Unusual presentation of plasmablastic lymphoma involving ovarian mature cystic teratoma: a case report.

BACKGROUND: Plasmablastic lymphoma (PBL) is relatively new clinical entity described as a distinct subtype of diffuse large B-cell lymphoma (DLBCL). It is characterized by its aggressive nature and proliferation of large neoplastic cells resembling immunoblasts including cells with more obvious plasmacytic differentiation. In this case report, we describe an unexpected finding of PBL associated with a mature cystic teratoma of the ovary in a young immune competent woman. CASE PRESENTATION: A 19-year old woman was admitted to the hospital with generalized lymphadenopathy, a pelvic tumor mass measuring 35 × 30 cm and a 4 cm lump in her right breast. She underwent a right salpingo-oophorectomy, lymphadenectomy, splenectomy, omentectomy, and a right breast lumpectomy. On macroscopic examination the right ovary was replaced by a thick-walled multilocular cystic tumor. Upon incision, the cysts were filled with thick, greasy sebaceous material and hair and there were several solid nodules within the cyst walls. Histological examination revealed a mature cystic teratoma and malignant non-Hodgkin lymphoma (NHL) within the solid nodules. Tumor tissue from the right breast, spleen and lymph nodes, all had the same histological, NHL morphology. After extensive immunostaining, a diagnosis of PBL was made. Following surgery, the patient was treated with different chemotherapy regimens, without any significant regression of the disease, and died of multiple organ failure. CONCLUSIONS: Primary NHL of the ovary is relatively rare occurrence while secondary involvement by lymphoma is much more common. PBL is a rare lymphoma, primarily reported in the jaw and oral mucosa, but also documented in extra-oral sites. To the best of our knowledge, this is the first case described in a mature ovarian cystic teratoma. Although the patient was HIV-negative and immune competent, she had progressive disease and died despite aggressive chemotherapy 11 months after the initial diagnosis.

Rapid Fatal Acute Peripheral T-Cell Lymphoma Associated With IgG Plasma Cell Leukemia and IgA Hypergammaglobulinemia.

Simultaneous occurrence of T-cell and B-cell neoplasms is rare, and etiologic relationships between these 2 malignancies are poorly understood. We describe the case of a 66-year-old woman who was admitted to the hospital because of fever, hemoptysis, lymphadenopathy, and skin rash. Enlarged lymph nodes in axillary, pectoral, paratracheal, and periportal regions as well as slight hepatomegaly and splenomegaly were confirmed. A peripheral blood smear revealed rouleaux formation and numerous circulating plasma cells, with plasmacytoid lymphocytes. Immunofixation-electrophoresis detected a monoclonal band defined as immunoglobulin (IgG)-lambda light chains with broad-band polyclonal IgA. The patient died from abrupt splenic rupture before diagnostic work-up was finished. Postmortem examination revealed infiltration of atypical lymphoid cells exhibiting high proliferative activity admixed with typical and atypical plasma cells in several organs. Thus, plasma cell leukemia (IgG-lambda) as a rare and aggressive variant of plasma cell myeloma in the present case was associated with aggressive peripheral T-cell lymphoma and polyclonal (IgA) plasmacytosis.

Concurrent Elevations of VEGF, Osteopontin and MCP-1 Serum Levels Are Independent Predictors of Survival in Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCL) are heterogeneous diseases, and the identification of additional DLBCL risk factors is especially important. METHODS: In this pilot study, we determined pretreatment serum levels of vascular endothelial growth factor (VEGF), osteopontin (OPN) and macrophage chemotactic protein-1 (MCP-1) in 67 newly diagnosed DLBCL patients before treatment with standard chemoimmunotherapy and in 30 healthy persons. RESULTS: Serum levels of all three cytokines were significantly elevated in untreated patients compared to controls. VEGF and OPN concentrations were higher in patients with advanced Ann Arbor stage, B symptoms, Eastern Cooperative Oncology Group score ≥2, International Prognostic Index (IPI) ≥3 and partial/no remission. A high MCP-1 level was associated with advanced stage, increased IPI and bone marrow infiltration. In univariate analysis, elevated OPN and VEGF, and concurrent elevation of all three biomarkers, were identified as significant predictors of poor survival. Multivariate Cox analysis revealed that elevated OPN combined with elevated VEGF levels was one of the best parameter subsets predicting poorest survival. CONCLUSION: According to our preliminary results, serum levels of VEGF and OPN before treatment predict response to therapy and survival after chemoimmunotherapy, and may help to further stratify DLBCL patients into risk groups.

