Phenotypic heterogeneity and cellular origins of T cell malignancies.
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Biomedical subjects
Publications and source records attributed to D Catovsky.
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A case of B-prolymphocytic leukemia (B-PLL) is reported in which intracytoplasmic inclusions were seen at transmission electron microscopy (TEM). The inclusions were electron dense, often membrane bound, and a proportion showed acid phosphatase reactivity.
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We describe four patients with mixed lympho- and myeloproliferative disorders. One patient had hairy cell leukaemia and acute myelomonocytic leukaemia, another lymphocytic lymphoma in leukaemic phase and chronic myelomonocytic leukaemia and the third patient had chronic lymphocytic leukaemia and polycythaemia rubra vera; none of these patients had received any prior therapy, and in two the diagnosis of the two malignancies was simultaneous. The fourth patient developed acute monocytic leukaemia 4 years after the diagnosis of chronic lymphocytic leukaemia after only 2 weeks of therapy with chlorambucil. The nuber of cases with concurrent or sequential but spontaneous occurrence of lympho- and myeloproliferative disorders reported so far is now 38. The questions relating to the pathogenesis of the two malignancies are discussed.
The proportion of T gamma and T mu lymphocytes was studied in 40 cases of B-chronic lymphocytic leukaemia (B-CLL) and six of B-prolymphocytic leukaemia (B-PLL). The significant increase in T gamma cells, previously reported in two small B-CLL series, was confirmed and shown to be directly correlated with the clinical stages of the disease (P less than 0.01 to less than 0.001). The normal T mu:T gamma ratio (2.3:1) was reversed in B-CLL (1:1.4) and B-PLL (1:1.9). The proportion of T mu cells was decreased but was not related to stage. Our findings suggest that the increase in T gamma cells may be responsible for the hypogammaglobulinaemia of B-CLL. This is supported by two sets of observations. First, serum Ig levels were more often normal in cases in Stages 0 and I than in Stages II-IV (P less than 0.05), while the levels of two or three Ig classes were below normal in Stages II-IV twice as frequently. Secondly, splenic irradiation in one case was followed by a fall in the absolute number of T gamma lymphocytes, a reversion to normal of the T mu: T gamma ratio and an improvement in serum Ig levels. Thus, the imbalance in ;the regulatory T-cell subsets may provide an important clue to understand the pathogenic mechanism of the immunodeficiency in the chronic B-cell leukaemias.
The degree of concordance in the morphological classification of ALL was assessed by the FAB group after two successive reviews of 200 and 100 slides respectively. As a result, a simple scoring system for types L1 and L2 is proposed based on the following four features: (1) nuclear cytoplasmic ratio, (2) presence, prominence and frequency of nucleoli, (3) regularity of nuclear membrane outline, and (4) cell size. By this method, the overall concordance by seven observers (agreement of 7:0 or 6:1 only) increased from 63% to 84%. A significant difference in the incidence of the ALL morphological types in children (less than or equal to 15 years) and adults (greater than 15 years) was found: 74% of L1 cases were children while 66% of L2 cases were adults (P less than 0.001). No significant differences were observed in the incidence of L3 in children and adults or between L1 and L2 according to the membrane phenotype of the blast cells. All L3 cases had B-cell characteristics. A better prognosis for L1 and a higher relapse rate for L2 has been found in several recent reports; The present study may facilitate the morphological analysis of ongoing clinical trials in ALL by improving the reproducibility of the FAB classification.
Twelve patients with B-cell prolymphocytic leukaemia (PLL) were treated with splenic irradiation at a weekly dose of 100 cGy to a maximum total dose of 1000 cGy. There was no morbidity associated with this treatment. SEven patients responded. Three achieved a good response and four a partial response. Two of the patients who had a partial response have subsequently died of unrelated causes. Four of the five patients who failed to respond have died as a result of their disease. When more than 25% of the prolymphocytes formed rosettes with mouse red blood cells (MRBC) the patients appeared to respond better to splenic irradiation. There was no correlation between response and the initial white cell count or the size of the spleen.
T-lymphocytes isolated by E-rosetting from 22 patients with B-cell chronic lymphocytic leukaemia (B-CLL) showed membrane phenotype features distinct from those of normal T-lymphocytes. These changes were particularly marked in advanced disease (Rai stages II, III, IV and WBC over 100x10(9)/l). The most significant finding was the demonstration, in 10 cases, of a major population of E-rosette positive cells (40-80%) unreactive with the OKT monoclonal antibodies against mature or immature T-cells; 15-30% of the cells were unreactive in seven other cases. A significant reduction in OKT4 positive (helper) lymphocytes was seen in 18 cases. The proportion of OKT8 positive cells was increased in two and normal or low in the rest. Only four patients with early disease (stages 0 and I) had a normal T-cell phenotype. These findings could explain abnormalities previously described in the T-lymphocytes of B-CLL and provide new insights into the pathogenesis of the disease.
