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Histological transformation, typically to diffuse large B-cell lymphoma (DLBCL) is reported to occur in 5%-10% of patients with WM and recent studies have highlighted a possible aetiological role for the nucleoside analogues. It is however becoming increasingly clear that histological transformation is a complex phenomenon and may include clonally unrelated disorders. In order to highlight this pathological heterogeneity we describe 5 patients with diverse histological progression events. These included EBV-associated events namely DLBCL, peripheral T-cell lymphoma and spontaneously resolving mucocutaneous ulcer. A further 2 patients demonstrated a localised plasma cell rich lesion simulating plasmacytoma and a de novo DLBCL arising in an unrelated B-cell clone. It is clear therefore that detailed pathological assessments are required in all suspected cases of transformation and that the pathological heterogeneity demonstrated by this study needs to be taken into account when potential aetiological factors are being assessed.

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BACKGROUND: Senior doctors report that mentoring skills are transferable to everyday medical practice and managing juniors. An analysis of views from consultants and general practitioners, who had trained together on a regional mentoring scheme, reveals significant potential for personal and professional development in such networks. CONTEXT: The Northern and Yorkshire Region Doctors' Development and Mentoring Network was set up in 1994. Since then there have been six programmes with 116 senior doctors participating. In 1997 there was an evaluation of the first four programmes. METHOD: Focus groups and postal questionnaire. RESULTS: There were responses from 71 senior doctors, giving a response rate of 86%, and responses from 78 professional stakeholders in 49 NHS organizations, a response rate of 54%. Results indicate that the programmes were highly valued by the participants, particularly with regard to: being part of a network of senior doctors; developing mentoring skills, and engaging in personal and professional development. The most difficult part of the programme was setting up mentoring networks for junior doctors, and reasons included: personal factors, such as levels of confidence in providing mentoring; cultural factors, such as juniors not wishing to be seen to need help, and organizational factors, such as lack of time allocated for mentoring. RECOMMENDATIONS AND ISSUES FOR FURTHER DEBATE: The positive benefits from the scheme raise questions about how to develop mentoring training for senior doctors. Issues include: developing mentors; who needs mentoring; mentoring and the organization; transferability of mentoring skills, and widening the network.

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Phenotypic characteristics, and correlations between the expression of membrane NK-associated (NKa) determinants (CD11b, CD16, CD56 and CD57) and T cell receptor (TCR) genotypic patterns, were examined in 25 patients with persistent (greater than 6 months) expansions of CD3+WT31+NKa+ (CD8+ and CD8dim+) lymphocytes. These studies showed that distinct NKa phenotypic profiles were restricted to cases with rearranged TCR configurations and that clonal CD3+NKa+ components could be predicted in most cases by assessing relationships between membrane CD16 and CD56 expression. For all normal NKa subpopulations, there was a high correlation (P less than 0.0001; n = 31) between the expression of these two membrane determinants. Markedly increased CD16 expression by CD3+NKa+ cells, in relation to CD56 (i.e. a high CD16:CD56 ratio), was found exclusively in cases with rearranged TCR (13/16 cases); 2/3 of the remaining cases showing significantly reduced CD16:CD56 ratios and high (greater than 2.0) CD3+CD56+ absolute numbers. In contrast, 7/9 of the germline TCR cases had a normal CD16:CD56 ratio and 2/9 a decreased ratio with low (less than 1.0) CD3+CD56+ absolute numbers. A high ratio of CD16:CD56 expression by CD3+NKa+ lymphocytes was therefore informative for 82% of TCR rearrangements in this series; and analysis of CD16 and CD56 expression was predictive for germline and rearranged TCR configurations in 24/25 persistent CD3+NKa+ expansions.

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Two cases of hairy cell leukaemia (HCL) presenting in brothers with a 14 year interval are described. Familial HCL has been described previously in two kinships but not in the UK. Both brothers had worked as car mechanics for some time but apart from this no other recognized shared environmental or genetic risk factors were identified.

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The alpha naphthyl acetate esterase (ANAE) cytochemical staining patterns were examined in 40 cases of acute myeloblastic leukaemia (AML: FAB groups M1 and M2) classified by morphological and immunological criteria. The blast cells in most cases (62%) were ANAE-negative with the remainder showing diffuse, granular or focal reactions of varying intensity. The nature of cytoplasmic ANAE enzymes was further characterised in 20 cases by isoelectrophoretic analysis of ANAE isoenzymes. The results suggest that the presence of significant cytoplasmic ANAE reactivity in leukaemic myeloblasts is not due to the presence of monocyte-associated isoenzymes, in otherwise well-defined myeloblasts, but may reflect abnormally increased synthesis or atypical localisation of normally-occurring ANAE isoenzymes. In particular, the results of this study indicate the lack of discriminatory value of ANAE cytochemistry in the differentiation of AML from other acute leukaemias of non-monocytic type.

