Hairy cell leukemia

III1|1(111[! I | | i l l | I[|

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HAIRY CELL LEUKEMIA Author:

Jan Jansen

Departments of Medicine and Pediatrics Indiana University; and Bone Marrow Transplantation Program Indiana University Hospitals Indianapolis, Indiana

Referee:

I_. T, Yam Department of Medicine Ll•ivetsily ol Louisvjlle School of Medichle; and Department oF Medlcal Service VA Medkal Center Louisville, Kentucky

I. I N T R O D U C T I O N Hairy cell ]eukemia (HCL) has received a large amount of attention during the 3 decades since its establishment as a separate clinicopathological entity. The interest in this disorder appears to be out of proportion with its incidence. Discussions about the origin of the neoplastic cell and about the best therapeutic approach have been prominent in the last 15 years and are still going on. In this review, an attempt is made to describe the clinieopathological entity, its complications, the progress made in understanding the origin of the neoplastic ceils, and the new advances in chemotherapy; furthermore, we try to identify gaps in our understanding of the disease. II. HISTORY Perhaps the first case report of HCL was published by Downey in 1938.' This author reported on a 53-year-old male who, after a period of general weakness, presented with severe anemia (hemoglobin 28%), and leukopenia ([130/mm a) with pronounced neutropenia (520/mm ~) and monocytopenia (20/ram*). The peripheral blood film showed toxic neutrophils, a few normoblasts, and anisocytosis and poikilocytosis. Between 1 and 6% "reticuloendothelial cells" were observed. The patient died 9 months later rrotn bronchopneumonia. At autopsy, the spleen was slightly enlarged (330 g) and ~howed no definite malpighlan corpuscles. There was "some rounding up and prolif;ration of splenic sinus cells". The lymph nodes were unremarkabie, but the bone narrow contained "abundant reticulum and reticular cells were large". Probably the !irst to recognize HCL as a separate entity were Rosenthal and Lee in 1952. 2 At a neeting of the American Society of Clinical Pathologists, they presented a paper which "eported 15 patients with a progressive disease characterized by enlargement of spleen, iver, and lymph nodes due to a uniform cellular infiltration of all these organs as well ts the hone marrow with the specific cell type frequently recognizable ila the peripheral ~lood. The cell type was reported to be remarkably uniform and to resemble closely he "reticulum cell found in smears of normal bone marrow, spleen, and lymph lodes"? A manuscript on this new entity was not accepted for publication, because he reviewers considered this to be a "commonly recognized condition for which the turbots propose a new name". 9 Thus, this series of patients was not published offi-

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cially until 1969.( Therefore, the credit of first reporting the clinical entity HCL should go to Bonronele et al. in 1958.s These authors reported 26 patients who had been followed and studied at Ohio State University between 1949 and 1957. All 26 patients were adults, and 21 were of the male gender. The median age was between 50 and 55, and the onset of the disease was usually insidious. The most common symptoms were caused by cytopenias. Splenomegaly was present at the time of diagnosis in 96% of the cases. In about half of them, the spleen was markedly enlarged. The majority of patients had anemia and thrombocytopcoia. Leukopenia was present in more than half the patients, and marked leukocytosis was very rare. Neutropenia was found in 71 ~ of the patients, Most strikingly, in the supravital stains of the peripheral blood, "free retioulum cells" were identified. These cells had pseudopods protruding from the cytoplasm, causing a serrated border for the usually round, oval, or polygonal ceils. In fixed films with Wright stain, the cytoplasm was irregular in outline and sky blue in color. Bone marrow aspirations resulted in repeated dry taps in most of the patients. Four patients died within 1 year from the onset of symptoms, and half the patients had died after 5 years. Bouroncle et al. located the neoplastic cell, which they considered to be a "free reticulum cell or hlstioeyte" very early in the differentiation scheme of hematopoiesis, earlier than myeloblasts, lymphoblasts, and monoblasts. They chose the name "leukemic reticuloendotheliosis" (LRE} for this disorder, referring to the first report of a case of leukemia characterized by "hyperplasla of the reticulum tissue in the blood forming organs with the appearance of reticuloendothelial ceils in the blood stream" by Ewald in 1923.6 Retrospectively, the latter patient probably suffered from acute monocytic leukemia. Mitus et al.' accepted the reticulum cell nature of the cells of LRE primarily on the basis of cytochemioal studies. However, they also recognized the morphological resemblance to lymphoid cells. These authors introduced the name "'neoplastic lymphoid reticulum cells". Sebrek and Donnelly in 1966 observed that the neoplastic ceIIs resembled both lymphocytes and monocytes but nevertheless could be differentiated from both these populations. They chose the less enigmatic, merely descriptive name "hairy cells". 6 I1a the years to follow, the term hairy cell leukemia has become more common than leukemic reticuloendotheliosis, although both are still being used interchangeably. Duhamel pointed to the diagnostic value of the bone marrow biopsy with its characteristic loose infiltration of neoplastic cells and increased reticulum fibers; his "myelofibrose lymphoide" is identical with HCL? Yam et al. discovered that the acid phosphatase activity found in HC was resistant to preincubation with tartaric acid (TRAP). ~ Since the acid phosphatase activity of neutrophils, monocytes, 1 lymphocytes, and many neoplastic hematopoietic ceils was not resistant to tartaric acid, this cytochemical reaction became of great value for the diagnosis of HCL. Thus, with the help of clinical data, morphology, and cytochemistry, the stage was set in the early t970s for a more extensive analysis of the typical and atypical features of HCL. TM

lII. C L I N I C A L FEATURES The actual incidence of HCL is not known. Bouroncle et al. reported an incidence of 2% of all leukemias seen at their center over a period of 7 years, s One other group reported an incidence of 5% of all leukemias." Since most publications about large numbers of patients come from referral institutions with a highly selected patient population, it is difficult to reach firm conclusions about the incidence of the disease. Nevertheless, an incidence of I to 3~/o seems reasonable, which would translate into about 2 cases per I million per year. It might well be that there are geographic differences in incidence, since Katayama et al. reported that the disorder was very rare in

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Table 1 CLINICAL FINDINGS AND L A B O R A T O R Y D A T A IN i~iCL A T T H E TIME OF DIAGNOSIS~3-~.z~-2s.~ % Spleen size No( palpable >10 cm under costal margin Lymphadenopathy Liverenlarged Hemoglobin <8.5 gldl > I2,r g/d!

Leukocytes <4,000/rnm ~ > 10,000/tuna~ Absolt~te granulocyte count <500/too9 >l,000/mm 3 Hairy cells <500/rams >5,000/ram~ Platelets <50,000/ram ~ >100,0~tmm 3

17--28 18-.29 5--26 19--20 24--35 19--29

57--6.2 11--24 33~.~1 15--32 46--50 18 19~30 21~43

Japan. ~z The median age at the time of diagnosis is 52 years with about half the cases occurring in the 5th and 6th decade, j~''* The youngest patient reported was 22, '7 and the oldest was 90. ~* A clear male predominance with a male to female ratio of 3-7:1 has been reported in all large series. ~3-~6 As is the case in most types of human leukemia, no clear etiology has been defined. In one instan,"~, HCL has been reported in a father and son who shared the same H L A types." In addition, a c•se of H C L has been reported associated with a fam.~lial lymphoproliferatlve disorder. 2~ Our group reported 3 physicians among the first 15 patients studied, 2' but no other representatives of this profession were encountered among the next 60 patients. Stewart and Keating suggested that radiation exposure might be an etiological factor in H C L , " but this observation has not yet been confirmed. In fact, in our series of 75 patients, only 1 had radiation exposure in his history. Nonspecific symptoms such as weakness, weight loss, and dyspnea are the most common reasons for presentation. In addition, many patients complain about recent pyogenic infections, while a minority has hemorrhagic diathesis or abdominal discomfort secondary to splenomegaly. '3''*z3 On physical examination, splenomegaly is the most prominent feature. The spleen is palpable in about 80~ of the patients; in 50 to 60%, the organ is palpable more than 4 cm under the left costal margin, while in 18 to 30%, it is massively enlarged to more than 10 cm under the costal margin (Table 1). '3"~,23-" Hcpatomegaly is far less prominent and only present in 20% of the patients; the enlargement of the liver is only very rarely massive. Palpable superficial adenopathy is rarely encountered (<5%) and then mostly still localized at a single site. ",z~ One case with massive lymphadenopathy has been reported, z* Therefore, in cases with pronounced Iymphadenopathy, a diagnosis of H C L should be made only with the utmost caution.

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The hematology iaboratory results at the time of diagnosis show pancytopenia in a large proportion of the patients. The hemoglobin is in the normal range (>12 g / d / ) in only 20 to 30070 of the patients, while it is severely decreased (<8.5 g/dl) in up to 35%. '3-'~'~-z~ Interestingly, the mean corpuscular volume (MCV) is nearly always towards the upper limit of normal and often definitely elevated? ~ z' Thus, Cawley et al. reported an MCV >96 fl in 70% of patients, )J and we reported such values in 60~ of patients. 24 Nevertheless, the anemia is usually described as normocytic and normocluomic. Mild anisocytosis, poikilocytosis, and occasional circulating nucleated red cells are very often observed even before splenectomy. The white cell count is decreased (<4,000/ram ~) in 50 to 60o70 of the cases, while leukocytosis (>10,000/mm 3) is only found in 15 to 25% of cases. 's-~zs Obviously, the total white cell count consists of a combination of normal cells and neoplastic cells. Therefore, the white cell count by itself gives very tittle information about the resistance against infection and the infiltration with HC. The absolute granulocyte count (AGC) is severely decreased (<500/ mm ~) in about one third of the patients, while only 10 to 20% have reasonably normal granulocyte levels (>lS00/mm~)? ~5 Consequently, the vast majority of patients with HCL at the time of diagnosis are at risk for pyogenic infections. The number of monocytes in the peripheral blood is mostly severely decreased. '*'~'2~ Not all series, however, report a signif!cant monocytopenia, j*'~9 In the experience of Cowley et aI. J~ aud our group, J' the presence of a fair number of monocytes in the peripheral blood often coincides with the presence of other atypical features. The platelet count is decreased (<150,000/mm 3) in more than 80o/0 of cases? 3-''''~'24 In 20 to 30~ of cases, severe thrombocytopenia (<50,000/mm ~) is found. The various eytopenias are often associated. Thus, pancytopenia with a hemoglobin <12 g/d1, absolute granulocyte count 0.7) did not have a satisfactory platelet level after splenectomy. Unfortunately, these authors did not study the relation between HCI and increase in hemoglobin level and absolute granulocyte count. 3~ Splenic sequestration and bone marrow failure both play a role in causing anemia, neutropenia, and thrombocytopenia. Nevertheless, on the basis of the evidence available, it appears reasonable to attribute the thromboeytopenia primarily to splenic sequestra-

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tlon, and the ueutropenia primarily to bone marrow failure. Consequently, spleneetomy can be expected to have more effect on the platelet count than on the neutrophil count. 1( With isotope methods, the contributions of bone marrow failure and splenic sequestration can be further elucidated. Lewis etal. demonstrated that the spleen of patients with HCL forms an exceptionally large pool of red cells compared to myeloproliferative and other lymphoproliferative disorders with the same degree of splenomegaly; the splenic red cell volume ranged between 200 and 700 ml and constituted 15 to 48% of the total circulating red cell volume.33 A significant correlation was found between the percentage of improvement in the hemoglobin level induced by splenectomy and the percentage of red cell volume contained in the spleen. This pooling of red cells may well occur in the splenic "pseudosinuses" reported by Nanba etal. as rather typical for t t C L ? ' With erythrokinetles, Castro-Malaspina et at. reported a quantitative erythropoietic defect in half the patients with HCL. j' The long-term survival of the patient correlated mainly with the degree of bone marrow failure as detected with these erythrokinetic studies. In patients in whom the decision of splenectomy is very difficult, such isotope studies may give valuable additional information. IV. DIAGNOSIS In many patients with HCL, the presentation is so typical that the diagnosis is relatively easy. As stated by Catovsky, "the careful examination of a blond film for the presence of hairy cells in a mlddle-aged male patient with pancytopenia and splenomegaly is probably the most important diagnostic step in this condition. ''~ HC are large cells, usually measuring 10 to 18 ~.m. The eccentric nuclei show a markedly variable configuration witll a round, ovoid, bean, dumbbeI1, horseshoe, or clover leaf shape. The nuclear membrane is distinct, the chromatin pattern delicate, lacy rather than clumped, but less so than in blast cells. Small nucleoli are sometimes present, and occasionally are prominent. The large amounts of pale, grayish blue cytoplasm have a delicately mottled appearance; sometimes small azurophilic granules or small vacuoles are seen. The fine, irregular, filamentous cytoplasmic projections, from which the HC obtained its name, are typical. These can be observed even better in phase-contrast microscopy s'~''J a technique which may be quite helpful in establishing the diagnosis. In <10% of the cases, no circulating HC can be found, t3 Very typical for HC is their cytochemical pattern. Mitus etal. reported that HC demonstrated acid phospbatase activity.7 in 1971, Yam et ak discovered that this acid phosphatase activity was resistant to preincubation with tartaric acid (TRAP). ~~This TRAP activity has become very important in the diagnosis of HCL. However, the reaction is certainly not pathognomonic for HCL. Thus, occasional cases are negative even with the most sensitive techniques. 37,a~On the other hand, TRAP activity has been observed in other cells such as in prolymphocytie leukemia, ~9lymphosarcoma cell leukemia, ~9'4~Sezary syndrome,~1 and even Gaueher cells.4~ The resistance of the acid pbosphatase activity to preineubation with tartaric acid is due to an increase in isoenzyme 5 on polyacrylamide gel electrophnresis. 4J Even though the demonstration of TRAP activity is not absolutely typical of HCL, it nevertheless can be a great help m the diagnosis. The final confirmation of the diagnosis of HCL should come from the histological examination of involved tissue. Even in the most typical case, it is wise to get histological confirmation. A bone marrow biopsy is probably the most appropriate procedure. It should be kept in mind that bone marrow aspirations are unsuccessful in at least half the patients with HCL. ~ The bone marrow core biopsy shows either partial or corn-