The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma.

Several studies have shown a gradual increase in the extent of bone marrow angiogenesis in various stages of proliferative plasma cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM). The main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow of patients with MGUS and MM. In addition, we wanted to determine their prognostic significance in active MM. Ninety-five patients were enrolled in the study: 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM. Computer assisted image analysis was used to determine the angiogenesis parameters, the quantity of microvessels per 1mm(2) (MVD), the area occupied by microvessels per 1mm(2) and the percentage of microvessel area in total section area (TVA). Double immunohistochemical methods CD138+VEGF and CD138+OPN were used to evaluate expression of these proteins in plasma cells, and OPN was also analyzed for its interstitial expression (iOPN). A significant positive correlation was determined between VEGF and iOPN with angiogenic parameters in the MGUS stage of the disease. In advanced stages of the disease, a significant negative correlation was recorded between OPN and iOPN with parameters of angiogenesis. Overall survival was significantly shorter for patients with negative iOPN (p=0.002) and higher angiogenic parameters, MVD (p=0.009), TVA (p=0.008) and area of microvessels per 1mm(2) (p=0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p=0.03; HR: 0.44, p=0.04). The results of our study suggested a possible key role of VEGF and OPN in the induction of angiogenesis in early-stage disease.

Plasma Levels of Monocyte Chemotactic Protein-1 Are Associated with Clinical Features and Angiogenesis in Patients with Multiple Myeloma.

The aim of this pilot study was to determine the plasma levels of monocyte chemotactic protein-1 (MCP-1) and possible associations with angiogenesis and the main clinical features of untreated patients with multiple myeloma (MM). ELISA was used to determine plasma MCP-1 levels in 45 newly diagnosed MM patients and 24 healthy controls. The blood vessels were highlighted by immunohistochemical staining, and computer-assisted image analysis was used for more objective and accurate determination of two parameters of angiogenesis: microvessel density (MVD) and total vascular area (TVA). The plasma levels of MCP-1 were compared to these parameters and the presence of anemia, renal dysfunction, and bone lesions. A significant positive correlation was found between plasma MCP-1 concentrations and TVA (p = 0.02). The MCP-1 levels were significantly higher in MM patients with evident bone lesions (p = 0.01), renal dysfunction (p = 0.02), or anemia (p = 0.04). Therefore, our preliminary results found a positive association between plasma MCP-1 levels, angiogenesis (expressed as TVA), and clinical features in patients with MM. However, additional prospective studies with a respectable number of patients should be performed to authenticate these results and establish MCP-1 as a possible target of active treatment.

Plasma levels of osteopontin and vascular endothelial growth factor in association with clinical features and parameters of tumor burden in patients with multiple myeloma.

The aim of this pilot study was to determine the plasma levels of osteopontin (OPN) and vascular endothelial growth factor (VEGF) and find possible association between them and main clinical features and parameters of tumor burden in patient with multiple myeloma (MM). Plasma levels of OPN and VEGF were determined in 44 newly diagnosed MM patients and 24 healthy persons by ELISA method. These values were compared with the presence of anemia, renal dysfunction, and bone lesions as myeloma related clinical manifestations and with serum beta-2 microglobulin and Durie-Salmon clinical stage as prognosticators related to tumor mass. The value of OPN was significantly higher in MM patients with evident bone lesions (P = 0.03) and there was also a positive correlation with serum beta-2 microglobulin (r = 0.366; P = 0.04). Furthermore, patients with lower Durie-Salmon stage had significantly lower OPN and VEGF levels (P = 0.05; P = 0.04, resp.). Our preliminary results found positive association between plasma level of OPN, tumor burden, and bone destruction. Further analysis should provide information about the possible use of OPN as useful clinical biomarker for monitoring bone disease and tumor mass, as well as a prognostic factor, or a possible target for pharmacological intervention.

