Genetic lesions in mantle cell lymphoma.
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Cell Division↗
Biomedical subjects
M M Ott
Publications and source records attributed to M M Ott.
Inverse correlation of cell proliferation and expression of progesterone receptors in tumor spheroids and monolayer cultures of human meningiomas.
OBJECTIVE: The progesterone receptor (PgR) can be detected in 60 to 70% of meningiomas using immunohistochemistry] in situ. Whereas in monolayer tissue cultures the PgR is only rarely expressed, we were able recently to demonstrate the preservation of the PgR in fragment spheroid cultures of meningiomas. The aim of the present study was to evaluate the stability of PgR expression in meningioma spheroids in vitro and the correlation of PgR expression and cell proliferation in spheroids and whether meningioma cells reaggregated to spheroids from monolayer cultures to reexpress the PgR again. METHODS: Tumor fragment spheroids (Weeks 1-6) and cell monolayers (Passages 1 and 3) of 15 PgR-positive meningiomas were investigated by immunohistochemistry for the expression of PgRs and their proliferative activity, as demonstrated by positivity for the proliferation-related antigen Ki-67. To study PgR reexpression in reaggregated spheroids, Northern blots were performed. In addition, a reverse transcriptase-polymerase chain reaction technique was established and evaluated in combination with immunohistochemistry. Growth of meningioma spheroids was quantified in the presence of progesterone and the specific antagonist onapristone. RESULTS: The PgR remained stable in spheroids for 6 weeks in 9 of 13 cases that were able to be evaluated. All tumor fragment spheroids exhibited a proliferation index of 5 to 40% Ki-67-positive cells. Monolayer cell cultures, on the other hand, failed to express PgRs but revealed higher proliferation indices (40-90%) to a significant extent. The detection of PgR messenger ribonucleic acid in reaggregated spheroids by means of reverse transcriptase-polymerase chain reaction correlated to the nuclear expression of PgR in immunohistochemistry. Neither progesterone nor its antagonist onapristone altered spheroid growth in vitro. CONCLUSION: The expression of the PgR in meningiomas is preserved in spheroid cultures with low proliferation indices for at least 6 weeks, whereas monolayer cell cultures with a high proliferative activity lack PgR expression. The inverse pattern of Ki-67-positive cells in the outer regions of the spheroids and PgR-expressing tumor cells in the spheroid centers leads us to the conclusion that proliferating meningioma tumor cells do not express PgRs. This might also explain why tumor cell growth in vitro was neither affected by progesterone nor by onapristone. Monolayer cell cultures can be reaggregated to spheroids, the consequence being a reexpression of PgRs and, therefore, a down-regulation of proliferation.
Antineoplastic Agents↗
The Epstein-Barr virus in malignant non-Hodgkin's lymphoma of the upper aerodigestive tract.
Sixty malignant non-Hodgkin's lymphomas originating in the upper aerodigestive tract have been analyzed for their cytologic type, immunophenotype and association with the Epstein-Barr virus (EBV). The majority of these tumors were B-cell lymphomas of blastic cytology (78%) with the exception of lymphomas in the parotid gland. Large B-cell lymphomas were the most frequent encountered in the sinonasal region and Waldeyer's ring. Twelve lymphomas were of T- or T/NK (natural killer)-cell lineage. They were in the nasal cavity and the paranasal sinuses (4), the tonsil (5), and the oral cavity (3). Epstein-Barr sequences were detected in five angiocentric T/NK-lymphomas, one peripheral T-cell lymphoma, one lymphoma of lymphomatoid granulomatosis type, one large B-cell lymphoma, and in a lymphoroliferative disorder in an HIV-positive patient. These results suggest that EBV is not involved in lymphomagenesis of B-cell tumors, but is associated with angiocentric T/NK-cell lymphoma in the upper aerodigestive tract.
Blotting, Southern↗
bcl-1 rearrangement and cyclin D1 protein expression in mantle cell lymphoma.
Centrocytic lymphoma, or mantle cell lymphoma (MCL), is characterized by a chromosomal translocation t(11;14) (q13;q32) involving the bcl-1 locus on chromosome 11. Cyclin D1 is a cell-cycle regulatory protein essential for G1-S transition and has been identified as a potential transforming gene affected by the translocation. In this study, 32 cases of MCL were analysed for the bcl-1 rearrangement and cyclin D1 protein expression. In 17 cases, a rearrangement at the major translocation cluster of bcl-1 could be detected. Twenty-four cases exhibited nuclear cyclin D1 expression that was not detectable in other B-cell lymphomas (n = 40) or in normal B-cells. In nine MCL samples, cyclin D1 was expressed without a detectable bcl-1 rearrangement. The detection of a t(11;14) by means of classical cytogenetics in one of these cases, however, may suggest that this discrepancy could be due to chromosomal breakages outside the typical translocation cluster region. In two cases, a bcl-1 rearrangement was not accompanied by cyclin D1 expression. This study provides further evidence that cyclin D1 is involved in the pathogenesis of MCL and can be exploited as a diagnostic marker in the differential diagnosis of B-cell lymphomas and in the identification of MCL.
