Pediatric Annals

The Histiocytoses

Sanford Leiken, MD

Abstract

1. Lichtenstein. L. Histiocytosis-X (eosinophilic granuloma of bone, Letterer-Siwe disease and Schul I er-Ch risii an disease). Bone Joint Surg. 46 (1964), 76.

2. Newton. W-., and Hamoudi, A. Histiocytosis: A histologie classification with clinical correlation. Perspectives in Pediatrie Pathology 1 (1973), 251.

3. Leikin, S., et al Immunologie parameters in histiocytosis-X. Cancer 32 (1973), 796.

4. Weinberg, A.. and Rogers, L. Hepatosplenomegaly , pancytopenia and fever. J. Pediatr. 82 (1973), 879.

5. McClure, P., Strachan, P.. and Saunders, E, Hypofibrinogenemia and thrombocytopenia in familial hemophagocytic reticulosis. J. Pediatr. 85 (1974), 67.

6. Omenn, G. Familial reticuloendotheliosis with eosinophilia. W. Engl. J. Med. 273 (1965), 427.

7. Barth. R., et al. Rapidly fatal familial histiocytosis associated with eosinophilia and primary immunologie disease. Lancet 2 (1972), 503.

8. Miller, D. Familial reticuloendotheliosis: Concurrence of disease in five siblings. Pediatrics. 38 (1966), 986.

9. Falfetta, J., et al. A fatal X-linked recessive reticuloendothelial syndrome with hyperglobulinemia. J. Pediatr. 83 (1973), V 549.

10. FaIk, W., and Gellei, B. Familial occurrence of Letterer-Siwe disease. Acia Paediatr. 46 (1957), 471.

11 . Bierman, H., et al. The ameliorative effect of antibiotics on non-lipid reticuloendotheliosis in identical twins. J. Pediatr. 40 (1952). 269.

12. Schoeck, V., Peterson. R., and Good, RFamilial occurrence of Letterer-Siwe disease. Pediatrics 32 (1963), 105.

13. Glass, A., and Miller, R. U.S. mortality from Letterer-Siwe disease, 1960-1964. Pediatrics 42 (1968), 364.

14. J u berg, R.. Kloepfer, H., and Oberman, H. Genetic determination of acute disseminated histiocytosis-X (Letterer-Siwe syndrome). Pediatrics 45 (1970), 753.

15. Rappaport, H, Tumors of the Hematopoietic System. Washington, D. C, : Armed Forces institute of Pathology. 1966.

16. Oberman, H. ldtopathic histiocytosis. Pediatrics 28 (1961). 307.

17. Lahey, M. Prognosis in reticuloendotheliosis in children. J. Pediatr. 60 (1962), 664,

18. Lucaya, J. Histiocytosis-X. Amer. J. Dis. Child. 121 (1971), 289.

19. Avioli, L,, Lasersohn, J., and LoPresti, J. Histiocytosis-X (Schuller-Christian disease): A clinico-pathological survey, review of ten patients and results of prednisone therapy. Medicine 42 (1963). 119,

20. Lahey, M. Comparison of three treatment regimens in histiocytosis-X in children (abstract). Houston, Tex.: Proceedings of the 10th International Cancer Congress. 1970.

21. Starling, K., et al. Therapy of histiocytosis-X with vincristine, vinblastine and cyclophosphamide. Amer. J. Dis. Child. 123 (1972), 105.

22 Komp, D,. et al. For the Southwest Oncology Group. Combination chemotherapy in histiocytosis-X (abstract). Chicago : Proceedings of lhe American Society of Hematology, 1973.

23. Jones. B. For Acute Leukemia Group B. Chemotherapy of reticuloendotheliosis. Cancer Chemother. Rep. 57 (1973), 110.

24. Starling, K., and Fern bach, D. Histiocytosis-X. In Sutow, W., Vietti, T., and Fernbach, D. (eds,), Clinical Pediatrie Oncology. St. Louis: C.V. Mosby Company, 1973.

25. Komp, D., et al. For Southwest Cancer Chemotherapy Study Group (abstract). Atlantic City, N.J. : Proceedings of the American Association (or Cancer Research, 1973.

