A review and reevaluation of the histiocytic disorders

REVIEWS

A Review and Reevaluation of the Histiocytic Disorders

MARTIN DAVID

J. CLINE,

M.D.

W. GOLDE,

M.D.

San Francisco,

California

From the Cancer Research Institute, University of California School of Medicine, San Francisco, California. This study was supported by U.S. Public Health Service Grant CA 11067 and American Cancer Society Grant C I-60. Requests for reprints should be addressed to Dr. Martin Cline, Cancer Research Institute, 1282 Moffitt Hospital, University of California, San Francisco, California 94122. Manuscript accepted March 5, 1973.

The current classification of malignant diseases of the monocyte-macrophage (histiocyte) series is confusing and encumbered by complex and uninformative nomenclature. The histiocytic disorders have been categorized largely on the basis of descriptions of overlapping clinical syndromes and the histopathology of fixed tissues. There has been little attempt to integrate current concepts of the functional, morphologic and biochemical aspects of histiocyte differentiation into schemes of disease classification. In this report the principal features of normal and malignant histiocyte differentiation are reviewed and correlated with clinical syndromes. A simplified classification of the malignant histiocytoses based on cellular differentiation is presented. Considerable confusion exists in the clinical and pathologic literature regarding the nosology of the various histiocytic malignancies. Uncertainties in classification result from the overlapping of clinical syndromes and the inadequacy of histology in defining the proliferative and functional capacity of early cells of the monocyte-macrophage (histiocytic) series. These disorders are most easily distinguished at the extremes of the clinical and cytologic spectrum. For example, acute monocytic leukemia with monoblasts and immature mononuclear cells in peripheral blood is readily differentiated from multifocal eosinophilic granuloma of bone with its characteristic clinical and cytologic picture. It is in the intermediate or “mixed” forms of these diseases that diagnostic difficulties arise. The histiocytic disorders have been classified largely on the basis of histopathologic findings and clinical manifestations. It is now possible to construct a classification of the malignant histiocytoses based on current knowledge of cell biology related to the morphogenesis and functional capacity of cells of the histiocytic series. The histiocytic* cell series may be viewed as a continuum of progressively more mature cells, which begins with progenitors in the bone marrow (monoblasts and promonocytes) and culminates in the mature tissue macrophage. The blood monocyte is an intermediate cell between the bone marrow precursor and the tissue macrophage (Figure 1). Macrophages may be further subdivided into immature “A” macrophages, which have loose nuclear chromatin and basophilic cytoplasm, and mature “B” macrophages, with dense chromatin and acidophilic cyto*The terms macrophage

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and hisfiocyte

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Figure 1. A large. multinucleate macrophage surrounded by smaller macrophages. These cells were grown in tissue culture for 21 days. The dark cytoplasmic inclusions are phagocytized Candida albicans. each measuring 2 to 3 p in diameter.

plasm 111. This distinction is important because the immature “A“ macrophage retains proliferative capacity whereas the mature “B” macrophage is generally a terminal, nonreplicating cell. Both mature and immature macrophages may assume a variety of morphologic forms, including those of the peritoneal macrophage, the alveolar macrophage, the giant cell of granulomas and probably the Kupffer cell of the liver. Coincident with morphologic maturation is a progressive expression of functional characteristics [l-3]. Functional attributes that develop with maturation include phagocytic ability, adhesivesurface, the presence of recepness to a charged G (lg tors on the cell surface for immunoglobulins complexes, and the interG) and immunoglobulin with lymphocytes in antigen processing action

MARROW

(Figure 2). The cellular content of lysosomal enzymes also changes with maturation. The reticulum cell is also a component of the reticuloendothelial system. We are uncertain about the maturational sequence and morphogenesis of reticulum cells, and we do not know the exact relationship between cells of this type and those of the monocyte-macrophage series. Cells identified as mature reticulum cells, however, do resemble the macrophage in having acid phosphatase and esterase activity. They may be phagocytic, but less avidly than macrophages; and normal reticulum cells are rarely observed in mitosis. The reticulin network, which is a distinctive feature of some histiocytic malignancies, is of uncertain origin. Reticulin is considered to be a collagen precursor and is thought to arise from fibro-

TISSUES

BLOOD

Immature Mocrophoge Proliferation

Glais

t

to ttt

t+

0

Phagoqtosis

+-

+

ttt

++++

Adherence

+

tt

+tt

t++

Lysosomes

t

tt

tttt

t+t+

+

t+

ttt

+++

,

tt

ttt+

t+++

IgG Receptors Lymphocyte Interaction

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+++-I

Mature

Mocrophage

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Figure 2. Changes in cellular functional characteristics with macrophage maturation.