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Following characterization of myeloid nonspecific esterases by isoelectric focusing (IEF), two main groups of alpha-naphthyl acetate (ANAE) esterase isoenzymes were defined and fractionated from cytoplasmic extracts by chromato focusing techniques according to differences in their isoelectric points (pI). The first of these ANAE enzyme groups was common to leukocytes of both granulocytic and monocytic lineage, while the other, which characteristically comprised a group of isoenzymes within the pI range 5.5-6.1, was specifically associated with monocytic differentiation. The properties of the two purified ANAE enzyme fractions were compared by inhibition (heat and sodium fluoride) and further electrophoretic studies, and the results discussed in relation to the cytochemical characterization of these enzymes as markers of specific myeloid cell differentiation.

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Blast cells from 70 cases of acute myeloid leukemia (AML), with a preponderance of monocytic variants (M4 and M5), were stained with a panel of 10 monoclonal antibodies (MoAb) that react with normal myeloid cells. Two McAb, UCHMI and UCHALF, stained cells from nearly every case of M4 and M5 leukemia, but not cells from cases of M1/M2 leukemia. Two other antibodies, E11 and UC45, were also specific for the monocytic leukemias, but stained cells from a lesser proportion of cases. The antibodies TG1, OKM1, Smø, DA2, 28, and 5.5 stained a differing proportion of cases in both the M1/M2 and M4/M5 subtypes. Routine morphology and alpha-naphthyl acetate esterase (ANAE) staining were largely in agreement with the antibody findings, though the interpretation of the fluoride sensitivity of ANAE was apparently misleading in 10% of cases. It is concluded that these antibodies, particularly UCHMI and UCHALF, will be of considerable value in the more precise subtyping of AML and that some of this panel of antibodies will be valuable tools for the investigation of normal monocytic differentiation.

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Alpha-naphthyl acetate esterases (ANAE) were examined by cytochemical and isoelectric focusing (IEF) techniques in 48 cases of acute myeloid leukemia that were classified by conventional morphological criteria. Four main types of ANAE isoenzyme patterns were found by IEF, and comparisons with the expression of membrane receptors (Fc-IgG and C3b) and monocyte-specific antigens (UCHM1, UCHALF, and E11) suggest relationships between ANAE isoenzyme synthesis and distinct myeloid maturational stages. The results further indicate that the blast cells of acute myelomonocytic leukemia (AMML) may represent an immature variant of monocytic leukemia (AMoL) and that morphological examination alone is inadequate in the assessment of monocytic differentiation in acute myeloid leukemias. Inhibition studies of cytochemical ANAE activity with sodium fluoride (NaF) show that the presence of NaF-sensitive or NaF-resistant ANAE enzymes is often unrelated to the diagnostic category of acute leukemia. The results of this study are examined in relation to current concepts of myeloid differentiation, and the application of these findings to the subclassification of acute myeloid leukemias is discussed.

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Expression of peripheral blood neutrophil (PBN) C3b receptors, as assessed by rosette formation with C3b-coated ox erythrocytes, was examined and compared with neutrophil alkaline phosphatase (NAP) activities in both normal and haematologically abnormal conditions. The results indicate that a small percentage of normal PBN are apparently C3b receptor-negative and that these neutrophils do not appear to differ with respect to age from those with detectable C3b receptors. Examination of PBN C3b receptors from 154 cases of various haematological disorders revealed a significant proportion of cases with increased numbers of C3b receptor-negative neutrophils. These abnormalities did not appear to be related to peripheral leucocyte counts, NAP activities or serum lysozyme concentrations and it is suggested that the increased numbers of C3b receptor-negative PBN may be related to intravascular factors such as immune complexes.

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The expression of Fc-IgG and C3b membrane receptors by granulocytes and their precursors was examined in 78 patients with primary myeloid dysplasia (MDS). The marrows were categorized into five morphological groups, broadly corresponding to those described by the FAB group, and further graded into mild and severe according to the severity of dysgranulopoiesis. Fractionated bone marrow and peripheral blood granulocyte receptors were assessed by rosette formation with optimally sensitized ox erythrocytes and the results compared with those found in 17 normal marrows and with those previously reported in megaloblastic anaemia. Fc-IgG and C3b receptor expression was generally increased in maturing granulocytes in all MDS diagnostic groups but premature expression was particularly marked in chronic myelomonocytic leukaemia and refractory cytopenia. Receptor patterns showed a better correlation with the severity of dysgranulopoiesis than with the morphological types. It is suggested that, as in megaloblastic anaemia, changes in membrane receptor expression reflect nuclear-cytoplasmic asynchrony. The results further indicate considerable immunological heterogeneity of granulocytes within individual MDS categories.

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Acid alpha naphthyl acetate esterase (ANAE) and combined ANAE-chloroacetate esterase cytochemistry was performed on 121 bone marrow aspirates from primary myelodysplastic syndromes (MDS) and a secondary dysplasia-megaloblastic anaemia (MA). The investigation demonstrated the presence of abnormal ANAE positive granulocyte populations in a significant proportion of cases. These cells, in which the staining patterns were characterized by atypical granular ANAE positivity and double ANAE-chloroacetate reactions, were shown immunologically to lack the receptor and antigenic characteristics of monocytes and morphologically to be granulocytes. Isoelectric focusing, however, indicated that the atypical esterase cytochemistry of these granulocytes was due to the presence of markedly increased concentrations of ANAE isoenzymes usually found in monocytes. Atypical ANAE-staining granulocytes were particularly evident in MDS marrows showing sideroblastic erythroid changes, whilst in MA they were mainly seen in cases of intermediate severity. It is suggested that these cells are associated with dysmyelopoietic changes in both malignant and non-malignant conditions.

