Splenic rupture in a patient with plasma cell myeloma following G-CSF/GM-CSF administration for stem cell transplantation and review of the literature.

Recipients of granulocyte-colony stimulating factor/granulocyte macrophage-colony stimulating factor are not only individuals with underlying disorders, but also healthy donors undergoing peripheral blood progenitor cell (PBPC) mobilization. In addition to the known adverse effects associated with G-CSF, complications such as splenic rupture have also been reported. A review of the English literature, with addition of a patient with plasma cell myeloma, reveals that splenic rupture occurs not only in patients with underlying disease, but also in healthy PBPC donors. Although the cause of splenic rupture does not appear to be associated with any specific condition, physicians should be alerted to the possibility of this potentially fatal complication in individuals receiving G-CSF therapy.

Interferon alfa-2a combined with phototherapy in the treatment of cutaneous T-cell lymphoma.

Escalating doses of recombinant interferon alfa-2a (Roferon-A), administered intramuscularly three times weekly, combined with psoralen plus ultraviolet light irradiation (PUVA), were tested in a phase I trial for the therapy of patients with cutaneous T-cell lymphomas (CTCL). Interferon doses were escalated in groups of three patients from 6 million to 30 million IUs three times weekly. Disease stages ranged from IB to IVB. Eighty percent of the patients entered in this trial had failed at least one prior therapy. Complete remissions were obtained in 12 of 15 patients, and partial responses were seen in two of 15 patients, for an overall response rate of 93%. The median duration of response exceeded 13 months (range, 3-15+). All patients who responded have been maintained on therapy. The dose-limiting toxic effects were constitutional symptoms such as fevers and malaise (93.3%), leukopenias (40.0%), mental status changes consisting of depression and confusion (33.3%), and photosensitivity (26.6%). These side effects were reversible with a decrement in dose or discontinuation of the interferon. No patient tolerated 30 million IU of the interferon for extended periods; the maximally tolerated dose was 18 million IU. Interferon plus PUVA appears to be a highly effective regimen for the treatment of patients with CTCL. Phase II studies investigating this combination, using 18 million IU of interferon alfa-2a three times weekly, should be undertaken to expand these findings, and to attempt to reduce the toxic effects associated with this therapy.

Correlation of karyotype with clinical features in acute lymphoblastic leukemia.

We studied the clinical and karyotypic features of 50 patients with acute lymphoblastic leukemia, including 33 American and 17 Japanese patients, at two institutions. Clonal chromosome abnormalities were found in 39 of the 50 patients (78%) at diagnosis. Eleven patients had diploidy (N patients). Among the 39 aneuploid patients, 17 had pseudodiploidy (A1 patients), eight had hyperdiploidy with 47 to 49 chromosomes (A2 patients), nine had hyperdiploidy with 50 to 59 chromosomes (A3 patients), and five had other chromosome abnormalities. Of 14 patients whose chromosomes were also studied at relapse, eight had karyotypic progression, five had abnormalities identical or similar to those observed at diagnosis, and one had a change of karyotype from diploidy to aneuploidy. The median age and the median WBC of A1 patients were higher than those of any other group of patients, although one-third of the patients had WBC below 20 x 10(3)/microliters, and they often had leukemic cells of T-cell or B-cell lineage. The A2 patients were relatively old and tended to have higher WBC. The N patients were relatively young and tended to have low WBC, although these tendencies were not as marked as those in A3 patients. The A3 patients had longer survival times than the A1 (p = 0.003) or A2 (p = 0.002) patients. Also, N patients had longer survival times than A1 (p = 0.03) or A2 (p = 0.05) patients. The difference in survival times between A3 and N patients was not significant. Our study demonstrated that the karyotype is correlated with survival and with other recognized prognostic factors. However, in some A1 and A2 patients, the karyotype was a more reliable factor in indicating a poor prognosis than was the WBC or age.

Banding studies of chromosomal abnormalities in patients with acute lymphocytic leukemia.

