Markus Bangerter

18-F-fluorodeoxyglucose-positron emission tomography as a new approach to detect lymphomatous bone marrow.

PURPOSE Bone marrow involvement in patients with malignant lymphoma is considered a sign of generalized disease with less favorable prognosis. Bone marrow biopsy (BMB), which represents the standard diagnostic procedure, however, is associated with a high rate of false-negative findings, which may lead to errors in management. The present study was undertaken to investigate the efficacy of positron emission tomography (PET) with 18-F-fluorodeoxyglucose (FDG-PET) as a new method to evaluate bone marrow involvement in patients with malignant lymphoma. METHODS Seventy-eight consecutive, untreated patients with either non-Hodgkins lymphoma (NHL; n = 39) or Hodgkins disease (HD; n = 39) were prospectively evaluated. Static FDG-PET imaging was performed following application of 270 MBq (F-18)-FDG. Attenuation correction was performed in 63 of 78 patients. Visual evaluation was performed by two examiners unaware of the clinical data. Material for BMB (70 bilateral, 8 unilateral) was obtained from the posterior iliac crest. Discordant results of PET and biopsy were settled, when possible, on the basis of further biopsy or magnetic resonance imaging (MRI). RESULTS In addition to seven concordant positive and 57 concordant negative findings, biopsy revealed another four cases with bone marrow involvement not detectable by FDG-PET analysis (+5.1%). On the contrary, PET showed bone marrow areas of intensive FDG uptake that suggested bone marrow lymphoma in 10 patients with negative biopsies (+12.8%). In eight patients, FDG-PET findings were confirmed by either histologic verification (n = 4), MRI (n = 2), polymerase chain reaction (PCR) for rearranged immunoglobulin H sequences (n = 1), or clinical presentation (n = 1). Two cases remained unresolved. CONCLUSION The results indicate that FDG-PET has a high potential to detect bone marrow involvement in malignant lymphoma. Besides confirming lesions found at BMB, FDG-PET provided additional information, which, in eight of 78 patients (10.3%), led to an upgrade of the tumor stage.

Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

PURPOSE Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. PATIENTS AND METHODS We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. RESULTS ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. CONCLUSION There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

Positron Emission Tomography with 18-Fluorodeoxyglucose in the Staging and Follow-up of Lymphoma in the Chest

The purpose of this retrospective study was to evaluate the accuracy of positron emission tomography (PET) using 18-F-fluorodeoxyglucose (FDG) in predicting lymphomatous involvement in the hilar and mediastinal regions in the staging and follow-up of patients with malignant lymphoma. One hundred forty-seven thoracic PET studies in 89 consecutive lymphoma patients were reviewed. Static FDG-PET imaging was performed following application of 270 MBq FDG (mean). Results of FDG-PET were compared with the findings of computed tomography (CT) in all patients and clinical follow-up examination. Eighty-nine of 147 (60%) PET studies showed no FDG uptake in the hilar or mediastinal regions, while 58 (40%) studies did detect FDG uptake in these regions. In 52 of 58 abnormal studies (90%), lymphomatous involvement of the hilar and/or mediastinal regions seen by CT was present. In the remaining six abnormal PET studies (10%), FDG uptake was considered as false-positive because of missing lesions on corresponding CT scans. In four patients false-positive FDG uptake was observed before treatment, in two patients after completion of therapy. In these two patients FDG uptake after therapy was caused by thymus hyperplasia. The remaining four cases before treatment remained unresolved. Sensitivity of FDG-PET was 96%, specificity 94%, positive predictive value 90%, and negative predictive value 98%, respectively. The present study suggests that FDG-PET has potential value in predicting lymphomatous involvement in the hilar and mediastinal regions. FDG-PET may obviate invasive diagnostic procedures in patients with lymphoma.

Fine Needle Aspiration Cytology and Flow Cytometry in the Diagnosis and Subclassification of Non-Hodgkin’s Lymphoma Based on the World Health Organization Classification

OBJECTIVE To determine the usefulness of fine needle aspiration cytology (FNAC) in combination with flow cytometry on the new World Health Organization (WHO) classification of malignant lymphoma. STUDY DESIGN Smears and flow cytometry reports of patients who underwent both methods at the same time were independently examined. Both methods were classified according to the new WHO classification of malignant lymphoma. RESULTS A group of 131 smears were examined. In 89 cases exact diagnosis was made by cytomorphology. Twenty-five cases were not classified exactly or were classified incorrectly, resulting in a sensitivity of 96.4% and a specificity of 85%. With flow cytometry, only 30 of 131 patients could be classified exactly, resulting in a sensitivity of 27% and specificity of 100%, respectively. The combination of methods showed a sensitivity of 85% and specificity of 100%. CONCLUSION The combination of FNAC and flow cytometry obtained by FNAC can distinguish between benign and malignant lymphoid infiltrates and support a diagnosis of lymphoma.

