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Wolfram Klapper,
Eva Hoster,
Lars Rölver,
Carsten Schrader, Dirk Janssen,
Markus Tiemann,
Heinz-Wolfram Bernd,
Olaf Determann,
Martin-Leo Hansmann,
Peter Möller,
Alfred Feller,
Harald Stein,
Hans-Heinrich Wacker,
Martin Dreyling,
Michael Unterhalt,
Wolfgang Hiddemann,
German Ott
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ABSTRACT: Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials.
We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial.
Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival.
The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.
Journal of Clinical Oncology 09/2007; 25(22):3330-6. · 18.37 Impact Factor
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American Journal of Surgical Pathology 06/2007; 31(5):812-3. · 4.35 Impact Factor
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ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive lymphoma with accepted risk factors such as proliferation markers. To date, the different follicular dendritic cell (FDC) patterns have never been analyzed in comparison with the overall survival time. Lymph node biopsy specimens from 96 patients were analyzed by conventional morphology and immunohistochemistry with antibodies against cluster differentiation (CD)20, CD5, CD23, cyclin D1, and FDC (Ki-M4P). Two groups can be distinguished with different FDC patterns: a nodular pattern in 79 cases and a diffuse pattern in 17 cases. A Kaplan-Meier analysis revealed significantly better survival for the nodular group (p=0.0312). This group was subdivided into a group with a nodular FDC pattern similar to the FDC distribution in primary follicles (PF-nodular in 72 cases) and one with a nodular FDC pattern resembling the colonization of germinal centers (GCs) by tumor cells (GC-nodular in seven cases). A Kaplan-Meier analysis showed that patients with MCL with a PF-nodular FDC pattern had a significantly better clinical outcome than patients with the other two patterns (p=0.0033). If only cases with classical cytology (n=79) were analyzed (blastoid types excluded), patients with a PF-nodular FDC pattern had a better clinical outcome (p=0.0008). The distribution of FDC in MCL is a diagnostic tool for identifying patients with a better clinical prognosis.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2006; 448(2):151-9. · 2.49 Impact Factor
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Birgit Burkhardt,
Wilhelm Woessmann,
Martin Zimmermann,
Udo Kontny,
Josef Vormoor,
Wolfgang Doerffel,
Georg Mann,
Guenter Henze,
Felix Niggli,
Wolf-Dieter Ludwig, Dirk Janssen,
Hansjoerg Riehm,
Martin Schrappe,
Alfred Reiter
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ABSTRACT: In the Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Munster (NHL-BFM) 95 trial, we tested, against the historical control of the combined trials NHL-BFM90 and NHL-BFM86, whether prophylactic cranial radiotherapy (PCRT) can be omitted for CNS-negative patients with stage III or IV lymphoblastic lymphoma (LBL) with sufficient early response.
Apart from the removal of PCRT in NHL-BFM95, the chemotherapy of the three trials was identical except for the amount of l-asparaginase and daunorubicin during induction. The therapy in NHL-BFM95 was accepted to be noninferior when compared with trials NHL-BFM90/86 if the lower limit of the one-sided 95% CI for the difference in the 2-year probability of event-free-survival (pEFS) between target patients of NHL-BFM95 and the historical controls of NHL-BFM90/86 did not exceed -14%. The target patient group consisted of stage III and IV patients who were CNS negative and responded well to induction therapy.
The number of target patients was 156 in NHL-BFM95 (median age, 8.6 years; range, 0.2 to 19.5 years) and 163 in NHL-BFM90/86 (median age, 8.4 years; range, 0.6 to 16.6 years). For the target group, the pEFS rates at 2 and 5 years were 86% +/- 3% and 82% +/- 3%, respectively, in NHL-BFM95 (median follow-up time, 5.1 years; range, 2.1 to 9.1 years) compared with 91% +/- 2% and 88% +/- 3%, respectively in NHL-BFM90/86 (median follow-up time, 10.7 years; range, 5 to 15.4 years). The lower limit of the one-sided 95% CI for the difference in pEFS was -11% at 2 years and -13% at 5 years. In NHL-BFM95, one isolated and two combined CNS relapses occurred compared with one combined CNS relapse in NHL-BFM90/86. Five-year disease-free-survival rate was 88% +/- 3% in NHL-BFM95 compared with 91% +/- 2% in NHL-BFM90/86.
