Leukemic reticuloendotheliosis (hairy cell leukemia): A review of the evidence concerning the immunology and origin of the cell

Leukemia Research.Vol.4. Nn. 5. pp. 489-503 © PergamonPress Ltd., 1980.Printedin Great Britain.

0145-2126/80/10014)489102.00/0

REVIEW ARTICLE

LEUKEMIC RETICULOENDOTHELIOSIS (HAIRY CELL LEUKEMIA): A REVIEW OF THE EVIDENCE CONCERNING THE IMMUNOLOGY AND ORIGIN OF THE CELL W . CRAIG HOOPER, DAVID H . B u s s * a n d CURTIS L. PARKER Departments of Anatomy and Pathology*, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27103, U.S.A. (Received 10 May 1980. Accepted 21 May 1980)

INTRODUCTION IN 1923 Ewald [33] introduced the term leukemic reticuloendotheliosis (LRE) while describing a hematological disorder which would now probably be classified as acute monocytic leukemia [54, 86]. It was not until 1958 that hairy cell leukemia, a synonym for LRE, was shown to be a distinctive hematopoietic disorder with unique hematologic and clinicopathological features [l l]. The disease usually follows a chronic course with its chief clinical feature being splenomegaly without peripheral lymphadenopathy, and in most cases it is accompanied by pancytopenia. The most significant finding~ however, is the presence of mononuclear cells with irregular cytoplasmic projections, hence the name hairy cell [80]. These cells, which appear in the blood, bone marrow, liver, lymph nodes and spleen usually give a positive reaction for the tartrate-resistant isoenzyme 5-acid phosphatase (T-ACP) [92, 93]. LRE which accounts for 2 ~ of all cases of leukemia [10, 24, 85] occurs predominantly in males [10, 11, 21], and has been observed in patients ranging in age from the second to the eighth decade, with the median age being 50 years [21]. Despite intensive research, the nature and origin of the hairy cell is unknown and surrounded by controversy. Some investigations claim that it is of monocyte/histiocyte origin [5, 11, 32, 46, 52, 65, 70, 77, 82]. Others believe that it is of lymphocytic origin [18,19,23,25,28,30,31,34,35,36,42,47,56,57,73,76,83,84,85,86,95], that it is a monocyte-lymphocyte hybrid [4, 9, 68, 94] or that it is the proliferation of a yet unidentified cell type [6, 16]. Since the clinicopathological and diagnostic features of LRE have been extensively reviewed elsewhere [10, 11, 14, 24, 37, 38, 39, 81, 87], only a brief discussion of these topics will be given here. The major portion of this review will be concerned with the controversy surrounding the nature and origin of LRE. Correspondence to: Curtis L. Parker, Ph.D. Department of Anatomy, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27103, U.S.A. Abbreviations: LRE, leukemic reticuloendotheliosis; T-ACP, tartrate-resistant acid phosphatase; CML, chronic myelocytic leukemia: AML, acute myeloblastic leukemia: CLL, chronic lymphocytic leukemia: ALL, acute lymphoblastic leukemia. 489

