Mara Dominis

Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance.

Notch signaling is implicated in the pathogenesis of multiple myeloma expressing high level of active Notch proteins NOTCH1 and JAGGED1 in tumor plasma cells. We investigated expression of NOTCH1 and JAGGED1 in bone marrow trephine biopsies of 80 newly diagnosed multiple myeloma and 20 monoclonal gammopathy of undetermined significance patients using immunohistochemical methods. The number of positive tumor cells was counted per 1000 tumor cells and the intensity of staining was assessed semi quantitatively. Multiple myelomas expressed NOTCH1 in 92.31% (72/78) and JAGGED1 in 92.21% (71/77) cases. NOTCH1 staining was strong in the majority of cases (59.7%), whereas JAGGED1 was predominately weak (67.6% of cases). In contrast, both markers were negative in all monoclonal gammopathy of undetermined significance cases. However, upon progression of disease from monoclonal gammopathy of undetermined significance to multiple myeloma (seen in 4 patients), analysis of the subsequent bone marrow biopsy showed weak expression of both markers in tumorous plasma cells. Immunohistochemistry results were compared with the pattern of bone marrow infiltration, plasma cell differentiation, and the presence of t(11;14)(q13,q32), t(14;16)(q32;q23),and t(4;14)(p16.3;q23) and overall survival in multiple myeloma patients. A significant correlation was found between strong NOTCH1 staining in multiple myeloma plasma cells and the diffuse type of bone marrow infiltration (P = .002) and an immature morphologic type of plasma cells (P = .043). After a median follow-up of 20.3 months, in multiple myeloma patients no difference in overall survival between NOTCH1 (P = .484) and JAGGED1 (P = .822) positive and negative cases were found. In conclusion, our results indicate importance of NOTCH1 and JAGGED1 expression in plasma cell neoplasia and a possible diagnostic value of their immunohistochemical evaluation of bone marrow infiltrates for multiple myeloma.

Cytogenetic analysis in ataxia telangiectasia with malignant lymphoma

We present the results of cytogenetic analysis in a brother and sister with ataxia telangiectasia (AT), one of whom had malignant T-cell lymphoma. In both children, cytogenetic analysis of phytohemagglutinin (PHA)-stimulated lymphocytes showed chromosomal instability and inv(7) in 10% of the cells examined. The malignant lymphoma was analyzed cytogenetically on slides obtained from short-term culture of the lymph node cells; 64 cells were analyzed. A heterogeneous cell population was noted. Fourteen cells (21.9%) had a normal male karyotype; t(7;14)(p14;q12) and inv(7)(p14q35) were observed in 6.3% and 3.1% of metaphases. Owing to low frequency, these cells are probably a characteristic of the basic disease and have no features of malignant cells. Forty cells (62.5%) had a pseudodiploid karyotype 46,XY,dup(1)(p22p36),del(5)(q33),del(12)(p11), without cytogenetically evident aberrations of chromosomes 7 and 14. The results of these investigations suggest that the cells with rearrangements of chromosomes 1, 5, and 12 are malignant cells and did not originate by transformation of cells with inv(7) and t(7;14).

Primary mediastinal large B-cell lymphoma: a single-center study of clinicopathologic characteristics.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a subset of LBCL with unique clinicopathologic features. Some studies have raised the question of differences in biological features and clinical course among patients from different parts of the world. We conducted a retrospective clinicopathologic analysis of 24 patients with PMLBCL from a single center in Croatia. We also conducted the first investigation of the frequency of lymphotropic viruses human herpesvirus 6 (HHV-6) and HHV-8 in lymphoid lesions of this disease.The clinical characteristics of the patients were as expected, with high International Prognostic Index scores, elevated serum lactate dehydrogenase (LDH) levels, and bulky disease being adverse prognostic factors. Only 6 patients (25%) showed CD30 expression, and Bcl-6 protein expression was, in our series, prognostically favorable (P = .0401). One patient’s tumor had detectable HHV-6 genome sequence, but no HHV-8 sequences were detected in any tumors. Two thirds of the patients received CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone) with a relatively low complete remission rate (43.8%; median follow-up, 33.8 months). This study confirmed the moderate preponderance among PMLBCL patients of young females with B symptoms and elevated LDH levels.The CHOP regimen proved effective as first-line therapy only in patients with limited disease. Therefore, other third-generation chemotherapy protocols may be considered for treatment, especially in patients with bulky and advanced disease.

MALT1, BCL10 and FOXP1 in salivary gland mucosa-associated lymphoid tissue lymphomas.