Karyotypes were analyzed by routine Giemsa and quinacrine fluorescence for 16 patients with acute lymphocytic leukemia [ten adults (18 to 51 years) and six children (3 to 15 years)]. Four patients had received previous therapy, but all 16 had active disease when they were first studied. Eight patients (five untreated) had a normal karyotype initially; however, three of these developed a chromosomal abnormality during relapse. Eight patients had a chromosomal abnormality in their initial samples. Each of the 11 patients had different abnormalities. All chromosomes except Nos. 3, 5, 15, 16, and Y were involved in the various aneuploidies. One patient had a Ph1 chromosome due to a translocation with No. 21: t(21;22)(q22;q11). A patient with B-cell acute lymphocytic leukemia had a 14q+ marker in addition to other abnormalities. The median survival of patients with initially normal karyotypes may be longer than that of patients whose karyotypes are abnormal initially.

Prognostic implications of ploidy and proliferative activity in diffuse large cell lymphomas.

Paraffin-embedded surgical biopsies from 50 patients with newly diagnosed diffuse large cell lymphoma (DLCL) were examined for proliferative activity and DNA aneuploidy by flow cytometry. These results were correlated with the clinical characteristics of these patients and the course of their disease. High proliferative activity, defined as less than 80% of cells in G0 or G1, was found to be the single most important pretreatment adverse prognostic factor in these patients. This relationship remained significant after correcting for poor performance status and advanced Ann Arbor stage, the other factors found to be associated with a shortened survival. DLCLs with high proliferative activity were more probable to present with extranodal involvement than those with lower proliferative activity. The mitotic count as determined by light microscopy did not correlate with flow cytometry-defined proliferative activity and may be a less accurate method for assessing this important biological characteristic in DLCL. DNA aneuploidy was detected in 62% of cases but did not appear to have any prognostic significance. Biopsies from patients who presented with lymphomatous bone marrow involvement, however, invariably demonstrated an aneuploid stemline. These results suggest that differences in proliferative activity may be an important biological basis for the variable prognosis seen in DLCL.

Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia.

PURPOSE: Cladribine (2-CdA), a purine analog resistant to adenosine deaminase, has significant activity in a variety of lymphoproliferative diseases. This study was designed to determine the efficacy of 2-CdA in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Twenty-six patients aged 40 to 88 years (median, 64) who either had relapsed after an initial response or were refractory to conventional chemotherapy with at least an alkylating agent were treated with 2-CdA 0.1 mg/kg/d by continuous intravenous infusion for either 5 or 7 days every 28 days for a maximum of six cycles. RESULTS: No complete remissions (CRs) occurred. Eight of 26 patients (31%) achieved a partial remission (PR). The actuarial median time to progression (TTF) in responding patients is 16 months (range, 6 to 22). The actuarial median survival duration of the responding patients is 12 months (range, 8 to 28). Eight of 26 patients (31%) sustained early toxicity. Seven of these eight patients died before the first reevaluation of infection (n = 3), pericardial tamponade (n = 1), Stevens-Johnson syndrome (n = 1), and stroke (n = 2). No nausea, emesis, alopecia, or renal, hepatic, or cardiac toxicity was observed. CONCLUSION: 2-CdA has activity in patients with relapsed or refractory CLL. However, patients who have received multiple prior regimens that included fludarabine are less likely to respond, and there can be significant morbidity. Treatment of patients with less prior therapy earlier in the natural history of the disease may lead to improved and more durable responses.

Granulocytic sarcoma is associated with the 8;21 translocation in acute myeloid leukemia.