Multiparameter flow cytometry is necessary for detection, characterization and diagnostics of composite mature B-cell lymphoproliferative neoplasms.

Composite mature B-cell lymphoproliferative neoplasms are rare entities characterized by the simultaneous presence of two or more distinctive B-cell derived monoclonal malignancies. This retrospective study used multiparametric flow cytometric analysis aimed at immunophenotypic profiling of composite mature B-cell lymphoproliferative neoplasms in a cohort of 413 subsequent patients with de novo leukemic B-cell chronic lymphoproliferative disorders diagnosed in our institution during a 30-month period. Biclonality was found in 16 (3.9 %) patients. The vast majority (88 %) of the cases had one of the clones phenotypically corresponding to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Only when composite cases were categorized by phenotype of the non-CLL/SLL malignant population did we find a statistically significant (P = 0.001) higher frequency of biclonality among cases with hairy cell leukemia (22 %). Biclonal cases had the overall B-cell membrane κ to λ ratio within the normal range (median, 1.9; reference interval 0.5-4.0), making recognition of malignancy somewhat challenging. Our analysis strategy was therefore based on the detection of aberrant B-cell phenotypes, with subsequent confirmation of the monoclonal nature of neoplastic clones with regards to light chain restriction analysis. Discrimination of the coexisting clones in biclonal cases was possible on the basis of the expression of other antigen(s) (63 %), light scatter properties (44 %), different surface light chain restriction (69 %) and/or pattern of expression (44 %). The most informative cell surface antigens proved to be CD22, CD20, surface IgM, and CD23. In conclusion, historic κ/λ ratio is not a reliable approach and is a poor measurement for the detection of composite lymphomas. More creative analysis techniques should be utilized for this purpose.

[Lymphoma diagnosis and treatment - second Croatian consensus]. / Dijagnostika i lijecenje limfoma - drugi hrvatski konsenzus.

New, extended and modernized recommendations for diagnostics and treatment of lymphomas were accepted at a meeting held in March 2012 with the participation of major Croatian experts. They encompass morphological, radiological and nuclear diagnostics, systemic treatment, radiotherapy and follow-up of most tumors of lymphoid tissues occurring in adults. The recommendations were agreed upon by consensus. Reporters presented data and suggested recommendations which had been first discussed in working groups and then agreed upon on the plenary session.

Myeloma cell morphology and morphometry in correlation with clinical stages and survival.

Multiple myeloma (MM) shows great variability in clinical course of the disease, and survival varies between a few months and more than 10 years. Myeloma plasma cells (PCs) can appear completely "normal" in morphology, but can also be overtly atypical, polymorphic, immature, as well as in all transitional forms. The aim of this investigation was to analyze the relationship between various morphological and morphometric parameters of myeloma cells, common staging/prognostic systems and survival in patients with MM. Sixty newly diagnosed MM patients were included in the study. Morphologic as well as basic morphometric features of myeloma PCs were analyzed in bone marrow (BM) aspirates, and compared with patient's clinical stage determined by Durie-Salmon and International Staging System, and with survival. We conclude that myeloma cell morphology has a prognostic potential. The most significant morphologic characteristics indicating shorter survival are: finding of >15% atypical PCs in BM aspirate, largest nuclear diameter/largest cytoplasmatic diameter of PCs ratio (maxND/maxCD)≥0.65, and anisocytosis expressed as standard deviation of maxCD ≥4.2 µm. Furthermore, PCs with irregular nuclei and absence of paranuclear clearing of the cytoplasm indicate more advanced stage of disease and worse prognosis. This preliminary results obtained on myeloma cells morphology and morphometry should be confirmed in the larger study which will include cytogenetic data as well as a therapeutic protocols applied.

