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Summary. A case of hairy-cell leukaemia was studied by conventional cyto-chemical, electronmicroscopic and immunofluorescence techniques. This condition is often known as leukaemic reticuloendotheliosis (LRE) but the nature of the proliferating cells has been in doubt. The accumulation of immunoglobulin-synthesizing cells in the peripheral blood suggests that the involved cells are lymphocytes and no evidence for a reticular or endothelial origin of the LRE cell could be found.

Summary The skin window (SW) has been used to investigate the local phlogistic response in 18 normal volunteers, in 36 neutropenic patients with or without splenomegaly and in 10 patients with a large spleen without neutropenia. The appearance of polymorphonuclear cell (PMN) on the abraded area was always depressed in neutropenia at the third hour. After that period the neutropenic patients with splenomegaly showed a normal PMN response, [n contrast, in neutropenic patients with a normal spleen, the PMN migration on the SW was virtually absent. Moreover patients with hairy cell leukaemia (HCL) presented a reduction of mononuclear cell infiltration on the SW. The SW represents therefore an useful tool to study in vivo the flogistic response and to distinguish between‘true and pseudo’neutropenia.

Periphere Blutzellen von Patienten mit Haarzell-Leukamie wurden in intraperitonealen Diffusionskammern kultiviert. Bei allen Patienten konnte eine Proliferation von Haarzellen beobachtet werden. Granulo-, Erythro- und Monozytopoese zeigten im Vergleich zu Normalpersonen keine anderung der Proliferation und Differenzierung. Damit blieb die Gegenwart von Haarzellen ohne Einflus auf das Kulturverhalten der restlichen Hamatopoese. Gleichzeitig darf nach diesem Befund ein normaler Gehalt an hamatopoetischen Stammzellen im Blut der Patienten vermutet werden. Dagegen wiesen das Verhalten der Lymphozyten und die Anzahl entstehender Plasmazellen deutliche Unterschiede zu Normalpersonen auf, deren Ursachen bisher nicht geklart sind.

In this study we investigated the splenic microvascular architecture in hairy cell leukaemia, in order to provide a morphological basis for the haemodynamic modifications occurring in the disease. When compared with controls, the four leukaemic spleens examined showed a set of changes involving both the arterial and the venous system. A real increase in the absolute volume, surface and length of pulp arterial vessels was present. This increase was not so great as the enlargement of the spleen, thus resulting in a reduced density of distribution of arterial vessels in the infiltrated pulp. Enlargement of pulp cords and sinuses was also present: the pulp cord enlargement was apparent in the unit volume, which resulted in a disproportionately higher increase of the absolute volume, compared with that of sinuses. The sinus-cordal rearrangement and, particularly, the increase in the volume of pulp cords may cause a slowing down of blood cell circulation with resultant increased phagocytosis and hypersplenism. Moreover, it is suggested that the changes observed in the arterial bed of the spleen in hairy cell leukaemia involve both a reduced blood supply per unit volume of splenic pulp and a more marked conditioning of blood cells prior to their screening by cordal macrophages.

Summary. A case of hairy-cell leukaemia (HCL) with IgG(k) paraprotein is described. The typical clinico-pathological features of the patient are stressed, and it is shown that the hairy cells (HCs) were producing and secreting IgGk. The case is placed in a more general context by the demonstration that HCs from other typical cases of HCL produce and secrete IgG. These findings conclusively demonstrate that HCL is a B-cell disease.

A case of hairy cell leukaemia complicated as a terminal event by massive retroperitoneal lymphadenopathy is described. The patient had recently been treated with lithium carbonate and had previously been demonstrated to suffer from a systemic vasculitis, either or both of which may have contributed to the development of this rare complication.

The sera of patients with hairy cell leukaemia (HCL) contain a factor which inhibits the binding of anti-IL-2R antibody to its target (activated T lymphocytes). The presence of this factor, which probably corresponds to the soluble form of IL-2R (sIL-2R), can be easily detected using a simple immunocytochemical inhibition assay. In a series of patients with chronic lymphoproliferative diseases the presence of sIL-2R appeared to be specific for HCL, using the sensitivity of our test, since it could not be detected in sera from normal subjects and patients with B-cell lymphocytic leukaemia or Hodgkin's disease. Thus it might be used as an additional tool for characterizing HCL patients.