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Differentiation

.-w

Erythrocyte

--+

Megokaryocyte

Granulocyte Pluripotent

Stem Cells

Figure 3. The relationship between cells of the monocyte-macrophage line and other hematopoietic cells.

Promonocyte

Monocyte Mocrophoge

blasts. Reticulin associated with malignancies may therefore represent a stroma formed by nonneoplastic cell elements or may indicate that the tumor cell itself is capable of reticulin synthesis [4]. The monocyte-macrophage cell line has its origin in the bone marrow. The relationship of monocytes and macrophages to other hematopoietic cells is shown in Figure 3. Monocytes and granulocytes originate from a common progenitor. Failure of normal differentiation resulting from neoplastic transformation can lead to proliferation of stem cells, which produce a wide range of clinical and cytologic manifestations. From our knowledge of malignant myeloproliferative and lymphoproliferative disorders, we can construct an analogous model for the malignant histiocytoses within the following general framework: (1) Histiocytic disease with the least cellular differentiation will have the highest degree of cellular proliferative activity and will be clinically most acute. (2) Histiocytic diseases in which ma-

ture macrophages of low proliferative capacity predominate will be clinically more chronic. (3) Although one cell type will predominate in a given patient, there may be a spectrum of cells at different levels of maturation. A certain overlap among disease syndromes can therefore be expected, although clinical and pathologic features relate mainly to the accumulation of histiocytes at a given stage of maturation. Disease manifestations may result from unrestrained proliferation of neoplastically transformed cells within the bone marrow or tissues, from phagocytosis of the formed elements of blood by mature histiocytes or from resorption of bone. Monocytes and macrophages may also produce endogenous pyrogen [5]. Consequently, the anticipated clinical findings include those related to anemia, leukopenia, thrombocytopenia, fever, osteolysis and tissue infiltration. Neoplastic proliferations of histiocytes must be distinguished from the accumulation of histiocytic

TISSUES

BLOOD

MARROW

Promonocyte

Mature

Immature

Monocyte

Macrophage

Macrophage k

Monocytic I-

Leukemia+ Reticulum

Cell

Sarcoma--

l-

Figure 4. A classification of the malignant histiocytic disorders based on mononuclear-macrophage differentiation.

+Hirtiocytic

Letterer-Siwe

Disease-----(

Medullary

Reticulosis

I-H

and

4 Schuller

Christian{

Eosinophilic Granutoma

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Malignant Histiocytic Disorders: Between Clinical Syndrome of Proliferating

Clinical Disorder

Diseases with Little or Variable Monoblast, promonocyte Promonocyte, immature macrophage

macrophage

Cellular

Cellular

Differentiation

Letterer-Siwe disease (acute differentiated histiocytosis) Histiocytic medullary reticulosis

Diseases with Well Differentiated Immature and mature macrophage Immature and mature macrophage Immature and mature macrophage --

Differentiation

Acute monocytic leukemia Reticulum cell sarcoma (poorly differentiated)

Diseases with Moderate Monocyte, immature macrophage

Correlation

and Differentiation

Cells

Predominant Cell

Immature

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Histiocytes

Hand-Schiiller-Christian Eosinophilic granuloma Localized histiocytoma

cells in response to an The macrophage is part against infection and is removal of damaged or plasia of the histiocytic lymph nodes, therefore,

“appropriate” stimulus. of the body’s defense normally involved in the senescent cells. Hyperelements of spleen and may be an appropriate

response to invasion by certain microorganisms or to the presence of abnormal or damaged erythrocytes. Similarly, histiocytes as “storage” cells reflect their normal function of removing cell debris. For example, histiocytes of the type seen in Gaucher’s disease arise under two conditions: (1) an enzyme deficit (gluco-cerebrosidase) that prevents the normal catabolism of cell lipids by the histiocyte; (2) excessive cellular destruction exceeding the capacity of normal histiocytes to catabolize the occur in chronic

debris. The latter myelocytic leukemia

Figure 5. Immature eral blood of a patient

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mononuclear with monocytic

is thought [6].