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plete replacement with HC24"4" In case of partial marrow involvement, the bone marrow often appears normocdlutar with subtle infiltrates of mononuctear cells inthnatcly intermingled with foci of apparently normal hematopoiesis," These mononnelear cells have well-defined nuclei and are clearly separated from one another by water-clear or finely reticulated zones of abundam cytoplasm which impart a "halo" appearance. +4 In cases with virtually complete replacement, the same obvious separation of the individual nuclei is present. Reticulum stains show an increase in retieulum fibers as a fine meshwork. Bartlet al., studying methyl-methacrylate imbedded bone marrow biopsy specimens of 134 patients with HCL, attempted to subdivide the eases on the basis of their morphology into three types/~ Of the cases, 47% were ovoid, 37% convoluted, and 16070indented. This classification had a significant effect on the prognosis, with the ovoid type having the best and the indented type the poorest survival time. In addition, these authors found a significant converse correlation between the degree of bone marrow involvement and the survival time. This is in llne with the observation by Golomb and Vardiman that patients with a high HCI have a poor response to splenectomy, 32 and the observation that patients who do not respond to spleneetomy with significant increases in their peripheral blood counts have poor survival." In some cases of HCL, unusual patterns of bone marrdw involvement are observed. Focal fibroblastic proliferation has been reported, 4+''+ and occasional cases are very hypocellular with small clusters of neoplastic ceils and severely reduced hematopoiesls. '~'~'s' The combination of clinical features, peripheral blood smear, and bone marrow biopsy should always allow the diagnosis. This, however, does not mean that every single case can be classified easily, since atypical cases of HCL certainly exist, and the transitions between HCL and other hematological malignancies are not always clear. V. C L I N I C A L C O M P L I C A T I O N S

A. Infections Infections are the major cause of death in HCL.'+'~6"~2"saPyogenic infections leading to septicemia or pneumonia are frequent in these patients who often have severe ncutropenia, s+'~6 Pseudomonas aeraginosa, Escherichia coil, and Staphylococcus aureus are microorganisms encountered frequently in these infections, A microbicida] defect of the neutrophils of patients with HCL, as reported by Child et al.,5' may add to the risk of pyogenic infections. In addition to these infectious, which are common in patients with neutropenia, unusual pathogens are also encountered in HCL. These organisms, such as myeobacteria, toxoplasmosis, and histoplasmosis, suggest defects in cellmediated immunity,s6++a'~~There is indeed extensive evidence for defects in cell-mediated immunity in patients with HCL. Although delayed-type hypersensitivity+ as assessed with skin tests, is normal, 5+and serum immunoglobulin levels are generally normal or increased, t~.~s,2~ functional T-cell defects exist. Sabbe et al. showed that the mltogen response by the T cells of patients with HCL was decreased; this response could be normalized by the addition of donor monocytes. +~This observation suggests that monocytopenia, which is typical in patients with HCL, ~7,28may be responsible for part of the defect in cell-mediated immunity. The response to antigens, such as PPD or tetanus toxoid, remained abnormal even after the addition of donor monocytes. +1 Several groups have studied the distribution of T-cell subsets in patients with HCL. Sabbe et al. reported a reduction in Tg cells, whereas the numbers of Ty cells were normal.+' Lauria et al. confirmed the imbalance between Tg and Ty cells, bat documented an increase in the proportion of Ty cells regardless of the clinical state of the disease. +2With the he~p of monoclonal antibodies, they showed in patients with active disease a significant increase in the proportion and absolute number of suppressor/

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cytotoxic T lymphoeytes (CD8), in combination with a significant reduction in helper/ inducer T cells (CD4). Patients in remission had a normal proportion of CD8-positive cells with only a moderate reduction of CD4-positive ceils. Worman and Cawley, however, reported normal proportions and numbers of CD4- and CD8-positive cells in untreated HCL at the time of diagnosis. '3 Following splenectomy, increased numbers of CD8 cells were found in the peripheral blood, suggesting that the spleen may have an important influence on circulating T-cell subpopulatlons? ~ The normal number of CD4-positive cells in treated patients is well in line with the normal helper T-cell functlon reported for such patlents 6s and with the essentially normal numbers of the CD4"Leug" helper fraction2' The discrepancy in the reports about the CD4 to CD8 ratio may be due to the definition of "active disease". Basically, the T-cell subsets appear to be largely preserved in patients with HCL. Several groups have studied the natural killer (NK) activity in HCL. Using K 562 tumor cells as a target, Ruco et al. found greatly decreased NK activity in the peripheral blood of ten patients. ~6 This activity could be potentiated in vitro by interferon, and was associated with reduced numbers of circulating monocytes and large granular lymphocytes. Similar results were reported by Hooper et at27 The latter group showed that a 3-day in vitro incubation with interleukin-2 markedly increased the NK activity of the mononuclear cells of HCL patients. In an unpublished study of 20 patients, our group found low NK activity in 14, moderate activity in 3, and normal NK activity in 3 patients/TM Lauria et at., however, reported decreased NK activity in only three of their seven patients. 62 Again, this discrepancy may be due to selection of patients. Furthermore, cells with NK phenotype but with deficient NK function have been reported in the peripheral blood of patients with HCL. 68 The combination of severe monocytopenia, defective NK function, and subtle deficiencies of T-cell function may lead to such a defect in cell-mediated immunity that many patients with HCL are at high risk for opportunistic infections. B. Hemorrhagic Complications At the time of diagnosis, 80o70 of the patients with HCL have thrombocytopenia; ta-a6'2a'~30070 of the patients have platelet counts <50,000/mmL Therefore, it is easily understood that many patients with HCL demonstrate signs of easy bruiseability. In addition, the platelets of patients with HCL have been shown to be defective. Levine and Katayama showed that the platelets of many patients have a poor aggregation response to epinephrine and ADP? 9 This was confirmed by other investigators. ~~ In addition to these defects in functional assays, the platelets of patients with HCL also have ultrastructurat abnormalities; they have few or no granules. ~'7' Consequently, the platelet defect in HCL can be considered to be a granule storage pool disease) ~ Interestingly, both the platelet function and morphology improve following splenectomy/~'.73 Since both thrombocytopenia and the qualitative platelet defect often respond very well to splenectomy, bleeding tendency should not be considered a contraindication to the operation. Even in the most thrombocytopenic patients, the operation can still be performed safely as long as platelet transfusions are available. These transfusions should preferably be given after the arterial blood supply to the spleen has been severed in view of the large pooling capacity of the organ in this disease. C. Bone Lesions Osteolytic lesions are a well-known, but rare, complication of HCL. In 1977, Rhyner et ai. reported 3 patients in whom 1 to 3 years after splenectomy focal osteotytic lesions or spontaneous fractures occurred.~' Although one of the patients developed skull, and

another spinal lesions, it has subsequently been shown that lesions of the femoral neck are the most typical. At least 20 patients with bone lesions have been reported and the vast majority had uni- or bilateral involvement of the femoral neck. '''~,'~-"~Clinically, the lesions mostly manifest themselves through hip pain, and occasionally through a spontaneous fracture. Hyperaalcemia is not observed, and the bone fraction of alkaline phosphatase is normal. Isotope bone scans show increased activity in the lesions, and radiographic studies show mottled lytic lesions often associated with severe demlneralization. Biopsies from the lesions show infiltration with HC, not different from other parts of the bone marrow. In fact, in one case we could study at autopsy, the immunological phenotype of the HC in the osteolytic lesion was completely identical to that of HC from other parts of the bone marrow; no maturation in the direction of plasma cells had occurred. 7~ Radiation therapy is the treatment of choice for these lesions. In our experlcnce, 2000 to 2400 rad was sufficient to produce symptomatic relief and stop the progression of the lesions. Radiation doses between 800 and 6000 rad have been used, and basically all patients have responded to the therapy, although sometimes the resolution of pain was slow. The incidence of the lesions is difficult to assess from the reports published. Weh et al. reported 5 cases of a total of 150 analyzed, which suggests an incidence of 3.3% .'~"Quesada eta[., on the other hand, found 4 cases out of 46, corresponding to 13~ Since Westb~onk et al. ~ documented cmly 1 case in 38 patients, and our own group only 3 out of 81 cases, the incidence will probably be <5%. Nevertheless, the incidence is high enough to warrant immediate pelvic X-rays in any patient with HCL who starts complaining about hip pain. The osteolytic lesions in patients with typical HCL should not be confused with the occasional association of HCL with multiple myeloma. Noseda et al. reported a patient with HC in the peripheral blood and bone marrow who also had increased numbers of atypical plasma cells, and many osteolytle lesions with multiple fractures of the thoracic spine. ~' Paraprotein of IgG class was found in the serum, and BenceJones protein in the urine. Since both the HC and plasma cells were of k type, the two diseases may have been related, and may have represented different maturation stages of one neoplasm. Catovsky et al. reported three patients who had typical features of HCL and multiple myeloma at the same time.a2 In one of them, the diagnosis of HCL had been made 2 years before the appearance of a paraprotein, bone lesions, and plasma cell infiltrate. In the two patients studied, the light chain types of the HC and the plasma cells were different, suggesting that either the two malignancies were not associated, or that the neoplastic event occurred at a very early stage before light chain committment was established. Although a chance association obviously cannot be ruled out, it is more attractive to interpret the simultaneous occurrence of two rare Bcell malignancies as different expressions of a single neoplastic process. In that respect, the coexistence of HCL and malignant lymphoma, reported in at least two cases, 63'84 should be I~,entioned. D. Autoimmune Syndromes An increasing number of reports have associated HCL with autoimmune diseases such as vseulitis, polyarteritis, or arthritis. Elkon et al. reported in 1979 four patients who developed a systemic vasculitis similar to polyarteritis nodosa within 2 years of the onset of HCL. s5 Arteriographic studies in two patients revealed microaneurysms, ,rod biopsy specimens in three patients revealed a vasculhis affecting medium-sized vessels. One patient had circulating immune complexes. One patient improved without chemotherapy, two patients responded to corticosteroids alone, and one required cyclophosphamide in addition to the steroids. Neutropbilie vascular infiltrates, and ale-

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vated absolute granulocyte counts, which are typically seen in polyarteritis nodosa, were lacking; the subnormal marrow leukocyte reserve and suboptimal neutrophil response as reported by Yam et alY' may have been responsible for this absence. Since this first report, at least nine additional eases of polyarteritis nodosa or systemic vasculitis have been reported, s2"*r-gj Furthermore, in our series of 81 patients, we observed one in whom a diagnosis of polyarteritis nodosa was made. The incidence of autoimmune disorders in H C L may be quite high. Westbrook and Golde found vaseulitis or other autoimmune disease in at least 9 and perhaps even in 11 out of 38 patients? 2 In addition to the group of systemic vasculitis/polyarteritis nodosa, which mostly presents as a severe progressive disease with visceral involvement, they recognized a group of patients presenting with joint manifestations (arthritis or arthralgias) in combination with nodular skin lesions? ~ Arthritis was first reported by Crofts et ,al. 92 Several additional cases of arthritis have been reported, ~2'~'~'~ and our group has observed at least 3 of such cases in 81 patients. The arthritis picture is mostly much more benign than systemic vasculitis, ~2 and responds much better to therapy with corticosteroids. A causative mechanism for the occurrence of autoimmune phenomena in HCL has not been detected. Obviously, a product produced by the neoplastic cells may serve as an antigen inducing an immune reaction. Alternatively, viral infections could lead to such phenomena. In this respect, it is important to mention that the sera of many patients with HCL contain markedly elevated titers to Epstein-Barr vlrus-specific antigens. 95'g6Not just antibodies to viral capsid antigens (VCA) were found, but also to early antigens (EA) suggestive of active infections. 9s,'~ VI. P R O G N O S I S In order to plan the most appropriate therapy for an individual patient with HCL, a careful assessment of the prognostic criteria should be made. Several studies have addressed the issue of prognostic parameters, ~a"6.2~-25.~2.a~and a staging system has been proposed. 2s The overall median survival for a patient with HCL has been reported to be between 2 and 5 years. ''"~'2a.a6 The age and sex of the patients do nut appear to be of prognostic importance, '4.~3,9~although in one large series female patients appeared to do slightly better. ~ In the total patient material, the size of the spleen is not correlated with survival. '~,'s,2~ However, the picture here is obscured by the splenectomy that many patients undergo as first treatment. When only nonsplenectomized patients are considered, the size of the spleen shows a significant inverted relation to the survival time. 2s Thus, spleen size should be interpreted as a prognostic factor at the time of diagnosis. Since infections are the most common cause of death in patients with HCL, one would expect the absolute granulocyte count also to be a prognostic parameter. Indeed, this has been claimed to be the case by a number of authors. '4,~s,~3"3~As in many other cases of leukemia, the cutoff for the absolute granulocyte count appears to be around 500. It is interesting, however, that when only patients who will not undergo splenectomy are studied, the neutrophil count does not appear to be of prognostic significance. 2s The number of HC in the peripheral blood does not appear to be of prognostic significance either.'"2s Obviously, entering the total white cell count into such studies does not make a lot of sense, since this count will include both granulocytes and HC, which are theoretically of "competing importance." The single most important hematological parameter to indicate the prognosis is the hemoglobin level. Patients with a low hemoglobin level (<8.5 g/dl) at the time of diagnosis have a significantly poorer outlook than patients with higher hemoglobin levels.~*'2a'2sThe platelet level has also been found to be of prognostic significance in a number of studies.t,.~3 On the basis of hemoglobin level and spleen size, Jansen and Hermans reporting for

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~ K ~ t . r l H c a l J~eYlews In U n c o t o g y / l ~ e m a t o l o g y

Table 2 C L I N I C ~ L STAGING FOR PATIENT W I T H HCL AT THE TIME OF DIAGNOSIS2a,2s.gs Stage 1 Hb >12.0 g/dl + s~ieen .~ 10 cm/ucm," or Hb >8.5 g/dl -b spleen <4 cm/ucm Stage 11 Hb >12.0 g/l + spleen>10 cm/ucm, or Fib 8.5--12.0 g/dl + spleen4.10 cm/ucm, or Hb <8.5 g/dl + spleen <4 cm/,ucm Stage Itt Hb 8.5--12.0 g/dl + spleen>tO era/acre, or Hb <8.5 g/dx$+ spleen>4 era/acre * Under costal margin. Table 3 CLINICAL STAGING SYSTEM FOR PATIENTS W I T H HCL AT 2--3 MONTHS AFTER SPLENECTOMY zJ-2s Stage A Fib >12.0 g/d! + neutrophils>~00/mrn~ Stage B Hb >12.0g/dl + neutrophilsgS00/mm~, or Hb 8.5--12.0 g/dr + neutrophils >500/rnm~ Stage C Hb 8.5--12.0 g/dl + neutrophils ~;500/mrn~, or Hb <8.5 g/dl a collaborative study group proposed a clinical staging system for patients with HCL at the time of diagnosis (Table 2)2 s In this system, three stages are distinguished. Patients with the highest hemoglobin levels or the smallest spleens are considered stage I. whereas patients with the lowest hemogtobin levels or the biggest spleens are considered stage IIl. The predicted survival for the three stages was sigttificantly different. Analyzing a group of 154 nonsplenectomized patients, the median survival for stage I was 72+ months, for stage 1I approximately 20, and for stage 111 approximately 14 months? s The validity of this staging system has been confirmed by Flandrin eta]. 2~ and the Italian C o o p e r a t i v e Group28 An additional important prognostic parameter is therapy, in particular splenectomy. Overall, patients who undergo the operation will do better than nonsplenectomized p,'~tients; ~'~-23"~z'~.gs,~9especially patients who respond to the operation with a normalization of hemoglobin level and neutrophil and platelet counts will have an excellent survival. ~'.a~,Zs,~ The beneficial effect of splenectomy is mostly clear within 2 months. Therefore, at that time, a new analysis of prognostic parameters can be made. Based upon the large material of a collaborative study group, which included data of 184 patients at 2 to 3 months after spleuectomy, Jansen and Hermans proposed a staging system using hemoglobin level and neutrophil count. ~ Thus, patients in stage A had the highest hemoglobin level and neutrophil count, and patients in stage C had the lowest hemoglobin level and neutrophil count (Table 3). ~s The patients assigned to the various stages showed a ~gnificant difference in median survival time. Thus, patients in stage A had a median survival of far more than 72 mouths, while patients in stage B had a median survival of approximately 60 and in stage C of approximately 16 months. Flandrin et al. using this staging system in their series of 85 splenectomized patients observed a trend towards difference in prognosis, but the difference was not significant (P = 0.09). 2~ Another way at looking at these postsp[enectomy patients was suggested by Catovsky26 This author defined "complete responders" as patients who had a hemoglobin above 11 g / d / , absolute granulocyte counts above 1000/ram 3, and platelet count above 100,000/ram ~. Patients with such a complete response had a sig-

