Malignant Subgroups Research Articles

Atypical Myeloproliferative Disorders: Diagnosis and Management

Myeloid disorders constitute a subgroup of hematological malignancies that is separate from lymphoid disorders. The World Health Organization system for classification of tumors of the hematopoietic system divides myeloid disorders into acute myeloid leukemia and chronic myeloid disorders based on the presence or absence, respectively, of acute myeloid leukemia--defining morphological and cytogenetic features including the presence of 20% or more myeloblasts in either the bone marrow or the peripheral blood. A recently proposed semimolecular classification system for chronic myeloid disorders recognizes 3 broad categories: the myelodysplastic syndrome, classic myeloproliferative disorders (MPD), and atypical MPD. Classic MPD includes polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and chronic myeloid leukemia. Both myelodysplastic syndrome and BCR/ABL-negative classic MPD were previously discussed as part of the current ongoing symposium on hematological malignancies. The current review focuses on the diagnosis and treatment of both molecularly defined and clinicopathologically assigned categories of atypical MPD: chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic neutrophilic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, idiopathic eosinophilia including hypereosinophilic syndrome, systemic mastocytosis, unclassified MPD, and eosinophilic/mast cell disorders associated with mutations of platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB), FGFR1, and KIT.

The JAK2 V617F Tyrosine Kinase Mutation in Myeloproliferative Disorders: Status Report and Immediate Implications for Disease Classification and Diagnosis

Janus kinase 2 (JAK2) is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the gamma-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme. The main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. The myeloproliferative disorders (MPD), a subgroup of myeloid malignancies, are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythroid, megakaryocyte, or monocyte lineage cells. Among the traditionally classified MPD, the disease-causing mutation has been delineated, thus far, for only chronic myeloid leukemia (ie, bcr/abl). In the past 3 months, 7 different studies have Independently described a close association between an activating JAK2 mutation (JAK2V617F) and the classic bcr/abi-negative MPD (ie, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia) as well as the less frequent occurrence of the same mutation in both atypical MPD and the myelodysplastic syndrome. The particular finding is consistent with previous observations that have implicated the JAK/STAT signal transduction pathway in the pathogenesis of bcr/abl-negative MPD, Including the phenotype of growth factor independence and/or hypersensitivity. The current article summarizes this new information and discusses its implications for both classification and diagnosis of MPD.

Pseudomyxoma peritonei.

Pseudomyxoma peritonei is an unusual condition in which gelatinous fluid collections are associated with mucinous implants on the peritoneal surfaces and omentum. The pathological origin and ideal treatment of the condition are subjects of debate. An unrestricted Medline search over 1986-1997 was performed for pseudomyxoma peritonei. There is increasing evidence that pseudomyxoma peritonei is a neoplastic condition which usually arises from a primary adenoma or adenocarcinoma of the appendix. Reported series include a spectrum of pathological lesions, from entirely benign ruptured mucocele to advanced carcinoma. This, and the rarity of the condition, limit the conclusions that can be drawn regarding its treatment and prognosis. Most authorities agree that a thorough surgical debulking should be made. In most cases this will be a difficult and time-consuming undertaking, possibly requiring cooperation between two or more specialists and consideration of delivering intraperitoneal adjuvant therapy during or immediately after surgery. Treatment therefore requires a planned approach with accurate preoperative assessment of the diagnosis and the extent of the condition. There is some largely anecdotal evidence in favour of intraperitoneal chemotherapy and radioisotope treatment. Ultraradical surgery, with heated intraoperative and further postoperative chemotherapy, is strongly advocated by one group but remains contentious. The majority of patients will eventually suffer recurrence. The 5-year survival rate ranges from 53 to 75 per cent, but outcomes vary widely between relatively benign and malignant subgroups.

Influence of glutamine and glycyl-glutamine on in vitro lymphocyte proliferation in children with solid tumors.

