Multiple myeloma (MM) is a heterogeneous and ultimately fatal disease. Risk stratification using prognostic biomarkers is crucial to individualize treatments. We sought to investigate the role of CD99, a transmembrane protein highly expressed in many hematopoietic cells including subpopulations of normal and neoplastic plasma cells, for MM risk stratification.
CD99 expression was measured in paraffin samples of bone marrow and extramedullary biopsies of 170 patients with MM. Patients were divided into those with high score (moderately and strongly positive) and low score (negative and weakly positive), with all staining being cytoplasmic and/or membranous.
High anti-CD99 immunostaining was observed in 72 of 136 (52.9%) bone marrow biopsies and 24 of 87 (27.6%) extramedullary biopsies in MM. High CD99 expression of extramedullary specimens was associated with significantly longer overall survival (OS; p=.016). High CD99 expression of extramedullary specimens was also associated with better prognosis in the nonautologous stem cell transplantation group of MM patients (p=.044). In multivariate analysis, International Staging System stage was an independent prognostic factor, whereas CD99 expression was no longer statistically significant.
Expression of CD99 in extramedullary specimens was correlated with longer OS, suggesting that CD99 may be a helpful immunohistochemical marker for risk stratification.
CD99; Multiple myeloma; Immunostaining; Autologous stem cell transplantation
Multicentric Castleman's disease (CD) is commonly associated with poor prognosis, and well-known prognostic factors are scarce. We performed a retrospective analysis to define the clinical features and prognostic factors for patients with multicentric CD.
Between 1990 and 2013, 32 patients with multicentric CD were identified from the database of the Asan Medical Center, Seoul, Korea. Clinicopathologic data were collected by reviewing the medical records. With the exclusion of 4 patients because of unknown human immunodeficiency virus infection status, 28 human immunodeficiency virus-negative patients with multicentric CD were included in this analysis.
Most of the patients were male (76%) and had a median age of 54 years. Hyaline vascular variant was the most common subtype (N=11, 39%). Hepatosplenomegaly (61%), fever (39%), edema (29%), and ascites (18%) were the most frequently reported symptoms and signs at diagnosis. With a median follow-up of 67 months, the 5-year overall survival (OS) was 77%. Patients with extravascular fluid accumulation (i.e., peripheral edema, ascites, and/or pleural effusions) were significantly associated with a poor survival rate (5-year OS, 94% vs. 56%; P=0.04). The extent of disease involvement was also a significant prognostic factor (5-year OS, 91% for involvement on a single side vs. 73% on both sides of the diaphragm; P=0.03). Other clinicopathologic factors were not significantly associated with patient survival.
Our findings suggest that the hyaline vascular variant is not a rare subtype of multicentric CD. Extravascular fluid accumulation and disseminated disease involvement seem to be significant prognostic factors.
Multicentric Castleman's disease; Giant lymph node hyperplasia; Angiofollicular lymphoid hyperplasia; Prognosis; HIV
Primary testicular diffuse large B-cell lymphoma (DLBCL) is a rare but aggressive extranodal lymphoma, and its relapse in the central nervous system (CNS) is a major concern during treatment. Despite this, the role of intrathecal prophylaxis in primary testicular DLBCL remains controversial.
We retrospectively reviewed the medical records of 14 patients with primary testicular DLBCL diagnosed between November 2000 and June 2012, and analyzed the CNS relapse rate in patients treated without intrathecal prophylaxis. Survival curves were estimated using the Kaplan-Meier method.
The median age at diagnosis was 57 years (range, 41-79 years). Unilateral testicular involvement was observed in 13 patients. Nine patients had stage I, 1 had stage II, and 4 had stage IV disease. The international prognostic index was low or low-intermediate risk in 12 patients and high-intermediate risk in 2 patients. Thirteen patients underwent orchiectomy. All the patients received systemic chemotherapy without intrathecal prophylaxis, and prophylactic radiotherapy was administered to the contralateral testis in 12 patients. The median follow-up period of surviving patients was 39 months (range, 10-139 months). Median overall survival was not reached and the median progression-free survival was 3.8 years. Four patients experienced relapse, but CNS relapse was observed in only one patient (7.1%) with stage IV disease, 27 months after a complete response.