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nificantly better survival than patients with a less complete response. This finding was confirmed in one study/' but not in another, u Disagreement exists about the prognostic significance of the immunological phenotype of the HC. Jansen et al. in a study of 64 patients with HCL reported that patients with HC expressing ~-light chains survived significantly longer than patients with HC carrying ~.-light chains. No difference was found for the various heavy chains. ~~176 This situation would be comparable to chronic lymphocytic leukemia and myeloma, in which patients with A type have been reported to have a poor prognosis. '~176 More recently, however, Golomb et al. were incapable of confirming these d a t a . ~ In fact, in their series, the survival of the A-type group exceeded that of the z-type group? ~ The difference between the two series is not easily explained, but differences in referral pattern, and perhaps even geographical differences in the clinical picture of HCL may have played a role. It should be clear that at the time of diagnosis several parameters are important in predicting the survival of an individual patient. Thus, the treatment strategy should be planned carefully, and the same therapeutic approach may not be beneficial for all patients. VII. T H E R A P Y In the last 2 years, the introduction of alpba-inter feron and 2'-deoxycoformycin has dramatically changed the therapeutic approach to HCL. An avalanche of reports on the successful treatment of HCL patients with these agents has been published. These agents may continue to change the therapeutical approach to patients with HCL, but for the time being have been reserved mostly for postspleneetomy failures. Consequently, sptenectomy should still be considered to be the initial therapy of choice in HCL. In early studies of HCL, the beneficial effect of splenectomy already became apparent. ~,99''~ Although no randomized studies on the effect of splenectomy have been performed, there is a fair amount of evidence that the operation is indeed beneficial for many patients. The operation is relatively safe with an overall mortality of <2%." Bleeding during surgery is not a major problem, in particular when platelet transfusions are used when the arterial blood supply to the spleen has been severed.'~ Postoperative infections, however, are common and perhaps antibiotic prophylaxis should be considered? ~ Most patients will have some benefit from the operation, and 40 to 60% will have a "complete response ' ' ~ with increase of the hemoglobin level above 11.0 g/dl, and the absolute granuloeyte count and platelet count above 1000~ and 100,000/ram 3, respectively. '(.is 2~.3~.~~ Many of these complete responders will need no additional therapy, and may survive for many years after the operation? ''t~ As discussed earlier, the response to splenectomy cannot be reliably predicted. Although the spleen size is adversely correlated with hemoglobin level, absolute granulocyte count, and platelet count, these correlations were poor even in a very large series. 2~'2'The proportional blood increase induced by splenectomy is also only weakly related to the spleen weight. 23.2(,3~Of the three cell lineages, the platelet count has the closest correlation with the weight of the spleen.24 Consequently, splenectomy will have the most effect on the platelet level. Interestingly, the removal of even small spleens sometimes leads to considerable increases in platelet level.32 There is no good data as to whether the removal of small, nonpalpable spleens is beneficial in patients with pancytopenia. The proponents of this approach point to the often excellent increases in platelet count induced by the operation. ~,Sz On the other hand, Jansen and Hermans did not find a better survival for I~atients without palpable

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spleens who underwent spleneetomy?~ They, in fact, suggested that n~anypatients with stage I disease would not benefit from the operation? ~ Similar observations were made by Flandrin et al. ~ and the Italian Cooperative Group? ~ This question is at the presenl time completely open. It will be a matter of personal preference whether a splenectomy will be performed followed shortly thereafter by alpha-interferon or 2'-deoxyeoformycin, or whether the splenectomy will be skipped and chemotherapy made the initial treatment. Many patients with small spleens, however, do not need any therapy at all for a considerable period of time. If pancytopenia necessitates therapeutic intervention, then perhaps the degree of cytopenia should dictate the approach. If the platelet count is extremely low, probably the first step should be splenectumy. On the other hand, if the ptatelets are at an acceptable level, chemotherapy should perhaps he preferred as initial treatment, For poslspleneetomy failures, a number of additiona~ t~erapeufic ~p~ons are available. For several years, conventional eytotnxic therapy has been advocated. In parlieular, low-dose alkylating agents, such as ehlorambucil or cyclophosphamide, have been used? 6'~ Golomb et al. analyzed 24 patients who completed 6 months of chlorambucil therapy. T M These patients could be subdivided into 11 with a leukemic form (>5000/ram ~ HC) and 13 with a leukopenic form. The patients with the leukemic form all had a significant drop in their leukocytes, and many had a considerable increase in their platelet counts. The leukopenic patients mostly had an increase in their platelet counts, but often became even more leukopenic. The overall effect of the therapy appeared to be beneficial, although the complications of infections were considerable?" It is a matter of debate, however, whether patients with the "leukemic form" really need treatment as long as they do not develop cytopenias. Vardiman et al. reported pulmonary infiltration by HC ia five patients at autopsy, which in one ease constituted the cause of c~eath?~ Nevertheless, most patienls with HCL tolerate high white cell counts, as do most patients with chronic lymphocytic leukemia. There is insufficient evidence to show that patients with high HC counts without accompanying eytopenias will truly benefit from chemotherapy. A numbe~ of studies have addressed the issue of aggressive chemotherapy in patients with progressive HCL. Regimens containing cyclophosphamide, cytarabine, vincristine, rubidazone, adriamycin, and prednisone have been used.'~3"'9 In summary, these data show that HC are rather sensitive to high-dose chemotherapy. Complete remissions can even he obtained and can last for many months. However, the chemotherapy is associated with prolonged pancytopenia with a major risk for severe bacterial and fungal infections. Therefore, this therapy should only be used under the optimal conditions of gnotobiotic care. Now that much simpler and safer therapy has become available, the p~ace for high-densecytotoxic therapy is becoming very sr~aIl. Additional evidence for the sensitivity of HC to high-dose chemotherapy can be derived from the two cases in which ablative chemoradiotherapy was followed by a bone marrow graft from identical twin donors. '~~ In both cases, complete eradication of the neoplastic clone could be obtained. The risk of this procedure, however, will limit its application to the rare circumstances in which the patient has an identical twin donor. Additional therapeutic modalities have been used. Immunosuppressive therapy with prednisone, as used in early series, ~6is not of proven value, and undoubtedly increases the risk of serious infections. Although the bone marrow function of some patients improved slightly, j2~ the main effect of cortlcosteroid therapy was on the spleen size and the I'-IC count? 6`m Splenic irradiation may result in a transient improvement in the hematological picture and a decreased spleen size, but the response is often delayed by weekz after the completion of therapy? ~-~'ta~ Such therapy can presently not be recommended. Leukapheresis as therapy for progressive HCL has been introduced by Fay et ai.'~'

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Since then, it has been primarily propagated by Yam and co-workers. ~s't~6The concept is that a very high number of neoplastic cells can be removed from the peripheral blood without excessive toxicity to other peripheral blood cells. The approach, used mostly in patients with a highly leukemic blood picture, is not uniformly successful, and its place should perhaps be limited to young patients with hyperleukocytosis.'26.~27Occasional patients with low white blood cell counts have also responded.~26 Androgens have been proposed as a therapeutic modality in HCL. Case reports have suggested objective improvement after treatment with methyl-testosterone, '~ oxymethylone, ~2~and with the androgen metabolite etiocholanolone mixed with prednisolone acetate. ~3~In addition to these case reports, a small series has been reported of 6 patients who were treated with oxymethylone or fluoxymesterone; 2 of the 6 patients showed correction of the eytopenia with persistent effect for up to 32 months. '3~ The total number of patients treated this way, however, is so small that no judgment about the role of androgens in the treatment of HCL can be made. In the last 3 years, an enormous amount of information has become available about the treatment of HCL with biologic response modifiers. In earlier studies, it had been shown that host defense factors such as antibody-dependent cellular cytotoxicity, (ADCC) delayed-type hypersensitivity, and lymphocyte blastogenie responses are related to the prognosis. ~2 Furthermore, attempts to restore these immune abnormalities, e.g., with the transfusion of allogeneic mononuclear cells or the injection of the methanol extraction residue of BCG, can result in improvement in hematological parameters and a significant decrease of infectlons. J~ Similarly, a case report of beneficial effect of hepatitis on the course of HCL was documented, again suggesting that augmentation of the patient's immune response suppressed the leukemia.~ Quesada et al. were the first to study the effect of alpha-interferon in patients with HCL. '~ Seven patients were treated with daily intramuscular injections of 3 x 106 units of leukocyte-derived alpha-interferon. Three patients were considered to have a complete response, defined as absence of hairy cells in bone marrow biopsy and peripheral blood, and restoration of normal hematological parameters in peripheral blood and bone marrow. The other four patients showed improvement of at least one hematological parameter in combination with a decrease in the number of hairy ceils. Although these results were impressive, one still could argue that several of the patients would also have done rather well without additional therapy. A large number of studies, often in patients with more progressive disease, have now confirmed the beneficial effect of alpha-interferon in HCL. A collaborative study in England, including 17 patients treated with a purified preparation of alpha-interferon, showed that in all patients HC were cleared from the peripheral blood, and platelet and hemoglobin levels improved after 2 to 14 weeks."~6 In 14 of the patients, the neutrophil count also increased. Just 2 of the 17 patients, however, fulfilled the criteria of complete remission. Similar results were obtained with recombinant alpha-2B interferon tJT-t4~ and alpha-2A interferon (Table 4). ~42.~"a The beneficial effect of alpha-interferon in HCL is much more pronounced than in other, probably closely related, B-cell disorders. Recombinant alpha-2B interferon has shown moderate activity in low-grade non-Hodgkin's lymphoma,'~2 but is not active in chronic lymphocytic leukemia. ~ There are several theories to explain the therapeutic effect of interferon in HCL. First, it may be necessary for neoplastic B cells, in order to be influenced by interferon, to carry cell surface receptors for this agent. Indeed, it has been shown that HC do express receptors for alpha- and beta-interferon, but not gamma-interferon.~' ~ However, no difference in density of cell surface interferon receptors was observed between HC of patients who did respond to therapy and chronic lymphocytic leukemia cells of patients who did not respond. ~5' Although on the basis of the absence of receptors for gamma-interferon it has been suggested

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CRC Critical Reviews in Oncology/Hematology Table 4 STUDIES W I T H V A R I O U S TYPES O F A L P H A - I N T E R F E R O N IN PATIENTS WITH HCL

Alpha.interferon type Leukocyte Lymphob]aslold 2a

2b

2c 2a (#tO),2b (#12), leukocyle (~5)

Dose (xlO~u/day) 3 2--5 3 3~12 3 12 3 3 3 3 3 3 5 5 3

No. of Respo~ses No. of patients Complete Partial Minor 22 4 17 30 15 1 12 14 9 13 6,~ 13 t 26 27

5 0 2 9 I 0 1 0 0 3 3 0. 1 3 2

13 I 13 17 t2 ] 8 6 5 l0 45 9 0 15 8

4 l 2 4 1 0 2 7 3 0 9 3 0 4 14

Re[,

135, 143 151 136 143, 144 149 150 137, 138 139 140 141" 148 146 t47 142

Includes the patients of References 138 to 140. that this agent would not be effective,'ss no results of such therapy have been published yet. Second, interferon may have a direct cytotoxic effect on HC. ~,~'~zs It is well known from chemotherapy studies that HC are rather sensitive to cytotoxic e f f e c t s . " - " ' Third, interferon may induce differentiation of HC, which then would keep the cells from proliferating. Such effects of interferon have been reported for myeloid ceils.'~6 Finally, interferon may act as an immune stimulator and increase the natural defenses of the body against the neoplastic process. Although some studies did not show an effect on NK cells, '~6 more recently evidence was presented that the NK ceil activity of peripheral blood lymphocytes, which was severely impaired before therapy in three patients with H C L , completely normalized under treatment with alpha-lnterferon. This improvement in NK function paralleled the improvement in clinical and laboratory findings. 'St The treatment with alpha-interfei'on has only minor effec',s on T-cell subsets with a decrease in T suppressor/cytotoxic cells leading to an increase in helper to suppressor ratio.'3~ In the context of immune stimulation as a mechanism of action of alpha-interferon in this disease, it is interesting to note that mononuelear cells of patients with H C L can be induced to produce gamma- but apt alpha-interferon.'S~ This may be associated with the severe monocytopenia that exists in most patients with this disease. 2r.3, it is beyond doubt that alpha-interferon is a very effective treatment in HCL. However, the subjective side effects should not be underestimated. Many patients complain of prolonged fatigue and general malaise. Besides, often a worsening of the neutropenia and thrombocytopenia is observed in the first weeks after treatment. The fraction of patients who obtain complete remission on alpha-interferon treatment is much smaller than originally hoped and probably not more than 10%. T M Therefore, upon cessation of therapy, one might expect a relapse of the disease in most patients. These negative features do not detract from the fact, however, that for patients with progressive disease after splenectomy, treatment with atpt, a-interferon is an exce[ient