Pregnancy in essential thrombocythaemia : treatment and outcome of 17 pregnancies

Abstract: Objective: To evaluate treatment and outcome of 17 pregnancies in nine patients with essential thrombocythaemia (ET) seen at our institution from 1988 to 1998. Methods: Treatment and outcome of 17 pregnancies in nine ET patients were retrospectively analyzed. Results: Seventeen pregnancies in nine patients with ET resulted in 11 (65%) live births and ended in six (35%) spontaneous abortions. Abortion could not be predicted from ET‐associated complications before (p=0.23) or during (p=0.39) pregnancy. Maternal complications occured during six pregnancies (35%): Three major bleedings in two patients with an acquired von Willebrand disease and two minor bleedings in patients treated with low‐dose acetylsalicylic acid (ASA) were observed during pregnancy or at term; one patient suffered from transient visual loss while pausing low‐dose ASA. Platelet counts prior to pregnancy were significantly higher as compared to the platelet nadir observed during pregnancy (p=0.0017). Postpartum clinical course was uneventful in all patients. No specific treatment was given during 11 pregnancies. Six women received low‐dose ASA during pregnancy followed by low‐molecular‐weight heparin until the end of the sixth week postpartum in five cases. This treatment was correlated with a favourable outcome (live birth versus abortion) when compared to no treatment (p=0.04). Conclusion: Pregnancy in ET can be complicated by first trimester abortion and/or maternal haemorrhage. Our limited observation suggest a positive impact of low‐dose ASA during pregnancy followed by low‐molecular‐weight heparin postpartum on pregnancy outcome in ET; nevertheless, confirmation by prospective documentation is mandatory.

Chronic myelogenous leukemia in blast crisis: retrospective analysis of prognostic factors in 90 patients

Abstract Ninety patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis were reviewed to identify significant prognostic associations. At diagnosis of blast crisis the main clinical, laboratory, and cytogenetic data were recorded and evaluated for prognostic significance. At the time of the analysis 89 patients had died, with a median survival of 11 weeks from diagnosis of blast crisis. Patient characteristics demonstrated in the univariate analysis to have significant association with shorter survival were: thrombocythemia, leukocyte count above 20×109, Karnofsky index <50%, nonlymphoid blast cell morphology, cytogenetic clonal evolution, the presence of a double Philadelphia chromosome or trisomy 8, and no response to therapy. In 17 of 59 patients (29%) evaluable for response to therapy a complete or partial remission was achieved. These responders had a significantly longer median survival (25 weeks) as compared with nonresponders (9 weeks). Response to therapy was significantly better in lymphoid blast crisis and in patients without clonal evolution. In a multivariate analysis containing all significant variables of the univariate analysis two parameters retained their prognostic significance: response to therapy and trisomy 8. In spite of the short overall survival in blast crisis, the determination of prognostic factors may be a useful tool for the clinician planning therapy, especially new therapeutic approaches.

Karyotype abnormalities and their clinical significance in blast crisis of chronic myeloid leukemia

Abstract We examined karyotypes and their prognostic significance in a series of 122 patients with chronic myeloid leukemia in blast crisis. Of 73 patients cytogenetically examined at the onset of blast crisis 63% had developed secondary cytogenetic abnormalities in addition to the Philadelphia chromosome. These newly emerging abnormalities included a double Philadelphia chromosome in 20 patients, a trisomy 8 in 17, and an isochromosome 17q in 11 patients. Development of such additional karyotypic abnormalities was significantly associated with a shorter median survival and less response to cytoreductive treatment and was significantly more common in nonlymphoid blast crisis than in the lymphoid-type blast crisis. Thus, assessment of karyotypes at the onset of chronic myeloid leukemia blast crisis appears to be of prognostic significance for both remission duration and survival.