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CLINICOPATHOLOGICAL FEATURES AND DIAGNOSIS It is paramount that LRE be diagnosed correctly because chemotherapy may be detrimental to patients with this disease, and in many cases the only effective therapeutic measure is splenectomy [2, 21, 39, 55]. The disease usually begins insidiously, characterized by episodes of infection and weakness. In the great majority of cases physical examination reveals splenomegaly without enlargement of the peripheral lymph nodes; approximately 50~ of patients also have hepatomegaly [21]. Other characteristic features of LRE are pancytopenia and infiltration of the bone marrow, liver, lymph nodes and spleen by hairy cells. The hallmark diagnostic feature of LRE is the presence of mononuclear cells with cytoplasmic projections which can be seen best in peripheral blood smears or imprints from the spleen or bone marrow (Fig. l a). The cells are best visualized using phase contrast or electron microscopy (Fig. I b and c). It must be remembered, however, that cytoplasmic projections can be artificially produced when blood is left standing or is improperly smeared [87], and that similar projections are sometimes seen in other leukemic processes [64]. Hairy cells have a distinct nuclear membrane and are usually strongly positive for T-ACP [92-93]. Caution must also be exercised in interpreting the T-ACP reaction since false-positive results are sometimes obtained [50], and also T-ACP cells may be found in other disorders such as malignant lymphomas although the reaction is usually much weaker in such conditions [21,64]. Thus, this cytochemical test should always be interpreted in light of other clinical findings. The serum and urine lysozyme concentrations are of value in differentiating LRE from myelomonocytic leukemia. Whereas the concentrations are normal in LRE patients, they are high in patients who have the latter condition. Although most LRE patients have normal serum immunoglobulin levels [21], a case of IgM macroglobulinemia has recently been reported [35]. Despite the excellent documentation of the clinicopathological features of LRE, this condition is most frequently confused with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphomas. One reason for this confusion is the positive T-ACP reaction as seen in some cases of CLL and in some lymphomas. Another reason is that hairy cells are often difficult to identify in peripheral blood or bone marrow smears. In making the differential diagnosis between these diseases, it is helpful to remember that peripheral lymph node enlargement seldom occurs in LRE, whereas the converse is true in CLL and in non-Hodgkin's lymphomas [87]. HISTOPATHOLOGICAL FEATURES

Cell morphology The morphology of the hairy cell is similar in peripheral blood smears and imprints of bone marrow or spleen. The characteristic cytoplasmic projections are not seen, however, in histological sections due to tight cellular packing. When Wright's stain is used, hairy cells are characterized by an irregular cell membrane and poorly preserved cytoplasm which appears "sky blue" and lacks granules. The nuclear membrane appears distinct and intact, and the chromatin appears "spongy" [ 10]. Supravital staining is an excellent method for preserving the various structural characteristics of the living cell. When stained in this manner, the hairy cell appears to be irregularly shaped, usually spherical or polygonal, with a serrated cell membrane. The cytoplasm contains mitochondria which can be counterstained with Janus Green [10]. The nucleus is oval shaped, about half the size of the cell, and eccentrically located [10].

FIG. 1. Typical appearance of hairy cells as seen in (a) peripheral blood, Wright's stain, 1000 x : Ibl transmission electron microscopy, uranyl acetate and lead citrate stain, 7600 x ; (c) scanning electron microscopy, 3600 x.

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FIG. 2. Hairy cell infiltrates of the bone marrow (a), spleen (b) and liver (c). A "pseudosinus" is present in the spleen (arrow heads). In the liver, hairy cells are present within both the portal areas to the left of the photomicrograph, and the sinusoids to the right. Hematoxylin and eosin stain, all illustrations 400 x.

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When wet preparations are viewed under a phase contrast microscope, the same characteristics are seen [ 10]. When the diagnosis is in doubt, transmission electron miscroscopy of the hairy cells may be useful in demonstrating a characteristic ribosome-lamella complex which is found in about 50% of LRE patients [21,24,48,49]. This complex, however, has also been documented in cases of CLL, monocytic leukemia, and Waldenstrom's syndrome [13, 21]. Scanning electron microscopy may also be valuable in establishing a diagnosis of LRE (Fig. l c). Hairy cells are said to exhibit distinctive surface ruffles which are not seen to a similar degree in any other leukemic disorder [12, 48, 86]. Bone marrow