to

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In the response to parasites or to tissue destruction, histiocyte proliferation is restrained and self-limited. In malignant proliferation, no such constraints are evident. A classification of the malignant histiocytic disorders is shown in Figure 4 and Table I. The thesis presented here is that these diseases represent clinically identifiable stopping points along a spectrum of histiocytic proliferative disorders with varying degrees of cellular differentiation. MALIGNANT HISTIOCYTIC DISEASES WITH LITTLE, OR A VARIABLE DEGREE OF, CELLULAR DIFFERENTIATION

Monocytic Leukemia. Cytologic aspects: Monocytic leukemia is recognized morphologically by the presence of immature cells of the monocyte-macrophage cell line in blood, bone marrow and tissues (Figure 5). These cells vary from primitive blast forms to morphologically and functionally well differentiated monocytes and macrophages. A similar spectrum may occur in murine myelomonocytic leukemia [2]. Occasionally, elongate cells with irregular cytoplasm and high cytoplasm:nucleus ratio resembling tissue macrophages may be present in the peripheral blood [7]. In acute monocytic leukemia the predominant cell types are the promonocyte and the monoblast. In most cases of monocytic leukemia there is a variable admixture of myeloblasts and more mature granulocytic elements. This is not surprising in view of the evidence indicating a common stem cell origin for granulocytes and monocytes [8] (Figure 3). Historically the term Naegeli type has been applied to the form of monocytic leukemia in which relatively large numbers of myelocytes and less mature granulocytes are found. The term Schilling type [9] has been used when more typical modblasts and monocytes predominate [lo]. These terms define rather arbitrary distinctions; the situation is simply that cellular heterogeneity is the rule in monocytic leukemia [ll]. Histochemical stains are of some value in the study of monocytic leukemia and other histiocytic disorders (Table II). Immature monocytes and their precursors in both man and the mouse are peroxidase positive [1,2,12]; mature cells are peroxidase negative. In general, more than 5 per cent of the cells stain with Sudan black, usually without the heavy localization seen in the myeloblastic leukemias [13]. The periodic acid-Schiff reaction is variable. Functionally the very early monocyte precur-

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TABLE II

Histochemical

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Stain Peroxidase Alkaline phosphatase Acid phosphatase Periodic acid-Schiff Sudan black Beta glucuronidase Esterase ASD chloroacetate Esterase alphanaphthyl acetate

Malignant Histiocyte

Normal Monocyte

Malignant Monocyte

2+ 0

o-2+ 0

0 0

2+ ?

3+ 1+ (diffuse)

3+ 2+ (diffuse) 2+ + 0

f * 0

4+

2+

sors of the marrow are characterized by mitotic activity, lack of phagocytic ability, little glass adhesiveness and lack of surface receptors for IgG. With maturation, functional capabilities increase and peroxidase activity disappears [1,2] (Figure 2). The morphologically differentiated mononuclear cells of monocytic leukemia qualitatively resemble their normal counterpart in these respects. In addition to proliferation within the Pathology: bone marrow, monocytic cells may be observed throughout the parenchymal and connective tissues of the body, especially in spleen, lymph nodes and liver [4]. Mitoses are frequent, and the normal architecture of nodes and spleen are destroyed. An occasional feature of the pathology of monocytic leukemia is erythrophagocytosis. Clinical features and course of the disease: The major clinical manifestations and course of monocytic leukemia are similar to those of acute myelocytic leukemia. Clinical manifestations include anemia, granulocytopenia with infection, thrombocytopenia with bleeding and signs of organ infiltration. The course is usually acute, and most patients succumb within a year. The course of monocytic leukemia is more likely to be variable than that of acute lymphocytic or myelocytic leukemia [lO,il]. Patients have been known to survive from 4 to 11 years [14,15]. The group with chronic disease probably comprises less than 5 per cent of all patients, although Osgood [14] put the figure at 11 per cent. Patients with the chronic form of monocytic leukemia usually have moderate or well differentiated monocytes and macrophages in the blood. This variant probably should be classified among the diseases with moderately differentiated malignant histiocytes. A variety of unusual variants in monocytic leukemia have been described, including prominent oroglossopharyngeal involvement [ 161 and chronic erythromonocytic leukemia [17]. Biochemical abnormalities: In 1966 Osserman and Lawlor [18] reported that untreated patients