Even without intrathecal prophylaxis, the rate of relapse in the CNS was lower in the Korean patients with primary testicular DLBCL compared to prior reports.
Diffuse large B cell lymphoma; Intrathecal prophylaxis; Primary testicular lymphoma
Abbreviated chemotherapy followed by radiotherapy or full cycles of chemotherapy is recommended as a standard treatment for limited-stage (LS) diffuse large B-cell lymphoma (DLBCL). After complete resection of tumors, however, Burkitt and childhood B-cell Non-Hodgkin lymphoma show favorable outcomes, even after abbreviated chemotherapy of only 2 or 3 cycles. We investigated the effectiveness of abbreviated chemotherapy in patients with LS DLBCL after complete tumor resection.
We retrospectively reviewed 18 patients with LS DLBCL who underwent complete tumor resection followed by either 3 or 4 cycles of chemotherapy between March 2002 and May 2010.
With a median follow-up period of 57.9 months (range, 31.8-130.2 months), no patients experienced disease relapse or progression; however, 1 patient experienced secondary acute myeloid leukemia during follow-up. The 5-year progression-free survival rate and overall survival rate were 93.3% and 94.1%, respectively.
These results warrant further investigation into abbreviated chemotherapy as an alternative treatment for patients who have undergone complete resection of LS DLBCL.
Diffuse large B-cell lymphoma; Limited Stage; Resection; Abbreviated chemotherapy
Previously, cutaneous lymphomas were classified according to either the European Organization for the Research and Treatment of Cancer (EORTC) or the World Health Organization (WHO) classification paradigms. The aim of this study was to determine the relative frequency of Korean cutaneous lymphoma according to the new WHO-EORTC classification system.
A total of 517 patients were recruited during a recent 5 year-period (2006-2010) from 21 institutes and classified according to the WHO-EORTC criteria.
The patients included 298 males and 219 females, and the mean age at diagnosis was 49 years. The lesions preferentially affected the trunk area (40.2%). The most frequent subtypes in order of decreasing prevalence were mycosis fungoides (22.2%), peripheral T-cell lymphoma (17.2%), CD30+ T-cell lymphoproliferative disorder (13.7%), and extranodal natural killer/T (NK/T) cell lymphoma, nasal type (12.0%). Diffuse large B-cell lymphoma accounted for 11.2% of cases, half of which were secondary cutaneous involvement; other types of B-cell lymphoma accounted for less than 1% of cases.
In comparison with data from Western countries, this study revealed relatively lower rates of mycosis fungoides and B-cell lymphoma in Korean patients, as well as higher rates of subcutaneous panniculitis-like T-cell lymphoma and NK/T cell lymphoma.
Cutaneous lymphoma; World Health Organization; EORTC; Classification
Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of non-Hodgkin lymphoma, which has no consensus for its ideal treatment or prognosis.
We reviewed the clinicopathologic features and clinical outcomes of 25 PMBL cases diagnosed at a single institution between 1993 and 2009 and compared them with 588 cases of non-mediastinal, diffuse large B-cell lymphoma (DLBCL, control group) diagnosed during the same period.
Thirteen (52.0%) PMBL patients had Ann Arbor stage III or IV disease, and 10 (40.0%) had B symptoms. Thirteen (52%) PMBL patients were classified as high-intermediate/high-risk according to the International Prognostic Index. There was a significant prevalence of young (median: 31 years; range, 15-78 years; P<0.001), female (68%; P=0.014) patients in the PMBL group compared to the control group (median: 56 years; range, 15-85 years; 43.2% female). Bulky disease and elevated levels of lactate dehydrogenase (LDH) were more frequent in the PMBL group (P<0.001 and P=0.003, respectively). Nineteen (76%) PBML patients achieved complete remission, and 18 were alive at the last follow-up (median: 43 months; range, 1-92 months). There was no difference in the 3-year, overall survival rate (72%, 95% confidence interval [CI]: 54.0-83.0 versus 70.1%, 95% CI, 109.0-126.0; P=0.686) between PMBL and control patients, respectively.