Increased Platelet Surface Expression of P-Selectin and Thrombospondin as Markers of Platelet Activation in Essential Thrombocythaemia

Essential thrombocythaemia (ET) is a clonal myeloproliferative disorder associated with an increased risk of both thromboembolic and bleeding complications. Platelet activation plays a crucial role in the pathogenesis of prethrombotic conditions. The platelet surface expression of p-selectin (CD62p) and thrombospondin (TSP) has been shown to correlate with platelet activation. In the present study, we used a flow cytometric assay to study whether the fraction of platelets expressing CD62p and TSP is increased in newly diagnosed ET. Thirty-four patients with newly diagnosed ET and 25 healthy control subjects were investigated. The proportion of platelets expressing the activation-dependent antigens CD62p and TSP was higher in patients with ET (CD62p: 14.7+/-15.0%; TSP: 12.4+/-9.9%) as compared with healthy control subjects (CD62p: 3.0+/-4.0%; TSP: 3.2+/-3.2%; p< 0.001). In ET, there was a linear correlation between platelet surface expression of CD62p and TSP (p<0.0001, r=0.83). At diagnosis of ET, 20 patients were symptomatic and 14 asymptomatic. Compared with asymptomatic ET patients there was no difference in the expression of CD62p (18.3+/-16.2% vs. 14.5+/-13.4%) and TSP (14.4+/-9.8% vs. 12.8+/-9.5%) in symptomatic ET patients. In conclusion, increased expression of platelet neoantigens is present at the diagnosis of ET. Both activation-dependent epitopes CD62p and TSP are increasingly expressed on the platelet surface in newly diagnosed ET patients.

Combined cytomorphologic and immunophenotypic analysis in the diagnostic workup of lymphomatous effusions.

OBJECTIVE To analyze the results of cytomorphology and immunophenotyping in 54 patients with lymphomatous effusions. STUDY DESIGN We report the results of cytomorphology and immunophenotyping in 54 patients with lymphomatous effusions. Twenty-three of the 54 had a previous diagnosis of NHL. In the remaining 31 patients, lymphomatous involvement was clinically suspected. RESULTS Thirty-three lymphomatous effusions were positive for involvement by NHL. Twenty-one of these 33 patients (64%) had a previous diagnosis of NHL. Of the remaining 12 patients with newly diagnosed NHL, 11 had high grade lymphoma, and one had follicular center lymphoma. Twenty effusions were considered to be reactive; only two of these patients had NHL. One effusion revealed involvement by a previously unknown carcinoma. We observed seven false negative results if only one of both methods was considered. A high grade NHL was not diagnosed by immunophenotyping in one case, and six cases of low grade NHL could not be detected by cytomorphology. The combined strategy of cytomorphology and immunophenotyping had a sensitivity of 100% and specificity of 100% in our study, confirmed by follow-up studies. CONCLUSION Both methods have shown difficulties in the examination of lymphomatous effusions. Cytomorphology has problems distinguishing reactive effusions from low grade NHL. The detection of high grade NHL by immunophenotyping is difficult. However, both methods together offer the advantage of dual staining ability and are most helpful in distinguishing clonal lymphomatous from reactive effusions.

Fine needle aspiration cytology in extramedullary plasmacytoma.

OBJECTIVE Extramedullary plasmacytoma is a rare plasma cell neoplasm. It can occur as the sole manifestation of plasma cell neoplasm, as a metastasis from another extramedullary plasmacytoma, as a solitary plasmacytoma of the bone or as a consequence of multiple myeloma. These plasma cell tumors can occur anywhere and have to be differentiated from other neoplasms, infectious processes and chloroma. STUDY DESIGN We report the findings of fine needle aspiration cytology (FNAC) in 18 patients with extramedullary plasmacytoma. In six patients extramedullary plasmacytoma was the initial presentation of plasma cell neoplasm. In the remaining 12 patients the tumors occurred under or after treatment of plasma cell disease. RESULTS Eleven lesions were located in the skin, seven in the lymph nodes, one in the liver and another in the spleen. Two patients with known diagnoses of plasma cell disease were thought, before FNAC, to have an infection, and two had a histologic diagnosis of non-Hodgkins lymphoma. In 13 of 18 patients, cytologic smears showed anaplastic plasma cells. CONCLUSION FNAC is a front-line investigative procedure in diagnosing extramedullary plasmacytoma.