Plasmacytoid urothelial carcinoma--diagnostic challenge in cytology.

Plasmacytoid urothelial carcinoma (PUC) is a very rare variant of urothelial carcinoma with an aggressive clinical course. According to small series reported to date, it is a high grade cancer usually diagnosed at an advanced stage, and with poor prognosis. Descriptions of the cytologic features of this type of carcinoma in literature are limited. Plasmacytoid appearance of tumor cells could cause diagnostic dilemma and potential incorrect diagnosis as multiple myeloma (MM). This report describes cerebrospinal fluid, bone marrow, and urine sediment cytomorphologic and immunocytochemical findings in a patient with meningeal carcinomatosis as the first manifestation of a PUC, initially misdiagnosed as MM with a brief review of the literature.

Assessment of bone marrow fibrosis and angiogenesis in monitoring patients with multiple myeloma.

The aim of our study was to emphasize the importance of accurate and standardized techniques for detailed monitoring of the microenvironment in multiple myeloma (MM). Bone marrow fibrosis, angiogenesis, and plasma cell infiltrates in bone marrow biopsy (BMB) samples at the time of diagnosis and on completion of therapy were analyzed for 42 patients with newly diagnosed MM. Computerized image analysis was used for all slides stained with anti-CD138 and anti-CD34. The patients with fibrosis in pretreatment BMB samples had significantly higher microvessel density (MVD) and plasma cell infiltrates. In posttreatment BMB samples, nonresponders had a significantly higher frequency and grade of fibrosis and higher values of MVD, total vascular area, and plasma cell percentage. The overall survival of nonresponders and patients with increased marrow fibrosis in posttreatment BMB samples was significantly shorter. The obtained results confirm that complex morphologic examination of the bone marrow microenvironment during the monitoring of MM can provide better prognostic significance.

Aggressive multifocal form of epithelioid hemangioendothelioma--case report.

Epithelioid hemangioendothelioma (EHE) is a rare tumor of the vascular origin. It was first described in its pulmonary form by Dail and Leibow in 1975 and named "intravascular bronchioalveolar tumor" (IVBAT). Since then, reports of occurrences of the tumor have been made for number of locations, but most often tumor can be found in soft tissues, liver, lungs, bone and skin. It is considered to be a low or borderline malignant tumor with, usually, slow progression, but aggressive forms have been described. We here report a case of a 46-year old female patient with multifocal malignant tumor spreading to lungs, liver, spleen and with synchronous involvement of lumbal vertebrae, illiac bones and central nervous system dissemination. To the best of the authors knowledge, no case of malignant EHE with multiorgan involvement of this proportions and synchronous central nervous system and bone involvement in one patient has been reported to this date in English-speaking literature.

Gorski Kotar--an endemic region for primary gastric non-hodgkin lymphoma?

Primary gastric non Hodgkin lymphoma (PGNHL) is a distinct group of extranodal lymphomas with interesting geographical distribution and variable prevalence in different countries. We analysed epidemiological data of our patients with PGNHL in Primorsko-goranska County. Clinical data of 30 patients with PGNHL diagnosed and treated in Clinical Hospital Center of Rijeka, Croatia between January 1995 and December 2005 were prospectively analyzed. We used statistical analysis (t-test, chi2-test) for small groups. Out of 30 pts with PGNHL, 19 were born in Primorsko-goranska County, part of Croatia situated by the Adriatic sea which consists of three regions: City of Rijeka, Islands and Gorski Kotar. 6 of 19 patients (31.6%) were originally from Gorski Kotar which made incidence rate of PGNHL in Gorski Kotar 7 times higher than in other two regions. Many authors emphasized that relative frequency of PGNHL is very variable in various countries and regions. Geographical distribution of our patients was very surprising because Gorski Kotar is the region with lowest number of citizens, rural area without any known pollutants, and ecologically one of the most preserved microsystem in this part of Croatia. Gorski Kotar is known to be an endemic region for multiple sclerosis and lyme borreliosis. Is it for PGNHL too?