1+ + ? +

Granulocyte

Lymphocyte

4-l3+

0 0 o-1+

3+ 2+ (diffuse) 3+ 3+ 4+ 0

3+ (granules) 0 0 0 0

with acute monocytic or myelomonocytic leukemia have increased concentrations of lysozyme (muramidase) in their serum and urine. The enzyme in these patients was antigenically and electrophoretically identical to the normal leukocyte enzyme. Lysozyme occurs in many mammalian tissues but most notably in kidney and lung and in leukocytes of the monocytic and neutrophilic series [19,20]. In acute myelocytic leukemia, serum lysozyme activity may be high, low or normal [21,22]. Activity levels are generally high in patients with acute myelomonocytic and monocytic leukemia [18,21]. Even leukopenic patients ‘with these disorders have a high level of serum enzyme activity. It is probable that the increased levels of lysozyme in serum and urine of patients with monocytic leukemia result from the rapid turnover rate of malignant mononuclear cells that are extremely rich in this enzyme. However, a contribution by abnormal renal function in this disorder has not been excluded [18,21]. Reticulum Cell Sarcoma (Histiocytic Lymphoma). Traditionally, reticulum cell sarcoma is classified with lymphoma and the lymphoproliferative disorders. We should, however, distinguish between lymphoid cells and elements of the reticuloendothelial system that are phagocytic, even though the two cell types are intimately related physically in lymphoid tissues and spleen, and function cooperatively in antigen processing and cellular immune responses. Since the proliferating cells in the tissues of patients with reticulum cell sarcoma resemble poorly differentiated histiocytes or reticulum cells more than they resemble lymphocytes, it is logical to classify reticulum cell sarcoma among the histiocytic proliferative disorders [4]. Cytologic features and pathology: In the undifferentiated syncytial form of reticulum cell sarcoma the predominant cell is relatively large, with a diameter of 15 to 35 p. The nucleus is large, round or oval in shape, with a delicate chromatin structure and prominent nucleolus (Figure 6). The cyJuly 1973

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Malignant Figure 6. patient wifh reticulum phoma).

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cells from the bone marrow cell sarcoma (histiocytic

of a lym-

toplasm is pale staining, varies in amount and often appears to form a syncytium. Reticulin fibers are generally scanty, and there is little evidence of histiocytic differentiation. In the differentiated or histiocytic variety of reticulum cell sarcoma, the predominant cell type resembles the tissue histiocyte. It is generally 15 to 25 p in diameter. The nucleus is usually oval or reniform. Chromatin is fine. Nucleoli are relatively rare. The cytoplasm is abundant, pale staining and usually acidophilic. Phagocytized red cells, nucleated cells and cell debris are occasionally found within the cytoplasm [23]. The reticulin meshwork may be highly developed. Undifferentiated reticulum cells have acid phosphatase activity but lack esterase and beta glucuronidase activity. With maturation, beta glucuronidase appears [24]. The proliferating cells of reticulum cell sarcoma therefore encompass a spectrum ranging between the promonocyte and the “A” macrophage. Clinical manifestations: The general symptoms associated with reticulum cell sarcoma are similar to those of lymphocytic lymphosarcoma [25]. There are, however, several important differences between reticulum cell sarcoma and the other lymphomas. An extranodal primary site is much more common in reticulum cell sarcoma and may occur in up to one fourth of all patients with this disease 1251. Extranodal sites frequently involved include the tonsils and lymphoid tissues of Waldeyer’s ring [26] and the gastrointestinal tract, particularly the stomach and jejunum [27]. Bony lesions can be identified roentgenologically in about 20 per cent of patients with reticulum cell sarcoma [28]. They are usually osteolytic and are generally a manifestation of disseminated disease 1291. Rare sites of involvement include the thyroid