It is reported that the proliferative response of lymphocytes is lowered in patients with solid tumors. Glutamine is a major nutrient for rapidly proliferating cells. Unlike glutamine itself, the dipeptide glycyl-glutamine as a source for glutamine is stable in aqueous solutions ex vivo. In order to evaluate the possible therapeutic role of glutamine in lymphocyte proliferation, we investigated its influence on lymphocytes of children with solid tumors before and after chemotherapy. Lymphocytes were collected from 21 children and adolescents suffering from solid tumors (before and after chemotherapy) and from healthy controls. Glutamine and glycyl-glutamine, respectively, were added to cell cultures at concentrations between zero and 1.0 mmol/l. ConA or SAC served as T- or B-cell mitogens, respectively. The lymphocyte proliferation in the healthy control group was similar in degree to lymphocyte proliferation seen in the patients with solid tumors, regardless of the mitogen used. No difference in the degree of lymphocyte proliferation before or after chemotherapy was seen with either source of glutamine. Specific subgroups of malignancies showed trends that differed from the overall findings, but these differences were not found to be statistically significant. Routine supplementation with glutamine in children with solid tumors to enhance lymphocyte function is not supported by the data gained from in vitro proliferation tests.

Use of cytokeratin fragments 19.1 and 19.21 (Cyfra 21-1) in the differentiation of malignant and benign pleural effusions.

Differentiation between malignant and benign pleural effusions is often difficult. Serum level of Cyfra 21-1, a marker of cytokeratin 19 fragments, has been used in the diagnosis and monitoring of epithelial tumours, especially bronchogenic carcinomas. This study is designed to establish the usefulness of effusion Cyfra 21-1 level in differentiating malignant from benign effusions. Forty-eight malignant effusion aspirates (proven by cytology or pleural biopsy) and 34 benign samples were compared. Cyfra 21-1 concentration was measured by a solid phase sandwich radioimmunoassay (Centocur, USA). Cyfra 21-1 level was significantly higher in malignant effusions (geometric mean 123.6 ng/mL, 95% confidence interval [CI] 76.6-199.4) than in benign ones (geometric mean 14.3 ng/mL, 95% CI 8.5-23.9), p<0.00005. By Receiver Operating Characteristics curve analysis, the sensitivity is 77% for a specificity of 79% if the cut-off is set at 32 ng/mL. No significant difference was observed (p=0.1) in Cyfra 21-1 concentration between adenocarcinoma and mesothelioma effusions. Cyfra 21-1 level was not influenced by the effusion protein concentration (r=0.29), or by renal function as measured by serum creatinine (r=0.1). There was no significant difference between Cyfra 21-1 levels in benign exudate and transudate effusions, p=0.28. Cyfra 21-1 is a useful adjunct in the workup of effusions but should not replace conventional investigations as there is considerable overlap in levels between benign and malignant groups. It is unable to differentiate between subgroups of malignancies.

Factors in improved survival from paediatric cancer.

In 1998, over two-thirds of children diagnosed with cancer will be cured of their disease. This has been accomplished by improvements in understanding the biology of the various forms of cancer and stratifying protocol-based therapies (surgery, radiotherapy and chemotherapy) based on predicted treatment outcome and risk of treatment failure. The excellent prognosis of subgroups of malignancies, including acute lymphoblastic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma and Wilms' tumour, has led to the modification of therapies to decrease or minimise long term adverse effects which may have a significant impact on the quality of life of survivors. The lessons learned from the treatment of paediatric cancer may lead to improvements in the treatment of adult cancers.

C-erbB-2 oncoprotein: a potential biomarker of advanced prostate cancer.

Overexpression of the c-erbB-2 oncogene has been implicated in the development and/or prognosis of several human carcinomas, including that of the prostate. Recently, c-erbB-2 protein was found to be released in the circulation. The present study was undertaken to study the significance of serum c-erbB-2 protein determination in men with prostate cancer. Serum c-erbB-2 protein determination was performed via immunoradiometric assay using two monoclonal antibodies that react with the extracellular domain of the protein. The study population consisted of 71 untreated prostate cancer patients. Of those, 33 with stage D2 disease entered a follow-up study. As control, serum c-erbB-2 protein levels were determined in 92 patients with benign prostatic hypertrophy. In addition, elevations of c-erbB-2 protein were examined in patients with various disease statuses: clinically well controlled (28 patients), disease progression (24 patients), and end-stage disease (17 patients). Elevation of serum c-erbB-2 protein level was observed in patients in advanced stages, such as stage D2 disease (30%), disease progression (42%), and end-stage disease (82.4%). In the follow-up study, patients with an elevated c-erbB-2 level had a significantly shorter interval to disease progression than did those with a normal level. The results suggest that c-erbB-2 can be used as a biomarker to identify a malignant subgroup in prostate cancer.

TEL Gene Is Involved in Myelodysplastic Syndromes With Either the Typical t(5;12)(q33;p13) Translocation or its Variant t(10;12)(q24;p13)

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet-derived growth factor receptor-B gene on chromosome 5 and a novel ETS-like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.

