Centrocytic Lymphoma Research Articles

The M factor: maintenance in mantle cell lymphoma

Mantle cell lymphoma was first characterised as centrocytic lymphoma in the Kiel classification, but renamed due to its similarities to the mantle zone of the lymph node architecture.1 Although originally classified as low malignant lymphoma, mantle cell lymphoma was regrouped as aggressive lymphoma on the basis of its clinical features (high initial response rate and early relapse pattern). Treatment standards in patients younger than 65 years are based on cytarabine-containing regimens (which seem to have an advantage in this lymphoma) and dose intensification, mostly by sequential high-dose consolidation with autologous haematopoietic stem cell transplantation (HSCT).

Testis-Isolated Mantle Cell Lymphoma: A Unique Case

Introduction Approximately 1%-2% of all lymphoma cases are primary testicular lymphoma. Testicular lymphoma usually arises in older men, nd the histiologic subtype is most often diffuse large B-cell lymhoma (DLBCL). Other histologies, for example, mantle cell lymhoma, are very rare. A relatively large series from Massachusetts eneral Hospital was published in 1994 that describes 69 cases of alignant lymphoma of the testis, epididymis, and spermatic cord. There was only 1 tumor consistent with the currently recognized entity of mantle cell lymphoma (described as centrocytic lymphoma histology Kiel subtype, diffuse small cleaved cell histology by Working Formulation). In a recently published series of 18 primary testicular lymphomas diagnosed over a 2-year period at an Austrian center, all were DLBCL except for 1 lymphoma, not otherwise specified (sparse biopsy material available), and 2 mantle cell lymphomas, pleomorphic subtype. The lymphoma group at MD Anderson Caner Center identified 1 case of mantle cell lymphoma with testicular nvolvement in more than 300 testicular lymphoma cases seen over a ecade at that institution. All 4 of the above testicular mantle cell ymphomas were at advanced stage. At our center, we recently evaluated a patient with mantle cell ymphoma localized to the testis. We systematically surveyed our

Mantle cell lymphoma: recent insights into pathogenesis, clinical variability, and new diagnostic markers

Mantle cell lymphoma (MCL; previously called centrocytic lymphoma or lymphocytic lymphoma of intermediate differentiation) is a distinct subtype of B-cell lymphoma, accounting for approximately 3%-10% of all lymphoma diagnoses. The name refers to the growth pattern in early disease presentation resembling the normal mantle zone that surrounds the germinal center of the B-cell follicle. The hallmark of MCL is the t(11;14)(q13;q32), resulting in aberrant expression of the CCND1 gene and expression of cyclin D1 in the tumor cells. Expression and genomic profiling of MCL have provided new insight into the pathogenesis and will be summarized in this review. Pitfalls in the differential diagnosis versus B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, cyclin D1-positive diffuse large B-cell lymphoma, hairy cell leukemia, and plasma cell tumors will be discussed, including the usefulness new diagnostic markers SOX11 and CD200. In situ MCL, MCL with an indolent clinical course, and cyclin D1-negative MCL are other topics of this review.

Long-Term Outcome and Prognostic Factors in Early-Stage Nodal Low-Grade Non-Hodgkin’s Lymphomas Treated with Radiation Therapy

Retrospective analysis of therapy results in patients with stage I-II and limited stage III nodal low-grade non-Hodgkin's lymphoma (NHL). The present retrospective study covers 65 patients treated between 1988 and 2006 at the Department of Radiation Oncology, University of Cologne, Germany. 50 patients were treated with radiotherapy alone (EF [extended field]: n = 35, IF/REG [involved field/regional field]: n = 9, TNI/TLI [total nodal/total lymphatic]: n = 6), 15 patients additionally received chemotherapy. Median age was 58 years. 58 patients presented with centroblastic-centrocytic or follicular lymphomas, seven patients had centrocytic lymphomas. Apart from overall and relapse-free survival, relapse patterns were examined and the impacts of patient characteristics and therapy modalities were analyzed. After a median follow-up of 9.1 years, overall 5-year and 10-year survival was 86% and 55%, relapse-free survival was 55% and 37%, respectively. Relapses occurred in 28 patients during the observation period. Overall survival was favorably influenced by low patient age (p = 0.037), centroblastic-centrocytic/follicular histology (p = 0.006), and early disease stage (p = 0.045). Favorable prognostic factors for relapse-free survival were low patient age (p = 0.035) and centroblastic-centrocytic/follicular histology (p = 0.001). Radiotherapy of early-stage low-grade NHL is a curative therapy option, particularly in younger patients and patients with follicular histology. Relapse analysis confirmed the benefits of total nodal or total lymphatic irradiation, although the small number of patients needs to be considered.