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[30.31], the testes, the genitourinary system [25.32,33] and the lung. Primary reticulum cell sarcoma of the brain is a well defined entity, but the precise cellular origin of this tumor is not known [34]. Reticulum cell sarcoma tends to be an aggressive tumor and the median survival is less than one year. This neoplasm may be quite radiosensitive, however, and frequently responds to chemotherapy. In cases in which a remission can be achieved with therapy, survival is significantly prolonged [35,36]. No comprehensive data exists that establish a relationship between the degree of histiocytic differentiation and the acuteness of the clinical course. The clinical disease generally reflects the rapid proliferation of poorly differentiated histiocytic precursors. In occasional patients the overlap between reticulum cell sarcoma and acute monocytic leukemia is clearly demonstrable. Starting within the lymph nodes, the malignant reticulum cells may subsequently involve the bone marrow and blood, producing a leukemic picture [24,25]. HISTIOCYTIC DISEASES WITH MODERATE CELLULAR DIFFERENTIATION Letterer-Siwe Disease (Acute Differentiated Histiocytosis [ 41. Clinical and pathologic features: In 1924 Letterer [37] described a 6 month old boy with a ten week history of fever, purulent otitis media, generalized purpura, lymphadenopathy, hepatosplenomegaly and purulent material draining from an incision over a postauricular lymph node. The child died, and microscopic examination of autopsy material revealed disruption of the architecture of lymphoid tissues by collections of cells characterized by abundant cytoplasm and nuclei. Similar cells were large,, “endothelial-like” seen in the liver, spleen, bone marrow, large intestine, skin and the adventitia of blood vessels. In 1933 Siwe [38] described a 16 month old child with a 3 month history of fever, hepatosplenomegaly, lymphadenopathy and destruction of bone. At autopsy, proliferation of the cells that were interpreted as histiocytes, reticulum cells and endothelial cells was noted. Siwe then described five cases from the literature. including the original case described by Letterer, and concluded that these comprised a single clinical entity. By this time the terms “reticulosis” and “retichad been coined. By 1936 uloendotheliosis” “Letterer-Siwe disease” was an established entity [39] with the following features: (1) occurrence in infancy, (2) hepatosplenomegaly. (3) lymphadenopathy, (4) bleeding diathesis. (5) tumors of bone, (6) generalized hyperplasia of nonlipid-stor-

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ing macrophages in many organs but prominently in skin, and (7) rapidly fatal downhill course. A number of investigators contributed cases (and new nomenclature) that more or less matched the original descriptions [40]. In general, the pathologic findings in these cases resembled those in the well differentiated form of reticulum cell sarcoma. In 1940 Wallgren [41] suggested that there were cases that were intermediate in character between Letterer-Siwe disease and other diseases with more localized, nonlipid, hissuch as Hand-Schiillertiocytic proliferation, Christian disease. A number of other investigators began to classify Letterer-Siwe disease, HandSchuller-Christian disease and eosinophilic granuloma of bone as variants of a single disease entity [42-441. In 1953 Lichtenstein [44] coined the term histiocytosis X to designate these diseases as a single nosologic category. This concept, however, has not received universal acceptance [40,45]. Most reports of Letterer-Siwe disease have dated the onset from infancy [39]. Congenital forms have been described [46,47]. The disease occurs in blacks and Caucasians and is with rare exception not familial [48,49]. Few patients live beyond the first few years of childhood; most die from complications such as bleeding or infection. The disease is not uniformly fatal, however. Lahey [50] reported a mortality rate of 70 per cent in children under the age of six months and concluded that the younger the child at the onset of the disease, the worse the prognosis. The major cytologic feature of Letterer-Siwe disease is the proliferation of moderately differentiated histiocytes (Figure 7). A resemblance to the well differentiated form of reticulum cell sarcoma is apparent. The cells generally have abundant acidophilic cytoplasm and ovoid or kidneyshaped nuclei with fine chromatin. The cytoplasm may be vacuolated or rarely foamy and may contain phagocytized inclusions and hemosiderin [51]. The possibility of a relationship between Letterer-Siwe disease and other less differentiated histiocytic proliferative disorders is suggested by the report of an illness which began as LettererSiwe disease and terminated in monocytic leukemia [52]. Histiocytic Medullary Reticulosis. The term histiocytic medullary reticulosis was originally used by Robb-Smith in 1938 [53] and further amplified by Scott and Robb-Smith in 1939 [54]. These investigators classified malignant lymphomas on the basis of anatomic sites within the lymph node and predominant cell type. They observed four patients whom they considered to have a unique