Compared to patients with non-mediastinal DLBCL, Korean patients with PMBL are predominantly young women with bulky disease and high LDH levels but with no significant difference in survival.
Lymphoma; B cell; PMBL; Prognosis; Treatment
Recent studies have reported the prognostic value of tissue-associated magrophages (TAMs) in classical Hodgkin lymphoma (cHL). In addition, TAMs are implicated in the tumor angiogenesis. In this study, we examined the prognostic relevance of TAMs in relation to vascular endothelial growth factor (VEGF) expression and angiogenesis in uniformly treated cases of cHL.
Diagnostic tissue from 116 patients with ABVD-treated cHL was evaluated retrospectively by immunohistochemical analysis for CD68, CD163 and VEGF expression and for CD31 expression as a measure of microvessel density (MVD).
High CD163 expression (≥35% of cellularity) correlated with VEGF expression (Pearson’s Chi-square test, P = 0.008) and MVD (Spearman correlation coefficient 0.310, P<0.001). High CD163 expression was associated with inferior event-free survival (EFS, P = 0.005) and overall survival (OS, P<0.001) in univariate analysis. In multivariate analysis, high CD163 expression was strongly associated with inferior EFS (P = 0.043) and OS (P = 0.008). Patients with high MVD had a lower OS than those with low MVD, but the difference was not significant (P = 0.071, respectively). While high expression of CD68 was also associated with inferior EFS (P = 0.007), it showed no correlation with VEGF or MVD.
Our data confirms that CD163 expression provides independent prognostic information in cHL. The correlation of CD163 with VEGF expression and MVD suggests the role of CD163-positive cells in tumor angiogenesis of cHL.
The gastrointestinal tract is the most common primary extranodal site for diffuse large B-cell lymphoma (DLBCL). However, there is no consensus on the most appropriate staging system for intestinal DLBCL. We evaluated the utility of the modified Ann Arbor system, the Lugano system, and the Paris staging system (a modification of the Tumor, Node, Metastases [TNM] staging for epithelial tumors) in 66 cases of resected intestinal DLBCL. The cases were treated with surgery, plus either cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy alone (n=26) or with the addition of rituximab immunotherapy (n=40). Median follow-up time was 40.4 months (range, 2.1-171.6 months). Fifty-six patients (84.8%) achieved complete remission. The overall 5-yr survival rate was 86.4% (57/66). Of the stage categories defined for each staging system, only the T stage of the Paris classification showed prognostic significance for overall survival by univariate analysis. However, none of the stage parameters was significantly correlated with patient survival on multivariate analysis. In conclusion, the results suggest that the T stage of the Paris classification system may be a prognostic indicator in intestinal DLBCL. The results also imply that in surgically resected intestinal DLBCL, the addition of rituximab to the CHOP regimen does not confer significant survival advantage.
Lymphoma, Large B-Cell, Diffuse; Intestines; Stage; Rituximab
Absolute lymphocyte count (ALC) in peripheral blood has recently been reported to be an independent prognostic factor in multiple myeloma (MM). Previous studies indicated that the absolute monocyte count (AMC) in peripheral blood reflects the state of the tumor microenvironment in lymphomas. Neither the utility of the AMC nor its relationship with ALC has been studied in MM.
The prognostic value of ALC, AMC, and the ALC/AMC ratio at the time of diagnosis was retrospectively examined in 189 patients with MM.
On univariate analysis, low ALC (<1,400 cells/µL), high AMC (≥490 cells/µL), and low ALC/AMC ratio (<2.9) were correlated with worse overall survival (OS) (p=.002, p=.038, and p=.001, respectively). On multivariate analysis, the ALC/AMC ratio was an independent prognostic factor (p=.047), whereas ALC and AMC were no longer statistical significant. Low ALC, high AMC, and low ALC/AMC ratio were associated with poor prognostic factors such as high International Staging System stage, plasmablastic morphology, hypoalbuminemia, and high β2-microglobulin.