Seventeen patients with hairy-cell leukaemia (HCL) and peripheral cytopenias were given human lymphoblastoid interferon (Wellferon), 3 megaunits daily or 6 megaunits on alternate days intramuscularly, for 4-24 weeks. Twelve of the patients had undergone splenectomy, three had no palpable spleen and had therefore not been offered surgery, and two patients with substantial splenomegaly were given interferon (IFN) as treatment of first choice. Toxic effects were minor except in one patient who experienced a severe form of somnolence syndrome. In all patients hairy cells (HCs) were cleared from the blood and platelet and Hb levels improved in 2-14 weeks. Neutrophils were improved in 14/17 of the patients. In the two patients with splenomegaly, the spleen became impalpable after 5-8 weeks therapy, and haematological improvement occurred at 12-14 weeks. HC infiltration of the marrow was reduced in all patients, but was complete (less than 5%) in only two, both of whom had impalpable spleens. Immunological surface-marker studies confirmed that light-chain-restricted B cells disappeared from the blood in parallel with the clearance of morphological HCs. There was no evidence of HC maturation and no increase in phenotypic NK cells. T cells were moderately reduced and the relatively greater reduction of Leu 2a+ suppressor cells resulted in increased Leu 3a+/2a+ helper/suppressor ratios in 11/17 of the patients. Early experience in the six patients who have stopped IFN suggests that, after an initial further increase in Hb and neutrophil levels, HCs gradually return with slow deterioration of haematological parameters. Interferon is now the treatment of choice for patients becoming cytopenic post-splenectomy or for patients without splenomegaly. IFN is effective first-line therapy in patients with splenomegaly, but further work is needed to establish whether the agent should replace splenectomy in such patients. Some form of maintenance or re-treatment therapy will probably be necessary.

The use of splenic radiotherapy in the treatment of hairy-cell leukaemia is discussed. Reference is made to the case of an elderly female whose cardiorespiratory state precluded splenectomy, and who responded well to splenic irradiation on two occasions.

Ribosomal lamellar inclusions of the type commonly seen in hairy cell leukaemia and less frequently in other disorders were noted in the lymphocytes of two patients with Waldenstrom's macroglobulinaemia. Serial sectioning of these inclusions, previously described as straight, hollow cylinders, revealed a variety of shapes, including apparently twisted and bent forms. Observation of such configurations suggests that these structures are flexible and that, rather than being, simple, open-ended cylinders, they may be part of a more complex, continuous tubular system.

Among 12 patients with hairy cell leukaemia two died without splenectomy and two more 11 months and 7 1/2 years after the operation. In all patients removal of hypersplenism led to improvement of haematological criteria over several months up to many years. This was particularly true for platelets and granulocytes and thus for the proneness to infection and haemorrhagic diathesis. In two patients normalisation of all haematological parameters including histologically scarcely detectable hairy cells was observed. Differential diagnosis from prolymphocyte leukaemia is difficult. Nuclear morphology permits recognition of different degrees of maturation of hairy cells. In cases where tartrate resistant acid phosphatase (TRAP) cannot be demonstrated cytologically, demonstration of isoenzyme 5 is sometimes possible using gel electrophoresis. Demonstration of TRAP remains valuable for the diagnosis of hairy cell leukaemia, however only in connection with other criteria indicating this form of leukaemia.

The first association of polycythaemia rubra vera (PRV) and hairy cell leukaemia (HCL) is reported. The secretion by spleen cells in short term culture of IfGlambda to the exclusion kappa demonstrated that despite aberrant surface marker studies the HCL was a monoclonal tumour of B cells. Chromosomal studies on splenic cells were not able to demonstrate the common clonal origin of the two tumours.

We report the case of a 65-year-old patient with a 15-year history of intermittent asymmetrical oligoarthritis, who subsequently developed splenomegaly, lymphadenopathy, and episodic leucopenia and thrombocytopaenia. Investigations revealed hairy cell leukaemia, and 'hairy cells' were detected in the synovial fluid. No other cause for this arthritis was found, and we consider the blood dyscrasia to be the likely cause. This case demonstrates a hitherto unreported association between arthritis and hairy cell leukaemia.