Most investigators agree that a bone marrow aspirate/biopsy examination is the most valuable tool available for the diagnosis of LRE since the bone marrow is almost always involved. However, because of increased reticulin fibers in the marrow, an adequate aspirate sample can be obtained in only half the patients [21,39, 87]. Golomb [37] suggests that an initial aspiration attempt should be made at the iliac crest instead of the sternum because the probability of a dry tap appears to be less at that particular site. In the event of an unsuccessful tap, the bone marrow should be biopsied. Microscopic examination of a biopsy reveals diffuse infiltration by hairy cells (Fig. 2a) along with an increase in marrow reticulin. In early stages of the disease, the hairy-cell infiltrate is often sparse and normal marrow elements may be preserved [1(3]. As the disease progresses, severe depletion of myeloid tissue occurs [24]. Mitotic figures are rare, and atypical cells are unusual [87]. According to Naeim and Smith [61], fibroblastic changes are seen in about half the cases. Spleen

The spleen shows the most extensive involvement of any organ. Grossly, it appears homogeneously firm and is enlarged, often massively; infarcted areas may be evident. The Malpigian corpuscles appear inconspicuous or absent. Microscopically, hairy cells can be seen permeating the spleen and diffusely infiltrating the red pulp and pulp cords (Fig. 2b). As the accumulation of hairy cells and the proliferation of histiocytes cause the red pulp to expand, the white pulp becomes compressed and ultimately disappears. The hypersplenism which is a major clinical feature of LRE results from the accumulation of hairy cells and the destruction of other cell types by the phagocytic histiocytes [61]. Observation of the splenic lesions described by Nanba et al. [62, 63], and others [7, 53] may be helpful in the differential diagnosis of LRE. These lesions are pseudosinuses (Fig. 2b) lined by hairy cells instead of the endothelial cells and ring fibers which line normal splenic sinuses. It is believed that pseudosinuses develop in either of two ways: (1) Through local hemorrhage within the pulp cord resulting in expansion of pre-existing reticulin fibers. When this occurs, a residual atrophic sinus can occasionally be seen in the center of the pseudosinus. (2) By central engorgement of the splenic sinus with red cells and hairy cells which dilate and damage the sinus wall causing the destruction and eventual disappearance of ring fibers. In this instance, sparse, widely separated sinus endothelial cells can be observed on the inner lining of the pseudosinus [62]. Liver

Kostich and Rappaport [54] have suggested that infiltration of the liver in lymphocytic and granulocytic leukemias takes place because of the large number of leukemic cells in the peripheral blood. This may not be true in LRE, since the white-cell count is typically decreased and pancytopenia is often severe [32]. However, in typical cases of

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LRE, the liver shows infiltration of both the portal areas and sinusoids by hairy cells (Fig. 2c) [10, 32, 87]. Delso et al. [32] have suggested that the infiltration patterns of the liver may be of diagnostic value in this disease. In the cases they examined, two distinct patterns were observed in the relationship between hairy cells and the sinusoid lining of the liver. In the first, hairy cells were observed to be wandering freely in the sinusoid lumen; in the second, they were closely connected to the sinusoid lining. These investigators state that these patterns are important because they are not seen in other lymphoproliferative disorders. Other organs

In the autopsy study of LRE patients conducted by Vardiman et al. [89], frequent pulmonary involvement was noted, a finding which is uncharacteristic of other leukemias. Others, however, attach no significance to this finding, since their studies showed infrequent pulmonary involvement [10, 11]. There is general agreement on the consistent occurrence of significant visceral lymph node enlargement despite the absence of peripheral lymphadenopathy in most LRE patients. Microscopically, lymph nodes show diffuse infiltration of hairy cells into the cortical paracortical, and medullary regions of the lymph nodes, with occasional infiltration into the pericapsular fat [89].