TABLE 1

CLASSIFICATION OF THE HISTIOCYTOSES

TABLE 2

CLINICAL MANIFESTATIONS OF HISTlOCYTOSIS-X

TABLE 3

DRUGS ACTIVE IN MALIGNANT AND BENIGN HISTIOCYTOSIS-X…

INTRODUCTION

The histiocytoses are a group of diseases characterized by the infiltration or proliferation of histiocytic cells within the tissues of the body. A number of other disorders closely resemble the histiocytoses from a clinical or pathologic standpoint but are not usually included in this group. These include Chediak-Higashi disease, the chronic granulomatous diseases, leukemia, lymphoma, and infections in which a secondary histiocytic proliferation may be seen in the tissues.

Table 1 lists the disorders that constitute the histiocytoses. At this time it is difficult to definitively separate these diseases from a clinical-pathologic viewpoint. Thus, the classification provided should be considered arbitrary and tentative, subject to revision as we learn more about these disorders, particularly as to their cause or causes. However, certain differentiating characteristics that help in distinguishing them have been identified. They are age at onset, inheritance, clinical presentation, rapidity of the course of the disease, sites of affliction, histopathology, evidence of immunodeficiency, and response to treatment. A number of these features will be reviewed.

Table

TABLE 1CLASSIFICATION OF THE HISTIOCYTOSES

TABLE 1

CLASSIFICATION OF THE HISTIOCYTOSES

Figura 1. SkIn showing infiltrates of malignant histiocytosls-X in the dermal papillae and superficial dermis associated with infiltration and crusting of epidermis. Epidermal separation is artifactitlous. (Hematoxylin and eosin, X120.)

Figura 1. SkIn showing infiltrates of malignant histiocytosls-X in the dermal papillae and superficial dermis associated with infiltration and crusting of epidermis. Epidermal separation is artifactitlous. (Hematoxylin and eosin, X120.)

HISTIOCYTOSIS-X

Histiocytosis-X is the most common form of the various histiocy toses. It consists of three disorders: disseminated acute and disseminated chronic disease and the solitary form. Lichtenstein1 has grouped all three under the term histiocy tosis-X, referring to the basic underlying proliferation in all three diseases and to the indefinite cause. These disorders can occur at any age but are most often found in infants less than a year of age and have even been reported in neonates.

The disseminated forms. The disseminated forms can affect skin (Figures 1, 2, and 3), lymph nodes (Figure 4), spleen, bone (Figure 5), bone marrow, lung, liver, and intestine. Since it may affect various combinations of organs, the clinical findings are variable. Table 2 lists the clinical findings in histiocytosis-X. Although exceptions occur, those patients with only bone lesions are likely to have low-grade fever, bone pain, and soft-tissue swelling over or around the bone lesions without other evidence of the disease, whereas those with visceral involvement may have any combination of manifestations.

The characteristic histologie alteration consists of a systemic proliferation of differentiated histiocytes. Mitoses are rare or absent. Multinucleated histiocytes are present. Newton and Hamoudi2 have divided their cases into two distinct histopathologic types -one with a malignant behavior, the other with a benign course. The malignant type showed a diffuse distribution of histiocytes within the reticuloendothelial system, with an absence of giant cells and eosinophils and no necrosis present. The histiocytes in this type were large, with abundant weak basophilic cytoplasm and relatively distinct cell membranes. Their nuclei had folded invaginateci nuclear membranes and dark, basophilic, clumped chromatin. The benign type had a focal arrangement of the histiocytes, with giant cells, eosinophils, and necrosis present. The histiocytes found in this type were usually polygonal with indistinct membranes, the cells forming a syncytial appearance. The malignant type was found only in patients less than two years of age, while the majority of patients with the benign form were more than two years of age at the time of onset of the disease. Although the benign type of histopathology was more often found in osseous lesions, a similar picture was found in nonosseous tissue, indicating that the changes did not represent a specific local tissue reaction in bone.

Figur· 2. Detail of dermal Infiltrate shown in Figure 1 . The predominant cells are discrete histiocytes mixed with a few lymphocytes and occasional neutrophlls. The histtocytic nuclei are oval to indented and show no pleomorphism or mitosis. (Hematoxylin and eosin, X480.)