Dacryocystitis provoked by recurrence of extramedullary plasmacytoma of the orbit: a case report.

Extramedullary plasmacytoma (EMP) of the orbit is an extremely rare tumor, which frequently manifests with nonspecific symptoms. In the case reported, the symptoms of relapsing dacryocystitis appeared before the diagnosis of orbital EMP in a 60-year-old man. Moreover, EMP of the right submandibular gland that had been excised and treated by radiotherapy preceded the orbital lesion by seven years. The present report emphasizes the importance of an extensive medical workup to rule out multiple myeloma or other malignant lymphoproliferative diseases, because their treatment and prognosis are very different. Additionally, it is necessary to consider all tumors that can provoke relapsing dacryocystits.

Macrophage chemotactic protein-1 mRNA levels in non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is one of the most common malignancies whose incidence increases, and the treatment results are not satisfactory. The aim of this study was to determine the capacity of NHL to produce MCP-1, chemokine that induces chemotaxis of macrophages and lymphoid cells. The mRNA expression and protein MCP-1 expression were determined in the samples of 20 patients with NHL and 8 reactive tonsils. MCP-1 mRNA was detected in 8/8 tonsils and in 19/20 patients with NHL by real-time PCR analysis. In addition, the amount of detected MCP-1 cDNA was significantly higher in patients with limited stage, good IPI, normal level of fibrinogen and LDH. Finally, in patients with aggressive NHL, the level of MCP-1 cDNA was higher than in indolent tumours. Immunohistochemical analysis revealed that majority of stromal elements such as macrophages, endothelial and smooth muscle cells in reactive as well as in neoplastic lymphoid tissue showed strong cytoplasmic MCP-1 expression. Moderate cytoplasmic MCP-1 expression was also observed in reactive lymphocytes, while tumour cells of indolent NHL were mostly pale in comparison with aggressive lymphomas which predominantly demonstrated intense MCP-1 staining. These intriguing preliminary results emphasize the need for further investigations that must be conducted on the representative sample with concordant measurement of serum MCP-1 level.

Significance of continuous medical education of general practitioners about common diseases--iron deficiency anemia.

Three years long, prospective study was performed in order to evaluate a possible influence of continuing medical education of general practitioners on managing the patients with common diseases such as iron deficiency anemia (IDA). Altogether 1586 patients that were referred to Hematology Outpatient Clinic, University Hospital Center Rtjeka, Croatia due to diagnosis of IDA were examined by clinical hematologist during the first visit and follow up period, were questioned by the means of questionnaire and complete laboratory analyzes were performed in order to: evaluate physical condition and laboratory findings, to assess duration of anemia, possible other specialists' consultation, iron supplementation therapy, and finally, determine the type of anemia present. Initial group of 983 patients was examined during one year period. Following the education campaign the same parameters were analyzed in comparable (final) group of 603 patients during next one year period. Following the education, the number of patients referred to Outpatient Clinic due to diagnosis of IDA was significantly decreased from 983 (61.97%) to 603 (38.02%) (p < 0.05) as was the number of patients referred as having IDA but finally established to have a different type of anemia, from 661 (97.24%) to 149 (24.71%) (p < 0.001). The number of patients started on iron supplementation therapy before establishing the type of anemia was significantly decreased from 543 (55.24%) to 76 (12.60%) (p < 0.001) as well as duration of iron supplementation therapy administered in these cases (21 +/- 9.8 vs. 6 +/- 8.7 weeks) (p < 0.001). We have detected a significant decrease in: time necessary for definitive diagnosis (49 +/- 19.2 vs. 28 +/- 9.1 weeks) (p < 0.001), number of visits to other specialists (2.9 +/- 1.35 vs. 1.1 +/- 0.94) (p < 0.05), duration of anemia before treatment initialization (41 +/- 29.8 vs. 26 +/- 18.7 weeks) (p < 0.001). Average hemoglobin (Hg) level in patients referred to hematologist was significantly lower following education (98.9 +/- 15.5 vs. 82.6 +/- 14.2) (p < 0.05). Continuing medical education of primary care physicians has significant role in diagnosis and treatment of patients with IDA. Education programs result in benefits for the patients and physicians.

