Search

Background. Chronic lymphocytic leukemia (CLL) may evolve into large cell lymphoma (Richter's syndrome), prolymphocytic leukemia, acute lymphoblastic leukemia, and myeloma. Methods. A patient with CLL that transformed into a lymphoma of true histiocytic type is described, and the literature on the association of these two disorders is reviewed. Results. Lymphomas of true histiocytic type developing as an aggressive terminal phase of CLL previously have been reported in nine patients. Fever and rapidly increasing lymphadenopathy and splenomegaly were the most common signs and symptoms. As with de novo lymphoma of true histiocytic type, extranodal involvement of the soft tissue, gastrointestinal tract, kidneys, bone marrow, liver, and lungs was documented among the 10 patients with lymphoma of true histiocytic type transformed from CLL. The median interval between diagnosis of CLL and the evolution to lymphoma of true histiocytic type was 25.5 months. Patients with lymphomas of true histiocytic type after CLL were treated with fludarabine and various other combination chemotherapy regimens with only short-lived responses. The median time to death after transformation was only 33 days (range, 10 days to 5 months). Conclusion. Lymphomas of true histiocytic type appear to represent an additional, though uncommon, form of transformation in CLL. Although their presentation is reminiscent of other intermediate to high grade lymphomas, they can be distinguished based on their morphologic and immunophenotypic features. In the patients described in this study to date, transformation of CLL to lymphomas of true histiocytic type is a poor prognostic sign, with survival generally of only days to weeks. Cancer 1995; 76:609-17. Key words: leukemia, lymphocytic, chronic, lymphoma, histiocytic, histiocytosis malignant, transformation, histiocyte, chromosomal aberration.

Background. CYCLIN D1, a cell-cycle control gene, recently has been shown to be identical to an oncogene alternatively known as BCL-1 and PRAD1 and implicated in centrocytic lymphomas and parathyroid adenomas, respectively. PRAD1 complexes to the product of the retinoblastoma (Rb) tumor suppressor gene, an event followed by Rb inactivation. Squamous cell carcinomas of the cervix and vulva are gynecologic tumors in which human papillomaviruses have been implicated as an initiating event, and proteins derived from these viruses also complex with an inactivate Rb. Because of the overlap in some of the molecular processes mediated by human papillomaviruses and by the PRAD1 oncogene, the authors analyzed the PRAD1 (CYCLIN D1/BCL-1) genomic structure and expression in vulvar and cervical squamous cell carcinoma cell lines. Methods. PRAD1 DNA and PRAD1 mRNA expression were assessed by Southern and Northern blotting, respectively, in 13 squamous cell carcinoma cell lines of gynecologic origin (10, cervical cancer; 3, vulvar cancer). Results. We found low baseline levels of a 4.5-kb PRAD1 transcript in a series of control cell lines, which were derived from normal fibroblasts, various hematologic malignancies, and a choriocarcinoma. PRAD1 mRNA overexpression ([greater than or equal to] 10-fold greater than that in control lines) was seen in all three vulvar carcinoma cell lines, two of which also showed amplification (5-fold and > 10-fold) of PRAD1 genomic sequences. Abnormalities of PRAD1 also were seen in 4 of the 10 cervical cancer cell lines and included overexpression of PRAD1 transcripts (3--9-fold) in 3 lines and rearrangement of PRAD1 DNA in an additional line that, however, did not shown any aberration in PRAD1 mRNA as discernible by Northern blotting. PRAD1 abnormalities were observed in three of the four cervical cell lines derived from metastatic sites and in one of the six cervical lines derived from primary tissue. Conclusions. Seven of 13 squamous cell lines of gynecologic origin showed abnormalities of PRAD1. These abnormalities included amplification and rearrangement of DNA and overexpression of mRNA. The role of PRAD1 as a cell-cycle regulatory gene and its interactions with the Rb tumor suppressor gene suggests that PRAD1 deregulation may be a significant molecular event in the evolution of these tumors.

Background. Five to 10% of patients with chronic myelogenous leukemia (CML) do not have the Philadelphia chromosome (Ph), but one-third of them have rearrangements of the breakpoint cluster region (BCR-positive). Methods. The authors analyzed the characteristics, treatment response, and prognosis of 23 patients with BCR-positive, Ph-negative CML, and compared them with patients with Ph-positive CML, Ph-negative BCR-negative CML and chronic myelomonocytic leukemia (CMML) treated during the same period. Results. Seventeen patients had early chronic phase CML, 3 had late chronic phase, 2 had accelerated phase, and 1 had blastic phase. The median age was 44 years (range, 14--71 years), median platelet count was 402 x [10.sup.9]/1, and median leukocyte count was 86 x [10.sup.9]/1. Fourteen of the 17 patients with early chronic phase CML received alpha-interferon; 12 (86%) achieved complete hematologic remission. Median survival in chronic phase CML was 60 months (range, 3--90 + months). Patients with Phnegative BCR-positive CML and those with Ph-positive CML had similar characteristics and outcome. Compared with patients with Ph-negative BCR-negative CML and CMML, patients with Ph-negative BCR-positive CML and Ph-positive CML were significantly younger, had a significantly higher incidence of leukocytosis, thrombocytosis, and peripheral and marrow basophilia, and a significantly lower incidence of anemia, thrombocytopenia, marrow blast percent, and peripheral and marrow monocytosis. The median survival was 60 months for Ph-negative BCR-positive CML, 73 months for Ph-positive CML, 25 months for Ph-negative BCR-negative CML, and 9 months for CMML (P < 0.001). When analyzed adjusting for their stage, patients classified with Ph-negative BCR-positive CML Stage I disease had a significantly better survival than did patients with Ph-negative BCR-negative CML (P < 0.02). Conclusions. Patients with Ph-negative BCR-positive CML are similar to those with Ph-positive CML and should be treated with the same approaches.

In chronic myelogenous leukemia (CML), the patient enjoys an average of three to four years of fairly normal active life. This chronic phase is followed by the so-called accelerated and blastic phases during which the patient deteriorates rapidly and generally dies of complications, such as internal bleeding or infection. Chemotherapy can induce a second ''chronic'' phase in patients with accelerated disease, but it is short-lived and relapse occurs after three to nine months. CML is characterized by an unusual genetic finding known as the Philadelphia chromosome. Somewhere in the ancestry of some blood cells, pieces of chromosomes 9 and 22 became interchanged. This translocation, as the geneticists call it, is easily observed under the microscope and is called the Philadelphia chromosome. Evidence suggests that abnormal bone marrow cells with the Philadelphia chromosome are capable of suppressing normal cells. However, there is some indication that the suppressed normal cells are not gone, and researchers have now shown that a combination of chemotherapy and autologous bone marrow transplantation can bring out these normal cells in patients with CML. In autologous bone marrow transplantation, some of the patient's own bone marrow is removed and stored during a period of remission following chemotherapy. When the patient relapses after the remission, a very high dose of chemotherapy may be used; the stored bone marrow may then be used to replace the bone marrow destroyed by the chemotherapy. This method was used in the treatment of 15 patients with CML. One patient died of infection during the treatment. Four patients achieved major cytogenetic responses, which means the percent of the cells with the Philadelphia chromosome was reduced to less than 35 percent. Three of these patients suffered relapses after 3, 4, and 12 months. One patient's response has continued for over 15 months. Curiously, of the seven patients who were known to be insensitive to alpha-interferon therapy before the procedure, three became sensitive to alpha-interferon therapy as a result of the autologous bone marrow transplantation. (Consumer Summary produced by Reliance Medical Information, Inc.)