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choice. In the vast majority of patients, it will lead to partial remission with normalization of peripheral blood counts and a marked decrease in bone marrow infiltration, '~.j~~ One might consider starting treatment in patients who have failed splenectomy with alpha-interferon, followed by a combination of alpha-interferon and chemotherapy once a good partial remission is obtained.'~ Since many patients who undergo splcneetomy will not need any additional therapeutic intervention, ~',~ at the present time alpha-interferon cannot be recommended as first line therapy. It would be worthwhile to study whether, in patients without palpable spleens who arc not likely to benefit from spleneetomy, ~ alpha-interferon would be the therapy of choice. It has been shown that splenectomy is not a prerequisite for the beneficial effect of alphainterferon in HCL. T M Areas that need more investigation include the optimal dose of alpha-lnterferon, and the prediction of response. A randomized study between 2 x 106 and 0.2 • 10' unit/m ~ is now under way. if the lower dose would prove to be as effective in inducing remissions, then one might hope that the side effects would be milder. As far as prognostic parameters are concerned, preliminary data have suggested that older patients, and those with higher absolute granulocyte counts prior to the start of alpha-interferon therapy, have a more delayed response. '~ Finally, it will have to be addressed in more detail in which patients interferon therapy can be discontinued, and which patients will need some type of maintenance therapy. It is surprising to see that after a decade of very slow progress in the treatment of HCL patients who relapse after splenectomy, within 1 year two very promising therapeutic options have become available: alpha-interferon and pentostatin (2'-deoxycoformyein). In fact, it may take several years to determine which of the two drugs is superior in this disease. Spiers et al. should be credited for introducing pentostatin to the field of HCL. ~'~ Pentostatin is a potent, tight-binding inhibitor of adenosine deaminse (ADA), and interferes with the intermediary metabolism of purines. Around 1980, the drug aroused a short burst of interest for the treatment of acute lymphoblastic leukemia, in particular the T-cell variant which has very high levels of ADA. '6.''*~ Although the drug certainly had activity, its use was almost completely abandoned due to serious side effects such as hepatocellular damage, acute tubular necrosis with renal failure, central nervous system depression, and high risk of infection. Spiers et al., however, continued its use in refractory lymphoid neoplasms, and found a number of responses. ''6 In 1984, they reported on three nonsplenectomized patients with HCL who were treated with low doses of pentostatin (5 mg/m~/day for 3 consecutive days) in intermittent courses. '6~ All three patients had prompt clearance of HC from the peripheral blood, regression of splenomegaly, and correction of pancytopenia. Even more surprisingly, two patients achieved complete remission as documented by bone marrow biopsy, and they remained in that state for at least 6 months. The side effects were tolerable, and consisted of a pruritic photosensitive rash and gastrointestinal symptoms. The Albany group has expanded their experience to 26 patients now.'" Four previously untreated patients received pentostatin 5 mg/m =i.v. on 2 consecutive days every 2 weeks. All four achieved complete remission with disappearance of HC from the bone marrow and clearing of fibrosis. These patients remained in complete remission from 5+ to 26+ months without maintenance therapy. Of another 18 evaluable patients, 13 were in complete remission, many off treatment. An additional five remained on therapy in partial remission; two patients died from complications of cytopenias. Interestingly enough, two of the responders had progressive disease that was unresponsive to alpha-interferon.'" Furthermore, even massive splenomegaly seemed to disappear after pentostatin therapy. The major side effects were gastrointestinal, skin rash, drowsiness, and exacerbation of eytopenias in the early stages of treat-

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ment. With similar doses of pentostatin, two other groups have reported excellent responses. Kraut et al. obtained three complete responses in seven patients with progressive disease; the remissions which occurred after an average of five treatments persisted without maintenance therapy. ''~ The other four patients also responded, albeit less completely, and one was in a maintained partial remission for over 1 year. Again, the toxicity was very mild. '6~ 2ohnston et al. treated eight patients, most of them recently diagnosed, and saw hematological and clinical improvement in each case. 's9 Complete remissions occurred in two patients, and four patients had partial remissions. In one of the complete responders, occasional HC were detected in the marrow 4 months after discontinuing therapy. Again, the toxicity was mild, and the response on the peripheral blood counts prompt. In the latter study, ADA activity was measured in the peripheral blood mononuclear cells. Prior to therapy, levels were below or in the lower normal range. The ADA activity was undetectable 24 hr following pentostatin. A sharp and prolonged increase in the level of deoxy-ATP was found in circulating mononuclear cells, lasting for more than 7 days, and accumulating after the next pentostatin injection.'~* The mode of action of pentostatin in HCL may well be related to the intracellular accumulation of deoxy-ATP, which may produce cell death by inhibiting ribonucleotide reductase tT~or depleting ATP pools2 r~ The marked sensltivity of HCL to pentostatin has led to the assumption that HC have either high kinase or low nucleotidase activity, resulting in accumulation of deoxy-ATP despite minimal elevation in plasma deoxyadenosine. ''9 The rapid response to pentostatin is striking, with a sharp decrease in the number of peripheral HC often already occurring after the first or second injection. The side effects such as hypersensitivity skin rashes and increased risk of infeclions may be associated with the action of pentostatin on the immune system of the patient, in particular the T lymphocytes. However, at the doses used, these side effects have been tolerable. The track record of pentostatin in HCL until now has been impressive. Among the most important features are the unmaintained complete remissions, the fast responses, and reduction of even massive splenomegaly. Obviously, much longer observation will be needed to see whether this drug can really cure patients. The potentially most dangerous side effects are the action on the immune system of the patient with decrease in immunosurveillance. Since far fewer patients have been treated with pentostatin than alpha-interferon, it is too early to say which drug ultimately will become first-line therapy for patients with progressive disease after splenectomy. If the high percentage of complete responders who remain in unmaintained remission is confirmed, however, pentostatin will probably become the drug of choice. In that case, one might even see that this chemotherapy agent would obviate tile need of splcnectomy. In such a rare disease as HCL, randomized studies are always difficult to perform. Nevertheless, a study comparing pentostatin and alpha-interferon for patients with progressive disease after splenectomy seems warranted. Similarly, one might want to compare splenectomy with pentostatin up front. VIII. ORIGIN OF T H E HC For the last 10 years, but in particular in the late 1970s, the origin of the neoplastic cell of HCL has been hotly debated. The investigators were largely divided over three camps. First, there were the advocates of a monocytic origin of HC. Second, many authors considered HCL to be a lymphoid neoplasm, particularly of B cells. Third, a few investigators believed that HC were lymphocyte-monocyte hybrids or had normal counterparts in an as yet unknown type of cell. Here, we review the various arguments

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Table 5 SURFACE IMMUNOGLOBULIN HEAVY-CHAIN DETERMINANTS IN 174 CASES OF HCL STUDIED BY 4 INVESTIGATORS No, of cases

Cawley Catovsky Golomb Jansen 26 42 42 64

p6 d

1

rd r~d a,~

1 7

3 13

a

ayd

2 2 5

3 2

7

8 1

1

8 4

6 6

16 5

2 20 16

l

3

l

!

None Ref.

3

3

a~

a/ad ar~ y ar

3 6 4

13, 177

2

5

2

186, 187

42

183,188

divided over the different categories such as cell surface markers and intraeytoplasmic markers. A. Cell Surface Markers Early studies on cell surface markers in HCL have been hampered by the fact that HC tend to bind all kinds of antibody, m.,7, Thus, HC tended to bind both antihumankappa and antihumanqambda antibodies. These findings suggested that passively absorbed immunoglobulins occurred on the cells.'7' When HC were demonstrated to have very avid receptors for the Fc portion of lgG (FclgG), it was suggested that the conjugates in the immunof[uorescent studies were perhaps bound via this receptor, m:16 This, then, would mean that the original reports of a B-cell origin of HCL were incorrect. ,72.,73 However, soon more sophisticated techniques were used to avoid the pitfalls of absorbed Ig or FclgG binding. Using preincubation in serum-free medium to release passively bound Ig, usually one light-chain type persisted on the HC. j77-~79 Similar results were obtained when Ig was first removed from the cell surface by trypsinization, followed by study of the reappearance of surface Ig. ~s'~s'~8~ Finally, an even more simple technique proved to be the mild fixation of HC with diluted formaldehyde prior to incubation with the immunoconjugates.'6' Again, using these techniques, HC were always found to bind either antikappa or antilambda antibodies, m.''~ With the presence of intrinsic surface immunoglobulin of one light-chain type, a very strong argument in favor of a B-cell origin of HCL had become available. As far as heavy-chain determinants were concerned, the situation was definitely different from chronic lymphocytic leukemia. Whereas in the latter disease most cases carry g-heavy-chain determinants, often in combination with d " ' in HCL, often y alone or in combination with other heavy chains was observed, z6,177,t~2,1~3.t~sIn Table 5, the surface immunoglobulin data on 174 cases of HCL studied in four centers are listed. From this table, it should be clear that there is wide variation in the expression

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of surface Ig on HC. There is also variation between the various centers. This can be explained partly by differences in antiimmunoglobulin antibodies, with their differ. ences in specificity and sensitivity; partly the variation between the various centers may also reflect differences in inclusion criteria and perhaps even geographic differences in HCL. There is general agreement, however, about the high percentage of cases with multiple heavy-chain determinants, and about the unusually high incidence of cells expressing alpha on the surface. 'B2 In the hypothetical scheme of B-cell differentiation~ this would locate HCL among the more mature B-cell disorders. ~77.~,~3.js~ The search for the presence of receptors for complement and the Fc part of immunoglobulins on HC has been performed primarily with rosette assays. In contrast with chronic lymphocytic leukemia, the neoplastic cells of HCL do not express receptors for the third component of complement. '~.''~.''3,'ag interestingly enough, although our group in a series of more than 40 cases did not identify a single one that expressed C3 receptors, :'3 other groups have sometimes reported such receptors in a considerable portion of cases studied.'P~ Although technical factors such as the presence of receptors for the Fc part of IgM ~a9may be responsible for this discrepancy, an alternative explanation may be that either geographical differences exist in HCL, or that cases of other chronic B-cell leukemias have been included irt such series. There is general agreement that HC ha 'e avid receptors for the Fc part of lgG.'~s'"~ These receptors can be demonstrated with rosette techniques, antigen-antibody complexes, and aggregated leG. Although the avidity of the receptor may vary, '~ basically in every case such receptors can he demonstrated. The same probably holds true for the receptor for the Fc part of fgM. ,s~.,~ This receptor, which is also found in neoplastic B cells of chronic lymphocytlc leukemia, can be detected in most cases of HCL,'93 but can vary considerably in avidity. '83 The neoplastic ceils of HCL can also form spontaneous rosettes with mouse erythrocytes, which is considered to be a feature of B lymphoeytes. ~*,*~s Such rosettes are also formed by the neoplastic cells of chronic lymphocytic leukemia, again suggesting a close association between this disorder and HCL.'94 Cases of HCL with the ontogenically more immature surface Ig including/~ tended to form spontaneous mouse rosettes, while the more mature cases with ;, did not form rosettes. '~ This would support the concept that HCL is closely related to CLL, but represents a more mature stage of B-ceU differentiation.~6 Most cases of HCL do not express surface markers of T lymphocytes. Nevertheless, a small number of such cases have been reported. Thus, at least five cases of HCL have been reported in which the neoplastic cells formed spontaneous rosettes with sheep erythrocytes, generally considered to be a reliable T-cell marker. '9~'~r-~~176 It is noteworthy that three of these five cases came from the Los Angeles area and, in two of them, a new T-ceU lymphotropic virus (HTLV-I[) was isolated. 2~ In addition to these cases with a pure T-cell phenotype, a number of patients had a mixed T and B phenotype. In these cases, part of the cells carry surface immunoglobulin and at the same time form spontaneous sheep erythrocyte rosettes or react with specific anti-Tcell antisera. )'~.a~ It has been shown that the extent to which the T- and B-cell characteristics are exhibited on the same cells can fluctuate widely. These fluctuations can either be due to compartmentalization between peripheral blood and spleen ~~ or to changes in time. 2~'~~ In this respect, it should be mentioned that HC with a pure B-con phenotype can acquire the capacity to form spontaneous E-rosettes after in vitro culture in the presence of PHA. 2os Under such circumstances, the cells can either switch from a B- to a T-cell phenotype, or to a B + T phenotype. Although these results were questioned on technical grounds, 2~ later studies have confirmed the switch in phenotype after culture in the presence of PHA. 2~ Furthermore, it was shown that not only HC, but

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also normal B lymphocytes and other leukemic B cells can express the sheep erythrocyte receptor after short-[line culture in the presence of PHA and T cellsP~ Consequently, the simultaneous expression by HC of surface immunoglobulin and T-cell markers may indicate an activated stage of B-cell development. With the introduction of monoclonal antibodies, new tools became available to study the origin of HC. All reports ilave provided evidence in favor of ~:heB.cell nature of these cells, jsT''ss'2o9-2'eThus, the cells are mostly recognized by antibodies against HLA-DR determinants, 2~ the B-1 antigen, '~8,2.~'2.6the By/Leu 12 antigen/*s.2j~ and the Y29/55 antigen? ss In addition to the reactivity with these markers that recognize most stages of B-cell differentiation, HC also react with a number of antibodies that are limited to certain stages of B-cell development. Less than half the cases are positive with ar~tlbody BA-1, ~'2~'~4.~s but this antigen appears in most cases after in vitro culture, a*9 The vast majority of cases of HCL react with antibody FMC7, which recognizes a rather mature stage of B.cell differentiation, m.~vs.~o.2.Similarly, HC also react with the plasma cell-associated antigen PCA-I, suggesting that HCL corresponds to a late stage of B-cell ontogeny. 2'~ With the help of monoclonal antibodies, a number of unexpected antigens have been found on HC. First, the cells were shown to react with antibody OKMI/ Mol.~Bs'2oP'mm8The reactivity of HC with these antibodies, which normally react with granulocytes, monocytes, and part of the T lymphocytes, is rather weak, and perhaps therefore has not been picked up by all investigators/~ Furthermore, the reactivity is not detectable in tissue sections. ~'z~4'2'~ Monoclonal antibody Leu-M5, which has been reported to react with H C / " may not be identical with OKMI/Mol, but is definitcly closely related. It should be stressed that reactivity with OKM I/Mol should not be interpreted as an argument in favor of a mouocytic origin of HCL. A large paneI of other antimonoeyte/macrophage antibodies has uniformly been negative with HC. ~r.taB.~o.2~2-n5 Furthermore, our group has shown that reactivity with O KM 1/Mol is not restricted to HCL, but can also be observed in some other, mostly mature, chronic B-cell leukemias, t~8'~9~It appears that during a brief stage of B-ceU development, the OKM 1/Mol antigen is expressed; this expression may coincide with the appearance of antigen FMC7 on B cells.'96 Second, HC have been found to react with monoclonal antibody RFBI, ~'z~~ an antibody shown to be reactive with early hematopoietie precursors and the majority of normal T lymphocytes. The normal B lymphocytes are nonreactive with RFBI, but chronic lymphocytic leukemia, prolymphocytic leukemia, and malignant lymphoma cells were also shown to be positive, albeit more weakly than FIC. a2~ Third, the neoplastic cells of HCL react with antibodies against the receptor for interleukin-2? ~'~2"223 This receptor was first considered a specific T-eeL[ activation marker,a~''2~ but more recently has also been detected on normal and neoplastic B cells. ~3'n~ In fact, interleukin-2 has been shown to be a potent activator of B-cell proliferationP ~7 A number of monoclonal antibodies have been developed specifically to react with HC. Thus, Posnett etal. made three antibodies (uHCI, oHC2, and uriC3) which reacted with many cases of HCL. 2~'~ In fact, eriC1 reacted with 14/20 cases of HCL, but not with other chronic B-cell leukemias. There was clear cross-reactivity with endothelial cells of capillaries, veins, and arteriesP ~ aHC2 and aHC3 reacted with virtually all HC, but not with normal peripheral blood cells. However, these antibodies also reacted with leukemic myeloblasts and some activated B cells,a~-'n~ It was shown that eHC2-positive normal B tymphocytes frequently coexpress surface lgG and the activation antigen AA1.2~ These data suggest that eriC2 recognizes activated B ceils, supplying ad(,itional evidence that HCL is a neoplasm of activated B cells. Monoclonal