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Sixteen patients with chronic granulocytic leukaemia (CGL) in blast cell transformation (BT) were studied by means of serial bone marrow trephine biopsies (BMB). The BMB were performed during the following stages of the disease: 1 at diagnosis of BT, 2 following ablative therapy and 3 during haematological recovery following autografting. In 10 of the 16 patients, BT was recognized by the presence of a distinctive infiltration with blast cells with a single large hyperchromatic nucleolus. In four of the 16 patients, the diagnosis of BT could only be made by BMB since simultaneous marrow aspiration yielded either a dry tap or no marrow fragments; in two of these four patients the BT was focal in the BMB specimen. Following ablative therapy and during haematological regeneration after autografting, BM aspirates were unsatisfactory in most cases and they were inadequate to assess cellularity or the presence of residual blasts. In contrast, sections of BMB showed clearly whether a decrease in cellularity took place or, in some, residual blasts were still present. BMB samples obtained 2 weeks after autografting showed haemopoietic regeneration consisting of discrete foci of either erythroid, granulocytic or megakaryocytic precursor cells. We conclude that BMB is essential for diagnosing CGL in BT, for monitoring the progress of these patients after therapy and in assessing the haemopoietic regeneration following autografting.
A serial study of the extent of bone marrow (BM) fibrosis was carried out in 14 patients with chronic granulocytic leukaemia (CGL) in blast transformation (BT) who received intensive treatment followed by autografts to restore marrow haemopoiesis. Some degree of marrow fibrosis (MF) was identified in 13 of the 14 patients when blast transformation was diagnosed. A transient increase in the amount of marrow fibrosis was observed in most cases immediately following intensive chemoradiotherapy or chemotherapy alone but this had regressed by 4-6 weeks when chronic phase haemopoiesis was established in the marrow. The presence of marrow fibrosis when blast transformation was diagnosed did not appear to impair the effectiveness of the autograft.
We describe 4 patients with a haemophagocytic syndrome resembling histiocytic medullary reticulosis (HMR) complicating chronic lymphocytic leukaemia (CLL) of 9 months to 8 years duration. Surface marker studies in 2 cases showed that the CLL lymphocytes were of B-cell type in one and of T-cell type in the other. 2 of the patients had histiological evidence of co-existing immunoblastic sarcoma at the time of diagnosis of the HMR-like syndrome and all 4 patients died within 3 weeks of this diagnosis. The pathogenesis of the HMR-like syndrome in these patients is discussed and it is concluded that it is probably reactive to an underlying opportunistic viral function related to their immunodepressed state secondary to CLL and/or the cytotoxic therapy.
A significant reduction in the proportion and absolute number of circulating T gamma (suppressor) lymphocytes was observed in 15 adult patients with idiopathic thrombocytopenic purpura (ITP). The proportion of T gamma cells was also reduced in the spleen of four patients so investigated. This abnormality was not seen in 5 patients cured by splenectomy whilst it persisted in 3 who remained thrombocytopenic after splenectomy. The proportion of Tmu (helper) lymphocytes in ITP was normal. These findings, similar to those reported in systemic lupus erythematosus, suggest that an inbalance of the immunoregulatory T-cell subsets may be important in the pathogenesis of ITP.
Material from 39 patients with acute leukaemia was investigated with the peroxidase cytochemical reaction using 3,3'diaminobenzidine (DAB) and other substrates in order to test their sensitivity in detecting myeloid differentiation. The proportion of positive blasts and of cases with Auer rods in acute myeloid leukaemia (AML) was significantly greater with DAB than with benzidine. In addition, Phi bodies were demonstrated in AML blasts only when DAB was used; Phi bodies were also observed in two out of seven cases of chronic granulocytic leukaemia in "myeloid" blast crisis but were not seen in any case of acute lymphoblastic leukaemia. Phi bodies were more numerous when the reaction was carried out at pH 9.7, and their number was significantly reduced in the presence of 3-amino 1,2,4-triazole. Both findings suggest that the Phi bodies derive from catalase-containing granules (microperoxisomes) and are distinct from Auer rods, which derive from peroxidase-containing (primary) granules. Like Auer rods, Phi bodies appear to be characteristics of immature myeloid cells in leukaemia but are seen with a higher frequency than Auer rods in acute myeloid leukemia.
Acute myelofibrosis (AM) or malignant myelosclerosis is a myeloprofilerative syndrome in which bone marrow fibrosis is associated with a proliferation of immature myeloid cells. In four patients with typical AM, investigated by the platelet-peroxidase reaction at ultrastructural level, the blast cells were found to be megakaryoblasts. One patient, treated with the drug combination DAT, achieved a complete remission of 5 mo duration. This study supports the view that megakaryoblastic leukemia is the most frequent underlying cause of AM and proposes that it should be classified as a form of acute myeloid leukemia.
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