PURPOSE: Since the only three cases of granulocytic sarcoma among patients with acute myeloid leukemia (AML) seen at our institution during the last 12 years were each associated with the 8;21 translocation [t(8;21)], we sought to determine if this association is specific and more frequent than previously recognized. PATIENTS AND METHODS: We report three patients with AML and t(8;21) who developed granulocytic sarcomas, and review the world literature. RESULTS: Between 1980 and 1992, 53 cases of AML French-American-British (FAB) M2 were identified at our institution. Eight (15%) patients had t(8;21). Three of these eight patients (38%) developed granulocytic sarcoma. All three of our patients received conventional intensive antileukemic chemotherapy yet had short relapse-free survival durations. Several series of patients with t(8;21) report that granulocytic sarcomas occur in approximately 18% of this population, which is four times the expected incidence in AML. Thirty-seven cases have been previously reported. Although karyotype analyses were not reported in many cases of granulocytic sarcoma in the literature, the vast majority of abnormal karyotypes in patients with AML involved t(8;21). Recent work with a cell line derived from a patient with t(8;21) indicates that such cells are unusually adherent to culture bottles and are aggregable CONCLUSION: Our data suggest that this association is more common than generally recognized and may be specific. Patients with t(8;21) should be observed closely for signs and symptoms of granulocytic sarcoma. These patients may have a less favorable prognosis than other patients with t(8;21). Cooperative oncology groups should retrospectively identify patients with AML and t(8;21) who had a poor outcome to determine if they had a disproportionate incidence of granulocytic sarcoma. If so, aggressive therapy such as bone marrow transplantation may be warranted early in the therapeutic strategy.

Human immunodeficiency virus-related lymphomas: a possible association between tumor proliferation, lack of ploidy anomalies, and immune deficiency.

In an attempt to identify a biologic basis for the aggressive clinical behavior of human immunodeficiency virus (HIV)-associated lymphomas (HAL), dual-parameter flow-cytometric analysis was performed on 22 paraffin-embedded biopsy specimens. Cases were analyzed for DNA ploidy, the percentage of cells in S-phase (proliferative activity), and content of a recently identified proliferation-associated nuclear antigen, p105. The DNA-content analysis of 22 HALs was compared with that of 109 cases of intermediate-grade non-Hodgkin's lymphoma (NHL) unrelated to the acquired immune deficiency syndrome (AIDS) studied previously in our laboratory and 125 cases of high-grade NHL reported in the literature. The proliferative activity was higher in intermediate-grade HAL relative to non-AIDS NHL (24.0% v 10.4%; P = .03), and in high-grade HAL in comparison with NHLs of similar histology unassociated with HIV infection (24.8% v 19%), although the latter did not reach statistical significance. The number of mitoses per 10 high-power fields was found to correlate with the percentage of cells in S-phase (r = .68; P = .0004). Although p105 content tended to be higher in HAL than in an AIDS-related complex (ARC)-associated hyperplastic lymph node control, no statistically significant associations were found between p105 content and proliferative activity or the number of mitoses per 10 high-power fields. When compared with non-AIDS NHLs of comparable grade, there was a trend toward a lower incidence of DNA aneuploidy in both intermediate- (25% v 56%) and high-grade (38.5% v 60%) HALs. The higher proliferative activity and lower incidence of DNA aneuploidy found in HAL relative to non-AIDS NHL of comparable histologic grade may represent differences in pathogenesis and may underlie the poor prognosis of HIV-associated NHL.

Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience.

PURPOSE: Since large numbers of patients with early-stage breast cancer now receive adjuvant chemotherapy containing cyclophosphamide, a known leukemogenic agent, it is important to determine the risk of secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Therefore, we identified all cases of AML or MDS developing in patients treated on six clinical adjuvant chemotherapy trials conducted by the Eastern Cooperative Oncology Group (ECOG). PATIENTS AND METHODS: The patients population included 2,638 patients with previously untreated primary operable breast cancer entered onto six clinical trials conducted by the ECOG between 1978 and 1987. There are 19,200 persons-years of follow-up study and a mean follow-up duration of 7.3 years. Clinical data were obtained from flow sheets submitted to the ECOG Data Management Office. RESULTS: Of 2,638 patients at risk with 19,200 person-years of follow-up study, three patients developed MDS (two with a characteristic cytogenetic abnormality). Two patients developed acute leukemia; however, one had adult T-cell leukemia associated with human T-lymphotrophic virus type 1 (HTLV-1) and a second patient developed AML after receiving additional cyclophosphamide for metastatic breast cancer. The estimated incidence rate for MDS is three per 19,200 or 16 per 100,000 person-years of follow-up study with a 95 percent confidence interval of three to 46 per 100,000 person-years. If all five patients (three MDS and two acute leukemia) are included, the estimated incidence rate is five per 19,200 or 26 per 100,000 person-years of follow-up study with a 95 percent confidence interval of eight to 61 per 100,000 person-years. CONCLUSION: These data suggest that the risk of secondary AML or MDS among patients with early breast cancer who receive standard-dose cyclophosphamide-containing adjuvant chemotherapy is not much higher than in the general population. However, physicians must remain alert to the possible long-term consequences of alkylating agent and anthracycline-based chemotherapy.

Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council Study.

A radiolabeled murine monoclonal antibody (T101) was used for imaging and therapy of six patients with cutaneous T cell lymphoma (CTCL). Radioimmunodetection was performed with a 5.6 to 13.1 mCi 131I-T101 preparation (9.6 to 10.5 mg). A therapeutic dose of 100.5 to 150.1 mCi 131I on 9.9 to 16.9 mg of antibody was administered to five patients, with subsequent retreatment following plasmapheresis in three patients at the time of disease progression. All patients responded to their initial therapy and two patients responded to retreatment. Regression of skin lesions and peripheral adenopathy was witnessed. All patients reported resolution of their chronic pruritus. The duration of response ranged from 3 weeks to 3 months. Acute toxicity included fevers, pruritus, and mild dyspnea in two instances. Myelosuppression was seen in patients receiving the 144.7 mCi, 145.0 mCi, and 150.1 mCi 131I-T101 doses. Radioimmunodiagnostic and therapy studies included gamma scintigraphy, plasma, urinary, and wholebody antibody clearances, and biodistribution determined from skin, bone marrow, and liver biopsies. Immunologic studies included immunoperoxidase staining of target tissues, immunofluorescent flow cytometric analysis on peripheral blood and bone marrow, assays for serum blocking factors, determination of a human antimouse antibody (HAMA) response, and quantitation of circulating T101 levels. These preliminary data suggest that 131I-T101 has therapeutic potential in CTCL and that myelosuppression will be the limiting toxicity.

Basophilic differentiation in acute promyelocytic leukemia.

A rare variant of acute promyelocytic leukemia (APL) is associated with basophilic differentiation. Such a patient presented with basophilia, headaches, and diffuse engorgement of superficial blood vessels, attributable to hyperhistaminemia. Karyotype analysis showed a clonal rearrangement of chromosome 12p13 in addition to the t(15;17). During treatment with all-trans-retinoic acid (TRA), the absolute basophil count rose steadily during the first week, then declined. By one month, the basophilia resolved, an abrupt rise occurred in both the platelet and absolute neutrophil count, and the bone core biopsy showed complete maturation of all cell lines. Abnormalities of chromosome 12p13 in acute myelogenous leukemia have been associated with basophilia. Since every cell in our patient with t(12p13;?) also had the t(15;17), we speculate that the basophilia was due to clonal evolution with acquisition of the t(12p13;?). In two out of five other reported cases, abnormalities of chromosomes known to be associated with basophilia were present in addition to t(15;17). It is possible that the basophilia in this variant is reactive; however, since TRA induces differentiation of leukemic promyelocytes into mature neutrophils, we speculate that the leukemic promyelocytes in our patient differentiated into basophils. Future studies employing either fluorescent in situ hybridization or polymerase chain reaction using a probe to the breakpoint on t(15;17) may establish whether or not the basophils derive from the leukemic clone.

Primary pulmonary Hodgin's disease: a case report.

A case of Hodgkin's disease occurred with pulmonary involvement as the initial feature. The disease was initially seen clinically and roentgenographically as a diffuse pulmonary infiltrate. To our knowledge, the pattern of diffuse pneumonic involvement without intrathoracic lymphadenopathy at presentation has been reported only in one other case. Differentiation of this diffuse pneumonic pattern of primary pulmonary Hodgkin's disease from the more common pattern of a focal mass or infiltrate is important in considering appropriate therapy.

Photochemotherapy alone or combined with interferon alpha-2a in the treatment of cutaneous T-cell lymphoma.