Base Sequence↗
Progesterone receptors in tumor fragment spheroids of human meningiomas.
Progesterone receptors (PgR) are detectable in about 60-70% of tissue specimens of human meningiomas. Despite these data, PgR are hardly to be found in monolayer tissue culture of meningiomas. Aim of this study was to elucidate whether PgR might be preserved in tumor fragment spheroids of meningiomas maintained in organ culture since the morphological appearance of the original tumor is preserved by this culture technique. Aliquots of meningioma specimens of 25 patients (17 females) were snap frozen in liquid nitrogen immediately after removal. Additionally, monolayer tissue cultures of the same specimen were obtained as primary culture and passage #3. Tumor fragment spheroids were kept on medium-agar with liquid medium overlay and harvested after 1 and 3 weeks in culture. PgR were detected by immunohistochemistry using a rat monoclonal antibody. 18/25 meningioma tissue specimens were positive for PgR. In 8 out of 15 PgR-positive tumors which formed spheroids we could detect PgR in fragment spheroids after 1 and 3 weeks in culture. In contrast, none of the monolayers depicted PgR. PgR is preserved in a considerable amount of tumor fragment spheroids of PgR-positive meningiomas. They remain detectable after 3 weeks of culture whereas monolayer tissue cultures are PgR-negative. Thus, tumor fragment spheroids seem to be a suitable tool to investigate progesterone/antiprogesterone effects in vitro.
Adult↗
Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma.
The origin of low-grade mucosa-associated lymphoid tissue (MALT)-type B-cell lymphoma is still unclear. Using a novel two-step procedure, we have sequenced the Ig VH genes expressed by cells from four patients with gastric low-grade MALT-type lymphoma. The nucleotide sequences of the complementarity determining region 3 (CDR3) of the genomic DNA were first amplified using consensus oligonucleotide primers, then sequenced. Based on the CDR3 sequence amplified from each MALT lymphoma, individual tumor-specific primers were synthesized and used directly in the polymerase chain reaction (PCR) to analyze the sequences of their Ig heavy-chain variable region. When compared with the germ-line sequence, many nucleotide substitutions, mainly in the CDRs, were found in the variable gene sequences of the four MALT lymphomas. The mutations showed a high replacement-to-silent ratio and were distributed in a way which suggested that the tumor cells had been positively selected through their antigen receptor. Our findings indicate that the MALT-type lymphoma B cells are hypermutated postgerminal center lymphocytes that have undergone antigen selection.
Amino Acid Sequence↗
Sex differences in hexachlorobutadiene biotransformation and nephrotoxicity.
Hexachlorobutadiene is nephrotoxic in rats, causing damage to the proximale tubules. Renal toxicity is presumed to be due to bioactivation by glutathione S-conjugate formation. Hexachlorobutadiene is conjugated with glutathione to S-(1,2,3,4,4-pentachlorobutadienyl)glutathione and further transformed to S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBC), which is N-acetylated in the liver to form N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (N-ac-PCBC). N-ac-PCBC is accumulated in the kidney. Renal acylases cleave N-ac-PCBC to PCBC, which is a substrate for renal cysteine conjugate beta-lyase and transformed to a reactive thioketene. Binding of this intermediate to renal macromolecules is most likely responsible for the nephrotoxicity of hexachlorobutadiene. In this study, we administered [14C]HCBD (200 mg/kg, per gavage) to male and female Wistar rats and compared the distribution and biotransformation. No significant differences in the disposition and rates of excretion of [14C]hexachlorobutadiene-derived radioactivity were observed between male and female rats. A portion of the dose (15.6 +/- 4.2) was excreted in the feces and 3.1% ( +/- 0.7) in the urine of male rats, and 11.1% ( +/- 3.8) of the dose was excreted in the feces and 4.5% ( +/- 1.5) in the urine of female rats. The major metabolite excreted by female rats was N-ac-PCBC, while small amounts of PCBC were also detected. In the urine of male rats, in addition to small amounts of PCBC and N-ac-PCBC, N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide and [14C]hexachlorobutadiene were identified. Formation of the electrophile N-ac-PCBC sulfoxide must be considered as an alternative, beta-lyase-independent, bioactivation pathway for hexachlorobutadiene-derived S-conjugates. In isolated rat renal tubular cells, N-ac-PCBC sulfoxide induced a significantly more marked loss in cell viability than N-ac-PCBC. After identical doses of hexachlorobutadiene, the extent of necrosis to the pars recta of the proximal tubules was increased in male rats compared to the necrotic changes in female rats. While female animals showed a normal liver histology, male rats revealed slight toxic centrilobular liver changes in addition to the renal necroses. In vitro, only liver microsomes from male rats catalyzed the formation of N-ac-PCBC sulfoxide from N-ac-PCBC. Our results describe a new pathway of hexachlorobutadiene biotransformation in male rats, the formation of a mercapturic acid sulfoxide. The formation of this Michael acceptor may contribute to sex differences in hexachlorobutadiene nephrotoxicity.