Figur· 2. Detail of dermal Infiltrate shown in Figure 1 . The predominant cells are discrete histiocytes mixed with a few lymphocytes and occasional neutrophlls. The histtocytic nuclei are oval to indented and show no pleomorphism or mitosis. (Hematoxylin and eosin, X480.)

Figure 3. The skin eruption of histiocytosls-X with papular, crusting seborrhelc, and hwno'trhagic lesions.

Figure 3. The skin eruption of histiocytosls-X with papular, crusting seborrhelc, and hwno'trhagic lesions.

Figure 4. Lymph node showing histtocytic infiltrate of malignant hlsttocytosls-X In subscapular sinus and sinusoids. (Hematoxylin arid eosin. X480.)

Figure 4. Lymph node showing histtocytic infiltrate of malignant hlsttocytosls-X In subscapular sinus and sinusoids. (Hematoxylin arid eosin. X480.)

Figure 5. Roentgenogram of the skull of a patient with histlocytosis-X showing typical osteolytic lesions.

Figure 5. Roentgenogram of the skull of a patient with histlocytosis-X showing typical osteolytic lesions.

Table

TABLE 2CLINICAL MANIFESTATIONS OF HISTlOCYTOSIS-X

TABLE 2

CLINICAL MANIFESTATIONS OF HISTlOCYTOSIS-X

The malignant variety described by Newton and Hamoudi conforms with what others have designated LettererSi we disease. This disorder usually shows widespread organ system involvement (skin, lymph nodes, liver, spleen, bone marrow, and lungs) and a rapid downhill course with a high mortality.

In contrast, the benign lesions invade only focal areas of the reticuloendothelial system, with one or many sites of bone and/or soft-tissue involvement. The clinical course of patients with this type of histopathology is one of a self-Hmited chronic process with an end-stage residuum ranging from no clinical sequelae to death due to scarring effects of earlier, active disease (Figures 6 and 7). Otitis media, hearing loss, exophthalmos, diabetes insipidus, gingival lesions, growth retardation, and osteolytic lesions of the skull, ribs and scapula, upper and lower extremities, pelvis, and spinal column are more common in the benign than the malignant form.

It should be remembered, however, that the malignant and benign types are not clearly separable, since some patients who are classified as benign on a histopathologic basis exhibit a clinical similarity to patients with the malignant histopathology.

The solitary form. Histiocytosis-X at onset may affect bone only. The histologie appearance is that of the benign type. When it appears as an isolated lesion, it is designated eosinophilic granuloma. Additional lesions may develop in the bone or parenchymatous organs of these patients even when the initial involvement is a solitary bone lesion. Although uncommon, solitary lesions of histiocytosis-X can also occur in nonosseous organs, as in lung or lymph node.

There are no clinical laboratory findings that are specific for histiocytosisX. The abnormalities that occur are the results of the proliferative and invasive nature of the disease, hypersplenism, or superimposed infection. Anemia may result from decreased red blood cell formation, blood loss (secondary to thrombocytopenia), and/or hypersplenism. Leukocytosis, increased reticulocytosis, and thrombocytopenia may be present. Hypoproteinemia may occur as a result of decreased protein synthesis stemming from histiocytic impairment of the liver and/or proteinlosing enteropathy secondary to diffuse histiocytic impairment of the gastrointestinal tract, Hyperbilirubinemia and jaundice may occur secondary to hemolysis and/or liver dysfunction.

A question in terms of characterization and etiology of histiocytosis-X concerns the presence or absence of immunologie abnormalities. My associates and I3 have recently performed a battery of immunologie studies in patients with histiocytosis-X. In most of the patients, delayed hypersensitivity, lymphocyte blastogenesis to mitogens and allogeneic cells, bactericidal action, and leukocyte nitroblue tetrozolium dye reduction were found to be within normal limits. One of six infants with acute disseminated disease and one of seven with the chronic disseminated form could not be sensitized to dinitrofluorobenzene. The lymphocytes from two infants were hyporeactive to mitogen stimulation. These reverted to normal after chemotherapy was instituted. Decreased immunoglobulin levels were found in two infants, but several other patients exhibited elevated immunoglobulin levels. In general, the immunologie abnormalities lessened following chemotherapy. No evidence was found of a combined immunodeficiency disorder in patients with either the acute or the chronic form of histiocytosis-X. It was concluded from these studies that the immunologie abnormalities that occurred were secondary to malignant cell replacement rather than an underlying cause of the disease.