For CNS-negative patients with stage III or IV LBL and sufficient response to induction therapy, treatment without PCRT may be noninferior to treatment including PCRT.
Journal of Clinical Oncology 02/2006; 24(3):491-9. · 18.37 Impact Factor
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ABSTRACT: Proliferation indices are important prognostic factors for the clinical outcome of patients with mantle cell lymphoma (MCL). We investigated whether the expression of repp86 (restrictedly expressed proliferation-associated protein 86 kDa), a new proliferation specific marker expressed in the cell cycle phases G(2), S and M, but not in G(1), correlates with the clinical course in patients with MCL. Patients and
Biopsy specimens from 94 untreated patients enrolled in two multicenter trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, and repp86 (Ki-S2).
Patients with 0-1% repp86 expression had a median overall survival time of 71.0 months, compared with 38.2 months for patients with 1-5% positive cells and 25.4 months for patients with 5-10% positive tumor cells. Patients with repp86 expression of more than 10% showed the shortest survival (median: 15.0 months). Kaplan-Meier analysis revealed a significant difference in the overall survival time between patients with very high (>10%) and very low (0-1%) repp86 expression (P < 0.0001) in the tumor cells. The multivariate analysis revealed repp86 expression to be superior to other clinical characteristics as a prognostic factor (P = 0.0016).
Based on these findings, repp86 expression is a new important prognostic factor in MCL.
European Journal Of Haematology 12/2005; 75(6):498-504. · 2.61 Impact Factor
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Markus Tiemann,
Carsten Schrader,
Wolfram Klapper,
Martin H Dreyling,
Elias Campo,
Andrew Norton,
Francoise Berger,
Philip Kluin,
German Ott,
Stephano Pileri, [......],
Alfred C Feller,
Hartmut Merz, Dirk Janssen,
Martin L Hansmann,
Han Krieken,
Peter Möller,
Harald Stein,
Michael Unterhalt,
Wolfgang Hiddemann,
Reza Parwaresch
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ABSTRACT: Mantle cell lymphoma (MCL) is a distinct lymphoma subtype with a particularly poor clinical outcome. The clinical relevance of the morphological characteristics of these tumours remains uncertain. The European MCL Network reviewed 304 cases of MCL to determine the prognostic significance of histopathological characteristics. Cytomorphological subtypes, growth pattern and markers of proliferation (mitotic and Ki-67 indices) were analysed. In addition to the known cytological subtypes, classical (87.5%), small cell (3.6%), pleomorphic (5.9%) and blastic (2.6%), we identified new pleomorphic subgroups with mixtures of cells (classical + pleomorphic type; 1.6%) or transitions (classical/pleomorphic type; 1.6%), which, however, did not differ significantly in overall survival time. Exactly 80.5% of cases displayed a diffuse growth pattern, whereas 19.5% of cases had a nodular growth pattern, which was associated with a slightly more favourable prognosis. A high proliferation rate (mitotic or Ki-67 indices) was associated with shorter overall survival. Cut-off levels were defined that allowed three subgroups with different proliferation rates to be discriminated, which showed significantly different clinical outcomes (P < 0.0001). Based on this large clinicopathological study of prospective clinical trials, multivariate analysis confirmed the central prognostic role of cell proliferation and its superiority to all other histomorphological and clinical criteria.
