.02) despite the absence of differences in other clinical characteristics. Multivariate analysis confirmed that CM expression was an independent prognostic factor, in contrast to phenotypic categorization (T-cell vs. null-cell group), which had no prognostic impact on disease-specific survival. CONCLUSION: CM expression is predictive of prognosis in HD-like ALCL.

Primary gastric T-cell lymphoma not associated with human T-lymphotropic virus type I: a case report and review of the literature.

Primary gastric T-cell lymphoma (PGTL) not associated with human T-lymphotropic virus type I (HTLV-I) is extremely rare and such a case is reported herein. The patient was a 58-year-old Japanese male presenting with submucosal tumor of the stomach identified on endoscopic examination. The lesion was diagnosed as non-Hodgkin's lymphoma by endoscopic biopsy and classified as peripheral T-cell lymphoma, unspecified, due to clonal rearrangement of the T-cell receptor beta (TCR) gene and expression of TCR beta protein in the absence of B-cell genotypes and phenotypes. Unlike previously reported cases of HTLV-I-unassociated PGTL, lymphoma in the current case was characterized histologically as "low grade" and phenotypically as CD4+, TIA-1+, granzyme B+, and CD103-. The lymphoma responded well to chemotherapy and radiation, and the patient was well with no detectable disease 10 months after initiation of therapy. A review of patients with PGTL in the literature revealed a few long-term survivors, and the investigation of therapeutic strategies for PGTL is, therefore, necessary.

Cytomorphologic diagnosis of malignant lymphoma arising in the heart: a case report.

BACKGROUND: Primary malignant lymphoma of the heart is extremely rare. Because its clinical signs and symptoms are typically nonspecific, it is often very difficult to detect cardiac involvement while the patient is alive. We describe a case of malignant lymphoma involving predominantly the heart and pericardium and diagnosed by pericardiac effusion cytology antemortem. CASE: An 83-year-old woman presented with dyspnea on exertion. Echocardiography revealed a low-echoic tumor mass close to the right ventricular wall and massive pericardiac effusion. Diagnosis of diffuse large B-cell lymphoma was made by cytomorphologic examination and flow cytometry of the tumor cells obtained from the effusion. Although chemotherapy was instituted immediately, the patient died of progressive heart failure. Diffuse large B-cell lymphoma predominantly involving the intracardiovascular region was confirmed at autopsy. CONCLUSION: From the experience in this case, we conclude that cytopathologic examination of sonographically guided aspiration of the cardiovascular region is very useful for antemortem diagnosis of primary malignant lymphoma of the heart.

Primary natural killer cell lymphoma of the lacrimal sac.

Primary lymphoid tumors of the lacrimal sac are quite rare, and all reported cases are of B-cell tumors with good prognosis. To our knowledge, this is the first case of primary natural killer (NK) cell lymphoma of the lacrimal sac. A 55-year-old woman presented with a lacrimal sac tumor, and histological diagnosis of NK cell lymphoma was made. Although disease was initially localized to the right lacrimal sac, it invaded into the adjacent ethmoidal sinus before chemotherapy was initiated (clinical stage IIE). Epstein-Barr virus (EBV)-encoded small RNA (EBER) was detected in lymphoma cells by in situ hybridization. Systemic chemotherapy combined with intrathecal chemotherapy followed by local radiotherapy was performed, and the patient achieved complete remission. However, shortly after completion of chemoradiotherapy, the lymphoma relapsed with rapid systemic dissemination. The disease was refractory to chemotherapy, and the patient eventually succumbed due to sepsis.

Immunoglobulin heavy chain variable region (VH) genes of B cell chronic lymphocytic leukemia cells from lymph nodes show somatic mutations and intraclonal diversity irrespective of follicular dendritic cell network.

We analyzed the immunoglobulin heavy chain variable region (VH) gene in 4 Japanese cases of B cell chronic lymphocytic leukemia (B-CLL) with enlarged lymph nodes to clarify the presence of somatic mutations and intraclonal diversity. We also attempted to determine the role of the follicular dendritic cell (FDC) network in some proliferation centers, where tumor cells are mitotically active. Immunohistochemical studies revealed that all 4 cases showed the typical immunophenotype: CD5+, CD23+, IgM+ and IgD+. DNA was extracted from paraffin sections (lymph node) and rearranged VH gene was amplified by PCR. All but one exhibited a moderate number of somatic mutations, with percentages ranging from 4.1 to 9.5, and one of which indicated the effect of antigen selection on its VH gene. Multiple clone analysis of whole tissues showed intraclonal diversity in one case, whose VH gene carried a somatic mutation but the effect of antigen selection was not apparent. We further examined microdissected tissues to elucidate the relationship between FDC network and VH gene status in 2 cases. In one case, intraclonal diversity was not apparent irrespective of FDC network, however, both tumor cells around the FDC network and those apart from the FDC showed signs of intraclonal diversity in another case, suggesting that intraclonal diversity was not related to the FDC network in B-CLL. Here we demonstrate that some cases of B-CLL involved in lymph node carried mutated VH genes and showed intraclonal diversity like the tumor cells in the peripheral blood. However, the significance of the FDC network in the proliferation center still remains to be resolved.