Figure ß. Exophthalmos associated with histiocytosis-X. At diagnosis this boy had mild swelling of the right eyelid, seborrheic dermatitis, lymphadenopatny. and hepatosplenomegaly. He was placed on chemotherapy and showed some improvement, but right exophthalmos developed. X-ray therapy was given to the orbit, but the exophthalmos worsened .

Figure ß. Exophthalmos associated with histiocytosis-X. At diagnosis this boy had mild swelling of the right eyelid, seborrheic dermatitis, lymphadenopatny. and hepatosplenomegaly. He was placed on chemotherapy and showed some improvement, but right exophthalmos developed. X-ray therapy was given to the orbit, but the exophthalmos worsened .

The diagnosis of histiocytosis-X should always be based on histologie examination of involved tissue. Newton and Hamoudi felt that skin biopsies were not helpful in differentiating between the malignant and benign forms of the disease. In addition, early in the disease the skin lesions may show only nonspecific changes. Therefore, to increase the probability of obtaining a definitive diagnosis and to better characterize the disease, a biopsy from a site in addition to skin should be obtained whenever possible. Further, it has been my experience that bone marrow aspiration is not very helpful in establishing the diagnosis of histiocytosis-X. Absence of increased histiocytes in the bone marrow does not rule out the possibility of this disease.

THE FAMILIAL HISTIOCYTOSES

Three histiocytic disorders are categorized as familial, based on the occurrence of the disease in several family members and in twins. The salient common differentiating features of these diseases will be described and compared with the histiocytic disorders discussed previously.

Familial hemophagocytic reticulosis. Familial hemophagocytic reticulosis (familial lymphohistiocytosis) was first described by Farquhar and Claireaux in 1952. 4 It has been discussed under various names by a number of authors (Table 1), indicating the confusion surrounding the nosology of this disorder. The disease has been described in siblings and in first cousins and appears to be inherited as a Mendelian recessive. Pathologically it is characterized by infiltration of histiocytes and lymphoid cells within the liver, spleen, lymph nodes, and bone marrow. Lymphoblastlike cells with pyknotic nuclei are also seen in variable numbers, but neutrophils, plasma cells, and evidence of necrosis, hemorrhage, and exudation of fibrin are usually lacking. The mixed cellular infiltrate is associated with erythrophagocytosis, which makes it difficult to differentiate pathologically from histiocytic medullary reticulosis, in which erythrophagocytosis can also be seen (see below). Involvement of the brain with extensive meningeal and perivascular cellular infiltration is a striking finding in many of the cases. In addition, the posterior lobes of the pituitary gland may be destroyed by this cellular infiltration.

Figure 7. Skull x-ray of patient in Figure 6 showing orbital sclerosis, which has occurred since onset of his disease and has aggravated the exophthalmos.

Figure 7. Skull x-ray of patient in Figure 6 showing orbital sclerosis, which has occurred since onset of his disease and has aggravated the exophthalmos.

Clinically familial hemophagocytic lymphohistiocytosis is an acute illness with fever, anemia, leukopenia, thrombocytopenia, hepatosplenomegaly, pneumonitis, and meningoencephalitis. Certain similarities between familial hemophagocytic lymphohistiocytosis and the acute disseminated form of histiocytosis-X can be recognized. However, the two entities differ in several important features. In familial lymphohistiocytosis (1) the typical skin features of histiocytosis-X are absent, (2) erythrophagocytosis, although nonspecific, is a prominent feature, (3) impairment of the central nervous system is frequent, and (4) the tissue infiltrates, addition to containing erythrophahistiocytes, often contain admixtures of immature, mononuclear cells resembling lymphoblasts. This last feature perhaps best serves histologically to separate the disease from acute disseminated histiocytosis-X.