THE NATURE AND ORIGIN OF THE HAIRY CELL If leukemic reticuloendotheliosis is to be correctly placed in the spectrum of myelolymphoproliferative disorders, the origin of the hairy cell must be determined. At present this determination cannot be made on a morphological basis. When LRE was first defined as a distinct clinicopathological entity, hairy cells were thought to come from a primitive reticuloendothelial cell which gave rise to both monocytes and lymphocytes [11]. The controversy over the origin and nature of hairy cells began when it was determined that monocytes and lymphocytes apparently develop independently in the bone marrow [8]. Most investigators now believe that the hairy cell is either monocytic [5, 11,32, 46, 52, 65, 70, 77, 82] or lymphocytic [17, 18, 23, 25, 28, 30, 31, 34, 35, 36, 42, 47, 56, 57, 73, 76, 83, 85, 88, 95] in origin. Some, however, contend that it is a hybrid cell with characteristics of both monocytes and lymphocytes [4, 9, 68, 74]. Others theorize that it may be a neoplastic proliferation of a yet undiscovered cell population [6, 16]. Monocytes in the circulating blood originate in the bone marrow. When these cells leave the vasculature and enter body tissues, they differentiate into macrophages. The monocyte/macrophage is generally characterized as possessing phagocytic properties and adhering to either glass or plastic. These cells also possess receptors for the third component of complement (C3) and for the Fc portion of the lgG molecule. The Fc receptor helps the macrophage to phagocytize antigens [27] and also mediates antibody-dependent cellular cytotoxicity in the monocyte/macrophage as well as in lymphocytes, polymorphonuclear leukocytes, and platelets [3]. The B-lymphocyte also has both C3 and Fc receptors although it has been reported that the C3 receptor is absent in some of these cells. A small population of B-cells apparently shows some phagocytic activity [96]. The distinguishing feature of the B-lymphocyte, however, is the presence of endogenously produced surface immunoglobulin (slg) [60, 67, 69].

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EVIDENCE FOR A MONOCYTIC ORIGIN Arguments in favor of the monocytic origin of the hairy cell are based on its cytochemical 1-70,79], phagocytic and bactericidal properties [29, 52], its ability to adhere to glass or plastic surfaces [5-1, the presence of receptors for cytophilic antibody 1,46], and the finding of monocytopenia in patients with LRE [66, 82]. C ytochemical properties

The evidence based on cytochemistry is conflicting and should be considered weak at best. Several investigators 1-70,79] contend that the positive reaction for tartrate-resistant acid phosphatase and for nonspecific esterase indicates a monocytic origin since 4ymphocytes show only weak enzymatic staining. However, these enzymatic markers, particularly the latter, are not seen in all hairy cells. Even T-ACP, which is accepted by most investigators as a salient feature of LRE, is sometimes not present in cells from these patients and sometimes is present in cells from patients with lymphoproliferative disorders 1,21, 50]. Catovsky 1,21], in a study of 17 patients, found no cytochemical characteristics of monocytes in the hairy cells of his patients. He also documented that T-ACP was absent in normal and leukemic monocytes. Furthermore, it was pointed out that in some instances lymphoid cells and erythroid precursors may show a strong positive reaction for non-specific esterase. Nanba et ai. [62] and others [92] also feel that histochemical evidence does not support a monocytic origin since other than acid phosphatase, no other hydrolytic enzyme was detected in any appreciable amounts. Recently, Higgy et al. [44] reported that a distinctive pattern of alpha naphthyl butyrate esterase positivity was observed in the hairy cells of 14 LRE patients studied. However, unlike monocytes, this reaction was not inhibited by sodium fluoride. In a definitive study of 24 patients, Variakojis et al. [90] concluded that the histochemical properties of hairy cells differ from those of any other cell group. Phagocytic properties