More than 50 patients with hairy-cell leukaemia have now been entered into the British Wellferon (IFN) study, at different centres under the coordination of the Wellcome Research Laboratories. While the treatment duration and dosage varied between patients, the initial dose was usually 3 megaunits daily by intramuscular or subcutaneous injection. Although flu-like symptoms and mild somnolence were commonly experienced side-effects; cessation of IFN treatment as a result of such effects was necessary in only three patients. All patients irrespective of previous treatment showed some response and a complete (less than 5% hairy cells, HCs) bone marrow response was observed in 17. The degree of response was related to the duration of therapy. Immunological markers showed that there was no apparent increase in natural killer (NK) cells and no return of normal B lymphocytes. Light-chain-restricted B cells became reduced in parallel with the disappearance of morphological HCs. Absolute numbers of T cells were reduced, Leu2a+ preferentially, resulting in an increase in helper/suppressor ratios. The ratios (saturation index, SI) of saturated to unsaturated 18 carbon fatty acids (C18FA) of erythrocyte or leukocyte membranes, while abnormal in untreated patients, approached normal levels during IFN therapy. It is concluded that prolonged alpha IFN therapy is highly effective in HCL. The mechanism of action of IFN remains unknown, but indirect surface-marker data favours a direct effect on HCs.

Pulmonary infection caused by Arachnia propionica in a patient with hairy cell leukaemia is described. The organism is highly sensitive to penicillin but the patient succumbed to his illness despite treatment with penicillin and various other antibiotics. Various types of opportunist infections are common in patients with hairy cell leukaemia but we believe this to be the first report of infection by Arachnia propionica in such a patient.

Summary Three cases of chronic leukaemia, two with chronic lymphoid and one with hairy cell leukaemia are reported. These three leukaemic patients belonged to a series of 58 leukaemic patients with chronic exposure to benzene. The low percentage of chronic leukaemias in this series is discussed.

The efficacy of recombinant interferon-α2 in the treatment of advanced hairy cell leukaemia is investigated in 31 patients. Preliminary results show a complete and partial response rate of

A 69-year-old man who had recently returned from a holiday in Majorca, presented with haemoptysis and fever. Chest radiograph showed right lower lobe consolidation. A diagnosis of Legionnaires' disease was made. He was treated with erythromycin and made an uneventful recovery.

Summary. Eight cases of ‘hairy’ cell leukaemia (leukaemic reticuloendotheliosis) were evaluated by scanning electron microscopy. The surface of critical-point-dried ‘hairy’ cells was characterized by prominent and exaggerated broad-based, ruffled membranes and scattered small clusters of stub-like microvilli. The surface morphology resembled that of normal and leukaemic monocytes, but differed from that of normal and leukaemic lymphocytes. Some cells with features of both lymphocytes and monocytes were difficult to categorize; the overall impression of the surface architecture of most ‘hairy’ cells suggests, however, that they are related to the monocytic series. From the examination of these cases it is evident that scanning electron microscopy may be used as a means of distinguishing chronic lymphocytic leukaemia from ‘hairy’ cell leukaemia on the basis of surface ultrastructure.

The splenic red cell volume has been measured directly by an isotope method with quantitative scanning in 10 patients with leukaemic reticuloendotheliosis (hairy cell leukaemia). The volume ranged between 211 and 726 ml (mean 410 ml, SD 158) and this constituted 15--48% (mean 28.1%, SD 9.5) of the total circulating red cell volume. This is an exceptionally large pool when compared with that found in myeloproliferative and lymphoproliferative disorders with the same degree of splenomegaly. It is consistent with the histological features which show marked red cell accumulation in the splenic cord areas. The red cell pooling in the spleen thus appears to be a significant factor in the anaemia and there was fairly good correlation between the percentage of improvement in the anaemia and the percentage of red cell volume contained in the spleen. By direct measurement of the splenic red cell pool, it is possible to predict the extent to which splenectomy will benefit the anaemia and this may also provide an indirect measure of the extent of bone marrow dysfunction in the causation of the anaemia.

Prolymphocytic leukaemia (PL) is a rare variant of CLL, clearly defined by Galton et al. [8]. Among 10 patients with PL 9 patients had B-cell characteristics, only 1 patient was described to have T-lymphocyte markers [2].

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.

It is probably not an incorrect generalisation to state that current methods of treatment of the lymphomas and lymphocytic leukaemias have met with limited success. In this chapter we will not discuss the details of treatments but will consider why treatment may be unsuccessful and will also discuss the potential of contemporary therapeutic approaches.