Recently a coagulation disorder peculiar to familial lymphohistiocytosis has been reported in association with thrombocytopenia.5 Although reduced fibrinogen levels were found, they did not seem to be due to disseminated intravascular coagulation. Additional features that seem to be more common in familial hemophagocytic lymphohistiocytosis than in histiocytosis-X include minimal peripheral lymphadenopathy, the presence of atypical lymphocytes in the peripheral blood, the occurrence of pancytopenia, and the presence of histiocytes with erythrophagocytosis in the bone marrow.

Histiocytosis associated with eosinophilia and primary immunologie deficiency. In 1965 Omenn6 described an extraordinary kindred in which 12 infants in six sibships died from disease of the reticuloendothelial system with eosinophilia. The pattern of incidence and the finding of parental consanguinity were consistent with an autosomal-recessive transmission. The characteristics of the syndrome are onset in the early days or weeks of life; an erythematous eruption; mild diarrhea; secondary infections of the skin, ears, and lungs; hypogammaglobulinemia; marked leukocytosis with eosinophilia; generalized lymphadenopathy; hepatosplenomegaly; mild anemia; failure to gain weight; and a course unresponsive to therapy. According to the case report of one of the affected infants, biopsy of the skin showed infiltration by eosinophils and mononuclear cells in the corium, with large collections of similar cells surrounding blood vessels and skin appendages. At autopsy a diffuse, intense infiltration with eosinophils was seen in the spleen and lymph nodes. The lungs demonstrated bilateral extensive interstitial pneumonitis characteristic of Pneumocystis carinii.

Recently Barth and his associates7 reported two new cases from this kindred; both patients had eosinophiíia, and hypogammaglobulinemia was present in one. The authors described a profound depletion or absence of lymphocytes in the thymus, lymph nodes, spleen, and lamina propria of the gut. These findings suggest a deficiency of both thymus-dependent (T cell) and thymus-independent (B cell) lymphocytes. Because of the presence of pronounced histiocytosis in the lymph nodes, spleen, bone marrow, and gastrointestinal tract, it was suggested that these findings might represent a graftversus-host reaction in children with immunodeficiency disease. However, the authors felt that the weight of the evidence indicated that this disease is a specific form of malignant histiocytosis.

Hyperglobulinemic reticuloendotheliosis. Two families have been reported with members having reticuloendotheliosis and hyperglobulinemia as prominent aspects of their disease. In other important features, however, the disease in these families differed. In the family described by Miller, ' a complete sibship of five sisters (four zygotes) was affected. Clinically, the early onset of failure to thrive, eczema, and recurrent infections were prominent. These symptoms were associated with lymphadenopathy, hepatosplenomegaly, pulmonary infiltration, and bone marrow plasmacytic and eosinophilic hyperplasia. Terminally, there was pancytopenia, hypergammaglobulinemia, bacteremia, and candidiasis. Based on immunoelectrophoretic examination, serum IgG, IgA, and IgM were all increased. At autopsy there was a diffuse mononuclear reticulum cell infiltration in the lungs, liver, spleen, lymph nodes, bone marrow, gastrointestinal and genitourinary tracts, and central nervous system. The lymphoid architecture was obliterated, and increased numbers of plasmacytes were present.

Recently Palletta et al.9 reported an unusual Latin-American family in which 17 preschool-age boys in two generations died following a brief illness characterized by fever, hepatosplenomegaly, lymph node enlargement, purpura, hyperglobulinemia, and anemia. All were related through their mothers, and the disorder occurred in the pattern of an X-linked recessive trait. Examination of tissues from 13 patients revealed a mononuclear cell infiltrate in the liver (portal areas), lymph nodes, spleen, bone marrow, lungs, thymus, kidneys, meninges, brain, adrenals, heart, intestines and testes, and, in one case, parathyroids. Mature plasma cells were also seen in most of the affected tissues, most prominently in the bone marrow. Serum globulins were moderately elevated in about half of the surviving family members, both male and female. Eight had gamma globulin levels greater than 2.0 gm. per 100 ml. in a polyclonal distribution. Fourteen had elevated levels of IgG, 21 had elevated IgM, and 13 had elevated IgA. Serum immunoelectrophoresis revealed an unusual protein band in the betagamma region in 10 of the 43 family members. Four of these 10 were found to have a similar protein in their urine. Nine additional family members had this finding in urine alone.