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Absolute T cell counts and the relative distributions of antibody-defined helper and cytotoxic/suppressor T lymphocytes are reported in 26 patients with chronic idiopathic thrombocytopenic purpura (ITP). T cell numbers are generally normal in ITP and alterations in relative helper (OKT4 positive) and suppressor (OKT8 positive) T cell numbers show no consistent patterns, although 35% of the cases examined showed inverted distributions. The combined percentages of helper and suppressor T cells consistently exceeded 100% in ITP indicating the presence of increased OKT4+8+ cells in these patients. A cell population, previously defined as SRBC positive and OKT3 negative, was found in the normal group and in ITP patients following splenectomy but was absent in those patients with intact spleens. The role of these changes in the pathogenesis of ITP is discussed.

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Membrane receptors for IgG and C3b were examined on blast cells from 57 cases of acute myeloid leukaemia. These acute leukaemias were classified as myeloblastic, myelomonocytic or monocytic following morphological, cytochemical, and immunological investigations. The membrane receptors of leukaemic blast cells appear to be directly related to the degree of monocytic differentiation with the lowest receptor activities found in acute myeloblastic leukaemia. A comparison was also made between receptor and cytoplasmic acid naphthyl acetate esterase (ANAE) activities in 29 morphologically and immunologically-defined myelomonocytic and monocytic leukaemias. This study revealed that the receptor-positive "monocytic component" in a significant proportion of cases showed unexpectedly weak or negative ANAE reactions suggesting a more cautious approach to the interpretation of ANAE cytochemistry in acute leukaemias. The normal development of cytoplasmic ANAE and membrane receptors is also discussed and compared with their abnormal patterns of expression associated with leukaemic transformation.

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The myelodysplastic syndromes (MDS) are disorders in which the abnormalities are thought to be confined to cells of the myeloid series. However, examination of peripheral blood from 56 patients with MDS showed that the majority had low lymphocyte counts. In a detailed study of 25 patients, using OKT3, OKT4 and OKT8 monoclonal antisera together with SRBC rosettes, it was shown that there is a consistent and significant reduction in peripheral blood T lymphocytes. This decrease was primarily confined to the OKT4-defined helper subpopulation. There is a consequent relative increase in the OKT8-defined subset but in absolute numbers however, suppressor cells are reduced compared to normal particularly in those patients with lymphopenia. No correlations between T cell abnormalities and the different morphological groups of MDS were found. The possible implications of the reversed helper/suppressor ratio in the pathogenesis of MDS are discussed.

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The expression of Fc(IgG) and C3b membrane receptors by granulocytes and their precursors was examined in 23 cases of megaloblastic anaemia which were graded I-III according to morphological severity. Fractionated bone marrow and peripheral blood granulocyte receptors were assessed by rosette formation with optimally sensitized ox erythrocytes and the results compared with those found in 14 normal marrows. Promyelocyte Fc and C3b receptor activities in megaloblastic anaemia did not differ from normal whilst the number of Fc receptor positive myelocytes and later cells showed a significant increase (P less than 0.05 in Grade I, P less than 0.01 in Grades II and III) proportional to the severity of megaloblastosis. An increase in the number of C3b receptor positive granulocytes was seen in early megaloblastic anaemias and, in contrast to Fc receptor expression, showed the highest receptor activities in the Grade II cases. The most significant changes in receptor expression were seen at the metamyelocyte stage and appear to be related to the numbers of these cells found in the megaloblastic marrows. It is suggested that these alterations are primarily related to asynchronous granulocyte maturation and the application of these findings to the study of granulocytic disorders is discussed.

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A possible correlation between Fc-IgG receptor expression and neutrophil alkaline phosphatase (NAP) activity was investigated in relation to maturation of granulocytes in human peripheral blood and bone marrow. NAP activity was studied in bone marrow from patients with normal peripheral blood NAP scores (20-100) and compared with those with high NAP scores. Results indicate that NAP activity is confined to segmented neutrophils (SN) in marrow and peripheral blood except when peripheral NAP activity is abnormally high. There is a normal increase of approximately 60% in mean NAP scores of peripheral blood compared to marrow SN. Granulocyte Fc-IgG receptor activity, known to increase with maturation, was studied in relation to NAP activity. A combined assay using a rosetting technique with ox-erythrocyte (oxE) antibody-IgG and subsequent NAP cytochemistry was used. Receptor expression was found to be virtually complete in normal granulocytic maturation before the appearance of detectable NAP activity. This was supported by findings in chronic myeloid leukaemia where no cases of low Fc receptor activity were found despite NAP scores of less than 5. The significance of these findings is discussed in the light of current concepts of the control of NAP activity.

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