Although early investigators were unable to demonstrate the phagocytic capabilities of hairy cells [11, 80,1, phagocytosis of varying degrees has been widely observed and reported since the advent of electron microscopy 1"25,29, 34, 88]. Several workers have suggested that this feature strongly implies a monocytic origin and excludes any possibility of a lymphocytic origin 1"29]. Some degree of phagocytic activity, however, has been demonstrated in a small population of normal lymphocytes [96], and Fu et al. [34] have conclusively shown both slg synthesis and phagocytic activity in hairy cells. The phagocytic activity of hairy cells, although varying considerably, is apparently greater than that of lymphocytes but less than that of the monocyte/macrophage. Although phagocytosis of latex particles has been reported and documented with both light and electron microscopy, this property has never been consistently shown. In one study, Daniel and Flandrin 1,29] demonstrated that one patient had the ability to phagocytize both latex and staphyloccocal particles. In microscopic sections, they found some evidence of pinocytosis which was more pronounced after phagocytosis, particularly in regard to staphylococcal particles. Zipper-like structural bonds between two adjacent hairy cells or areas of the cytoplasm of the same cell were also observed after phagocytosis. This feature had previously been noted in monocytic leukemia after phagocytizing latex particles but could not be observed in sections of normal bone marrow and spleen 1,74]. Several investigators have suggested that the phagocytic activity of hairy cells may be more apparent than real. Cohen et al. [28,1 observed that latex particles accumulate in

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clusters on the surface of the hairy cell, a phenomenon not observed with phagocytosis by normal monocytes. Jansen et al. [47] suggested that latex particles trapped between the villi on the cell surface can appear to be completely surrounded by the cell membrane, thereby giving the impression that phagocytosis has taken place. Adherent properties

Adherence to glass or plastic, long regarded as a monocyte/macrophage characteristic, is also a property of hairy cells [52]. Once attached, however, the monocyte differentiates into a macrophage, whereas the hairy cell does not [23, 29]. Another difference is that the hairy cell fails to flatten out completely and is less strongly adherent to the substrate than the macrophage [23, 29]. Cell surface markers

Over the past several years, surface markers have become important guidelines in distinguishing between various cell types and in classifying leukemias [67, 69]. In the case of LRE, however, the markers have only added to the controversy. Hairy cells, in common with monocytes and most B-cells, possess receptors for the Fc portion of the IgG molecule and, in some cases, for C3 [46, 77]. While these receptors may have functional implications, they do not neccessarily suggest origin [12]. Furthermore, it has been reported that not all monocytes bind complement under every condition and that lymphocytes which have the Fc receptor may not be true B cells [12, 51]. Most investigators agree that hairy cells have receptors for the Fc portion of the IgG molecule [21]. The presence of this receptor can be detected by both EA-IgG rosetting and the use of aggregated IgG [34, 46]. Some workers have contended that the presence of an Fc or cytophilic receptor indicates a monocytic origin [46]. Jaffe et al. [46], using EA-IgG rosetting techniques, demonstrated that hairy cells have a cytophilic receptor. Under their laboratory conditions they were able to differentiate between the Fc receptor of the B-lymphocytes and the cytophilic receptor of the monocyte/macrophage. As a result they were able to show that hairy cells as well as monocytes have cytophilic receptors. In support of Jaffe and co-workers, Scheinberg et al. [77], found that 7S EA-IgG selectively bound to monocytes and hairy cells whereas, 19S EA-IgM only bound to B cells. The only difference in the 2 studies was that the latter workers were able to detect a receptor for C3 in one patient. Since it is not clear whether the cytophilic and Fc receptors found on monocytes are identical, care should be taken in assigning a monocytic origin to LRE on the basis of their reactivity with EA-IgG. The literature contains conflicting reports concerning the presence of the receptor for C3 on hairy cells. Burns et ai. [15-16] believe that the different techniques used in various laboratories have led to varying degrees of steric hindrance by complement in the interaction between IgM and an undiscovered receptor for IgM on the hairy cell. The explanation suggested by Jaffe et al. [46] is that surface receptors on different cells may be species-specific, thereby explaining why some indicator cells fail to form rosettes. Rosette systems utilizing either ox or human red blood cells with IgM and complement [21] have succeeded in demonstrating the C3 receptors on hairy cells. In an attempt to resolve the controversy surrounding the C3 receptor, Burns et al. [17] used yeast particles, which fix complement by the alternate pathway, and failed to detect the C3 receptor. They attributed the detection of C3 by EAC rosettes to the fact that a receptor for IgM was being shown instead of the C3 receptor. They support this fact by showing that monomeric IgM can block EAC rosette formation. They suggest that the failure of earlier workers to detect C3 or IgM receptors with EAC-IgM rosettes was probably due to the fact that they used sheep red blood cells, which adsorb much less IgM than ox cells.