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antibodies Leul4 and Leu-M5 were also raised against HC. ~" Leu-M5 recognizes an antigen that is not identical, but closely related, with the OKMI/Mol antigen; in addition to HC, it also reacts with macrophages, monocytes, and neutrophiis. ~j~ It would be interesting to determine whether reactivity of this antibody with chronic B-col[ leukemias is also similar to OKM1/Mol. `'',tg6 Antibody Leul4 stains HC brightly, but also reacts with chronic lymphocytic leukemia, prolymphocytic leukemia, and malignant lymphoma. In fact, the antibody basically recognizes all B lymphocytes.2j9 Monoelonal antibodies HD6 and HD39 were also raised against cells from patients with HCL. TM HD6 reacted strongly with 12/12 cases of HCL and more weakly with a proportion of cases of malignant lymphoma; only 2/24 cases of CLL were weakly positive. HD39 reacted in studies with ceils in suspension with only HCL and prolymphocytic leukemia. In immunohistology, however, the antibody reacts with an antigen that occurs in the cytoplasm of all B-cell malignancies and that is expressed on the ceil surface only in a certain maturation stage. TM Finally, antibodies have been reported recently against a p69 antigen found exclusively on chronic lymphocytic leukemia and HCL. z'~ This antigen is definitely different from the more common p65-71 (CDS) which occurs on chronic lymphocytic leukemia cells but only tardy on HCL. ~7''"~'2~176 B. Cell Membrane Characteristics In this section, two topics are discussed. First, the capacity of HC to engulf particles through the process of phagocytosis is discussed. Second, data concerning the building blocks of the ceil membrane are briefly reviewed. Early studies about immunological characteristics of HC suggested that the ceils were capable of ingesting latex particles as well as Candida and StaphyJococeus particles.~ ' ' t ~ 2 " t T ~ ' z ~ The evidence was derived from light microscopical and electron-microscopical pictures showing particles within the cytoplasm of HC surrounded by "phagosomes". It was suggested that a spectrum of phagocytic capacity existed between the various cases of HCL. ~ More elaborate studies, however, have questioned whether HC are truly phagocytic cells. ~2,234In these studies, first functional assays were used to approach the problem. This was deemed necessary because tangential sectioning of HC with particles trapped between their many long cytoplasmic protrusions might result in false images of phagocytosis. Using the enzyme lysostaphin, which kills extracellular Staphylococcus aureus but does not penetrate into living cells, it was shown that virtually no "ingested" bacteria were truly internalized. ~'z~' Second, true phagocytes consume increased amounts of oxygen when they start their phagocytosis process. In contrast with monocytic leukemia, HC did not show increased oxygen consumption upon incubation with bacteria and opsonizing antibodies. TM Therefore, functionally, HC appear to be nonphagocytic calls. More in-depth studies using dectron microscopy gave conflicting results. Using lanthanum nitrate during the fixation procedure for electron microscopy, the outer cell membrane of HC was stained following exposure to latex particles. The phagosomes around nearly all ingested particles were stained with lanthanum, suggesting that these phagosomes in fact were still part of the cell membrane, and therefore the particles still extracellular. TM Other investigators, however, did find evidence of phagocytosis.23s'2~' Thu3, using ultrastructural acid-phosphatase cytochemistry, evidence was provided that HC indeed phagocytose some latex particles, but do not phagocytose other particles such as Candida and opsonized erythrocytes?3~ So, the jury is still out on the phagocytic capacity of HC. Whatever the final judgment, there is no doubt that HC are not "professional phagocytes". The engulfment of occasional particles has also been reported for ceils of chronic lymphocytic leukemia and prolymphocytic leukemia, ~' and would, therefore, not be incompatible with the B-cell nature of HC.

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An interesting feature of HC that was recognized early is the extensive adherence to glass and plastic surfaces? 72.~r~,2a~.2~7This adherence has been used as an argument in favor of a monocytic origin of HC, ~' Recently, evidence has been published that the eytoskeleton organization in HCL is aberrant~y rearranged with F-actin-containing microfilaments associated with the microvilii responsible for the hairy appearance. This results in adhesion structures, analogous to "podosomes" described in other cell types. "9 The cytoskeleton abnormalities may also be responsible for the rapid "capping" when HC are incubated with antiimmunoglobulin antisera ~Ts'a'~or lectins. TM The cell surface structures result in an electrophoretic mobility distribution which distinguish HC from normal lymphocytes and rnonocytes and from cells of chronic lymphocytic leukemia?" They may also be responsible for the extreme sensitivity to potassium EDTA reported for HC. 24~ It should be kept in mind, however, that all these cell sur face characteristics do not necessarily imply neoplastic changes. They could well be associated with the state of activation HC have been suggested to be in. ~''3s~'~ The cell membrane structures obviously are closely related with the building blocks of the cell membrane. Using polyacrylamide gradient gel eleetrophoresis, Spiro et al. detected a number of membrane-associated molecules which defined subsets of patients with HCL. ~4~One of these proteins, p35, was identified as the human homolog of the routine Ii, an electrophoretically invariant molecule that assocfates wi~h the two (alpha and beta) glycoprotein subunits of the la complex. " s ' " The p35 band is heavily expressed in EBV-transformed cells, and may again indicate a state of activation/' Using the same SDS-polyacrylamide gel electrophoresis technique, other investigators found HC to have consistent protein patterns which were distinctly different from chronic lymphocytic leukemia, acute lymphocytic leukemia, acute monoeytic leukemia, and malignant lymphoma.2'7"~" Using column chromatography to study glycopeptidcs, HC were also shown to differ considerably from other leukemia cells. "" Interestingly enough, in an unpublished study, we found that the glyeopeptide pattern could be used to distinguish between typical and atypical cases of HCL. "9 The glycolipids pattern provided additional evidence that HC are lymphocytic ceils, probably related to chronic lymphocytic leukemia."""' Presently, however, all these analyses are still in a very basic stage and have not been applied to the diagnostic work-up and therapeutic approach of patients with HCL. C. Intracellular Characteristics In a number of cases, HC have been reported to show cytoplasmic immunoglobulin. 1~2't~'jp~'asz'253The situation, however, can be rather complex because the surface immunoglobulin present on HC can result in false cytoplasmic staining when the cells are fixed on slides. T M Probably, the proportion of cases in which cytoplasmic lg can be detected with immunofluorescent techniques is rather low. '63 With immunoelectron microscopy, it was shown that intracytoplasmic immunoglobulin was limited to the rough endoplasmie retlculum, as would be expected from B cells.~'J,25~* A number of studies have revealed that HC can synthesize and secrete immunoglobulin in vivo and in vitro. In vivo production has been documented in the rare cases of HCL with paraproteinemia/~''r'.'~,'s IgG appears to be the most common paraprotein, 7~,a" but IgM paraproteins have also been reported. "g''2 Not in every case of HCL with paraproteinemia, however, is the M protein truly synthesized by HC. As discussed before, several cases of simultaneous occurrence of HCL and multiple myeloma have been documented, s),a2 Nevertheless, in a few cases of HCL with paraproteinemia, in vitro studies documented the production of the M protein by HC from peripheral blood and bone marrow.76'2~5'2~Furthermore, in many cases of HCL without paraproteinemia, the neoplastic cells have been shown to synthesize immunoglobulin in vi-

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tro.".~79.z57.2~"Obviously, this production of immunoglobulin both in vivo and in vitro is an indisputable argument in favor of the B-cell nature of HCL. Viero et al. recently reported the production of procoagulant activity by HC in response to endotoxin and phorbol ester. 2s' This procoagulant activity was identified as tissue factor, and would be better compatible with a monocytic origin of HC. Other enzymatic activities found in HC are also more reminiscent of monocytes than of lymphocytes. Thus, HC have been demonstrated to have alpha-naphthyl butyrate esterase activity in their cytoplasm 2t+ in addition to alpha-naphthyl acetate esterase activity2 +' These esterase activities, however, consist of a mixture of scattered fine granules together with coarser granules sometimes localized in a crescentic configuration. 2~176 This pattern is completely different from monocytes which have a diffuse cytoplasmic pattern; in addition, the esterase activity is not inhibited by fluoride, as is the case in monoeytes, z~176 The presence of another lysosomal enzyme, acid phosphatase, has been discussed earlier in this paper, and the conclusion was drawn that the activity of isoenzyme 5, which is responsible for its resistance to preincubation with tartaric acid, +~is typical but not pathopneumonic for HCL, since it has also been observed in other chronic B-cell leukemias, sg.+~More difficult to explain for a B cell is the peroxidase activity that can be detected with transmission electron microscopy. ~+z It should be stressed that in light microscopy, HC are never positive for peroxidase. ~'z'' Ultrastrucrurally, however, with very sensitive techniques, peroxidase activity could be demonstrated in the endoplasmic reticulum of HC. so2 The Golgi apparatus and granules were always negative. This reactivity pattern was closely related to activated blood monocytes and tissue macrophages, and is not found in B or T lymphocytes. This peroxidase activity, which has not been confirmed yet by other investigators, would be difficult to explain in a B-cell neoplasm. Since there is ample evidence that the lysosomal enzymes of HC are at a high level, perhaps the peroxidase activity is merely a manifestation of cell activation. In this respect, it would be very interesting to study activated normal B lymphocytes and B-cell neoplasms with a maturation arrest comparable with HCL for titis ultrastructural peroxidase activity. Very strong evidence for the B-cell nature of HC came from studies by Korsmeyer et al. about the rearrangement and expression of immunoglobulin genes. 2"a22 These investigators showed that the neoplastic cells of all cases of HCL studied had rearranged heavy- and light-chain genes and also contained the corresponding mRNA for heavy- and light-chain immunoglobulin production. The light-chain rearrangement corresponded with the light chain of the surface lg. Although occasionally immunoglobulin gene rearrangement has been observed in malignancies of cells not committed to the B-cell lineage, the consistent pattern of rearrangement in HCL basically should end the discussion of the origin of the disease. IX. M A T U R A T I O N ARREST OF HC As discussed above, there is extensive and very strong evidence that HCL concerns a neoplasm of B lymphocytes. It cannot be denied, however, that certain features, such as the ultrastructural peroxidase activity, u2 the procoagulant activity, 2s' an4 the questionable phagocytosis of small particles 23~'23~are not easily explained for B cells. An easy way out would be to assume that these features result from the derepression of genes as part of the neoplastic transformation. Alternatively, it may entice investigators to study whether these features cannot be found in a very small proportion of B cells, which then perhaps would be the normal counterpart of HC. From many studies cited before, it was concluded that HC represent "activated B cells". Thus, the presence of multiple heavy-chain determinants of surface lg, '~.'B~ of

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Table 6 MDNOCLONAL ANTIBODY REACTIVITY IN HCL AND RELATED CHRONIC B-CELL NEOPLASMS

Mzrker BI (CO 20} 8A-[ (CD 24) BA-2 (CD q} B-2 (CD 2[) B4/Leul2 (CD 19) FMC7

Chronic lymphocytic la~akera~a

Prolymphoaytic leukemia

+ + +or44- (6r +}

+ 4- (or -) -or4'~ 4§ (or -)

4- or • - (or +} 4"

+ 7 -or+ .9 - or +

eriC2 HLA-DR IL-2R (CD 25) OKMI/Mo[ (CD 11) PCA-I p67 (CD 5)

HCL

+ - or + - (Qr +) + + (or -) + + + (or -) +(or-) + (or -) - (or +)

Myr

-(or+)

9 +

Ref. 188, 213,216,263 188, 196,212 188, 196, 209 216, 263 216, 263 196, 210, 217 228, 197, 274 209--214 221,223 209.211,216 216, 263 187. 196, 209, 210

Note: (), occasional eases; + or ~. majorityof cases positive;- or +. majorityof cases negative. activation antigens such as ~,HC2, 2J~ of the receptor for interleukin-2y t and of heavy expression of the human homolog of li 2'~ are all compatible with an activated B cell. The surface lg determinants and reactivity patterns with monoclonal antibodies lo.cate the maturation arrest of HCL at a rather mature B-cell stage somewhere between chronic lymphocytic leukemia and myeloma. ~2"",'~,~6,2Q9,2'6 For the more precise localization, the reactivity with a number of monoclonal antibodies can be used. The typical immanophenotypes of HC with these markers as they relate to other chronic Bcell neoplasms are shown in Table 6. The most important markers perhaps are p67(CD5), FMC7, O K M I / M o l , aHC2, and PCA-I. These antibodies in combination not only allow a positive diagnosis of HCL, but also pin down the maturation arrest to the stage of "activated B-cell". Additional information about the relation between the various chronic B-cell neoplasms may be obtained from induction experiments. In such studies, an attempt would be made to induce the immunological phenotypr of a more mature neoplasm in the cells of a more immature one. Most of these studies until now have been performed with the tumor promoter tetradecanoyl.12,13-phorbol acetate (TPA), which activates protein kinase C, mimicking the physiological activator diacylglycerol.2'~ Among the many effects of TPA on HC are an enormous increase of the adherence to surfaces, resulting in very long cytoplasmic processes as seen in macrophages? ~4,a6s Since this effect cannot he prevented by cytochalasia D y 's the primary effects of TPA are ~robably on the call membrane. Catigaris-Cappio et al. showed that these long cytoplasmic processes of HCL upon T P A induction are rich in submembraneous F-aetin, which makes intertwined networks. ~* The same authors also investigated the relationship between chronic lymphocytic leukemia and HCL with TPA. ~6"'~ They reported that after incubation with TPA, FMCT-negative cells from patients with CLL became FMC7 positive; simultaneously, the cells lost their capability to form spontaneous mouse rosettes, and they acquired TRAP activity and cytoplasmic i m m u n o g l o b u l i n ) " They also acquired reactivity with Leu-M5, and receptors for interleukin-2?~' On the basis of these data, the authors claim to have induced HC out of CLL cells. Several important parameters have not yet been studied, however. In particular, one would have to show that multiple heavy-chain determinant~ appear on the surface of the cells,