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form of lymphoma with focal proliferation of histiocytes within the medullary portion of lymph node, hence the rather long and cumbersome name of histiocytic medullary reticulosis. They, as well as subsequent workers, believed that this was a distinctive disorder that could be differentiated from monocytic leukemia on the basis of absence of peripheral blood involvement and prominent erythrophagocytosis by the histiocytes. In fact, neither of these features is unique to those cases classified as histiocytic medullary reticulosis. Blood and bone marrow involvement occurs in patients with otherwise typical features of histiocytic medullary reticulosis [55], and erythrophagocytosis may be a feature of both reticulum cell sarcoma and monocytic leukemia. It is likely that histiocytic medullary reticulosis is merely a variant of the well differentiated form of reticulum cell sarcoma. Cytologic features: The cells in this disorder resemble moderately well differentiated histiocytes with a high proliferative capacity and well developed phagocytic activity (Figure 8). They most closely resemble the immature “A” macrophage. Clinical features: Histiocytic medullary reticulosis is a rapidly progressive and fatal disease with a median survival of less than 6 months; patients rarely survive more than 15 months after the appearance of symptoms [56-581. No sex predilection has been noted, and the disease has been observed in young adults and the aged [56]. Occurrence before 20 years of age is rare, however, and familial occurrence has been infrequently observed [59]. Prominent clinical features of this disease include (1) hepatosplenomegaly, (2) lymphadenopathy, (3) anemia, (4) fever and (5) pancytopenia.

Figure

trating ease.

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7. Moderately differentiated histiocytes the spleen of a patient with Letterer-Siwe

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the xanthomatoses with normal levels of serum lipids and cholesterol [71]. Subsequently, this disorder was regarded as a variant intermediate in severity and degree of cellular differentiation between Letterer-Siwe disease and eosinophilic granuloma of bone. Hand-Schuller-Christian disease came to be referred to as chronic disseminated histiocytosis X [ 721. Current opinion favors regarding this interesting disorder again as a separate nosologic entity with multiple, localized areas of histiocytic proliferation distinct from Letterer-Siwe disease [40]. Histologically. Hand-SchulCytologic features: Figure 8. Malignant histiocyte containing phagocytized normoblasts from the bone marrow of a patient with hlstiocytic medullary reticulosis (moderately differentkfted malignant histiocytosis).

Phagocytosis of blood elements by histiocytes may contribute to the anemia and pancytopenia [60-621 (Figure 8). Rarely, abnormal cells circulate in the blood, and the clinical picture may resemble acute leukemia [55,57,63]. Even more unusual is histiocytic proliferation within the bowel wall, producing symptoms including that of protein-losing enteropathy [55,64]. In all, over 50 cases of histiocytic medullary reticulosis have been reported [ 55-581. In general, treatment of this condition has been unsatisfactory, and only transient responses to corticosteroids and cytoxic agents have been reported. PROLIFERATIVE HISTIOCYTIC DISEASES WELL DIFFERENTIATED CELLS

WITH

Hand-SchtilHand-Schirller-Christian Disease. ler-Christian disease is a rare histiocytic disorder of childhood that, in the classic form, consists of the triad of defects of membranous bone, diabetes insipidus and exophthalmos. It is unusual, however, for all three abnormalities to be present in the same patient. In 1921 Hand [65] published a paper in which he reviewed the histories of two of his own patients and the four patients of Dr. Kay [66-681. in 1893, One of Hand’s patients, first described [69]. In was thought to have had tuberculosis 1928 Rowland [70] wrote a now classic description that provided a firm histologic basis for the clinical syndrome. He initiated an era of investigation of Hand-Schtiller-Christian disease as a possible metabolic storage disorder. However, by 1938 the old concept that this was a primary disorder of lipid metabolism was discarded, and HandSchljller-Christian disease was classified among