P69,71 Antigen Complex Detected by Monoclonal Antibody Leu 1 in the Identification of Particular Stages of Malignant B-Cell Differentiation

Lymphomatous cell samples from 86 patients with B-cell neoplasia (34 chronic lymphocytic leukaemia, 8 hairy-cell leukaemia, 5 prolymphocytic leukaemia, 20 immunocytic lymphoma, 9 centrocytic lymphoma, 3 centroblastic/centrocytic lymphoma, 3 lymphoblastic lymphoma, 1 plasma cell leukaemia and 3 plasmacytoma) were studied using the monoclonal antibody Leu 1, detecting a p69,71 antigen complex present on nearly all thymocytes, most (greater than 85%) peripheral T-lymphocytes as well as some malignant B-cells. Furthermore, we compared the reactivity of Leu 1-positive B-cells with those exhibiting conventional surface markers such as mouse-erythrocyte-receptor, FcIgG-receptor, C3b- or C3d-receptor and surface immunoglobulins of the various heavy- and light-chain types. Our results demonstrate a correlation between the expression of p69,71 antigen complex and distinct phenotypes revealed by conventional markers and underline the value of Leu 1 monoclonal antibody in the differential diagnosis of human B-cell neoplasia.

Maligne lymphomatöse Polypose des Gastrointestinaltrakts

Two years after endoscopic excision of several polyps of the colon (histological examination revealing infiltration by a malignant non-Hodgkin lymphoma) a 67-year-old man was again found to have blood and mucus in his stool. Because local recurrence was suspected a coloscopy was performed. This revealed multiple polyps throughout the entire colon, predominantly in the sigmoid and rectum. Biopsy showed focal infiltration of the submucosa and mucosa with centrocytic non-Hodgkin lymphoma, compatible with the diagnosis of malignant lymphomatous polyposis of the gastrointestinal tract. Gastroduodenoscopy then demonstrated duodenal polyps and massive coarsening of the gastric folds due to infiltration. For the first time tumour masses were also found in the epipharynx. After 6 chemotherapy cycles according to the CHOP scheme (day 1: cyclophosphamide, 1500 mg, adriblastin, 100 mg and vincristine, 2 mg; days 1-5: prednisolone, 100 mg) all lymphoma infiltrates regressed completely. The patient has been symptom-free for 9 months.

Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression

Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed.

A model for single and multiple knowledge based networks

The inherent black-box nature of neural networks is an important drawback with respect to the problem of explanation of neural network responses. Although several articles have tackled the problem of rule extraction from a single neural network, just a few papers have investigated rule extraction from several combined neural networks. In this article we describe how to translate symbolic rules into the Discretized Interpretable Multi-Layer Perceptron (DIMLP) and how to extract rules from one or several combined neural networks. Our approach consists of characterizing discriminant hyperplane frontiers. Unordered rules are extracted in polynomial time with respect to the size of the problem and the size of the network. Moreover, the degree of matching between extracted rules and neural network responses is 100% on training examples. We applied single DIMLP networks to 17 data sets related to medical diagnosis and medical prognosis problems. Results based on 10-fold cross-validation showed that the DIMLP model was on average as accurate as standard multi-layer perceptrons (MLP). Furthermore, DIMLP networks were significantly more accurate than CN2 on eight problems, whereas only on one problem CN2 was better than DIMLP. Finally, a non-Hodgkin lymphoma diagnosis problem based on classification of electrophoresis gels was defined. It turned out that ensembles of DIMLP networks were significantly more accurate than CN2 (96.1%±1.4 versus 82.7%±4.0). Finally, symbolic rules revealed the presence of five important spots for the discrimination of the class of Lymphocyte Leukemia/Chronic Lymphoid Leukemia (Lc/LLc), and the class of Centrocytic Lymphoma (Cc).