[Primary lymphoma of the vagina].

Primary vaginal non-Hodgkin's lymphomas (NHL) are rare, and are clinically difficult to differentiate from inflammatory diseases or vaginal cancer. Here, we present such a case in a 74-year-old woman complaining of fever and difficulty with urination. Pelvic examination revealed a tumor involving most of the vaginal wall, and pelvic MRI demonstrated vaginal wall thickening. A biopsy of this lesion confirmed NHL (diffuse large B-cell lymphoma), and the patient was admitted. Abdominal CT and MRI detected a vaginal tumor, and Ga scintigraphy confirmed accumulation in the pelvis, but no abnormalities were seen in other areas. Therefore, the patient was diagnosed as having NHL at clinical stage IB with low-intermediate risk (international prognosis index) (LDH 1,309 IU/L). The patient underwent three courses of CHOP therapy followed by radiotherapy, and complete remission was achieved. Primary vaginal NHL often affects women younger than 50 years of age, and abnormal hemorrhage is the initial symptom in many cases. There have been a number of reports of long-term survival following appropriate early chemotherapy and radiation therapy, suggesting that early diagnosis and treatment based on vaginal biopsy findings greatly influence the prognosis.

Primary central nervous system lymphomas express Vh genes with intermediate to high somatic mutations.

Primary central nervous system lymphoma (PCNSL) is a rare disease, especially among non-AIDS patients. Although almost all PCNSLs belong to the diffuse large B-cell lymphoma (DLBL) category, its clinical course differs from that of other types of DLBL. To elucidate the histogenesis of PCNSL, we analyzed the source of the cells from its variable region (VH) sequences using the polymerase chain reaction (PCR) method to amplify the immunoglobulin heavy chain (IgH) gene of DNA extracted from paraffin sections. Fifteen patients with AIDS-unrelated PCNSL of DLBL type, (7 males and 8 females), were evaluated. Only one case showed positive evidence of EBV infection. The prognosis was very poor with a median survival of 9 months. Analysis of the VH sequences revealed that the VH4 family was used in 4 cases and the VH3 family in 2 cases. The homology with previously published germline sequences was random, ranging from 82.7-93.2%, showing intermediate to high somatic mutations. In 3 of 6 cases, the existence of intraclonal diversity was suspected. These findings suggest that PCNSLs are histogenetically derived from antigen selected B cells in the germinal center (GC) environment.

Blastic natural killer cell lymphoma arising from the mediastinum with terminal deoxynucleotidyl transferase expression.

Blastic natural killer (NK) cell lymphoma/leukemia is a relatively rare NK cell malignancy. We report the second case of blastic NK cell lymphoma arising from the mediastinum with an aggressive clinical course. The patient was a 63-year-old Japanese man with an anterior mediastinum tumor. The biopsy specimen showed diffuse proliferation of tumor cells with frequent mitotic figures and apoptotic bodies. Both angiocentric features and small foci of coagulative necrosis were found in this section. The tumor cells had medium to large nuclei with a fine chromatin pattern, inconspicuous nucleoli and scanty cytoplasm. The nuclear contour was oval to moderately irregular, showing slight pleomorphism as compared with typical lymphoblastic lymphoma. The tumor cells were positive for CD2, CD56 and terminal deoxynucleotidyl transferase, but negative for other T-cell antigens, B-cell antigens and myeloid markers. In situ hybridization for Epstein-Barr virus encoded small ribonucleic acid 1 was negative.

Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases.

