Carsten Schrader

Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network

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.

Chronic sclerosing sialadenitis of the submandibular gland is mainly due to a T lymphocyte immune reaction

The aim of our study was to investigate the role of immunopathological processes in the pathogenesis of chronic sclerosing sialadenitis of submandibular glands (Küttner tumor). For this purpose, biopsy specimens from submandibular glands of 22 patients with the histological diagnosis of chronic sclerosing sialadenitis were analyzed. Paraffin-embedded tissues were immunostained for T-lymphocyte subsets (CD3, CD4, CD8), cytotoxic T cells (granzyme B), B cells (CD20, Ki-B3), and macrophages (Ki-M1P). Polymerase chain reaction and capillary electrophoresis were used to detect rearrangements of the T-cell receptor gamma chain and the CDRIII region of the immunoglobulin heavy chain. In all cases, abundant cytotoxic T cells were found, especially in close association with ducts and acini. T-cell receptor gamma chain rearrangements showed a monoclonal pattern in 6 cases (27.3%), an oligoclonal pattern in 8 (36.4%), and a polyclonal pattern in 8 (36.4%). The B-cell reaction was less pronounced and largely restricted to lymph follicles. Molecular analysis of immunoglobulin heavy chain revealed a polyclonal rearrangement in 17 cases (77.3%). In conclusion, there is an intimate relationship between the T-cell-dominated inflammatory infiltrate and acinar and duct cells. This, together with the frequent demonstration of monoclonal and oligoclonal populations of cytotoxic T cells and their histopathological behavior, suggests that chronic sclerosing sialadenitis may be the result of an immune process triggered by intraductal agents.

Tumor Sclerosis but Not Cell Proliferation or Malignancy Grade Is a Prognostic Marker in Advanced-Stage Follicular Lymphoma: The German Low Grade Lymphoma Study Group

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Repp86: a new prognostic marker in mantle cell lymphoma.

Abstract:  Objectives: 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 G2, S and M, but not in G1, correlates with the clinical course in patients with MCL. Patients and Methods: 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). Results: 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). Conclusion: Based on these findings, repp86 expression is a new important prognostic factor in MCL.

Growth pattern and distribution of follicular dendritic cells in mantle cell lymphoma: a clinicopathological study of 96 patients

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.

Blastoid variant of mantle cell lymphoma : late progression from classical mantle cell lymphoma and quantitation of minimal residual disease

Abstract:  Objectives: Classical mantle cell lymphoma (MCL) and its blastoid variant (MCL‐BV) are characterized by an extremely poor prognosis. Long‐time survivors are rare, only very few patients with an overall survival over 10 years have been reported. We present a case of a 41‐year‐old male with a 12 yr history of MCL stage I to show, that very late relapses in MCL are possible and may present as a transformation into an aggressive blastoid variant and to illustrate the value of quantitative minimal residual disease (MRD) monitoring for treatment guidance. Methods: Diagnostic lymph node and bone marrow samples were investigated by immunohistochemistry. Clonality analysis was performed by immunoglobulin heavy chain gene (IGVH) and t(11;14) PCR. The MRD assessment was done by real‐time quantitative PCR (RQ‐PCR) on available follow‐up samples. Results: By histologic review and sequencing of the clonal IGVH and t(11;14) PCR products we demonstrated a common clonal origin of the leucemic MCL‐BV and the classical MCL diagnosed 12 yr earlier. Quantitative MRD assessment revealed significant MRD levels after intensive conventional chemotherapy including Rituximab. Therefore, treatment was early intensified by myeloablative radio‐chemotherapy and allogeneic peripheral stem cell transplantation from an unrelated HLA‐identical donor. This did not translate into a sustained remission as reflected by persisting MRD levels after transplantation and the patient died from rapid progressive disease 3.5 months after transplant. Conclusion: This report presents a rare case of long‐term survivor of MCL with a progression of the original MCL cell clone to MCL‐BV and demonstrates the clinical value of quantitative MRD assessment for optimized therapeutic management.

Transforming growth factor beta in chronic obstructive sialadenitis of human submandibular gland

BACKGROUND The exact pathomechanism of inflammation progress and fibrosis in chronic obstructive sialadenitis is unknown. The aim of the present study was to assess whether there is an association between transforming growth factor beta (TGF-beta) and fibrogenic process of chronic sialadenitis. METHODS Tissue samples of 12 patients with chronic sialadenitis and 4 normal tissue samples of the submandibular gland were examined immunohistochemically for identification of TGF-beta. TGF-beta1 messenger RNA (mRNA) expression was analysed semiquantitatively using reverse transcription polymerase chain reaction and gel electrophoresis to correlate its expression levels with stages of the disease. RESULTS TGF-beta positive cells could be found in the secretory duct system of all examined samples. However, an intense TGF-beta immunoreactivity was observed in inflamed salivary glands. With progress of disease TGF-beta1 mRNA expression increases significantly. CONCLUSION Expression of TGF-beta in chronic sialadenitis and its apparent increase in advanced stages of the disease, suggests that this growth factor may play a role in glandular fibrosis.