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M onocytopenia

In support of a monocytic origin for LRE, Seshadri et al. [82] cited 5 cases in which severe monocytopenia was observed. This deficiency, which may be a contributing cause of the infections which occur so frequently in LRE, could not be related to pancytopenia since other blood values were in the normal range after splenectomy. Monocytopenia was further documented by the absence of macrophages in the exudate from skin windows, and by the small number of macrophages present in the spleens of their five patients when compared to the spleen from a patient who had lymphocytic leukemia. In contradiction to these investigators, Braylan et al. [12] found many macrophages in the spleens of LRE patients~ In explaining this discrepancy, Braylan et al. noted that if macrophages are firmly attached to the splenic stroma when cell suspensions are prepared, very few will appear in the cytoeentrifuge preparations. Thus, they explain monocytopenia not only in terms of low monocyte production but as a result of macrophage sequestration in the spleen as well. The fact that hairy cells accumulate in the liver sinusoids and splenic pulp, the site(s) where macrophages usually gather, also supports the hypothesis of Seshadri and his associates concerning the monocytic origin of LRE.

EVIDENCE FOR LYMPHOCYTIC ORIGIN Arguments for the lymphocytic origin of hairy cells are based not only on cellsurface markers but also on the presence of slg on these cells [19, 23, 28, 30, 31, 34, 36, 41, 45, 46, 83], and their ability to synthesize immunoglobulins both in vioo [35. 36] and in vitro [76]. Some investigators argue that slg is not endogenously produced in the cell but is rather adsorbed from the serum via the Fc receptor. By demonstrating the presence of a cytophilic receptor, Jaffe et al. [46] maintained that the hairy cell was either coated with the cytophilic IgG molecule in vivo, or bound the fluoresceinated anti-immunoglobulin reagent by the Fc receptor. Further evidence that the slg seen on hairy cells is adsorbed rather than synthesized is afforded by the studies of Palutke and Tabaczka [65] in which hairy cells failed to show slg synthesis after being treated with trypsin and incubated for 24 hours in serum-free medium. Once the cells were returned to autologous serum, slg reappeared. Huber et al. [45] believe that slg, in addition to being bound by the Fc receptor, is nonspecifically attached to the villous membrane of the hairy cell. Banergee et al. [5] theorized that the presence of slg on hairy cells is an expression of an antibody response directed against the cells. Their studies showed slg caps on the majority of hairy cells even though noncapping conditions were used throughout the experiment. Capping could occur if auto-antibodies were attached to the membrane of the hairy cell. This type of reaction is not without precedent since it has been shown that CLL and CML elicit an auto-antibody response [5]. Even though Banergee's findings are based on one case, it suggested to the investigators that LRE represents a proliferation of malignant monocytes which stimulate an anti-LRE antibody response. In spite of these arguments to the contrary, intrinsic production of sIg by hairy cells has now been well documented [19, 28, 30, 31, 34, 36, 41, 56, 83, 88]. Through the use of radiolabeled amino acids, Debusscher et al. [30] demonstrated that hairy cells synthesize IgM-type lambda chains. Because of the adherent nature of the hairy cells, these investigators were further able to ascertain that the cells themselves and not some contaminating lymphocytes were synthesizing IgM. Since, as these authors pointed out, B-lymphocytes have been shown to stick to nylon fibers, the ability of hairy cells to adhere to glass and plastic should not rule out the possibility of a lymphocytic origin. By pulse-labeling hairy cells with 3H-leucine, Cohen et al [28] were able to show that newly synthesized