Miscellaneous II, Abstract 244–252, Posters

In smear preparation of lymph nodes escised from 36 patients with a malignant lymphoma the DNA content was estimated in different tumor cells following Feulgen staining by means of quantitative cytophotometric measurements. The tumors investigated included 11 Hodgkin lymphomas and various types of Non-Hodgkin lymphomas (altogether 25). Whereas the small lymphoid cells found in Hodgkin lymphomas show a diploid DNA content with a wide scattering, in the large mononuclear reticular cells (Hodgkin cells) as well as in Sternberg's giant cells only aneuploid DNA values are seen lying in the hyperdiploid, hypertetraploid and hyperoctoploid regions. DNA stemlines are found in the aneuploid regions, but in some cases they are missing. This indicates that we are dealing with malignant tumor cells.In Non-Hodgkin lymphomas with a low grade of malignancy (centrocytic-centroblastic lymphoma, centrocytic lymphoma, CLL) an aneuploid DNA content is found particularly in the large cells (centroblasts, lymphoblasts) with or without a DNA stemline. These cells must be considered as primary malignant tumor cells. In the immunoblastic lymphoma of high malignancy only aneuploid tumor cells are present showing a particularly intense DNA content in the large immunoblasts, whereas a DNA stemline is usually missing. The range of aneuploid values, the number of polyploid tumor cells and the presence or absence of a DNA stemline are important criterions in determining the degree of malignancy. By means of cytophotometric measurements of the DNA content in the tumor cells of malignant lymphomas it is possible to assertain the degree of malignancy and to establish an objective prognosis.

From centrocytic to mantle cell lymphoma: A clinicopathologic and molecular review of 3 decades

Mantle cell lymphoma (MCL), described almost 3 decades ago as centrocytic lymphoma and by a variety of other names, was initially recognized morphologically. MCL is a classic illustration of how the field of hematopathology and our basic understanding of neoplasia have evolved. The advent of immunophenotypic and increasingly sophisticated genotypic and cytogenetic studies, together with clinical investigations, have led to a better practical and biologic understanding of MCL and have broader implications as well. MCL is now recognized as an aggressive, difficult to treat, B-cell lymphoma with a broader morphologic spectrum than was initially appreciated and a characteristic phenotype (CD5+, CD10−, CD23−, FMC7+). Virtually all MCLs carry the translocation t(11;14)(q13;q32) with overexpression of the involved CCND1 (cyclin D1) gene. Additional cytogenetic and molecular abnormalities have been identified, including some that are early events (such as ATM gene deletion and mutation) and others that appear to be late events (such as deletions and mutations in the negative cell cycle regulatory elements p53, p16, and p18). The latter are often associated with a blastoid morphology and more aggressive clinical course. Ongoing clinical and basic investigations including microarray analysis will undoubtedly provide additional insights into MCL and perhaps more effective and specific therapeutic modalities. HUM PATHOL 33:7-20. Copyright © 2002 by W.B. Saunders Company

The synthesis of Bcl-2 and other proteins in the neoplastic follicles of follicular lymphoma.

The bcl-2 proto-oncogene was discovered at the chromosomal breakpoint of the t(14;18) translocation found in human follicular lymphoma; t(14;18) juxtaposes the bcl-2 gene from chromosome 18 with the immunoglobulin heavy...