Eighty-two patients with either mycosis fungoides (MF) or parapsoriasis en plaques were treated with psoralens ultraviolet A light (PUVA). Clinical and histologic parameters were followed for a period from 6 months to 10 years. Complete clinical clearing of lesions was observed in 51 patients (62%) and most of them were in limited-plaque MF group or parapsoriasis en plaque. The mean total dose of PUVA for complete clearing was less for early MF. Thirty-one patients (38%) relapsed and responded to additional PUVA. Patients in early stages of the disease remained clear for up to 68 months after the first course of PUVA. Post-treatment skin biopsies with early MF showed histologic clearing. A new combination therapy for MF is presented in 15 patients. Recombinant interferon alpha-2a (Roferon-A), administered intramuscularly combined with PUVA were tested in a phase I trial. Interferon doses were from 6-30 million units three times weekly. Disease stages ranged from I-B to IV-B. Complete responses were obtained in 12 of 15 patients, and partial responses seen in 2 of 15 patients, for an overall response rate of 93%. The median duration of response exceeded 23 months (range, 3 to 25 months). All responding patients have been maintained on therapy. The dose-limiting toxicities were constitutional symptoms such as fevers and malaise (93.3%), leukopenias (40.0%), mental status changes consisting of depression and confusion (33.3%), and photosensitivity (26.6%). Interferon plus PUVA appear to be highly effective regimens for the treatment of patients with cutaneous T-cell lymphomas.

Serum soluble CD23 level correlates with subsequent development of AIDS-related non-Hodgkin's lymphoma.

The cytokine soluble CD23 (sCD23) has been shown to act as a B cell growth factor and to be elevated in serum prior to development of AIDS-related non-Hodgkin's lymphoma (AIDS NHL). To further characterize the elevation of serum sCD23 in AIDS NHL patients and investigate its potential as a diagnostic test, a matched case-control study of AIDS NHL (n = 101) was nested within the Multicenter AIDS Cohort Study. Serum sCD23 was measured in cases' and controls' serum specimens at three different time periods (0-6, 6-12, and 12-18 months) and CD4+ thresholds (0-99, 100-199, and 200-299 cells/microl) prior to the case's NHL diagnosis. Changes in serum sCD23 over time were examined in AIDS NHL cases relative to controls, and t tests were performed to determine whether cases' serum sCD23 exceeded that of controls at each time period and CD4+ threshold. Overall, cases' median serum sCD23 levels were approximately double those of controls. Serum sCD23 concentration was positively correlated with lymphocyte counts for both cases and controls. The difference in cases' and controls' serum sCD23 levels became greater as AIDS NHL diagnosis date approached: in the 18 months preceding the case's NHL diagnosis, serum sCD23 was stable in cases but dropped in controls. Although this difference was statistically significant (P < 0.05), it was not clinically significant. It is unlikely that serum sCD23 would make a useful test for AIDS NHL because the magnitude of the difference between cases and controls was small and there was no change in serum sCD23 in cases that would indicate disease.

Cat scratch disease. Identification of bacteria in seven cases of lymphadenitis.

A retrospective study of lymph node biopsy specimens from nine patients with the clinical findings and histologic features of cat scratch disease was undertaken to determine whether the recent report by Wear et al. that pleomorphic bacteria are present in the lymph nodes of cat scratch disease could be confirmed. In seven of our nine cases, pleomorphic bacteria were demonstrated with the Warthin-Starry (WS) silver stain. These were gram-negative with the Brown-Hopps tissue Gram stain and were almost at the limit of microscopic resolution. Lymph node specimens from 13 additional patients with nonspecific lymphadenitis who had neither clinical nor histologic findings of cat scratch disease were studied similarly; in none of these were bacteria demonstrated with the WS silver stain. After examining the distribution of the organisms and the related morphologic features in cat scratch disease, we conclude that demonstration of pleomorphic, gram-negative, WS-positive bacteria in the appropriate clinical and histologic setting can firmly establish the diagnosis of cat scratch disease.

The effect of short-term and chronic immunosuppression on Theiler's virus demyelination.