Animals↗
Localized gastric non-Hodgkin's lymphoma of high-grade malignancy in patients with pre-existing chronic lymphocytic leukemia or immunocytoma.
Analyses for clonality in cases of Richter's syndrome have provided evidence for a clonal evolution of high-grade lymphoma in most patients, while in others an independent cellular clone seems to exist in the secondary neoplasm. Richter's syndrome with an isolated high-grade lymphoma of the stomach has been rarely reported in patients with pre-existing B cell chronic lymphocytic leukemia (CLL). We investigated four cases of CLL or lymphoplasmacytoid immunocytoma (LPIC) with development of a localized high-grade B cell lymphoma in the stomach. Southern blotting showed different rearrangements of the immunoglobulin light and heavy chain genes in the tumor cells of the low-grade lymphoma and the gastric tumor in two cases. Comparison of the DNA sequences of the CDR3 region of the immunoglobulin genes revealed different clones in another case. By means of chromosomal in situ hybridization, trisomy 3 was detected in two cases of high-grade lymphoma of the stomach, but not in the cells of the associated low-grade tumor. Our findings indicate that high-grade non-Hodgkin's lymphomas arising localized in the stomach of patients with CLL or immunocytoma are not clonally related to the pre-existing low-grade lymphoma and, therefore indeed, present true secondary neoplasms.
Aged↗
Epstein-Barr virus, B cells, T cells, and a lymphoproliferative disorder.
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Adult↗
Vaginal clear cell carcinoma in a young patient with ectopic termination of the left ureter in the vagina.
The association of clear cell adenocarcinoma of the vagina and vaginal adenosis with prenatal exposure to diethylstilbestrol (DES) is well-documented in the United States. In Europe, however, DES was never used in the therapy of threatened abortion and, therefore, clear cell adenocarcinoma and vaginal adenosis remained rare diseases. We report on the clinical and pathological features of a case of clear cell adenocarcinoma of the upper vagina in a 17-year-old German girl, who had a history of hypoplasia of the left kidney with an ectopic termination of the ureter in the upper vagina, removed surgically 2 years before. No previous report of a similar coincidence of vaginal clear cell carcinoma and a congenital disorder of the genitourinary tract exists. Congenital anomaly of the ureter interfering with the development and the differentiation of the distal Müllerian tract and its epithelium might have provided a similar histological basis for carcinogenesis in our patient to that in those provided exposed to DES.
Adenocarcinoma, Clear Cell↗
[Granulomatous endocarditis caused by streptococcus].
Two cases of granulomatous endocarditis are reported. The patients developed aortal endocarditis refractory to antibiotics. Therefore, aortal valve replacement was performed. In both cases, Streptococcus viridans was demonstrated in culture and bacterioscopically to be the cause of infection. Histological examination of the valves showed characteristic endocarditis with fibrinoid necrosis and histiocytic granulomas. Streptococci were found in the cytoplasm of macrophages. The possible causes of this special form of infectious endocarditis are discussed.
Adolescent↗
Large cell anaplastic (KI-1) brain lymphoma of T-cell genotype.
Three cerebral lesions were neuroradiologically detected in a 63-year-old man without evidence of an extracranial neoplasm. The biopsy specimen from one lesion showed a large cell anaplastic lymphoma (LCAL). Immunohistochemically, tumor cells were positive for CD3, CD30, CD45RO, and HLA-DR. The polymerase chain reaction (PCR) of the rearranged T-cell receptor beta chain genome (TcR beta) derived from paraffin sections showed monoclonality. This case shows that primary cerebral T-cell lymphomas genotypically correspond to nodal T-cell lymphomas, a correspondence that has previously been demonstrated for the more common brain lymphomas of B-cell lineage.
Brain Neoplasms↗
The anaplastic variant of centrocytic lymphoma is marked by frequent rearrangements of the bcl-1 gene and high proliferation indices.