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slg was seen within 1 hour and reaches a peak within 2 hours. A small amount of labeled immunoglobulin was also found in the medium. Fu et al. [34] have conclusively demonstrated the presence of IgD and IgM on hairy cells from 4 patients with hairy cell leukemia. Since IgM and IgD are not cytophilic, it is highly unlikely that these immunoglobulins were adsorbed from the serum. Other investigators have since shown that IgD and IgM are the predominant classes of immunoglobulins synthesized in hairy cells C21]. Most reports indicate that IgG is passively adsorbed from the serum via the Fc receptor and can be washed off, but work has been reported which indicates that IgG can also be synthesized by hairy cells [19, 56]. A continuous in vitro study conducted by Saxon and co-workers [75] showed that one line of hairy cells secreted IgM consistently, whereas another line switched production from IgG to IgM. Reports of polyclonal sIg can be addressed in at least 3 ways [84]: (1) They represent serum immunoglobulins adsorbed from the serum and bound to the cell surface by the Fc receptor, or auto-antibodies directed against the hairy cell; (2) they are all endogenously produced; or (3) some classes are endogenously produced while others are adsorbed from the serum. At present, the third explanation seems to be most likely. The concept of a B cell origin for LRE is further supported by the work of Stuart et al. [85], who prepared antisera against hairy cells. This antisera reacted not only with hairy cells, but also with normal B cells, cells from patients with CLL, and mononucleated Reed--Sternberg cells. Lemon et al. [56] have recently demonstrated that the EpsteinBarr virus normally found in B-lymphocytes is present in hairy cells. Several investigators have reported that the hairy cells of some patients show characteristics of T-lymphocytes [26, 43, 75]. In one case reported by Saxon et ai. [75] the hairy cells were positive for T-ACP, formed spontaneous rosettes with untreated sheep cells, and reacted with anti-T-lymphocyte antiserum. These workers found no evidence for sIg, C3, or Fc receptors on these cells, but did find that the cells retained their T-cell characteristics, along with a positive reaction for T-ACP, after several passages in vitro. Burns et al. [20] have documented a case in which the hairy cells expressed markers for both B- and T-lymphocytes. To find a T-lymphocyte variant of LRE is not surprising, since many other predominantly B cell neoplastic disorders in some cases have a T-lymphocyte origin [75].

EVIDENCE FOR OTHER ORIGINS A hybrid cell

Several workers have described the hairy cell as a hybrid cell since it expresses both lymphocytic and monocytic characteristicg Boidt et al. [9] showed that hairy cells produce sIg endogenously, possess complement and Fc receptors, phagocytize both latex and zymosan particles, adhere to glass, have a delayed response to erythroagglutinating phytohemagglutinin (a response similar to the one seen in CLL), and are able to stimulate a mixed lymphocyte reaction. These authors concluded that LRE may represent "a heterogeneous group of diseases at the molecular and functional level" [9]. An unidentified cell type

Burns and co-workers [16] described a receptor for IgM found in seven patients with LRE. Blocking studies showed that this receptor was specific for IgM. This receptor was present on a small number of circulating mononuclear cells, but absent from other cells that characterize various hematologic disorders. These investigators concluded that hairy cells may represent a neoplastic proliferation of a yet unrecognized cell type.

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T w o cell lines

Another possibility is that LRE is really made up of two cell lines--one lymphocytic in nature, the other possessing characteristics of both monocytes and iymphocytes [4]. It has been suggested that the lymphocyte-type cell is derived from the bone marrow, while the monocyte-type cell comes from the spleen [8, 52,1.