Other reports have been made of patients with disseminated histiocytic disease and a familial occurrence. In one consanguinity had been present,10 and in two others the disease was found in twins.11'12 These reports of the occurrence of histiocytosis in families have been labeled familial Letterer-Siwe disease. Glass and Miller13 reported on mortality in the United States from "Letterer-Siwe disease" from 1960 to 1964. In the five-year period 270 deaths were attributed to that disease, with peak mortality under one year of age. Five pairs of siblings, including one set of twins, died with "Letterer-Siwe disease" during that period. The authors estimated that, based on these facts, the risk of "Letterer- S iwe disease" in the siblings of a child with that ailment is about 1,400 times the normal risk.

The hypothesis that histiocytosis-X is genetically determined is supported by the careful analysis performed by Juberg, Kloepfer, and Oberman.14 From their study it was concluded that at least some instances of histiocytosis result from a single autosomal-recessive gene with slightly reduced penetrance. In light of the fact that several familial histiocytic entities distinct from histiocytosis-X have now been characterized, it would be unwise to draw the broad conclusion that all cases of histiocytosis-X are genetically determined. Some of the previously described cases may have been instances of familial histiocytic diseases other than histiocytosis-X. In the future, it will be necessary to carefully analyze all patients with histiocytosis from a clinical, pathologic, and genetic aspect to determine the exact incidence of familial histiocytosis-X.

Figura 8. Phagocytosis of red cells and platelets in a histiocyte (upper right) of the bone marrow from a patient with malignant histiocytosis. (Weight's stain, X1 ,200.)

Figura 8. Phagocytosis of red cells and platelets in a histiocyte (upper right) of the bone marrow from a patient with malignant histiocytosis. (Weight's stain, X1 ,200.)

MALIGNANT HISTIOCYTOSIS

Malignant histiocytosis is a systemic, progressive, invasive proliferation of atypical histiocytes and their precursors. 15 This rare disease occurs in adults and in children. The onset is insidious, and the course is usually acute or subacute and febrile.

In malignant histiocytosis there are multifocal proliferations of histiocytes and their precursors in almost every organ of the body, particularly in the skin, spleen, liver, and lymph nodes. The characteristics of the histiocytes found in this disorder consist of features of an aggressive malignant growth, variation in nuclear size and shape, hyperchromatism, irregular distribution of chromatin, mitoses, and large prominent nucleoli. The neoplastic histiocytes may contain phagocytized material, including erythrocytes (Figure 8). In some instances the histologie picture is pleomorphic, binucleated giant cells resembling Reed-Sternberg cells.

Two clinical forms of malignant histiocytosis have been recognized: (1) the cutaneous form, in which a nodular skin eruption is an early manifestation, and 2} the visceral form, which is characterized by early involvement of the hematopoietic organs. In the latter, enlargements of the spleen and liver and generalized enlargement of the lymph nodes are prominent features. In both clinical forms anemia, leukopenia, and thrombocytopenia are common. The neoplastic histiocytes and their immature precursors may be found in bone marrow aspirates and occasionally in the blood. This contrasts with histiocytosis-X, in which it is unusual to find histiocytic impairment of the marrow except in the terminal stage of the disease. Jaundice has been reported as a characteristic clinical feature of so-called histiocytic medullary reticulosis, which is a variant of malignant histiocytosis. The jaundice is probably caused by hemolysis.

The duration of the illness varies from a few months to several years. Although instances of long survival have occasionally been reported, the disease usually follows a rapidly progressive course. In infants and young children the clinical aspects of malignant histiocytosis may resemble disseminated histiocytosis-X. Morphologically the two diseases differ, however, by the unequivocally malignant character of the histiocytic proliferation in malignant histiocytosis, contrasted to the differentiated histiocytes found in histiocytosis-X.

The following sections deal with the staging, prognosis, treatment, and survival of the his tiocy toses. The greatest bulk of experience and results of treatment have been with histiocytosis-X. Therefore, the ensuing statements will apply specifically to that disease and only in a general way to the familial and malignant histiocy toses.