Immunostaining for cyclin D1 is essential for reliable diagnosis of mantle cell lymphoma (MCL). However, a small number of cyclin D1-positive lymphomas other than MCL have been encountered. Our goal was to investigate the morphological spectrum of MCL as a disease entity, based on cyclin D1 overexpression. We reviewed 181 biopsy specimens obtained from 168 cases of cyclin D1-positive MCL. Typical findings were the presence of nodular (53.9% of cases) or diffuse (46.1%) histological patterns, containing mantle zone patterns (16.8%), naked germinal centers (33.5%) and perivascular hyaline deposition (83.2%). Unusual findings of residual germinal centers with a mantle cuff (four cases) and follicular colonization (two cases) were seen. High magnification showed a monotonous proliferation of tumor cells with cytological diversity including small (3.0%), intermediate (43.1%), medium (34.1%), medium-large (13.2%) and large (6.6%) cells. Pleomorphic and blastic/blastoid variants were encountered in 9.6 and 7.2% of cases, respectively. Three cases had foci of cells of considerable size, with a moderately abundant pale cytoplasm resembling marginal zone B cells. Two cases showed an admixture of cells which appeared transformed and mimicked the histology of chronic lymphocytic leukemia/small lymphocytic leukemia. In one, neoplastic mantle zones were surrounded by sheets of mature plasma cells, resembling the plasma cell type of Castleman's disease. An admixture of areas characteristic of MCL and of other larger cells, indicating histological progression or a composite lymphoma, were observed in seven cases. In high-grade lesions of five cases, nuclear staining of cyclin D1 was rarely detected. In our experience, cyclin D1 expression was also found in nine lymphomas other than MCL (five plasma cell myelomas, three Hodgkin's disease and one anaplastic large cell lymphoma). The application of cyclin D1 staining prompted us to recognize the broad morphological spectrum of MCL. MCL can be diagnosed with the application of cyclin D1 immunostaining, if careful attention is given to architectural and cytological features.

Involvement of the appendix in a relapsed case of primary nasal NK/T-cell lymphoma.

We report here a 20-year-old man presenting with primary nasal NK/T-cell lymphoma which showed an aggressive clinical course spreading to the spleen and skin despite various treatments. Eight months after high dose chemotherapy followed by autologous peripheral blood stem cell transplantation, acute appendicitis with perforation occurred and the patient underwent appendectomy. The histopathological diagnosis was NK/T-cell lymphoma of the appendix. Lymphoma of the appendix is extremely rare and the majority of appendiceal lymphomas are of B-cell origin. This is the first report of involvement of appendix by nasal NK/T-cell lymphoma.

Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma.

Mantle cell lymphoma (MCL) is a distinct clinicopathologic entity of non-Hodgkin's lymphoma, characterized by a monotonous proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and frequent t(11;14)(q13;q32) translocation. We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry. 128 cases (85%) showed positive nuclear staining for cyclin D1, while the remaining 23 (15%) were negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1-positive and -negative groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1-positive group showed a higher age distribution (P =.04), larger cell size (P =.02), higher mitotic index (P =.01), more frequent gastrointestinal involvement (P =.05), higher international prognostic index score (P =.05), and lower p27(KIP1) expression (P <.0001). Of particular interest is that cyclin D1-positive MCL showed significantly worse survival than cyclin D1-negative lymphoma (5-year survival: 30% versus 86%, P =.0002), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1-positive and -negative groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL. We therefore propose that cyclin D1-positivity should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored on the basis of the new criteria.

Combination chemotherapy with irinotecan and adriamycin for refractory and relapsed non-Hodgkin's lymphoma.

Twenty-five patients with relapsed or refractory non-Hodgkin's lymphoma were treated by combination chemotherapy with irinotecan hydrochloride (CPT-11) and adriamycin (ADM): CPT-11, 25 mg/m2 on days 1 and 2; ADM, 40 mg/m2 on day 3. Nine (36%) of twenty-five patients achieved CR. Fairly good responses were seen in relapsed B-cell lymphomas (4 of 8 in diffuse large B-cell lymphoma and 2 of 2 in follicular lymphoma grade 1), and substantial responses in T-cell lymphomas (1 of 4 in peripheral T-cell lymphoma and 2 of 7 in adult T-cell leukemia/lymphoma). Leukopenia was frequent but tolerable, and diarrhea minimal. Combination chemotherapy with a reduced dose CPT-11 and ADM was useful in the treatment of relapsed non-Hodgkin's lymphoma.

Multiple lymphomatous polyposis overexpressing cyclin D1.

A case of mantle cell lymphoma (MCL) associated with multiple lymphomatous polyposis (MLP) is reported is a 62-year-old woman, with special reference to the patient's clinical features and response to treatment. There were multiple widespread polypoid lesions in the entire gastrointestinal tract, with ileocecal masses. Ileocecal resection was performed on immunohistochemical examination, the neoplastic cells in the polypoid lesions stained positively for cyclin D1. Two conventional anthracycline-containing regimens (adriamycin-cyclophosphamide-vincristine-prednisolone [CHOP] and mitantroxone-etoposide-vindesine-prednisolone [MEVP]) were administered, but had limited success. The patient has since been receiving an irinotecan-adriamycin regimen (irinotecan, 25 mg/m(2), days 1 and 2; adriamycin, 40 mg/m(2), day 3, once a month) as an outpatient and has achieved good partial remission. She is well with disease 48 months after the initiation of the initial treatment.