In view of the certain anatomic site‐dependent frequency of chromosomal translocations involved in extranodal marginal zone B cell lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) pathogenesis, 17 salivary gland MALT lymphoma cases were analyzed for MALT1 and FOXP1 translocations. B cell CLL/lymphoma 10 (BCL10) and forkhead box PA (FOXP1) protein expression were studied by immunohistochemistry and translocations identified using fluorescence in situ hybridization (FISH)‐specific probes FOXP1, t(11;18)(q21;q21)/API2‐MALT1 and t(14;18)(q32;q21)/IgH‐MALT1. None of the 11 analyzed cases showed FOXP1 rearrangement or amplification. The t(11;18) was present in five of 13 cases and the t(14;18) in three of 13 cases. MALT1 translocations were mostly mutually exclusive except in a single case. FOXP1 protein expression showed differences in the proportion of tumor cells with nuclear expression but not in their intensity, with the exception of one case where very intense nuclear staining was noted. BCL10 nuclear expression was present in four of 17 cases, two of which lacked t(11;18). Our results suggest that MALT1‐specific translocations and FOXP1 rearrangements are not commonly involved in pathogenesis. A case with strong FOXP1 protein expression indicates the possibility that the upregulation of FOXP1 expression is significant in a small subset of salivary gland MALT lymphomas. Also a single case in which both MALT1 translocations were present indicates that these are not always mutually exclusive.

Jumping translocations involving 11q in a non-hodgkin lymphoma

This paper presents the results of a cytogenetic analysis in an 11-year-old boy with non-Hodgkin lymphoma. The investigation was performed on slides obtained from short-term culture of lymph node cells. The analyses revealed an abnormal clone with loss of Y, gain of an X chromosome, t(3;22), trisomy 11, and three cytogenetically-related subclones with jumping translocations involving 11q13 as the common breakpoint region. This region is an unusual site of chromosome breakage in jumping translocations, and has not been reported thus far. Contrary to most published reports, the jumping translocation in our patient is associated with long survival.

Embryonal rhabdomyosarocoma with 92,XXYY, +dmin and evidence of spontaneous cell fusion

The results of a cytogenetic analysis in an embryonal rhabdomyosarcoma are presented. A tetraploid karyotype with double minute chromosomes (dmin) was identified using a direct method of tumor tissue treatment. In 5% of the examined cells, evidence of spontaneous cell fusion was observed.

Cytology of experimental teratomas and teratocarcinomas.

Von bei Mäusen erzeugten Teratomen und Teratocarcinomen entstehen in der Hälfte der Fälle ungefähr gleich häufig bösartige wie gutartige Mischtumoren. Bei der Punktion und der nachfolgenden cytologischen Untersuchung war es jedoch nicht möglich, aus den Abstrichen maligne und benigne Tumoren zu trennen.

Role of MYC in B Cell Lymphomagenesis

B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

Follicular and mantle cell lymphoma characteristics present simultaneously in the same lymph node.

Follicular lymphoma is composed of clonal germinal center B cells. It shows a follicular pattern lacking mantle zones, with a network of interfollicular dendritic cells. Transformation to more aggressive lymphomas is documented, but the only connections to mantle cell lymphoma are described cases of composite lymphoma consisting of these 2 entities. We discuss here a case of a lymph node harboring CD20+, CD10+, BCL2+, BCL6+/−, cyclin D1−, CD5+, Ki67+, and SOX11+ with CD21, showing an almost intact network of dendritic cells in one part of a lymph node, and CD20+, CD5+, SOX11+, BCL6−, cyclin D1−, CD10−, Ki67+, and CD21+ cells restricted to the mantle area in another part of the same lymph node. Both parts of the lymph node had BCL2 rearrangement, a lack of t(11:14)(q13;q32), the presence of SOX11 expression, and the same clonal band. The described case suggests heterogenous development of small cell lymphomas and indicates the possibility of differentiation regression.

FOXP1 expression in monoclonal gammopathy of undetermined significance and multiple myeloma

Multiple myeloma (MM) is a clonal disorder of terminally differentiated B cells. In some cases the premalignant state is monoclonal gammopathy of undetermined significance (MGUS). Neoplastic plasma cells in both entities carry multiple and complex chromosomal abnormalities that make understanding of the disease development difficult. New insight into malignant mechanisms that underlie multiple myeloma may come from forkhead box P1 transcription factor (FOXP1) analysis in neoplastic plasma cells. FOXP1 is known to be important for B‐cell maturation and differentiation and could play a significant role in plasma cell tumors. The purpose of the present study was therefore to analyze FOXP1 protein presence and FOXP1 gene abnormalities in 13 cases of MGUS and 60 cases of MM. It was found that FOXP1 protein was expressed in neoplastic plasma cells, unlike in their normal counterparts, and that additional FOXP1 gene copies could be found in both MGUS and MM. Based on FOXP1 presence in MM and its role in diffuse large B‐cell lymphoma and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue, FOXP1 might play an important role in plasma cell neoplasm.