CONCLUSION The hairy cell that is characteristic of leukemic reticuloendotheliosis has been reported many times by various investigators, to have properties of monocytes, of lymphocytes or a combination of the two. These observed differences have generally been attributed to technical variations or to the fact that the hairy cell is an unidentified cell type, a hybrid cell. a subset of the lymphocyte series or a neoplastic monocyte. As a working model, we choose to view hairy cell leukemia along with CLL, ALL, CML and AML in terms.of clonal hemopathy. McCulloch et al. [58] in proposing a model for the differentiation of the myeloblastic leukemias, set forth four major tenets for defining a clonal hemopathy. Adapting these tenets, we present the following model, as taken from the context of McCulloch et al. [581, with the exception of the first in which we set forth another set of hematologic disorders. (1) LRE, CLL, CML, AML and ALL are all derived from a pluripotent stem cell. Following genetic transformation, a single stem cell expands in each of these diseases. (2) A major characteristic of such clones is increased genetic instability compared with normal clones: the phenotypic characteristics of each clone may vary from apparent normality through any of the recognized preleukemic states to leukemia. (3) The usual pathogenesis of leukemia is by clonal evolution occurring in a preexisting abnormal clone; continued clonal evolution is responsible for further changes observed in the natural history of leukemia. (4) Capacity for differentiation along several different pathways, possessed by normal pluripotent stem cells, is retained by abnormal stem cells, and mechanisms regulating proliferation and differentiation are also preserved. Consequently, abnormal clones including those phenotypically leukemic, are heterogeneous and may contain not only continued myelopoiesis but also cells proceeding along other differentiative pathways. Our reason for grouping these leukemic entities together is that a single pluripotent stem cell has been shown to give rise to both the myeloid and lymphoid series [1]. Further supportive data have suggested that the neoplastic cell involved in CML is a stem cell that can differentiate into both granulocytes and B-cells [72]. Once transformed, the pluripotent stem cell representing LRE, CLL, ALL, CML and AML begins to expand in a clonal fashion while continuing a program of differentiation. With heterogeneity being a key feature of such clonal expansion, McCulloch et al. [59] noted that different fates are available at each stage as a cell gives rise to descendants. The example that they give is as follows: A pluripotent stem cell may either renew itself or differentiate; if differentiation occurs a daughter cell may enter one of a number of possible pathways .... this is compatible with a stochastic model, where cells enter one of a number of alternative pathways at random, governed only by definite probabilities. Thus. because of its genetic instability, the precursor clone can appear morphologically

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W. CgAIG HOOPER, DAVID H. Buss and CuRns L. PARKER

normal; and it can suddenly change, depending upon where it is in the pattern of clonal evolution. In the context of this model, the hairy cell can be thought of as a stem cell which is not committed to any particular pathway but which comes from the same cell that is responsible for CLL, ALL, AML and CML. The morphological differences reported in the literature can be explained in part in terms of clonal makeup and evolution. With respect to the model, the LRE clone, as are the other clones, is characterized by heterogeneity. Accordingly, the LRE clone contains cells proceeding along various pathways, with the direction being dictated to a certain degree by the microenvironment. As the clone evolves, certain features that are controlled by the cell's genetic apparatus are present at one time but may be absent at another time. It should be noted that the concept of LRE being a proliferating stem cell is not new I-1 ll. We are merely trying to suggest a place for LRE in the spectrum of hematological disorders. We believe further that the immunologic markers may provide a clue to the severity of the disease and to the best course of treatment. Also, it may provide a model for studying the mechanism(s) that are responsible for committing a pluripotent cell to a particular pathway. A quotation from Lobuglio ~57:] seems an appropriate conclusion for this review, "Leukemic reticuloendotheliosis: a defined syndrome of an ill-defined cell." Acknowledoements--Th~ authors wish to thank Dr. Hyman Muss of the Department of Medicine, Hematology/Oncology Section for critically reviewing the manuscript, and Ms. Debbie Meadows for assistance in preparation of the review. This review was supported in part by a grant from the Forsyth Cancer Service or Winston-Saiem, North Carolina. U.S.A.

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