British Journal of Haematology 10/2005; 131(1):29-38. · 4.94 Impact Factor
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Christian Hoffmann,
Markus Tiemann,
Carsten Schrader, Dirk Janssen,
Eva Wolf,
Mathias Vierbuchen,
Reza Parwaresch,
Karen Ernestus,
Andreas Plettenberg,
Albrecht Stoehr,
Gerd Fatkenheuer,
Christoph Wyen,
Mark Oette,
Heinz-August Horst
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ABSTRACT: This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.
Blood 10/2005; 106(5):1762-9. · 9.90 Impact Factor
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ABSTRACT: Juvenile xanthogranuloma (JXG) is an uncommon non-Langerhans cell histiocytosis. We investigated 148 biopsy specimens from 129 patients collected in the Kiel Pediatric Tumor Registry (KPTR) between 1965 and 2001. The clinical, histologic, and immunohistochemical characteristics of JXG were evaluated to gain more and deeper insights into the morphology and clinical behavior of JXG. Conventionally stained lesions were classified into the following morphologic subtypes: early JXG (EJXG), classic JXG (CJXG), transitional JXG (TJXG), or combined lesions with more than one basic pattern (combined JXG). Immunohistochemistry included antibodies against macrophages (Ki-M1P), S-100 protein, CD1a, and factor XIIIa (FXIIIa). Clinical data were obtained by means of a standardized questionnaire. The relative incidence of JXG in the KPTR is 0.52%. The male/female ratio was 1.4:1. The mean age was 22.4 months (median, 5 months; range, 0-244 months). A total of 34.5% of the cases of JXG were congenital, and 71.0% of the lesions were diagnosed within the first year of life. Most cases of cutaneous JXG were solitary (81.0%). Five cases (3.9%) presented with visceral (systemic) involvement. Histologically, CJXG was most frequent (47.2%), followed by EJXG (27.1%) and TJXG (16.0%). A total of 9.7% of the lesions represented combined JXG. Histiocytes, including giant cells, were positive for Ki-M1P (100%) and in most cases for FXIIIa (99%). The CD1a and S-100 protein reactions were generally negative. Clinical and follow-up data showed a generally favorable prognosis with a low relapse rate (7.0%) and even complete involution after incomplete resection. Only 1 of 5 patients with widespread congenital systemic disease died after 34 days. JXG is an uncommon, mostly cutaneous, and prognostically favorable histiocytic tumor of infancy. Simple tumor excision is the therapy for choice except in the very rare systemic JXG, in which multimodal chemotherapy is indicated.
American Journal of Surgical Pathology 02/2005; 29(1):21-8. · 4.35 Impact Factor
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New England Journal of Medicine 02/2004; 350(4):418-9. · 53.30 Impact Factor
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ABSTRACT: Candida albicans (CA) is a frequent opportunistic pathogen in cancer patients. Usually, human surfaces are protected, apart from physical barriers, by the production of human beta-defensins (hBD). hBD-2 shows a potent antimicrobial activity against CA. We therefore investigated whether CA induces hBD-2 expression in primary oral cells and if immunosuppressive betamethasone alters hBD-2 expression. Additionally, we studied, whether a lack of hBD-2 expression could explain opportunistic infection of tonsillar cancer. Primary oral epithelial cells and fibroblasts were stimulated with Candida albicans in a time- and dose-dependent manner with or without betamethasone preincubation. Total RNA from oral cells and specimens was isolated and hBD-2 expression was analyzed by semiquantitative RT-PCR. Our data demonstrate that opportunistic CA induced hBD-2 expression in a time- and dose-dependent manner, suggesting hBD-2 to be a fast antifungal, epithelia-derived immune response. Treatment with glucocorticoid could lead to diminished innate immunity based on suppression of inducible AP. Malignant transformation induces alteration of hBD-2 expression and leads to a reduced hBD-2 expression and subsequentially to Candida colonization on oral SCCs.
Anticancer research 24(2B):1025-30. · 1.73 Impact Factor