Expression of Cell Cycle Regulating Proteins in an Unusual Transformation of Mantle Cell Lymphoma

We describe here two patients with mantle cell lymphoma (MCL) who after a few years, developed to the diffuse large cell lymphoma (DLCL)(anaplastic centrocytic lymphoma) growing in a diffuse sheets without the classical MCL component. In both the initial and second biopsy specimens, in each case, tumor cells were positive for cyclin D1, sIgM, sIgD, and CD5, but were negative for CDlO and CD23. In a study of immunoglobulin heavy chain (IgH) gene rearrangement, using the polymerase chain reaction (PCR) method, the products obtained from each paired biopsy tissue sample were the same size, and in one case had an identical sequence to the non-mutated VH gene.Immunohistochemistry was used to examine the expression of p53, p27kipl and cyclin E. Interestingly, there was clear overexpression of p53 protein in case 1 but not in case 2, compared with other typical MCL cases. The expression of p27kipi in the second biopsies of each case was decreased compared with those in the initial biopsies. In case 2, however, p27kipi was clearly expressed in the first and second biopsies, in contrast to other typical MCL cases.Thus these 2 cases demonstrate not only that the variant form of MCL may arise de novo, but also that MCL may transform to DLCL at the time of relapse. Although the mechanism of tumor rogressiodtransforrnation is still poorly understood, the overexpression of p53 or p27kipi may be linked to a cellular mechanism involved in the development of the variant form of MCL.

High-dose chemotherapy with hematopoietic stem cell transplantation in patients with mantle cell or diffuse centrocytic non-Hodgkin's lymphomas: a single center experience on 18 patients.

Between 1985 and 1996, 18 patients with diffuse centrocytic lymphoma (DCL), including nine patients with an established histological and phenotypic diagnosis of mantle cell lymphoma (MCL), received 19 courses of high-dose chemotherapy (HDCT) followed by hematopoietic stem cell transplantation. Five patients received HDCT as consolidation treatment after first-line standard chemotherapy, and 14 after a relapse or progression, including one patient in early relapse after the first transplant. Six patients (33%) were in complete response (CR) prior to HDCT and 12 (67%) were in partial response: 10 (83%) of these 12 patients achieved CR at day 60 following HDCT. With a median follow-up of 30 months after HDCT, the 2-year overall and progression-free survivals of the whole series are 91 and 75%, respectively. The 2-year progression-free survivals are 74 and 75%, respectively, in the MCL and DCL subgroups.

Mantle Cell Lymphomas: Characteristics, Natural History and Prognostic Factors of 45 Cases

We reviewed 77 cases considered as lymphocytic lymphomas of intermediate differentiation or diffuse centrocytic lymphomas. Forty-five cases were diagnosed as mantle cell lymphoma (MCL). The architectural pattern was diffuse in 95%, 8 cases presented large blastoid cells and CD5 positivity was observed in 28/34 cases. Of 20 cases studied, 8 presented a t(11;14)(q13;q32). Patient characteristics were: median age 59 years, B symptoms in 38%, 87% stages 111-IV, bone marrow involvement in 67% with peripheral leukemic cells in 24%. Forty-four patients were treated with chemotherapy and 7 received radiotherapy. The complete response (CR) rate was 58%. Of the 26 CR, 19 relapsed at a median of 15 months. Disease-free survival was 42% and overall survival was 73% at 3 years. In a univariate analysis, overall survival was related to liver and bone marrow involvement, the presence of peripheral lymphomatous cells and achieving a complete response.

Bcl-1 rearrangement and cyclin D1 protein expression in mantle cell lymphoma.

Centrocytic lymphoma, or mantle cell lymphoma (MCL), is characterized by a chromosomal translocation t(11;14) (q13;q32) involving the bcl-1 locus on chromosome 11. Cyclin D1 is a cell-cycle regulatory protein essential for G1-S transition and has been identified as a potential transforming gene affected by the translocation. In this study, 32 cases of MCL were analysed for the bcl-1 rearrangement and cyclin D1 protein expression. In 17 cases, a rearrangement at the major translocation cluster of bcl-1 could be detected. Twenty-four cases exhibited nuclear cyclin D1 expression that was not detectable in other B-cell lymphomas (n = 40) or in normal B-cells. In nine MCL samples, cyclin D1 was expressed without a detectable bcl-1 rearrangement. The detection of a t(11;14) by means of classical cytogenetics in one of these cases, however, may suggest that this discrepancy could be due to chromosomal breakages outside the typical translocation cluster region. In two cases, a bcl-1 rearrangement was not accompanied by cyclin D1 expression. This study provides further evidence that cyclin D1 is involved in the pathogenesis of MCL and can be exploited as a diagnostic marker in the differential diagnosis of B-cell lymphomas and in the identification of MCL.