Theiler's virus (TV)-infected mice were treated with antithymocyte serum (ATS), cyclophosphamide or pepstatin (a protease inhibitor) to determine the effect on demyelination. When ATS and cyclophosphamide were begun at the time of infection there was significantly less demyelination at 2.5-3.5 weeks than in pepstatin or non-treated infected controls. When immunosuppression was continued for 5 weeks, or when it was not started until 5 weeks post-infection, no significant decrease in demyelination was seen compared to controls. The findings indicate that timing of immunosuppression is critical in determining the extent of TV demyelination. Such demyelination may occur by different mechanisms that are active at different times. The "bystander effect' may be important in early demyelination, but late demyelination may be due to other causes, such as oligodendrocyte lytic infection.

Papillary clear cell carcinoma of the thyroid gland.

A case of an unusual papillary clear cell carcinoma of the thyroid gland is described. The patient expired 17 days after operative biopsy and thyroxine suppression. Special stains were helpful in differentiating renal cortical carcinoma and parathyroid malignant disease from primary papillary clear cell carcinoma of the thyroid. Ultrastructural features of this tumor may relate to the effects of thyroid stimulating hormone as well as the malignant nature of the tumor.

Primary histiocytosis X of the parieto-occipital lobe.

Immunohistochemical and ultrastructural evidence support the concept that histiocytosis X is the result of proliferation of pathological Langerhans' cells. Central nervous system involvement by histiocytosis X has been commonly described in multisystem disease and in association with lytic skull lesions. Unifocal brain involvement by histiocytosis X without concomitant osseous involvement is rare, with only 14 cases reported in the literature to date. Ten of these cases have involved the hypothalamus; the remaining four have involved the frontal lobe (two cases) and the temporal lobe (two cases). The fifth case of extrahypothalamic unifocal histiocytosis X, the first female case, and the first case with parieto-occipital lobe involvement, is reported. Pathology demonstrated infiltration of brain parenchyma by clusters of characteristic histiocytosis X cells with an admixture of morphologically related giant cells, eosinophils, and lymphocytes. Langerhans' granules were identified in the histiocytosis X cells by electron microscopy. Immunohistochemistry showed strong S-100 protein, HLA-DR, and T6 antigen positivity by the histiocytosis X cells. Therapy included complete surgical excision and postoperative radiation therapy for the incompletely excised lesion. Patients with unifocal extrahypothalamic histiocytosis X may have a better prognosis than patients with localized hypothalamic disease.

Immunohistochemical analysis of small cell tumors of the thyroid gland: an Eastern Cooperative Oncology Group study.

The majority of small cell anaplastic tumors of the thyroid gland are generally believed to be non-Hodgkin's lymphomas, including most of those formerly classified as small cell carcinomas. Using a panel of antibodies capable of detecting epithelial, neuroendocrine, and B and T cells in paraffin-embedded tissue sections, we studied 68 thyroid neoplasms in which the original diagnosis was small cell carcinoma or lymphoma. Sixty-three of the tumors were identified as lymphomas of B-cell origin on the basis of L26 reactivity used in conjunction with light chain restriction and MB2 immunostaining. Two additional tumors were classified as lymphomas of indeterminate phenotype. Immunophenotyping indicated an epithelial origin in the remaining three tumors. No cases of medullary carcinoma were detected by immunostaining. Histologic review revealed a predominance of large cell and immunoblastic lymphomas, with low-grade lymphomas of mucosa-associated lymphoid tissue histology accounting for only five cases. Our findings indicate that the majority of small cell anaplastic tumors of the thyroid are B-cell lymphomas. Although primary small cell carcinoma of the thyroid may rarely occur, this diagnosis should not be made without immunohistologic confirmation.

Multicentric giant lymph node hyperplasia.

A patient with retroperitoneal and axillary lymphadenopathy and splenomegaly was demonstrated histologically to have the hyaline vascular type of giant lymph node hyperplasia, with plasma cell infiltrates in each region. The abdominal lesions were not surgically resectable and did not respond to radiotherapy. The clinical findings included polyclonal gammopathy, high cold agglutinin titers, neuropathy, and bilateral papilledema. All of these abnormalities have persisted three years since the initial diagnosis.