Serum IL-6, IL-8, IL-10 and beta2-microglobulin in association with International Prognostic Index in diffuse large B cell lymphoma.

AIMS AND BACKGROUND: Diffuse large B-cell lymphoma displays striking heterogeneity at clinical, genetic and molecular levels. The International Prognostic Index is useful to predict the outcome of diffuse large B-cell lymphoma patients. However, patients with identical International Prognostic Index values in clinical practice exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each category. Since cytokines such as interleukin-6, -8 and -10 play important roles in the pathogenesis of lymphomas, and plasma level of beta2-microglobulin is associated with the outcome of patients with diffuse large B-cell lymphoma, the aim of the present study was to determine whether these parameters combined with the International Prognostic Index would better stratify these patients to predict their prognosis. PATIENTS AND METHODS: The study included 46 untreated diffuse large B-cell lymphoma patients. RESULTS: All study parameters (International Prognostic Index, Ann Arbor stage, extranodal involvement, performance status, lactate dehydrogenase, beta2-microglobulin, interleukin-6 and -10, and response to therapy) except for patient age and serum interleukin-8 level were associated with overall survival. In addition, the International Prognostic Index was strongly correlated with beta2-microglobulin, interleukin-6, -8 and -10, and when combined these parameters significantly better stratified patients according to survival. On multivariate analysis, therapeutic response to the primary treatment, elevated interleukin-6 and -10 levels, and the International Prognostic Index were significant predictors of overall survival. CONCLUSIONS: Our data imply that interleukins and beta2-microglobulin evaluation should be used in association with the International Prognostic Index to define prognostic subgroups in diffuse large B-cell lymphoma patients.

Correlation of anaemia and cognitive functions measured by the complex reactiometer Drenovac.

Cognitive impairment impinges significantly on the quality of life. Previous research revealed that anaemia can have a major influence on cognitive functioningt. The article is a correlational study examining the relationship between anaemia levels and cognitive functioning in adult patients. Sixty-one patients (both inpatients and outpatients), among them 30 anemic and 31 non-anaemic, 33 female and 28 male, aged 32-60 (median 43) treated at the Dept. of Hematology, Clinical Hospital Center Rijeka, Croatia were analysed according to hemoglobin (Hb) level and cognitive ability. Assessment of cognition (convergent inductive thinking) was performed by the Complex reactiometer Drenovac (CRD). The results showed that anaemia significantly undermines cognitive functions in adult patients (p < 0.01). Even in non-anaemic patients (Hb higher than 120 g/L), Hb level is related to better cognitive ability.

A comparison of lymphocyte subpopulations simultaneously on local and systemic levels in acute rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is one of the most destructive inflammatory and autoimmune joint diseases, most frequently accompanied by extraarticular complications. The pathophysiologic mechanism and the importance of cell subpopulations in the initiation and perpetuation of synovitis are not sufficiently understood. In this study the frequency of lymphocyte subpopulations simultaneously in the synovial fluid (SF), the synovial membrane (SM) and peripheral blood (PB) of acute RA patients is determined, using flow cytometry procedures. The changes in the distribution of T lymphocyte subpopulations were significant on local levels in acute RA patients, resulting in a decreased CD4/CD8 ratio in SF, but an increased CD4/CD8 ratio in SM, compared to the ratio found in PB. The differences observed in the frequency of cells positive on natural killer (NK) cell markers suggest the role of CD16-CD56+ NK cell population in SF of RA patients. Significant differences in the observed frequency of lymphatic subpopulations suggest certain specificities of local immunological events in SM and SF in acute RA. These results confirm the T-lymphocyte hypothesis in initial pathogenic events in RA.