17p anomalies in lymphoid malignancies: diagnostic and prognostic implications.

Eighteen patients with lymphoid malignancies and abnormalities of the short arm of chromosome 17 were evaluated, in order to analyse whether this anomaly was associated with a particular subgroup of lymphoid malignancies. The patients suffered from acute lymphoblastic leukemia, high-grade non-Hodgkin's lymphoma or plasma cell leukemia. No 17p anomaly was found in any patient with chronic lymphocytic leukemia or low-grade non-Hodgkin's lymphoma. In four cases the aberration of the short arm of chromosome 17 was the sole cytogenetic abnormality, in fourteen patients additional chromosomal aberrations were found. Five out of 18 cases were Burkitt's lymphoma/leukemia showing the typical rearrangement of 8q24. In cases with a karyotype evolution the 17p anomaly was always a late event. Concerning the clinical outcome of the patients with abnormalities of the short arm of chromosome 17 eight of nineteen patients died within 90 days after the diagnosis of the 17p anomaly only three were alive at the last follow up (26 months to 40 months after diagnosis of a 17p aberration). Rearrangements of 17p, especially as secondary cytogenetic events, seem to be associated with a poor clinical outcome in lymphoid malignancies.

11q deletions in human colorectal carcinomas: cytogenetics and restriction fragment length polymorphism analysis.

Deletions and/or allelic losses of a portion of the long arm of chromosome 11 were discovered by cytogenetic and restriction fragment length polymorphism analyses in 23 of 39 (59%) informative cases of colorectal carcinoma. By comparing the patterns of loss of heterozygosity and chromosome rearrangements in different patients, we could map a common target region to 11q22-23. This region may contain a tumor suppressor gene, the inactivation of which may be involved in the development of tumors of the large intestine. The subgroup of malignancies with 11q alterations seemed to be enriched by tumors that were located in the rectum, that were Dukes' stage A, and that were well differentiated and mucin producing.

An immunohistologic evaluation of C-erbB-2 gene product in patients with urinary bladder carcinoma.

Amplification or overexpression of the c-erbB-2 gene have been reported to correlate with poor patient prognosis in human breast, gastric, and ovarian cancer. Recently, the c-erbB-2 gene product was found to be expressed frequently in the urinary bladder carcinoma. In the current study, the presence of the c-erbB-2 gene product in urinary bladder carcinomas was compared with patient outcome to evaluate whether c-erbB-2 gene product could identify a subset of patients who are destined to have a poor prognosis. Immunohistologic study of the c-erbB-2 gene product was done in formaldehyde-fixed paraffin-embedded tissue specimens obtained from 88 transitional cell carcinomas of the human urinary bladder. Eighty-three patients who underwent complete tumor resection by total cystoprostatectomy (30 patients) or by bladder-preserving operations such as transurethral surgery (50 patients) or partial cystectomy (3 patients) entered a follow-up study. The other five patients did not enter the follow-up study because of lost follow-up (2 patients) or distant metastasis at the time of surgery. The c-erbB-2 gene product was expressed in 23 of 88 patients (26%), showing an increase in the expression rate corresponding to the advancement of tumor grade (P < 0.05) and tumor stage (P < 0.2). The 5-year disease-free survival rate was 48.5% for patients with c-erbB-2 negative tumors versus 9.7% for those with c-erbB-2 positive tumors (P < 0.01). The 5-year actuarial survival rate was 65.5% for patients with c-erbB-2 negative tumors versus 41.8% for those with c-erbB-2 positive tumors (P < 0.05). Multivariate analysis using Cox regression model showed that the c-erbB-2 gene product tissue status was a significant prognostic factor independent of grade and stage of the tumor. The results suggest that the c-erbB-2 gene product could be a tumor marker to identify a malignant subgroup in bladder carcinomas.

Grading and prognostic significance of urologic carcinomas.

The extent of surgical therapy of urological tumors and the intensity of post-surgical or primary chemo- or radiotherapy are dependent on staging and grading. Since the proliferative activity determines the size of the tumor, the primary prognostic evaluation corresponds with the grading. The histologic, cytologic, immunohistochemical and cell kinetic methods of examinating urological tumors are discussed considering their significance. Two tumor subgroups of malignancy are differentiated, one with a low risk and one with a high risk. The tumor group of intermediate malignancy (G II) consists of a mixture of both prognostic groups. Possibilities of an easy-to-use subgrading are given in order to differentiate a particular group from other subgroups at risk. A clear distinction between two subgroups of urologic tumors, namely with high or low malignancy, is a presupposition for the successful application of a differentiated therapy nowadays. Prognostic studies have corroborated this tumor subdivision.