Univariate analysis demonstrated that changes in ALC, AMC, and the ALC/AMC ratio are associated with patient survival in MM. Multivariate analysis showed that, of these factors, the ALC/AMC ratio was an independent prognostic factor for OS.
Multiple myeloma; Lymphocytes; Monocytes; Lymphocyte/monocyte ratio; Prognosis
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous clinicopathological entity, and its molecular classification into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes using gene expression profile analysis has been shown to have prognostic significance. Recent attempts have been made to find an association between immunohistochemical findings and molecular subgroup, although the clinical utility of immunohistochemical classification remains uncertain.
The clinicopathological features and follow-up data of 68 cases of surgically resected gastrointestinal DLBCL were analyzed. Using the immunohistochemical findings on tissue microarray, the cases were categorized into GCB and non-GCB subtypes according to the algorithms proposed by Hans, Muris, Choi, and Tally.
The median patient age was 56 years (range, 26-77 years). Of the 68 cases included, 39.7% (27/68) involved the stomach, and 60.3% (41/68) involved the intestines. The GCB and non-GCB groups sorted according to Hans, Choi, and Tally algorithms, but not the Muris algorithm, were closely concordant (Hans vs. Choi, κ=0.775, P<0.001; Hans vs. Tally, κ=0.724, P<0.001; Choi vs. Tally, κ=0.528, P<0.001). However, there was no prognostic difference between the GCB and non-GCB subtypes, regardless of the algorithm used. On univariate survival analyses, international prognostic index risk group and depth of tumor invasion both had prognostic significance.
The Hans, Choi, and Tally algorithms might represent identical DLBCL subgroups, but this grouping did not correlate with prognosis. Further studies may delineate the association between immunohistochemical subgroups and prognosis.
Diffuse large B-cell lymphoma; Gastrointestinal tract; Immunohistochemistry; Prognosis
Radioimmunotherapy agents have a highly significant role in autologous stem cell transplantation as they improve tolerability and increase the efficacy of the conditioning regimen.
We retrospectively analyzed the efficacy and toxicity of yttrium-90 ibritumomab tiuxetan (Zevalin) combined with intravenous busulfan, cyclophosphamide, and etoposide (Z-BuCyE) compared with those of BuCyE alone followed by autologous stem cell transplantation in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). The efficacy, toxicity, and engraftment characteristics were compared between 19 patients who received Z-BuCyE and 19 historical controls who received BuCyE.
The 2 treatment groups shared similar baseline characteristics. The median time to platelet engraftment (>20×109/L) and neutrophil engraftment (>0.5×109/L) did not significantly differ between the Z-BuCyE group (12 days and 10 days, respectively) and the BuCyE group (12 days and 10 days, respectively). No significant differences were observed between the groups with respect to toxicities and treatment-related mortality. The median follow-up period was 30.4 months, and median event-free survival was generally better in the Z-BuCyE group (12.5 months) vs. the BuCyE group (6.2 months, P=0.236). No significant difference in overall survival between the groups was noted.
Adding ibritumomab tiuxetan to BuCyE high-dose chemotherapy may benefit patients with relapsed or refractory B-cell NHL with no risk of additional toxicity.
Yttrium-90 ibritumomab tiuxetan; BuCyE; Autologous stem cell transplantation; Non-Hodgkin lymphoma
Bortezomib targets molecular dysregulation of nuclear factor-κB activation and cell cycle control, which are characteristic features of diffuse large B-cell lymphoma (DLBCL). We evaluated the safety and efficacy of bortezomib treatment with dose-dense cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) every 2 weeks (CHOP-14).