Summary. Erythrokinetics were studied in 29 patients with hairy-cell leukaemia. In all cases there was an increase in plasma volume, closely correlated to the size of the spleen, indicating that the true degree of anaemia can only be appreciated by red cell volume measurement. Moderately increased haemolysis was observed in most cases, which did not correlate with the spleen size. Simultaneous study of autologous and isologous red cell life-span suggested an extra-corpuscular mechanism for the haemolysis in most patients. A quantitative erythropoietic defect, either relative or absolute, was found in half the cases, without any qualitative defect. Only one case showed erythroid metaplasia of the spleen. Thus marrow failure appears to be largely responsible for the anaemia and granulocytopenia in hairy-cell leukaemia. A clear correlation was shown between the short-term prognosis after splenectomy and the degree of hypersplenism. However, long-term survival correlated chiefly with the degree of bone marrow failure, whether splenectomy had been carried out or not. The results indicate that isotope studies in hairy-cell leukaemia are useful both in determining the best form of treatment and predicting survival.

We analysed by liquid scintillation counting and by autoradiography the DNA repair synthesis induced by UV irradiation in mononucleated cells from peripheral blood of 'hairy cell leukaemia' patients. In 9 out of 12 patients the repair activity values obtained in repeated assays were found to be significantly lower than those of healthy donors.

The ability of neutrophils from patients with hairy-cell leukaemia to kill Candida guilliermondii and Staphylococcus aureus in vitro was investigated. Of 10 patients, 8 showed defective candida killing, 5 defective bacteria killing, in comparison with normal controls. Study of those patients who underwent splenectomy suggests that neutrophil function can be improved by splenectomy. The possible causes of defective function in this disease are discussed.

A patient whose hairy cell leukaemia had begun to respond to alpha interferon therapy developed overt atypical mycobacterial infection. This eventually responded to combination antimicrobial therapy. The clinical difficulties involved in this unique case included difficulty in isolation of the organism, failure of an empirical trial of antituberculous therapy and false attribution of the patient's infective symptoms to alpha interferon.

We have treated 10 patients with hairy-cell, or hairy-cell-like leukaemia, for more than 6 months, with alpha interferon 3 X 10(6) IV/day I.M. or subcutaneously. All patients were severely pancytopenic before treatment. 7 patients had a typical hairy-cell leukaemia, whereas 3 lacked hairy cells but had the characteristic bone-marrow infiltration. The peripheral blood counts improved in all patients during treatment and the lymphoid infiltration of the bone-marrow was shown to decrease. 1 patient obtained complete remission, 6 partial remission and 3 had a minor response. It is concluded that alpha interferon is effective in the treatment of patients suffering from hairy-cell leukaemia.

Although lymphoid malignancies comprise a relatively rare form of human cancer (~3–4%), the pivotal role of the immune system in most biological processes has led to disproportionate interest in malignancies derived from the lymphoreticular system. The ready access to material for investigation in blood and superficial lymphoid tissue has also provided further stimulus to investigation of these malignancies. Nonetheless studies of lymphoid malignancies have revealed important new concepts governing tumour differentiation and behaviour that have much wider application.

Methods used in the study of human mononuclear phagocytes in vitro were applied to surgical specimens from 49 patients with non-Hodgkin lymphomas and eight patients with hairy cell leukaemia. Two of the tumours (both classified as “true histiocytic” neoplasms by the Kiel criteria) were distinguished by the presence of atypical macrophages in the in vitro system. In one the atypical cells were adherent; In the other example they were non-adherent. These tumours were the only examples of mononuclear phagocyte neoplasia identified in this series. All the remaining 47 cases of non-Hodgkin lymphoma were judged to be of lymphoid origin. While initial observations on hairy cell leukaemia-derived spleen cells suggested macrophage neoplasia, this impression does not stand up to more detailed analysis. The findings are more in keeping with a B lymphoid cell lineage. In hairy cell leukaemias and low grade lymphoma the proportion of macrophages per gram weight of tissue is diminished. This suggests a deficiency of macrophage functional activity compared with normal; the nature of this defect is not clear.

Using stereological techniques at the ultrastructural level, 7 quantitative parameters for 7 patients with hairy cell leukaemia, 27 patients with chronic lymphocytic leukaemia, and 8 normal individuals. These quantitative data show clear differences between normal lymphocytes, CLL cells and the abnormal cells of HCL. They also show that it may be possible to subdivide CLL into distinct groups on quantitative criteria.