A 38-year history of natural-killer-cell lymphoma.

To the Editor: In February 1965, a 19-year-old man presented with an extranodal natural-killer-cell–T-cell lymphoma, nasal type, affecting the nasal cavity. One of us made the diagnosis of “granulo...

Antikörpertherapie in der Hämatologie und Onkologie – Teil 2*

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Antikörpertherapie in der Hämatologie und Onkologie – Teil 1*

KasuistikBei einem 67-jährigen Mann wird im August 2000 die Diagnose eines klassischen Mantelzelllymphoms mit generalisiertem Lymphknotenbefall ohne B-Symptomatik gestellt (Stadium III A). Im Rahmen einer multizentr ischen Therapiestudie erfolgt eine Polychemotherapie mit Cyclophosphamid, Doxorubicin, Vincristin und Prednisolon (CHOP). Bei einer Zwischenuntersuchung nach vier Zyklen CHOP lassen sich keine vergrößerten Lymphknoten mehr nachweisen. Es werden daher noch zwei CHOP-Zyklen zur Konsolidierung verabreicht. Anschließend wird der Patient im Rahmen einer Erhaltungstherapie mit Interferon-α behandelt.Unter fortlaufender Erhaltungstherapie tritt Anfang 2004 eine zunehmende Nachtschweißsymptomatik auf. Bei einer Kontrolluntersuchung werden erstmalig wieder generalisierte vergrößerte Lymphknoten entdeckt. Die histologische Untersuchung des Knochenmarks ergibt eine Infiltration mit 40% Mantelzellen. Im peripheren Blutblut zeigen sich bei 11,3/nl Leukozyten etwa 10% zirkulierende Mantelzellen bei einem relativen Lymphozytenanteil von 45% und 42% neutrophilen Granulozyten. Die Thrombozytenzahl liegt bei 150/nl, das Hämoglobin bei 13,3 g/dl. Der ansonsten in einem guten Allgemeinzustand befindliche Patient wird im Rahmen eines Rezidivtherapieprotokolls jetzt mit einer Immunchemotherapie mit Rituximab in Kombination mit Fludarabin, Cyclophosphamid und Mitoxantron (R-FCM) behandelt. Die erste Rituximabgabe erfolgt initial mit 20 mg/h in der 1. Stunde, 50 mg/h in der 2. Stunde und 100 mg/h ab der 3. Stunde. Nach 2,5 h treten massiver Schüttelfrost und Dyspnoe auf. Die Rituximabinfusion wird daraufhin sofort gestoppt, und 100 mg Prednisolon und 25 mg Pethidin werden verabreicht. Die Beschwerden bilden sich rasch zurück. 2 h später wird die Rituximabinfusion mit einer Infusionsgeschwindigkeit von 20 mg in der 1. Stunde, dann 50 mg/h ab der 2. Stunde ohne weitere Dosiserhöhung erneut unter engmaschiger Kontrolle des klinischen Zustands, Pulses und Blutdrucks gestartet und ohne weitere Probleme zu Ende geführt. An den 3 darauffolgenden Tagen wird die FCM-Therapie gegeben. Bei der Wiedervorstellung 4 Wochen nach Beginn des ersten Zyklus hat sich der Nachtschweiß vollkommen zurückgebildet, die hämatologische Verträglichkeit der ersten R-FCM-Therapie war bis auf eine passagere Neutropenie von 900/nl und eine Thrombopenie von 65/nl ohne Auftreten von Fieber oder sonstigen Auffälligkeiten gut. In der Durchflusszytometrie sind Mantelzellen im peripheren Blut jetzt nicht mehr nachweisbar. Die Rituximabgabe erfolgt ab dem zweiten Zyklus ohne Komplikationen mit einer Gesamtfusionsdauer von 4 h. Nach vier Zyklen R-FCM wird eine erneute Vollremission des Lymphoms erreicht, welche mit jeweils vier Gaben Rituximab in jeweils wöchentlichem Abstand nach 3 und 6 Monaten konsolidiert wird. Diese Remission hält 3 Jahre an.