Detection of membrane and soluble interleukin-6 receptor in lymphoid malignancies.

We studied the membrane expression of the gp80 chain of IL-6 receptor (IL-6R) by quantitative flow cytometry in chronic lymphocytic leukaemia (CLL) and leukaemic centrocytic lymphoma using a panel of seven monoclonal antibodies. IL-6R was detected in 18/26 CLL cases and 4/7 lymphoma cases, with a mean antigen density < 3000 molecules/cell. Multiple labelling experiments confirmed the IL-6R expression by neoplastic cells. Specific mRNA was found by RT-PCR in neoplastic cells. A specific ELISA test was designed using two anti-IL-6 receptor MAbs to measure the serum soluble IL-6R (sIL-6R) in CLL (n = 48). B-cell non-Hodgkin's lymphoma (NHL; n = 40), and monoclonal gammopathy (MG; n = 32). SIL-6R was higher in CLL (170 +/- 12.6 ng/ml) in NHL (160 +/- 12 ng/ml) and MG patients (183 +/- 23 ng/ml) than in age-matched controls (100 +/- 5.6 ng/ml; P < 0.001) and higher in high-grade than low-grade NHL. No correlation was noted with a previous treatment. Among CLL cases the patients classified as stage B according to the Binet's staging of the disease had the highest sIL-6R values, thus suggesting a link with tumour cell mass.

Human cyclin D1 oncogene and esophageal squamous cell carcinoma.

Oncogene activation and tumor suppressor gene inactivation have been implicated in the genetic basis of esophageal squamous cell carcinoma (ESCC). Cyclin D1, an oncogene that has a critical role in G1 progression of the cell cycle, has been observed to be amplified in carcinomas of the breast and head and neck, and translocated in parathyroid adenomas and centrocytic lymphomas. Established ESCC cell lines were assayed for cyclin D1 amplification and overexpression by Southern, Northern, and Western blot analyses. In addition, cyclin D1 overexpression was determined in primary tumors and adjacent normal mucosa by differential polymerase chain reaction (PCR) and immunohistochemical staining. The authors observed that approximately 50% of ESCC cell lines with cyclin D1 DNA amplification also had RNA and protein overexpression. Related genes, cyclin D2 and D3, were not amplified or overexpressed in these cell lines with rare exception. The cyclin D1 protein was able to associate with the cell-cycle-dependent kinases, cdk4 and cdk6, but not always with proliferating cell nuclear antigen in selected cell lines tested, representing a novel finding. In addition, approximately 50% of primary tumors had cyclin D1 overexpression that was not present in adjacent normal mucosa. Cyclin D1 overexpression based on PCR correlated with enhanced cyclin D1 protein nuclear staining in malignant cells. Cyclin D1 is amplified and overexpressed in ESCC and may be important in its molecular pathogenesis.

Absence of cyclin D1/PRAD1 point mutations in human breast cancers and parathyroid adenomas and identification of a new cyclin D1 gene polymorphism.

PRAD1 (cyclin D1) has been implicated in the molecular pathogenesis of a variety of tumors, including parathyroid adenomas, t(11;14)-bearing B-lymphoid tumors, and breast cancer. The sequence of the overexpressed PRAD1 genes has been directly analyzed in only two tumor specimens, a benign parathyroid adenoma and a malignant centrocytic lymphoma. Thus, little is known about PRAD1 sequence in the vast majority of human primary tumors, including breast cancers. Using single-strand conformational polymorphism (SSCP) analysis, we have examined the coding region of the PRAD1 gene in 30 primary breast cancers and 25 parathyroid adenomas. Polymerase chain reaction (PCR)-SSCP analysis of the coding region of exons 1-5 of the PRAD1 gene did not reveal any tumor-specific mutations. During the course of screening for mutations, we found and established the sequence variants of a new DNA polymorphism at codon 241 within exon 4 of the PRAD1 gene. Since this polymorphism is located within the coding region of the PRAD1 gene, it will allow determination of allele-specific expression of the gene and the detection of allele imbalance. At least in breast and parathyroid neoplasms, overexpression of the wild-type PRAD1 sequence, rather than point mutational activation, appears to be the predominant mechanism by which PRAD1 exerts its oncogenic action.