PROGNOSIS AND STAGING

In most surveys, a consistent finding has been the relationship of age at onset of histiocytosis to outcome. The greatest mortality exists in infants diagnosed when less than six months of age. After that age mortality drops significantly; by the age of two to three years, it is negligible. On the other hand, the greatest morbidity exists in those with a later age of onset - i.e., after one to two years of age. In these patients there is a greater incidence of growth retardation, diabetes insipidus, and deafness as late sequelae. Sex may play a role in the outcome of the disease, since more deaths have been reported in girls.

Oberman16 has pointed out that rapidity of the progression of the disease is an accurate guide to the ultimate outcome. Since this may require a period of observation of several months, however, it is not very helpful for prognostication at the time of diagnosis.

Determination of the extent of the disease at diagnosis is valuable for predictive purposes. Lahey17 has devised a system of scoring based on the clinical and laboratory examination of the patient. A score of 1 is given for evidence of involvement of skin, liver, spleen, lungs, or pituitary. Involvement of the skeleton or hematopoietic system is evidenced by significant anemia (hemoglobin less than 10.5 gm./lOO ml.) and/or abnormality in the leukocyte count (fewer than 3,000 or greater than 14,000 white cells/cu. mm.) or thrombocytopenia (fewer than 200,000 pîatelets/cu. mm.) and/or hemorrhagic cutaneous lesions. Using this scoring system, he and others have found good correlation between it and mortality; i.e., the higher the score, the poorer the outlook.

A staging method employed by Lucaya18 was that of Oberman's as modified by Ekert and Campbell. Group A comprised patients in whom the disease was confined to a single bone; in group B the disease affected more than one bone; in group C the disease involved bone and soft tissue; and in group D soft tissues only were involved. Lucaya found that all fatal cases belonged to either group C (mortality 41 per cent) or group D (mortality 50 per cent). Among the survivors such sequelae as growth retardation and hearing loss were almost equally distributed among patients belonging to group A (20 per cent), group C (29 per cent), and group D (29 per cent). No deaths occurred beyond three years after the time of diagnosis.

MANAGEMENTAND TREATMENT

When confronted with a patient with histologically proven histiocytosis it is important, for prognostic and treatment purposes, to determine the degree of disease spread. This will require the following studies for complete evaluation: (1) complete history, including intensive search for other affected family members; (2) careful physical examination with particular emphasis on looking for exophthalmos, skin rash and/or purpura, lymphadenopathy, and hepatosplenomegaly; (3) chest xray; (4) complete blood count, reticulocyte and platelet counts; (5) bone marrow examination; (6) a battery of liver function tests, including bilirubin and total protein and serum protein electrophoresis; and (7) immunologie evaluation, including skin tests for delayed hypersensitivity and immunoglobulin determinations.

Treatment will depend on the findings. The solitary form (eosinophiiic granuloma of bone) can usually be managed by local measures - i.e., curettage and/or radiotherapy. The recommended dose of radiotherapy has not been clearly established; however, in most instances the total tumor dose varies from 500 to 1,500 rads. Chemotherapy is not usually required.

Although remissions occur spontaneously or after antibiotic therapy in histiocytosis-X, the great majority of responses have occurred in association with chemotherapy. Table 3 lists the drugs and drug combinations that have shown activity as remission inducers in chemotherapy trials of disseminated histiocytosis-X. Other single agents that have been reported to be active in selected cases of histiocytosis include nitrogen mustard, 6-mercaptopurine, and daunomycin. It is interesting that the active agents have differing mechanisms of action. The greatest incidence of response has been with corticosteroids; however, the criteria for response used in the analysis of patients treated with the corticosteroide19 were not as rigid as those for the other agents reported, so strict comparison between them is not possible. No single drug or drug combination has yet emerged as the choice method of treatment for remission induction or as a remission maintainer. Unlike the situation with leukemia, it appears that combination chemotherapy does not increase the response rate in this disease.