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that the cells start expressing lgG. It is noteworthy that, in induction studies of CLL with TPA, an "antibody switch" as seen in normal B cells has never been observed, 26~,~69In fact, upon induction with TPA, the surface Ig of CLL cells completely disappears or becomes much weaker, not stronger as observed in HC, ~ In addition, in unpublished studies by our group, the TPA-induced CLL cells did develop undulating cell membranes, but morphologically were still completely different from HC. Nevertheless, it can be hoped that through induction studies such as the ones performed by Caiegaris-Cappio et at., more information can be obtained about the relation between HCL and related chronic B-cell neoplasms. It probably would be worthwhile also to use other cell activators/inducers, such as interleukin-2, pokeweed mitogcn, and B-cell growth factor. X. A T Y P I C A L HCL Generally, HCL is accepted as a clinicopathologic entity. Yet, both the clinical characteristics and the immunological features of the neoplastic cells can show a rather wide variation. This obviously raises the question as to which variation can still be accepted within the spectrum of HCL. Since it may well be that the chronic B-cell leukemias form a continuum as far as their maturation arrests are concerned, the distinction between the various entities will always be rather arbitrary. Some preliminary data suggest geographic variations within the entity HCL. Katayarea et al. provided evidence that, in Japan, HCL is not only very rare, but also has eharacteristic~ different from the non-J'apancse cases. ~ Thus, m~sive splenomegaly and high white cell counts were more prominent in Japanese patients. Pancytopenia, monocytopenia, and high leukocyte alkaline phosphatase indexes were much less common. Furthermore, TRAP activity was less common (50%). Consequently, many of these cases would have been considered atypical if they had occurred in non-Japanese patients. On the basis of data from the literature, there may also be some differences between patients with HCL in North America and Northwestern Europe. It appears that in some American series, t~8'tg~ severe monocytopenia is less universally present than in European series2 ~.~6~Although it cannot be excluded that in some patients HC were erroneously scored as monocytes, our impression is that this difference in incidence of monocytopenia is real. Similarly, leukocytosls (>10,000/mms) appears to be more frequent in American series '~;,z'~than in European series2 T M Finally, our group found some preliminary evidence of immunological differences between 8 American cases of HCL and 65 cases from The Netherlands and Belgium. In particular, surface immnnoglobulin of lgM class and reactivity with monoclonal antibody BA-1 seem to be more frequent in American cases. Obviously, many more American patients will have to be studied before a definitive answer can be given in His respect. Even with the acceptance of a spectrum of features of HCL, dearly there are cases that should he diagnosed differently but mimic HCL, and cases that cannot be definitively classified but fit better within the entity HCL than in any other entity. Neiman et al. documented ten patients with a lymphoproliferative disorder reminiscent of HCL. 2', The patient had massive splenomegaly with only mil~imal lymphadenopathy and varying degrees of blood cytopenias. Atypical lymphoid ceils with hairy cytoplasmic projections were found, and these cells were TRAP positive. The majority of the patients had IgM paraproteins. On closer examination, the hairy projections were not the slender viUi of HC, but more spike-like or bleb-like protrusions. The cytoplasm was darker, and the nuclear chromatin finer with more prominent nucleoli than seen in HCL. Histological examination of spleen and lymph nodes was best compatible with well-differentiated lymphocytic lymphoma,m Seven similar cases were re-

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ported by Fohlmeister et al. 2~2 Again the cells had TRAP activity, but more spikelike cytoplasmic projections. In all these cases, the histological examination of the spleen showed primary infiltration of the white pulp, in contrast with the primary involvement of the red pulp in HCL. In our experience, often clinical parameters in addition to careful morphological examination of the neoplastic ceils in the peripheral blood can lead to the correct diagnosis. Nevertheless, histological confirmation through a bone marrow biopsy should be obtained. Clinical parameters we find very useful in this respect are the monocyte count, leukocyte alkaline phosphatase index, and mean cell volume (MCV) of the erythrocytes. Whereas in low-grade malignant lymphpmas these three parameters are mostly within the normaI range, ~n HCL one expects severe monocytopenia, elevated leukocyte alkaline phosphatase indexes, and increased MCV. ~.2s.~ Cawley et al. reported on two patients who had splenomegaly without lymphoadenopathy, and many neoplastic ceils in the peripheral blood with cytoplasmic projections, so The white cell counts were high and there was no neutropenia or monocytopenia. Furthermore, the MCV and leukocyte alkaline phosphatase indexes were normal. They gave this variant of HCL the name "type 11 hairy cell leukemia". In fact, these cases are reminiscent of the eases of HCL reported from Japan. '2 A case reported by Palutke etal. 27~ may well represent an example of this type II HCL, although the authors finally chose for lymphocytic lymphoma. Similarly, the case reported by Catovsky et al. as an intermediate disease between HCL and prolymphocytie leukemia TM probably also represents type il HCL. Finally, our group, in a series of 51 patients, reported 7 with atypical features) Bs Several of these probably represented type I1 HCL, which would indicate that this variant is not extremely rare. The immunological phenotype of these type [I cases has not yet been determined conclusively. Several cases with lgG as surface Ig were reported, ~~ but also eases with IgM plus lgD occurred. 's~,2~a Too few eases have been studied with monoclona[ antibodies to allow any conclusions. TM In order to make the distinction between "true" HCL and type 11 HCL, again we and others found the MCV, the monocyte count, and the leukocyte alkaline phosphatase index helpful. J~ Whereas in "true" HCL the monocyte count is almost invariably decreased, 27.~s.3,,z'oin atypical or type II HCL the monor count is mostly normal or even increased, a~ Similarly, in typical HCL, the leukocyte alkaline phosphatase index is mostly elevated, '~,2~;'2r~whereas in type I1 HCL, the index is mostly normal or even low: ~ Finally, the MCV is increased in tlae majority of cases of "true" HCL, but tends to be normal in atypical HCL) ~ In fact, on the basis of these three simple parameters, in our own patient material we could nearly always distinguish between typical and atypical cases. A more laborious technique to distinguish between these two types was the analysis of the giycopeptides of the cell membrane.2s~With this technique, objective differences between the typical and atypical cases of HCL were obtained, compatible with the concept that there truly are two variants. At the present time, there is insufficient data to conclude whether the distinction of two types of HCL has clinical importance.

REFERENCES I. Downey, H., Monocytic leukemia and leukemic reticuloendotheliosis,in Handbook of Hematology, rot. 2, Downey, H.. Ed., P. n. HoebeL New York, 1938, 3273. 2. Ro~nthal, N. and Ler S. L., Renculum celtleukemia, in 31st An,u. Meet. Am, Soc. Ctin. Pathol..

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3. Rosenthal, R, L., Steiner, G. C,, and Golub, B. S., Hairy cell leukemia: historical aspects and bone involvement, Mr, Sinai J. &led., 46, 237, 1979. 4. Ice, S. L., kosher. F., Rosanthal, N., and gosenthal, g. L,, Reticulum cell leukemia. Clinical and hematologic entity, N, Y, Stale J, Mad., p.422, 1969. 5. Bouronclr B. A,, Wiseman, B. K,, and Doan, C. A., Leukemic reticuloendotheliosis, Blood, 13, 609, 1958, 6. Ewa[d., O., DOeLeukamisehe geticu[oendotheliose, D~sch. Arch, Kiln. Mad., [42, 222, 1923. 7. MJtus, W. J., Medniooff, 1. B,, WitleJs, B., and Dameshek, W., Neoplastic Iymphoid reticulum calls in the peripheral blood: a histocheraical study, Blood, 17,206, 1961. 8. Sehrek, R. and DonnelIy, J., Hairy cells in biood in lymphoreticular neoplastic disease and "flagellated'" celia of normal lymph nodes, Blood, 27. 199, 1966. 9. Duhamel, P. G. and Ouerra, L., Un syndrome bematologique dirt[ella a definir: ]a myelofibrose lymphoide. Etude nosologique do six observations, Presse Mad., 74. 585, 1966. I0 Yam, L. T., Li, C. Y., and Lain, K, W., Tartrate-resistant acid phosphatase [soenzyme in the retieu|um cells of leukemic retieuloendotheliosis, N Engl. 7. Mad,, 2$4,357, 1971. 1I. Bezwoda, W, R,, Derman, D, P., Bothwell, T. H., et al., The diagnosis and management of hairycell leukaemia, South Aft'. Mad. J., 55,577, 1979. 12. Katayama, 1,, Mochino, T., Hooma, T., and Fukuda, M., Hairy cell leukemia: a comparative study of Japanese and non.Japanese patients, Semio. Oncol., 11(Suppl. 2), 486, 1984, 13. Cawley, J, C., Burns, G. F., and Hayhoe, F. G, J., Hairy-Cell Leukaemia, Springer-Voting, New York, 1980. 14. Jansen, J. and Hermans, J., Spleneetomv in h~iry cell ieuketnla: a retrospective malt[center analysis, Cahoot, 4"~, 2066, 19gl. 15. Golomb, H. M., Catovsky, D,, and Oolde, D, W., Hairy cell leukemia. A clinical review based on 71 cases, Ann, Intern9 Mad., 89, 677, 1978. 16. Turner, A, and Kjeldsherg, C, g., Hairy cell leukemia: a review, Medicine, 57,477, 1978. 17. Outman, A., Tatarski, A., Taragan, R. et al., Spleneetomy for hairy cell leukemia, Harefuah, 91, 4, 1976. 18. Betesh, J. and Major, D., Hairy cell leukemia presenting in a patient aged 90, J. Am. Geriatr. Soc., 29, 460, 1981. 19. Ramseur, W. L., Golomb, H. M., Vardiman, J. W. et at., Hairy cell leukemia in father and son, Cancer,48,182.;, 1981. 20, Cohen, H. J., Shimm, D., Paris, S. A. at al., Ha~ry cell Icukemla-assoeiated familial lymlahc~prolifaralive disorder. Imr~unologic abnormalities ta unaffected family membet~, Ann. Intern. &fed., 90, 174, 1979. 21. Jansen, J., Hermans, J., Remme, J. et al., Harry-cell leukaemia. Clinical features and effect of splenectomy, Sound. J. Flaamatol., 21, 60, 1978. 22. Stewart, D. J. and Kent[nO, M. L, Radiation exposure as a possible etiologic factor in hairy cell leukemia (leukemic retieuloendotheliosis), Cancer, 22, 1577, 1980. 23. Flandrin, G., Siganx, F., Sebahoun, G., and Bouffette, P,, Hairy cell leukemia: clinical presentation and follow-gp of 211 patients, Samin. Oneol., 1l(Suppl. 2), 458, 1984. 24, Jansen, J., Den Ottolunder, G. J,. Holdtincl. R. S. G. et al., Prognosis and therapy in hairy cell leukemia, Semin. OncoL, 1l(SuppL 2}, 472, 1984. 25. Jansen, J. and Hermans, J., Clinical staging system for Miry-cell leukemia, Blood, 60, 571, 1982. 26. Budman, D. R., Kozlner, B., Arlin, Z. et at., Massive lymphadenopathy mimicking lymphoma in leukemic l~ticuloendothelioels, Am. 2". Mad., 66, 160, 1979. 27. Seshadri, R. S., Brown, E. J., and Zipursky, A,, Leukemic retieuloendotheliosis. A failure of monoeyte production, N, EaRl, J. Mad., 295, 181,1976. 28. Jansen, J.. Den Ottolander, (3. J., Te Velde, J., and Lopes Cardozo, P , The clinical diagnosis of hart5 cd[ Ieukaemia, Acta HaamatoL (Basel), 64, l gl, 1980. 29. Oolomb, H. M., Hairy cell leukemia: an unusual lymphoproliferative disease. A study of 24 patients, Cancer, 42. 946,1978. 30. Cawlay, J. C., Burns, (3. F., and Hayhoe, F, G, J., A chronic lymphoproliterative disorder with distinctive features: a disti,ar variant of hairy-cell taukaemia, Leak. Res., 4, 547, 1980. 31. Den Ottolander, G. J., Van Der Burgh, F. J., Cardozo, L. et al., The hemalog D automated differential counter in the diagnosis of hairy cell leukemia, Leuk. Res., 7, 309, 1983. 32. Golor,ab, H. M. and Vardimano J. W., Response to splenectomy in 65 patients with hairy cell leukemia; an evaluation of spleen ",,vaightand hvnr marrow involvement, Bto~d, 61,349,1983. 33, Lewis, S. M., Catovsky, D., Hows, J, M., and Ardalan, B., Splenic red cell pooling in hairy cell leukaemia, Br, J. HaematoL, 35,351, 1977. 34. Nanba, K., Soban, E. J., Bowling, M. C,, and Berard, C. W., Splenic pseudosinuses and hepatic angiomatous lesions. Oisfinctiva features ol hairy cell leukemia, Am. J. Clio. Parhot., 67, 415.1977.