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ler-Christian disease is characterized by the focal accumulation within bone, and sometimes within skin and lungs, of masses of tissue macrophages some of which have a foamy appearance (Figure 9). These lesions may have a variable admixture of lymphocytes, plasma cells, neutrophils and eosinophils. Eosinophilic infiltration is not usually outstanding. Clinical manifestations: Although in the great majority of cases onset occurs before the age of four years, occasional reports document the onset of illness in early adult life [73]. In general, there has been a predominance of males over females in most series of cases 174.751. The classic triad of diabetes insipidus, exophthalmos and skull lesions in a young child occurs relatively rarely, perhaps in 1 patient in 10 [73]. Roentgenologically the common sites of proliferation of tumor cells include the calvarium, petrous and mastoid bones, mandible and sinuses. This pattern of distribution of lesions is similar to that of eosinophilic granuloma [75]. The defects in bone may be single or multiple and vary in size from barely perceptible to large, irregular, geographic

defects.

Histiocytes from Figure 9. with Hand-SchUller-Christian a foamy appearance.

a bone lesion in a patient disease. Some cells have

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In large series of patients with Hand-Schuller-Christian disease, about one-half have diabetes insipidus. The presumed mechanism is involvement of the posterior pituitary stalk or hypothalamus; associated destruction of the sella turcica is rare. Exophthalmos occurs in about one third of patients. It may be unilateral or bilateral and results from orbital infiltration with typical proliferative lesions. In one series, chronic otitis media was the most common complaint of children with HandSchuller-Christian disease [73]. Otitis media is often accompanied by roentgenologic changes in mastoid bone or the petrous portion of the temporal bone. Skin involvement occurs in about one third of patients. Because of the erythematous and scaling nature of the rash the initial diagnosis is often seborrheic dermatitis or eczema. When pulmonary involvement is present, it is usually restricted to the central and perihilar areas, with the periphery of the lung being clear. Although readily apparent roentgenologically, lung involvement only rarely gives rise to serious symptoms. However, extensive interstitial fibrosis with car pulmonale has been described [76]. and hepatosplenomegaly Lymphadenopathy may rarely be prominent manifestations of disease [40,77]. Other organs, such as the thyroid, may also be infiltrated [73]. Occurrence of disease early in childhood may be associated with moderate to severe stunting of growth. Course and prognosis: The course of HandSchuller-Christian disease is extremely variable. In general, the disease is chronic, often waxing and waning in severity. In at least one third, and probably over one half, of the patients the disease

10. Histiocytes and eosinophils cells) in a lesion of eosinophilic granuloma

Figure

(small, dark of bone.

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eventually “burns out,” and the lesions slowly heal and resolve. In a small fraction of patients (probably less than 15 per cent) the disease is fatal within months or a few years as a consequence of complications such as infection or, rarely, pulmonary insufficiency [40,73]. The disease rarely, if ever, makes the transition to a more fulminant type of histiocytic proliferation. The clinical pattern is reflected in the histologic changes in tissue. During an active phase of disease, rapidly developing lesions resemble inflammatory histiocytosis with a variable degree of eosinophilic infiltration. With a more chronic illness the histiocytes become lipid laden and fibrosis appears. Ultimately the lesions are densely fibrotic. Unifocal and Multifocal Eosinophilic Granuloma of Bone. In 1940 Otani and Ehrlich [78] and Lichtenstein and Jaffe [79] drew attention to a group of patients with solitary eosinophilic granuloma of bone “simulating primary neoplasm.” An example of one of the first patients described was an 11 year old boy with an isolated rib lesion that was treated with local radiation and excision. The patient did well postoperatively. In 1942 Green and Farber [80] published an important article discussing the nature of solitary eosinophilic granuloma pf bone. They introduced the idea that this disease entity was part of a spectrum encompassing Letterer-Siwe and HandSchuller-Christian disease. As already noted, this concept has not achieved universal acceptance. Clinical manifestations and prognosis: Eosinophilic granuloma of bone may be’unifocal, as well as multifocal. It is generally a disease of childhood, presenting in most patients before the age of 10 years. Cases with onset well into adult life are not rare, however. Presentation of disease is usually with bone pain, and the head, ribs, femur and pelvis are the most common sites of involvement. Systemic manifestations are rare with unifocal disease. With multifocal disease there is clear overlap in symptoms with Hand-Schiiller-Christian disease, and the two entities may be difficult to separate by either clinical or histologic criteria (Figure 10). Unifocal eosinophilic granuloma behaves almost invariably as a benign lesion and responds readily to excision or to radiation therapy. Extraosseous Eosinophilic Granulomas and Focal Histiocytosis. A body of literature has accumulated documenting the appearance of “eosinophilic granulomas” in various organs. Whether such lesions bear any relationship to similar granulomas in bone or whether they are neoplastic in nature is