The results of a recent study by Children's Cancer Study Group A20 showed patients who were resistant to one of three treatment regimens (prednisone plus vinblastine, prednisone plus 6mercaptopurine, and vinblastine alone) usually did not respond to a different regimen. On the other hand, a number of remissions could be obtained in responsive patients. The Southwest Oncology Group also found that remissions occurred with single agents after different prior therapy.21

Table

TABLE 3DRUGS ACTIVE IN MALIGNANT AND BENIGN HISTIOCYTOSIS-X

TABLE 3

DRUGS ACTIVE IN MALIGNANT AND BENIGN HISTIOCYTOSIS-X

In the study reported by Children's Cancer Study Group A,20 patients less than two years of age were more responsive to the treatment regimens mentioned above than were older children. The Southwest Oncology noted that in children more than one year of age the remission rate was better for combination chemotherapy (prednisone, vincristine, and cyclophosphamide) than for vincristine or cyclophosphamide alone. Children less than one year of age receiving combination chemotherapy did markedly worse than similar children receiving single agents. It was suggested that the latter results may be related to increased immunosuppression and/or bone marrow suppression. Since the number of patients in the latter study was small, however, a broad conclusion cannot be made concerning these age-related differences. It appears that further trials of drugs, taking into consideration age and stage, will be helpful in understanding the disease and in improving the treatment. Relevant to this, the Children's Cancer Study Group is now performing a prospective study to determine whether single or combination chemotherapy is more effective for remission induction in the malignant and benign forms of histiocytosis-X with and without organ dysfunction.

The response to chemotherapy may be slow. When it occurs gradually, improvement may be associated with reactivation of old lesions or new areas of involvement. These minor exacerbations should not be considered as drug failure unless there is progressive systemic deterioration or rapid progression of disease.

Although numerous remissions can be obtained in responsive patients, it appears that some type of maintenance therapy is preferable to attempting to induce remissions. This impression is supported by the results of a recent study by Acute Leukemia Group B,23 which demonstrated that maintenance therapy improved the duration of remission. The duration of maintenance therapy has not been established but should be at least one to two years. Prolonged observation is necessary after remission is established, since a recrudescence has been reported as late as 13 years after the disease had been quiescent.

It is important to recognize that all methods of support for cancer patients should be used in these patients. These include the early detection and treatment of infections with appropriate antibiotics and the use of red blood cell and platelet transfusions. In addition, vasopressin tannate (Pitressin®) is helpful in the care of patients with diabetes insipidus. Splenectomy has been useful in those cases where hypersplenism is thought to play a role in the cytopenias that occur in this disease. Even when the disease is disseminated, it should be remembered that local x-ray treatment to affected areas may be most helpful in relieving pain and pressure necrosis.

OUTLOOK

In the past, a pessimistic attitude prevailed concerning the eventual outcome of patients with histiocytosis. This was especially true for those patients with the malignant and familial forms of the disease. It has recently become apparent, however, thai chemotherapy and present-day supportive care have modified the prognosis of histiocytosis. In 1962 Lahey17 reported a mortality of 70 per cent in patients less than six months of age, 50 per cent in patients six to 12 months of age, and 40 per cent for patients 12 to 24 months of age. In the recent Children's Cancer Study Group A report cited abovewhich employed either vinblastine alone, prednisone plus vinblastine, or prednisone plus 6-mercaptopurine - the mortality was found to be 40 per cent in patients less than six months of age, 30 per cent in patients six to 12 months of age, and 20 per cent for patients 12 to 24 months of age. This improved survival gives hope that additional improvements in classification of these diseases, better staging, and the application of drug and other therapies may yield better results than heretofore obtained.

SUMMARY

The histiocytoses consist of a group of diseases characterized by the presence in various tissues of differentiated or malignant histiocytes and other cell types. The common sites of invasion are the reticuloendothelial system, skin, bones, lungs, and pituitary gland. The clinical manifestations of the histiocytoses depend on the degree and site of tissue involvement and/or the scarring that may occur because of necrosis of parenchymatous tissue from tumor invasion. Appropriate management of these patients requires an accurate histiopathologic diagnosis and assessment of the extent of the disease. X-ray and chemotherapy and supportive care may be helpful in obtaining a remission in these patients and in some instances establishing a cure.

BIBLIOGRAPHY

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TABLE 1

CLASSIFICATION OF THE HISTIOCYTOSES

TABLE 2

CLINICAL MANIFESTATIONS OF HISTlOCYTOSIS-X

TABLE 3

DRUGS ACTIVE IN MALIGNANT AND BENIGN HISTIOCYTOSIS-X

10.3928/0090-4481-19750201-06

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