Quantitative and qualitative studies of leukaemic cell dipeptidylpeptidases II and IV

Cellular concentrations of dipeptidylpeptidases (DAP) II and IV were determined by fluorimetric assay in 152 cases of leukaemia and 24 permanent T-cell lines. Whilst its estimation appears to have few diagnostic applications, it was found that DAPII levels were generally higher in prolymphocytoid CLL variants (CLL-Pro) compared with “typical” CLL cases. Qualitatively, DAPII extracted from leukaemic B- and T-cells did not differ significantly with respect to molecular weight ( M r 82 kD: FPLC gel filtration) or substrate affinity ( K m). Similarly, a single molecular weight species ( M r 189 kD) of DAPIV was also detected in all leukaemic sonicates examined although, in quantitative terms, increased DAPIV levels were primarily associated with a subgroup of CD4-positive post-thymic malignancies. Studies of immature T-cell proliferations however indicated that DAPIV expression was unrelated to either stage of immunological differentiation or CD4 expression. No evidence of lineage restriction was found for either enzyme and it is concluded that variations in DAP cytochemical staining patterns reflect quantitative rather than qualitative differences.

The correlation of adenosine deaminase and purine nucleoside phosphorylase activities in human lymphocytes subpopulations and in various lymphoid malignancies

Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) were measured in normal human and in malignant lymphoid cells. Thymocytes had high ADA activity (21.2 ± 6.8 10 3 nM/h/mg) and low PNP activity (1.2 ± 0.6), whereas T peripheral blood lymphocytes (PBL) had low ADA activity (1.20 ± 0.22) and high PNP activity (2.8 ± 1.3). Moreover cortico-thymocytes had higher ADA and lower PNP levels than medullary thymocytes. A linear correlation was observed between ADA and PNP activities in both thymocytes and T-PBL. Cells from 13 patients with T acute lymphoblastic leukemia (ALL) and 10 patients with T lymphoblastic lymphoma (LL) had very high levels of ADA (respectively 13.0 ± 5.4 and 22.8 ± 14) and low levels of PNP (respectively 1.9 ± 0.8 and 2.5 ± 1.4). However no clear relationship appeared between subgroups of these T-cell malignancies defined by their patterns of surface antigens, revealed by reactivity with monoclonal antibodies, and ADA and PNP levels, and there was no correlation between the two enzymes. In contrast, cells from 31 patients with HLA-DR + common ALL had significantly low values of ADA as compared to cells from six patients with HLA-DR − common ALL and a linear correlation was observed between ADA and PNP in cells from children with non-T, non-B ALL. These results show that specific stages of T-cell development may be characterized by the relationships and the correlation between the two enzymes and suggest that T-ALL and T-LL appear to be the group of lymphoid malignancies with a high degree of incoordination between ADA and PNP activities.

Chromosome 14 translocations in non‐burkitt lymphomas

Chromosome studies were performed on malignant cells obtained from 27 patients with non-Burkitt lymphomas. A marker chromosome affecting the long arm of No. 14 (14q+) was the single most frequent abnormality and was noted in 17 of these patients. The frequency of the 14q+ marker varied with the type of lymphoma. For patients with malignant lymphoma, histiocytic, the frequency was 5 of 8; for mixed-cell type, 1 of 3; for poorly differentiated lymphocytic, 8 of 8; for well-differentiated lymphocytic, 0 of 3; for lymphoblastic, 0 of 1; for Hodgkin's disease, 2 of 3; and for mycosis fungoides, 1 of 1. The donor chromosome involved in the 14q translocation was identified in 12 cases; certain chromosomes appeared to be affected more frequently than others. Although the break point was band 14q32 in most cases, the exact location of the receptor site on 14q was not always consistent. The distal part of 14q24 was also involved as a receptor site in at least one translocation. These findings suggest that, in some types of lymphoid malignancy, cells with a 14q translocation have a proliferative advantage over cells with other chromosome rearrangments. The presence of the 14q translocation may be important in the future for the distinction among morphologically different, but functionally comparable, subgroups of lymphoid malignancies.