Untreated DLBCL patients were enrolled. A phase I dose-escalation study with 1.0, 1.3, and 1.6 mg/m2 bortezomib administration on day 1 and 4 in addition to the CHOP-14 regimen was performed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Lenograstim 5 µg/kg/d was administered on day 4-13. The bortezomib dose from the phase I study was used in the phase II study.
Nine and 37 patients were enrolled in the phase I and phase II studies, respectively. The analysis of the phase II results (40 patients) included data of the 3 patients in the last MTD dose cohort of the phase I trial. During the phase I trial, no DLT was observed at any bortezomib dose; therefore, the recommended dose was 1.6 mg/m2. In phase II, the overall response rate was 95% (complete response: 80%; partial response: 15%). Nine out of the 40 patients showed grade 3 sensory neuropathy, and 22 required at least 1 dose reduction. Three patients could not complete the intended 6 cycles of treatment because of severe neuropathy.
Bortezomib plus CHOP-14 was highly effective for the treatment of untreated DLBCL patients, but in many cases, dose or schedule modification was required to reduce neurotoxicity.
Bortezomib; CHOP-14; Diffuse large B-cell lymphoma
Primary central nervous system lymphoma (PCNSL) rarely relapses in extracranial sites, and no specialized guidelines for follow-up evaluation have been proposed.
We analyzed 65 patients with newly diagnosed PNCSL to evaluate the pattern of relapse and prognostic factors.
Of the 65 patients analyzed, 55 had only parenchymal brain disease, and 10 had both intracranial and extracranial lesions. As a first-line treatment, 29 patients received chemotherapy only (CTx), 13 received chemotherapy followed by whole brain radiotherapy (CTx-WBRT), 18 received chemotherapy followed by autologous stem cell transplantation (CTx-ASCT), 2 received palliative WBRT, and 3 received best supportive care. The overall response rate to the initial treatment was 75.8%, with specific response rates of 62.1% to CTx, 84.6% to CTx-WBRT, and 100% to CTx-ASCT. The complete response (CR) rate was higher with CTx-ASCT than in the absence of ASCT (77.8% vs. 43.2%; P=0.025). After a median follow-up of 18.8 months, the median failure-free survival (FFS) and overall survival (OS) were 13.0 and 36.1 months, respectively. No systemic relapse without a CNS lesion was noted. Multivariate analysis showed that ASCT was predictive of better FFS but not of OS. Age and the Memorial-Sloan Kettering Cancer Center prognostic score were predictive of survival.
We observed no systemic relapse without a CNS lesion, suggesting that regular systematic evaluation of extracranial sites may not always be necessary. Age was prognostic of survival irrespective of treatment scheme. ASCT may improve CR rate and FFS.
Primary CNS lymphoma; Relapse; Prognostic factor
Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages.
We utilized two murine colon cancer models: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe.
Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa.
NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.
Colon cancer; Inflammatory bowel disease; Near-infrared fluorescence; Matrix metalloproteinases
In this study, the authors explored the effect of human mesenchymal stem cell (MSC) implantation on the restoration of degenerative intervertebral discs (IVDs) in the rat. A unique rat coccygeal model was used to investigate the effects of transplanting human MSCs and to examine MSC survival in degenerative discs. MSC implantations into rat coccygeal IVDs were performed at 2 weeks post-injury. Radiologic and histologic evaluations were performed at 2, 4, 6, and 8 weeks post-injury. MSC-injected segments (TS) retained disc height and signal intensity, but injured non-injected segment (IS) progressively lost disc height. Pathological results revealed that the TS group showed relative restoration of the inner annulus structure; however, the IS group showed destruction of the inner annulus structure. Immunohistochemical staining using Anti-Human Nucleic Antibody (#MAB1281 Chemicon) revealed positive staining in the TS group at 2 weeks post-transplantation (4 weeks post-injury). This study shows that human MSCs survive for 2 weeks after transplantation into the IVDs of rats, and that MSCs increased the heights and signal intensities of intervertebral disc.
Mesenchymal stem cell; Animal model; Intervertebral Disc; Degeneration