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unknown. Probably the most common site of such disease is in the gastrointestinal tract, including

blasts at functional

the stomach and large and small bowel [81-831. These granulomas may be either focal or diffuse; the former are often polyploid.

(3) Neoplastic diseases of the histiocytic cells also embrace a wide spectrum, from disorders in which there is extensive proliferation of poorly differentiated cells (e.g., acute monocytic leukemia) to disorders in which there is limited and circumscribed proliferation of well differentiated cells. Clearly, there will be overlap among these diseases, depending on how “tightly” or “loosely” the neoplastic clone is regulated in its differentiation. (4) It is convenient to catalogue these diseases on the basis of cellular differentiation. The grouping proposed here is (a) disease with little cellular differentiation, including acute monocytic leukemia and undifferentiated reticulum cell sarcoma; (b) disease with a moderate degree of histiocytic differentiation, including chronic monocytic leukemia, well differentiated reticulum cell sarcoma, Letterer-Siwe disease and histiocytic medullary reticulosis; (c) disease with well differentiated histiocytes, including Hand-SchullerChristian disease, unifocal and multifocal eosinophilic granuloma of bone, and localized histiocytoma.

Eosinophilic granuloma of the lung is also well described [84-881. It is unlikely, however, that all the descriptions are concerned with a single disease entity. It is more likely that histiocytic and eosinophilic accumulation occurs in response to a multiplicity of stimuli. In some instances diffuse fibrosis occurs in association with eosinophilic granulomas. In addition to mixed eosinophilic and histiocytic granulomas, localized histiocytic tumors are recognized [89], as well as disseminated histiocytic lesions (multicentric reticulohistiocytosis) [90931. These entities are usually clinically benign. CONCLUSION

Opinion Regarding Nosology. In our opinion unifocal and multifocal eosinophilic granuloma of bone and Hand-Schuller-Christian disease are variants of the same basic disease process, manifested as localized or widespread lesiohs. These disorders are distinctly less “malignant” than Letterer-Siwe disease and reticulum cell sarcoma, and bear no definite relationship to them. Their cytologic hallmark is the differentiated histiocyte. Letterer-Siwe disease is clinically and cytologically similar to a childhood variant of differentiated reticulum cell sarcoma, with progressive and generalized proliferation of immature and moderately differentiated hlstiocytes; whereas unifocal and multifocal eosinophilic granulomas of bone behave like a “reactive” histiocytic lesion. Several points emerge from the foregoing discussion of malignant histiocytic diseases. (1) Cells of the monocyte-histiocyte series may become malignant, i.e., undergo a transformation that permits unrestrained proliferation. This concept is supported by recent observations of malignant transformation of animal macrophages induced by an oncogenic DNA virus. (2) Malignant cells of the monocyte-macrophage series may show a variable degree of differentiation, from relatively undifferentiated mono-

the one extreme to well differentiated histiocytes at the other extreme.

Although there is little dispute about the malignant nature of the disorders in groups a and b. it is not certain that the entities listed in group c are indeed neoplastic. The clinically chronic disorders characterized by proliferation of well differentiated histiocytes may represent a reactive response to an unidentified antigen or parasite. In this regard, they may be viewed as having more in common with sarcoidosis than with a true malignancy. We are now entering an era in which it is possible to evaluate malignant histiocytic disorders by several methods: standard morphology, histochemistry, and functional and proliferative assessment of isolated cells. Combining these approaches, it should be possible to classify the histiocytic disorder in a given patient in a manner that reflects the biologic properties of the proliferating cell. Such an approach has more to recommend it than the present attempts to force complex and varying constellations of clinical findings into rigid disease categories with uninformative and unpronounceable names.

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