Mucosal mantle cell (centrocytic) lymphomas

The morphology, phenotype, genotype and clinical behaviour of four cases of mantle cell lymphoma (centrocytic lymphoma) presenting primarily in mucosa (two gastric, one in large bowel and one tonsillar) are reviewed. Their relationship with the broader group of mantle cell and mucosa-associated lymphoid tissue (MALT) lymphomas is also discussed. All four tumours showed a monomorphic picture of mantle cells (centrocytes) arranged in a diffuse, or vaguely nodular, pattern. Scattered non-neoplastic germinal centres were entrapped within the tumour cells, although there was no follicular colonization. In two cases distinct epithelial infiltration by tumour cells was observed. All four tumours had a CD19, CD20, CD5, IgD, Leu8 immunophenotype, whereas KiM1P and CD10 expression were absent. DRC antibody showed loose aggregates of dendritic cells in three of four cases. Three cases showed PRAD-1/Cyclin D1 overexpression by Northern blot analysis. Although we were not able to detect bcl-1 rearrangement in the major translocation cluster (MTC) breakpoint, the possibility of bcl-1 rearrangement involving other cluster breakpoints cannot be ruled out. The four cases evolved as a disseminated disease, involving either peripheral lymph nodes, spleen or bone marrow. The biological behaviour of mantle cell lymphoma presenting in mucosa appears, irrespective of localization or macroscopic presentation, similar to that of nodal mantle cell lymphoma. Their tendency to dissemination contrasts with MALT lymphomas, which tend to remain localized, and from which mucosa mantle cell lymphoma must be distinguished. The presence of lymphoepithelial lesions does not seem to be a useful differential feature, since occasional epithelial infiltration was seen in two cases. Reactivity with CD5 appears to be especially useful in distinguishing these, since all four cases were clearly positive, in contrast with what is usually found in MALT lymphomas.

Patterns of survival in mantle cell lymphoma

The term mantle cell lymphoma (MCL) describes a subtype of non-Hodgkin's lymphoma that includes those lymphomas previously defined as centrocytic lymphoma, intermediate lymphocytic lymphoma, and mantle zone lymphoma. Since MCL has only recently been recognised as a distinct entity, the clinical literature is sparse and very little information is available about its treatment. We retrospectively attempted to analyse the clinical features and outcome of 65 patients with mantle cell lymphoma (MCL) treated from 1979 to 1993 at two institutions in the same geographic area. Univariate (Log-rank test) and multivariate (Cox regression) analyses of the major prognostic factors were performed. At the time of analysis the median follow-up was 49 months. Median age was 64 years with a range of 27-85 years. The male to female ratio was 2:1. Forty-seven patients (72%) had stage IV at presentation and 20 (31%) had B-symptoms at presentation. The patients usually presented with generalised adenopathy (78% of cases) and bone marrow involvement (58%). Serum LDH were analysed at diagnosis in 61 patients and found to be elevated in 30%. beta 2-Microglobulin was determined at presentation in 42 patients and was higher than normal in 54% of them. In comparison with the other subtypes of NHLs in our series, MCL appears to have a very poor survival pattern. The median overall survival was 42 months. The CR rate was 51% with a median DFS of 44 months. Good performance status, normal LDH, normal beta 2-microglobulin, younger age (< 65 years), and a low prognostic risk according to the International Index were significantly associated (p < 0.05) with a better outcome. The characteristics of the patients in this study appear to be in general agreement with those in most of the previously reported series except for the somewhat lower rate of bone marrow infiltration observed in this series. Despite the limitations of a retrospective analysis and the lack of randomization between the treatment options, this study seems to suggest a survival advantage with anthracycline-containing regimens in some patients with MCL. However, this benefit was evident only for the patients with favourable International Index prognostic scores (i.e., low- and to low-intermediate-risk disease) who may already have a better prognosis. Patients with intermediate-high and high-risk disease according to the International Index have a poor prognosis regardless of the type of therapy given.