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35. Castro-Malaspina, H., Najaan, Y,, and Flandrln, G., Erythrokinetiz fladies in hairy-cell ]eukaemia, Br. J. Haematol., 42, 189, 1979, 36. Catovsky, D_. Hahy-ce]l laukaemla and psolymphvcylic leukaemia, Clin. Hacrn~toL,6, 245,1977. 39. Katayama, 1 and Yang, J. P. S., Tartrate-rcsistant acid phosphatase reactions n~t specific for hairy cell leukemia, Am. J. Clin. PathoL, 6g. 482, 1979. 38. Schaefer, H., Hellriegel, K., Zach, L, and Fischer, R,, Zytochemischer Poiymorphismus der Sauren Phosphatase bei HaarzelI-Lenkamie, Blut, 31,365, I975. 39. Leder, L. D., Alkaline phosphatase and tartrate resistant acid phnsphatase activity in ceils of prolymphocytie leukemia, Klin. Woohenschr,, 56,313, 1978. 40. Buskard, N. A,, Catovsky, D., Okos, A. etal,, Prolymphoeytic leukaemia: cell studies and treatment by leueaphercsis, HaematoL BluttransftJs., 18,237, 1976. 41. Naeim~ P., Capostagno, V. J., Johnson, C. E., Lthrer, R., and Gatti. R. A., Sezary syndro ,,, Tartra~e-res~staat acid pbosphatase i~ the neoplastic ceils, Am. J. Cllm Palhol., 7I, 528, 1979. 42. Woodruff, L. T., Schumacber, H. R., Blink, M. C,, and Stass, $. A,, Am..1 Cfin. PaIhoL, 71, 361, 1979. 43, Li, C. Y., Yam, L, T., and Lain, K. W., Acid phosphatase isoenzyme in human leukocytes in normal and pathologic conditions, J. Hislochem. Cytochem., 18,473, ] 970. 44. Burke, J. S., The value of the bane-marrow biopsy in the diagnosis of hairy cell leukemia, Am. J. Clln, Pathol., 70, 876, 1978. 45. Burke, J. S, and Rappaport, H,, The diagnosis and differential diagnos!~ 9f hairy cell leukefuia iu hone inarlt,w and sNeen, Semin. Oncol., 11,334, 1984. 46. Vykoupil, K. F., Thiele, J., and Georgii, A., Hairy cell leukemla. Bone marrow findings in 24 pa. dents, Virchow~zgh, A,370, 273, I976. 47. Hahnet, U. and Burkhardt, R , Knoehetnmarksdiagnostik bei Haarzell-Leukamie, Kiln. Wochenschr,, 55,933, 1977. 48. Bartl, R., Frisch, B., Hill, W, etal., Bun< marrow histology in hairy cell leukemia. Identification of subtypes and their prognostic significance, Am. J. Clin. Pathol., 79, 531, 1983, 49. Anderson, R. E. and Walford, R. L., Fibrnblastle type of leukemic reticuloendotheliosis, Cancer, 16, 993, 1963. 50. Lee, W. M, F. and Bookstand, J. H., Hairy cell leukemia with bone marrow hypoplasia, Cancer,50, 2207, 1982. 51. Brearley, R. L., Chapman, R. M,, and Brownie,B., Hairy-cell laukemia presenting as aplastic anemia. A~n. Intern. Mad., 91,226, J979. 52. Westbrook, C. A. and Guide, D. W., Autoimmune disease in hairy-ceil Icukacmia: clinical syndromes and treatment, Br, J. HaematoL,61, 359, 1955. 53. Westbrook, C. A. and Guide, D. W., Clinical problems in hairy ceil leukemia: diagnosis and management, 5emia. Oncol., 1l(Suppl. 2), 514, 522, 1984. 54. Bouza, E., Burgaleta, C., and Guide, D. W.~ Infections in hairy-ceil leukemia, Blood, 51, 851,1978. 55. Golomb, H, M. and Hanaoer, S. B., Infectious complications associated with hairy cell leukemia, J. Infect, D&., 143,639, 1981. 56. Stewart, D. I. and Bodey, G. P., Infections in hairy cell leukemia (leukemic reticuloendothellosis), Cancer, 47, g01.1901. 57. Child, I, A., Cawky, J. C,, Martin, S,, and. (}hunr T. M., Microhicidal function of the neutrophils in hairy-cell le~kaemia, Aeta Haematol., 62, 191, t979. 58. Mackowiak, P, A., Demian, S, E,, Sutker, W, L. eta[., Infections in hairy cell leukemia, Am. J. Met/., 68, 718, 1980, 59, Kneeht, H., Rhyner, K., and Streuli, A., ToxopIasmosis in hairy-cell leukaemia, Br. J. Haematol., 62, 65, 1986. 60. Rice, L., Shenkenberg, T., Lynch, E. C., and Wheeler, T. M., Granutomatous infections complicating hairy cell leukemia, Cancer, 49, 1924,1982. 61. Sabbe, L~ J. M., Meijer, C. J. L. M,, and Jansen. J., T-lymphocyte function in hairy-cell leukemia. Cli~. E*p. lmmunof., Z3, 69, 1979. 62, Lauria, F,, Fo~, R., Gobbi, M. et ~., Characterization of T-lymphocyte subsets in hairy-ceil leukar mia (HCL) by monoclonal antibodies: comparison with For, Fop receptors and correlation with disease activity, Hr, J. Haematol., 52,657, 1982. 63. Worman, P. C, and Cawley, J. C., Monocloua[ antibody defined T-cell subsets in hairy-ceil leukemia, Stand. J. Haematol., 29, 338, 1982. 64, Cawley, J. C.. Armitage, R. J., and Worman, C. P., T Cell subsets in hairy cell leukemia, Semin. Oncol., 11,4~5,1984. 65. Foa, R., Lauda, F., Raspadori, D. et ak, Normal helper T-cell function in hairy-cell leukaemia, Stand. Z Itaematol.. ~1,322, 1983.

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66. Ruco, L. P., Procoplo, A., Maccallini, V. ct al., Severe deficiency of natural killer activity in the peripheral blood of patients with hairy ceil leukemia, Blood, 61, i132, 1983. 67. Hooper, W. C.. Bar'.h, R. F., and Shah, N. T., Lack of natural k~ller ceil activity in hairy cell leukemia patlenla and partial restoration with interleukln-2, Cancer, 57,988, 1985, 68. Smith, B. R., Roseothal, D, S., and Ault, g. A., Natural killer lymphocytes in hairy cell leukemia: presence of phenotypi:ally identifiable cells with defective functional activity, Exp~ Hematol., 13, 189, 1985. 69, Levine, P. H. and Katayama, I., The platelet in leukemic retieuloendothdiosis. Functional and morphological evidence of a qualitative disorder, Cancer, 36, 1353, 1975. 70. Zuzel, M,, Cawley, J. C., Patoo, R, C. r aL, Platr function in hairy-cell leukaemia, .L Clio. PathoL, 32, 814, 1979. 71. Rosove, M, H,, Naeim, F., Harwig, S., and Zighelboim, J., Severe platdet dysfunction in hairy ceil leukemia with improvement after splenectomy, Blood, 55,903, 1980. 72. Feiner, A. S., Myers, A. M., and Moore, G. E., Leukemic retleuloendotheliosis. Loss of platelet defect afler spleneetomy, JAMA, 240, 238, 1978. 73. Sweet, D. L. and Golomb, H. M., Correction of platelet defect after splene;tomy in ilalry ceii leukemia~ JAMA, 241, 1684, 1979. 74. Rhyner, K., Streuli, R., and Ki~tler, G. S., HaarzelI-Leukamie (hairy-cell leukemia) mlt Osteolytischen Knochenveranderungen, Sehweiz, Med. Woehenschr., 107, 863, 1977, 75. Weh, H. J., Katz, M., Bray, B. et al,, Lesions osseuses au cours des ]eucemles a tricholeucocytes, Nouv. Presse Med., 8, 2253. [979. ?6. Demanes, D. J., Lane, N.~ and Beckstead~ 2. H., Bone invoIvement in hairy-ceII Ieukemia, Cancer, 49, 1697, 1982. 77. Quesada, J. R., Kcating, M. J., Libshitz, H. I,, and Llamas, L., Bone involvemem in hairy cell leukemia, Am. J. Meal.,74, 228, 1983. 78. Jansen, J., Bolhuls, R. L. H,, van Nieuwkoop, J, A, et al,, Paraproteinaemla plus osteolytie lesions in typical hairy-cell leukaemia, Be. J. Haematol,, 54, 531, 1983. 79. Arkel, Y. S., Lake-LewJn, D., Savopoulos, A. A,, and Berman, B., Bone lesions in hairy cell leukemia, Cancer, 53, 2401, 1984. 80. Lembersky, B, C., Rataln, M. J,, Bennett, C. L. et al., Osseous complications in hairy cell leukemia (HCL), Blood, 66(Suppl. 1), 178a, 1985. 81. Noseda, G., Reiner, M,, and Stall, G., Haarze]I-Leukamle und Myelom, Schweiz. Med. Woch. enscbr,, 110, 1494, 1980. 82. Calovaky, D,, Coslr C,, Loukopoulos, D, et al., Hairy cell leukemia and myelomatosis: chance association or clinical manifestations of the same B-cell disease spectrum, Blood, 57,758, 1981, 83. Franssila, K. O., Coincidental hairy cell teukemia and large ceil malignant lymphoma, Arch. Pathol. Lab. Med., 103,437, 1979. 84. Adler, S. S., Shetty, J., and Golomb, H. M., Coexistence of leukemic retlculoendotheliosis and histioeytic lymphoma. A case report, Cancer, 43, 1872, 1979. 85. Elkon, K. B., Hughes, G, R. V., Catovsky, D. et al., Hairy-cell leukaemia with polyar teritis nodosa, Lancet, 2, 280, 1979. 86, Yam, L. T,, Chaudhry, A, A., and Janckila, A. J., hnpaired marrow granuJocyte reserve and leukocyte mobilization in leukemic retieuloendotheliosis, Ann. Intern. Med., 87,444, 1977. 87. Pope, A., Lazarchiek, J., Hoyer, L,, and Weinstein, A., Hairy ceil leukemia and vaseulitis, J, gheumatof., 7, 895, 1980. 88. Rudolph, g, 1,, Vasculltis associated with hairy cell leukemia, Arch. Dermatol., 116, 1077, 1980. 89. Gocdert, J. J., Ncefe, J. R., Smith, F. S, et al., Polyarteritis nodosa, hairy celt leukemia and splenvsis, Am. J. Med., 71,323, 1981. 90. LePogamp, p., Ghandour, C., and LePrisr P. Y., Hairy cell leukemia and polyarteritis nodosa, J. RheumatoL, 9, 441, 1982. 91, Dorsey, J. K. and Penick, G. D., The association of hairy cell leukemia with unusual immunologic disorders, Arch, Intern. Med., 142, 902, 1982. 92, Crofts, M. A. J., Sharp, J. C., and Joyner, M. V., Rheumatoid artilritis and hairy-cell leukaemia, Lancet, 2, 203, 1979. 93. Faenhini, A., Mariani, E., Ferrolli, A. et ai., Hairy cell leukemia and rheumatoid arthritis: cause or effect.'?, Arthritis Rheum,, 2M, 1587, 1981. 94. Sattar, M. A. and Cawley, I. D., Arthritis associated with hairy cell leukaemia. Case report, Ann, Rheum. Dis.,41,289, t982. 95. Caaareale, D.. Sakamoto, K., Aiba, M. et al.. Sera of patients with hairy cell leukemia immunoprecipitate EBV-relamd antigens. Leuk. Res.. 5, 107, 1981. 9ft. Sairenji, T., Lane, M. A., Reisect, P. S. r at., Characterization of Epstein-Burr virus infection of hairy cell leukemia patients, Semin. Oncol., 11,439, 1984.

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97. Kamlner, L. S., gataln, M. 2 . Golomb, H, M., and Vardlman, J. W., A comparison of the presentation and clinical courses of hairy ceil leukemia in men and women, Blood. 66{Suppl. l), 177a. 1985. 98. DamasJo, E. E., Spriano, M., gepetto, M. ~t at., Hairy ~elI ieugemia: a retrospective study of 235 cases by the halian Cooperative Group (ICGHCL) according to Jansen's clinical staging system, Acta Haematol., 72,326, 1984. 99. Katayama, I. and Finkel, H. E., Leukemic reticuloendothellosis. A cllalcopathologic study with review of the literature, Am. J. Med., 57, 115, 1974. 100. Jansen, J., Sohuit, H. R. E., Hermans, J., and Hijmans, W., Prognostic significance of immunologic phenotype in hairy cell leukemia, Blood, 63, 1241, 1984. 101. Hamblin, T, and Hough, D., Chronic lymphatic leukaemia: correlation of immuno fluorescent characteristics and clinical features, Br. 2, Haematol., 36, 359,1977. 102. Acute leukemia group B: correlation of abnormal immunoglobulln with clinical features of myeloa~a, Arch. Intern, Med., 135, 46, 1975, 103. Golomb, H., Strehi, S., Oleske, D., and Vardiman, J,, Prognostic significance of immunologic phenotype in hairy cell leukemia: does it existT, Blood, 66, 1355, ] 985. I04. Yam, L. T,, Li, C., and Finkel, H. E., Leukemic reticuloendothdiosis, Arch, Intern. Med., 130, 2a8, 1972. 105. Ingoldby, C. J. H., Aokroyd, N., Catovsky, D,, and Spencer, L, Splenectomy for hairy ceil leukaemla, Clio. Oncol,, 7,325, 1981. 106. Mints, U. and Golomh, H. ld., Spleneetomy as initial therapy in twenty-six patients with. leukemic reticuloendotheliosis (hairy ceil leukemia), Cancer Res,, 39, 2366, 1979. I07. Myers, T. d., Ikcda, Y., Schwartz, S. et at., Primary splenic hairy celt leukemia -- remission for 2i years following splenectomy, Am. J. HematoL, ]l, 299, 1981. 108. Golomb, H. M. and Mints, U., Treatment of hairy cell leukemia (leukemic reticuloendotheliosis). I1. Chloramhucil therapy in postsplenemomy patients with progressive disease, Blood, 54, 305, 1979. 109. Golomb, H. M., Progress report on chloramhucil therapy in postsplenectomy patients with progressive hairy cell leukemia, Blood, 57,464, 1981. 110. Krigel, R., Liebes, L. F., Pelle, E., and Silber, R., Chlorambucil therapy in hairy cell leukemia: effects on lipid composition and lymphocyte subpopulatloos, Blood, 60, 272, 1982. 11I. Golomh, H. M., Sohmidt, K., and Vardiman, J. W., Chlorambucil therapy of twenty-four postspleneclomy patients with progressive hairy cell leukemia, Semin. Oncol,, 1l(Suppl. 2), 502,1984. 112. Vardiman, J. W., Variakojis, D., and Golomh, H. M., Hairy cell leukemia. An autopsy study, Cancer, 43, 1339, 1979. 113. Davis, T. E., Waterbury, L., Abeloff, M., and Burke, P, J., Leukemic reticuloendotheliosis, Arch. Intern. M'ed., 136, 620, 1976. 114. McCarthy, D. and C,tovsky, D., Response to doxorubicln in hairy cell leukaemia, Scand, J. Haematol.,21, 445, 1978. 115. Stewart, D. J., Benjamin, R. S., McCredir K. B. et at., The effectiveness of rubidazone in hairy cell leukemia (leukemic reticuloendotheliosis), Blood, 54,298, 1979, 1[6. Case, D. C. Jr., Combination chemotherapy of hairy cell leukemla with cyelophosphamide, vincrisline and predtaisone. J. Maine Meal. Assoc., 71,136, 1980. 117. Marry, M,, Calvo, F,, Castaigne, S., and Flandrin) O., Leucemies a tricholeacocytes a la phase d'insuffisance medullaire severe. Remission complete apres polychimiotherapie chez deux malades, None. Presse Med., 10, 2977, 1981. 118. Stewart, D. J., Keating, M. J., Youness, E., and Burgess, M. A., Long-term chemotherapy-induced remission in a probable case of hairy cell leukemia, Cancel Treat. Bop,, 65, 313, 1981. 119, Cairo, F., Cartalgne, S., Siganx, F. et al., Intensive chemotherapy of hairy cell leukemia in patients with aggressive disease, Blood, 68, 115, 1985. 120. Cheerer, M. A., Fefer, A., Grecnberg, P. D. et al,, Treatment of hairy-ceil leukemia with r dlotherapy and identical-twin bone-marrow transplantation, N. Engl, J. Med., 307,479, 1982. 121. Izzi, T., Polehl, P., Muretto, P., and Lucare[ll, G., Syt,geneie bone marrow transplant in a patient 9~ith hairy cell teukemla, Exp. HernatoL, 12(Suppl. 15), 102, 1984, 122. Bouronole, B. A., Leukemic reticuloendotheliosls (hairy cell leukemia), Blood, 53,412, 1979. 123. Sharp, R. A. and Mac Walter, R. S,, A role for splenic irradiation in the treatment of hairy.cell leukaemia. Case report and review of the literature, Acta Idaematol., 70, 59, 1983. 124. Fay, J. W., Moore, J, O., Logue, G. L., and Huang, A. T,, Leukapheresis therapy of leukemic reticuloendothdiosis (hairy cell leukemia), Blood, 54, 747, D79. 125. Mielke, C. H., Jr., Dobbs, C. E., Winkler, C, F,, and Yam, L. T., Therapeutic Icukapheresis in hairy cell lenkemia, Arch. Intern. Med., 142, 700, 1982. 126, Yam, L. T., Klock, 3. C., and Mielke, C. H.. Therapeutic Ieukapheresis in hairy cell leukemia: review of literature artd personal experience, Semin. O~r 1l(SupI~I. 2), 493,1984.