Non-dividing lymphocytes from patients with chronic lymphocytic leukaemia were more sensitive than normal lymphocytes to reagents as prednisolone, cytarabine, vincristine and colchicine. The maximum difference was obtained when the cells were incubated with colchicine at 37 degrees C for 20 h. The sensitivity was measured by a 'sensitivity index' which was an estimate of the average percentage of lymphocytes killed by 1.0 and 0.1 mug/ml of colchicine. The index was 0-15% for lymphocytes from the blood of 14 normal persons and was 61-98% for 23 of 25 leukaemic patients with absolute lymphocyte counts of 8,000 X 10(9)/l or more. 3 of 4 untreated patients with presumptive diagnoses of early leukaemia had low absolute counts of 3,300 to 7,600 X 10(9) lymphocytes/l and high sensitivity indices of 41 to 83%. Tests on treated patients with lymphocytes counts less than 8,000 X 10(9)/l suggested a correlation of the index with remission and relapse. Hairy cells from 3 patients with hairy cell leukaemia were resistant to colchicine. Sensitivity to colchicine seemed useful at a test for leukaemic lymphocytes and as an aid in the haematologic evaluation of patients with chronic lymphocytic leukaemia and malignant lymphoma.

A patient is reported, in whom clinical and biochemical evidence of connective tissue disease preceded the diagnosis of hairy-cell leukaemia by at least 2 years. The pathogenetic mechanism(s) responsible for the coexistence of hairy-cell leukaemia with vasculitis and rheumatic disease is discussed. It is proposed that the 2 diseases may share a common predisposing factor, or that the hairy cells may elicit disturbances in immune homeostasis, implying a dysfunction of T suppressor cells. Hairy-cell leukaemia should be considered in the differential diagnosis in cases of unexplained febrile illness associated with pancytopenia and signs of connective tissue disease.

Une observation chez une femme de 64 ans. Les infections sont des complications frequentes dans la leucemie lymphohistiocytaire, mais c'est la premiere fois qu'une pneumopathie due a Paecilomyces varioti est publiee

From a series of consecutively studied spleens, perfusion-fixed and investigated according to a standardized procedure allowing morphometric investigations at the light and electron microscopic levels, 33 spleens causing splenomegaly syndrome (12 lymphoproliferative diseases, 10 hairy cell leukaemia, 11 myeloproliferative diseases) were compared with data in controls and autoimmune haemolytic anaemia and hereditary spherocytosis from previous studies. In splenomegaly syndrome, especially in hairy cell leukaemia and myeloproliferative diseases, less so in lymphoproliferative diseases, there is a disproportionate increase in the volume of pulp cords in the red pulp. Values for erythrocyte volume density are of the same order as splenic erythrocyte concentration determined by scintigraphic kinetic methods. Cases with complicating immunohaemolysis show a rather high proportion of erythrocyte profiles with nearly spheric shape as in autoimmune haemolytic anaemia and hereditary spherocytosis.

50 patients with hairy cell leukaemia (HCL) were treated with recombinant interferon (IFN) alpha-2b 2.0 x 10(6) IU/m2 subcutaneously three times weekly to evaluate the efficacy of low-dose IFN therapy in inducing and maintaining remission of the disease. At the time of this report 48 patients, of whom 22 were splenectomized, had been treated for at least 3 months and were considered evaluable for response. The median observation time on IFN-alpha-2b was 11 months (range 3 to 20). 4 cases with atypical disease (spongy lymphoid myelofibrosis) were also included. All patients responded to IFN. After 3 months 11/48 patients (23%) had achieved a partial remission (PR) with normalization of peripheral blood values. After 6 months 27/43 patients (63%) had achieved a favourable response; complete remission (CR) was recorded in 4 and PR in 23 patients. The proportion of patients with favourable responses (CR + PR) increased with the duration of therapy and after 12 months of therapy 23/28 (82%) patients showed CR or PR, 9 patients (32%) being in CR. Splenectomized patients disclosed a trend towards a more rapid response. It is concluded that IFN-alpha-2b is a highly effective first-line therapy for HCL.

Summary. With the development of different treatment schedules for acute and chronic leukaemias it has become essential that a uniform, standardized classification of malignant cell type is achieved. Without a standardized diagnosis it is impossible to compare the results of differing treatment regimes. Present diagnosis is still based on clinical criteria and subjective assessment of cell morphology; objective and quantitative data are required. Stereological analyses are capable of providing quantitative data. Stereological techniques have been applied to the study of malignant cell types in different leukaemias for the first time and quantitative data has been obtained. The nuclear and mitochondrial volume fractions of the cells have been estimated for normal lymphocytes, the lymphocytes of chronic lymphocytic leukaemia, acute lymphoblastic leukaemia, the abnormal cells of hairy cell leukaemia and several other haematological malignancies. The results clearly indicate that the cell types of different leukaemias possess measurably different properties and that stereological methods can be used to investigate the leukaemic cell quantitatively.