Ten cases of classic centrocytic lymphoma as defined in the Kiel classification system were investigated for their immunophenotype, their proliferation activity and by means of molecular diagnostics. The findings were compared to those obtained from a group of nine cases of anaplastic centrocytic lymphoma. Both groups showed virtually identical immunohistochemical characteristics with positivity for CD5 and negativity for CD10 and CD23. In the group of anaplastic centrocytic lymphoma, there were considerably higher proliferation indices as documented by staining for the Ki-67 antigen, up to 80% of the tumour cells being positive. Moreover, the cases of anaplastic centrocytic lymphoma had bcl-1 gene rearrangements in eight out of nine cases compared with three out of 10 cases of classic centrocytic lymphoma. DNA analysis was not able to detect bcl-2 gene rearrangement in any case, pointing to a difference compared with lymphomas of germinal centre origin. The coincidence of anaplastic and sometimes blast-like morphology of the tumour cells, high proliferation index and a rearranged bcl-1 gene in nearly all cases of anaplastic centrocytic lymphoma support their classification as high-grade malignant variants of centrocytic lymphoma and suggest a possible role for the bcl-1 locus not only in the origin but also in the progression of centrocytic lymphomas.
Aged↗
[Characterization of clonal B-cell populations in gastric MALT lymphomas and chronic gastritis by means of the polymerase chain reaction].
Amplification of the CDR3-region of the immunoglobulin (Ig) heavy chain gene rearrangement by means of the PCR yielded clonal products in the tumor DNA of 12 high or low grade gastric B-cell lymphomas of MALT-type. In four cases, additional clonal bands were found in different areas of tumor free mucosa diagnosed as chronic gastritis associated with Helicobacter pylori (HP). Most of these small clonal populations were found to share identical DNA sequences in their clone specific CDR3-regions with the main lymphoma in each patient; a finding consistent with the multifocal character of the disease. In two cases however, single clonal populations with different CDR3-regions revealed the existence of rare additional clonal B-cell-populations not related to the lymphoma and therefore possibly representing further independent foci.
B-Lymphocytes↗
Gene rearrangement of bcl-1 and bcl-2 is confined to distinct subgroups of high-grade malignant B-cell lymphomas.
The occurrence of bcl-1 and bcl-2 gene rearrangements was investigated in 37 cases of high-grade B-cell lymphomas. Bcl-2 rearrangement was detectable only in single cases of primary centroblastic lymphoma with a follicular growth pattern, whereas secondary centroblastic lymphomas evolving from a centroblastic-centrocytic lymphoma were positive in up to 60 per cent of the cases analysed. Bcl-1 rearrangement was found only in one case of immunoblastic B-cell lymphoma with a history of pre-existing lymphoplasmacytoid immunocytoma. It is concluded that there may be a subgroup of centroblastic lymphomas with a biology similar to that of centroblastic-centrocytic lymphomas. The detection of bcl-1 rearrangement in high-grade lymphomas may indicate a secondary high-grade lymphoma.
DNA, Neoplasm↗
Prevalence of Epstein-Barr virus DNA in different T-cell lymphoma entities in a European population.
The Epstein-Barr virus (EBV) has been classically associated with nasopharyngeal carcinoma and Burkitt's lymphoma, a monoclonal B-cell non-Hodgkin's lymphoma. Since the EBV genome has also been found in post-transplant lymphomas and lymphomas arising in individuals infected with the human immunodeficiency virus, evidence has now accumulated that EBV might be the initiator of a multi-step process leading from polyclonal B-cell hyperplasias to monoclonal lymphoma. In a retrospective study of 60 T-cell lymphomas of various types, we found EBV DNA in 21 (35%) using Southern- and/or dot-blot techniques. Eight of 14 nodal samples of angio-immunoblastic lymphadenopathy (57%) were shown to harbour detectable EBV DNA. The tumour with the next highest frequency, 47% (7/15 cases analyzed) was pleomorphic T-cell lymphoma, medium- and large-cell type; EBV was found both in nodal and in extranodal lymphomas of this type. Lymphoepitheloid (Lennert's) lymphoma and large-cell anaplastic lymphoma were positive in 2/5 and 3/8, respectively, of the cases analyzed. No viral DNA could be demonstrated in 3 T-immunoblastic and 5 T-lymphoblastic lymphomas. Clonotypic analysis revealed monoclonal as well as oligoclonal virus populations. Our data suggest that, at least in some of these entities, the presence of the EBV genome might be due to secondary mechanisms such as escape from immune surveillance.
DNA, Viral↗
[Detection of Epstein-Barr virus genomes in various entities of low and high grade T-cell lymphomas].
72 T-cell lymphomas were analyzed for the presence of Epstein-Barr virus DNA using Southern or dot blot hybridization. EBV DNA was found in 25 peripheral T-cell lymphomas and in none of 6 T-lymphoblastic tumors. A high prevalence of EBV was detected in AILD type, Lennert's, pleomorphic medium and large cell nodal lymphomas and in upper aerodigestive tract lymphoma biopsies. Clonotypic analysis revealed monoclonal as well as oligoclonal viral populations. The possible influence of EBV in lymphomagenesis, the impact of virus-mediated interactions in the B- and T-cell system and factors involving site of tumor development are discussed.
Biopsy↗
A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma.
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Aged↗