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127. Golomb, H. M., Kraut, E. 14., Oviatt, D. L. et aL, Absence of prolonged benefit of inhial leukapheresis therapy for hairy eel]leukemia, Am. L Hematol., 14, 49, 1988. 128. Gardner, F. Pl. and Prlngle, J. C., Jr.,Androgens and erytbropoiesis,Arch. Intern,Med., 107, 846, 1961. 129. Luseh, C. J., Ramsey, H. E., and Katayama, I., Leukemic retieuloendotbelinsis.Report of a case with peripheral blood remission on androgen therapy, Cancer,4I, 1964, 1978. 130. Besa, E. C., Wolff, S. M., Dale, D. C., and Gardner, F. H, Aetlocholanolone and prednlsolone therapy in patients with severe bone-marrow failure,Lancet, 1,728, 1977. 131. Magee, M., Gee, T. S,, Arlin, Z,. and Clarkson, B., Androgen therapy in postspleneetomy patients (PTS) with hairy cell leukemia (HCL), Blood, 66(Supp]. I), 145a, 1985. 132. Hersh, E. M., Quesada, 3., Pleating, M. J. et ah, Host defense factors and prognosis in hairy cell leukemia, Leuk. Res., 6, 625, ] 982, 133, Quesada, J. R., Hersh, E. M,, Keating, M., Zander, A,, and Hnster, J,, Hairy cell leukemia: clinical effects of the methanol extraction residue (MER) of BCG, lithium carbonate and mononndear cellenriched leukocyte transfusions, Leuk. Res.. 5,463, 1981. 134. Brady, S. A., Russell, W. G., Krantz, S. B., and Graber, S. E., Beneficial effect of hepatitis in leukemic reticuloendothe[iosis, Arch./nter. Med,, 141,1080, 1981. 135. Quesada, 3. R., Reuben, 3",, Manning, J, T. et aL, Alpha interferon for induction of remission in hairy-cell leukemia, N. Engh J. Mud.,310, 18, 1984. 136. Worman, C, P., Catovsky, D.. Bevan, P. C, st at,, Interferon is effective in hairy-cell leukaemia, Br. d. Haematol,, 60, 759, 1985. 137. Jacobs. A. D., Naiem, F., Champiin, R. E., and Golds, D. W., Toxicity and hone marrow response of patients with hairy cell leukemia treated with biosynthetic (recombinant) a-2-interferon, Blur, 50, 33, 1985, 138. Jaeobs, A. D., Champlln, R. E., and Golds, D. W., Recombinant o-2-interferon for hairy cell leukemia, Blood, 65,1017, 1985. 139. Retain, M. J., Gnlomb, H. M., Vardiman, J. W. et aL, Treatment of hairy cell leukemia with recombinant alpha; interferon, Blood. 65,644, 1985. 140. Thompson, J. A,, Brady, J., Kidd, P., and Fefer, A,, Recombinant alpha-2 interferon in the treatment of hairy cell leukemia, Cancer Treat Rep,, 69, 791.1985. 141, Golomb, H, M., Jacobs, A,, Fefer, A. et el., Alpha-2- interteron therapy of hairy-cell leukemia: a multieenter study of 64 patients, J. Clio. Oneol., 4, 900, 1986. 142. Castaigne, S., Sigaux, F., Cantell, K. et al., Interferon alpha in the treatment of hairy cell leukemia. Cancer, 57, 1681, 1986. 143. Quesada, J. R., Gutterman. J, U., and Hersb, E. M,, Treatment of hairy ceil leukemia with aloha interferons, Cancer, ~7, 1678, 1986. 144. Foam K. A., Maluish, A. E,, Abrams, P. G. et el. Recombinant leukocyte A interferon therapy for advanced hairy ceil IeukemJa. Therapeutic arid immunoiogic results, Am. J. &fed., 80, 351, 1986, 145. Combo, L. and Joyner, M. V,, T-cell hairy cell leukaemia presenting with disseminated intravascnlar coagulation: rapid response to al0ha-interferon, Br. J. HaematoL, 62,393, 1986. 146. ,ranssen, J, Th. P., DePauw. B. E,, and Holdrinet, R, $. G., Treatment of hairy-cell leukaemia with recombinant human a2-interferon, Lancet, I, 1025, 1984. 147. Huber, C., Fisher, R., and Gastl, O., Interferon-alpha-2e in the treatment of advanced hairy-cell leukemia. Results of a phase I1 trial, Oneology, 42(Sup01. I), 7, 1988. 148. Plofmann, V., Fehr, J., Sourer, C., and Ottino, J., Hairy cell leukemia: an interferon deficient disease?, Cancer Treat. Bey.. 12(Suppl. B), 33,1985. 149. Knecht, Pl., Bndmiger, H., Groscarth, P., and Streuli, R. A., Central nervous system involvement in hairy cell leukemia, Kiln. Woehenschr., 63,423, 1985. 150, Halmrmann, 1"., Hoagland, 14., Chang, M., and Phyliky, R., A phase 11 trial of alpha recombinant leukocyte interferon (arlFN) in hairy cell leukemia in patients with advanced disease. Marked improvement in bone marrow, peripheral blood parameters, and decreased red blood cell transfusions, Blood, 66(Suppl. 1), 20On, 1985. 15I. Porzsolt, F., Thoma, J,, Unsold, M. et el., Platelet-adjusted IFN dosage in the treatment of advanced hairy cell leukemia, Blot, 51, 73, 1985. 152. Foon, K. A., Sherwin, S. A., Abrams, P. G. et el., Treatment of advanced nun-Hodgkln's lymphoma with recombinant leukocyte A interferon, N. Bog1. 3.. Med., 311, 1148, 1984, 153. Foon, K. A., Bottino, G. C,, Abrams, P. O. et a/., Phase II trial of recombinant leukocyte A i~terreran in patients with advanced chronic lymphocytic leukemia, Am..L Med., 78, 216, ]985. 154. Faltynek, C. R., Princler, O. 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] 56, Tomida, M., Yamamoto, Y., and Hozumi, M,, Stimulation by interferon vf differentiation of human promyeloeytic leukemic cells, BJophy•. ~es. Commun., 104, 30, ] 982. 157. Semenzato, G., Fizzolo, G., Agost~ni, A. ~t al., ~+[ntetferon activates the naturat killer system in patients with hairy cr leukemia+ Blood, 68, 293, 1986. 158. Porzsolt, F., Janik, R., Hell, G. et aL, Defici,~ut IFNa production ie h~iry ceil leukemia, Blur, 52, igS, J986. 159. Ratain, M. J., Vardiman, J. w., Golomh, H. M. et a]., Peripheral blood and bone marrow changes after discontinuance of o-interferon therapy in patients with hairy cell leukemia (HCL), BMod, 66(SuppL i), 207a, 1985. ] 60. Fiandrln, G,, Sigaux, F., Castaisne, S., and Degos, L., Quantltative analysis o1 bone marrow changes during the treatment of hairy cell leukemia with interferon alpha, Cance~ Treat. Roy., 12(SuppL B), 17, 19g5. 161, Ehma~, W. 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184. Preud'Hommn, J. L. and Seligmann, M . Surface hound irnmunoglobullns as a cell marker in human lymphoproliferative diseases, Blood, 40, 777, 1972, 185, Golomb, II. M., Davis, S., Wilson, C., and VardJman, J,, Surface immunoglobulins on hairy cells of 58 patients with hairy cell leukemia, Am. J. Hematol, 12, 397, 1982. 186. Catovsky, D,, Pittman, S.. O'Brien, M. et el,, Multiparameter studies in lymphoid leukemias, Am. 1. C/in. Pathol., 72(Suppl_), 736, 1979, 187. Male, J, V,, San Miguel, J. F., Moss, V. E., and Catovsky, D., The membrane phenotype of hairy cell leukemia: a study with monoelonal antibodies, Semin. Oncot.. ] l. 381. 1984. t88, Jataser~, I,, dee Ottolander, G. J., $chait, t'L R, E. et aI., Hairy ceil Ieukerata: its place among the chronic B cell leukemlas, Sem/n. OncoL, I t, 386, 1984. 189. Burns, 0. F,, Cowley, J. C., Barker, C, K., and Hayhor F. G. L, Absence of a receptor for fixed C3 on the hairy cells of ieukaemic reticuloendotheliosis, Clio, Exp. lmmunol., 29, 442, 1977, 190. Braylan, R. C., 1afro, E. S., Triche, T. J. r el., Structural and functional properties of the "hairy" ceils of leukemic retieuloendotheliosis, Cancer, 41,210, 1978. 191, Zidar, B. L., Wiokelstein. A., Whitcsidr T. L, et at,, Hairy cell Ieukaemia: seven cases with probable B-lymphocytic origin, Br. J. Haematol., 37,455, 1977. 192. Naaim, F,, Gatti, R. A.. Johnson, C, E. et al., "Hairy cell" leukemia, A heterogeneous chronic lymphoproliferative disorde/, Am. J. Mad., 65,479, 1978. 193. Burns, G. F., Cowley, I. C., Worman, C. P. et el., The distribution of a receptor for IgM (u FcR) on haemic cells, Am. J. Hematol., 6, 243, 1979. 194. Catovsky, D., Chcrchi, M.. ekes, A. et al., Mouse red-celi rosettes in B-lymphoproliferative disorders, Br. J. HaematoL, 33,173, 1976. 195. Burns, G. F. and Cowley, J. C., Spontaneous mouse erythroeyte-rosette formation: correlation with surface immunoglobulin phenotype in hairy-cell lenkaemia, Clio. Exp. lmmunoL, 39, 83, 1980. 198. Den Ottolander, G. J., Schuit, H. R. E,, Wanyer, J. L. M, r el., Chronic B-cell leukemias: relation between morphological and immunological features, Clln. 1mmunoL lmmunopathol., 35, 92. 1985. 197. Saxon, A., Stevens, R, H.. and Goldr D. W., T-lymphocyte variant of halry-celI leukemia, Ann. Intern. Mad,,88,323, 1978. 198. Advani, S. H., Talwalker, G. V., Nadkarni, 1. S. et al., Hairy-cell leukaemia. Indian I. Cancer, 13, 283, 1976. 199. Hcrnandcz, D., Cruz, C., Carnot, J. et hi., Hairy cell leukaemia of T-cell origin, Br, J. Haematol., 40, 504, 1978. 200. Roseoblatt, J. D., Golde, D. W., Wachsman, W. et al., A second isolate of HTLV-II associated with atypical hairy.cell leukemia, N. Engl. 3. Mad., 315, 372, 1986. 201. Cawley, J. C , Burns, G. F., Nash, T. A. et al., Halry-cell leukemia with T-cell features, Blood, 51, 61, 1978. 202. Jansen, J., Schuit, H. R. E., Schreuder, G. M. Th. et el., Distinct subtype within the spectrum of hairy-cell leukemia. Blood, 54, 459, 1979. 203. Burns, G. F., Worrnan, C. P., and Cawley, 1. C., Fluctuations in the T and B characteristics of two cases of T-cell hairy-cell leukaemia, Clio. Hxp. lmmunol,, 39, 76, 1980. 204, Cawley, J. C,, Burns, G. F., Worman, C. P, et aL, Clinical and hematologic fluctuations in hairycell leukemia: a sequential surface-marker analysis, Blood, 55,784, 1980. 205. Guglidmi, P., Pread'homme, J. L., and Flaadrin, G., Phenotypic changes of phytohaernagglutininstimulated hairy cells. Nature (London), 286, 166.1980, 206. Han, T., Dadey, B.. Pollard, C. el el., Lack of T cell antigen expression on hairy cells of B cell origin after in vitro exposure to PHA, Blood, 63, 958, 1984. 207. Worman, C. P., Beverley, P. C. L., and Cowley, J. C., Aherations in the phenotypr of hair'/cells during culture in the presence of PHA; requirement for T cells, Bfo~d, 59, g95, 1982. 208. Worman, C. P.. Mills, K. H. G., arid Cowley, J. C,. Non-T Lymphoid ceils can express T cell sur face characteristics: n~rmal, HCL, and a range of leukemic B cells express T cell antigens after appropriate in vitro stimulation, Semin. Onr 11,401.1986. 209. Jansen. J.. LeBien, T. W., and Kersey. J. H., The phenotype of the neoplastic cells of hairy cell leukemia studied with monoclonal antibodies, Blood, 59, 609, 1982. 210. Worman, C. P., Brooks, D. A., Hogg, N. et el., The nature of hairy cells -- a study with a panel of monoclnnal antibodies, Scand. J. Haematol,, 30, 223, 1983. 211. Janckila, A. J., $telzer, G. T., Wallaee~ L H., and yarn, L. T., Pheuotype of the hairy ceils of leukemia reticuloendotheliosls defined by monoclonal antibodies, Am. J. Clio. Pathol., 79, 431, 1983. 212. Hsu, S., Yang, K., and Jaffa, E. S., Hairy cell leukemia: a B cell neoplasm with a unique antigenic phenotype, Am, J. Clio. PathoL,80, 421, 1983.

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