Eosinophilic granuloma of bone, HandSchüller-Christian disease, and Letterer-Siwe disease are syndromes resulting from a common histologic lesion that can assume a variety of clinical manifestations and a wide spectrum of severity. The clinical manifestations range from a benign single bone defect to a widespread fatal disease. It is imperative to recognize not only the pathology but also the prognostic implications of each stage in the clinical presentation. The unification of the three syndromes under the term "histiocytosis X," while recognizing the common histology and its elusive etiology, does not help the clinician in deciding the therapeutic course to follow. This requires a thorough determination of the extent of the disease, its specific distribution, its behavior prior to diagnosis, and, no less important, the age of the patient at onset of the disease.
The major histologic feature is an infiltrate characterized by histiocytes and a variable proportion of eosinophils, at times mixed with plasma cells, neutrophils, or lymphocytes.1 The histiocytes may have a relatively small amount of pale reticular cytoplasm, may be large and vacuolated, may become multinucleated giant cells, or may accumulate cholesterol, leading to the formation of xanthomas in the presence of normal serum lipids and cholesterol (Figure 1).
Figure 1. Histopathology in histiocytosis. Mixed infiltrate of histiocytes and eosinophils, with formation of multinucleated giant cells (H and E stain, x 200).
The histiocytes lack specific features of malignancy that could help in differentiating them from normal histiocytes. Similarly, the eosinophils and the other cellular components of the infiltrate have no distinguishing features. This characteristic infiltrate may affect discrete areas, such as one single bone, or may diffusely involve skin, mucous membranes, lymph nodes, lungs, liver, spleen, and the central nervous system.
ETIOLOGY AND CLINICAL FEATURES
The etiology remains obscure. So far there has been no evidence that histiocytosis is due to an infectious agent, a metabolic abnormality, or a genetic defect. It does not appear to be a true neoplasm, although it responds to antineoplastic drugs and radiotherapy.
Sites of infiltration. Bone, skin, mucous membranes, and lymph nodes are the most common sites of infiltration. Deep-organ involvement (liver and spleen) occurs in the more severe forms of the disease. The central nervous system, the lungs, the bone marrow, and the intestinal mucosa may also be severely affected.
Bones. While asymptomatic bone lesions may remain undiagnosed for a long time, they eventually become evident because of pain in an extremity, pelvis, scapula, or spine. A skull defect may become apparent because of accidental palpation of a "hole" or a mass on the head. Asymmetry of the eyes and proptosis occur with mass lesions of the orbital bones; torticollis and splinting may be the first signs of a vertebral lesion. Sometimes the silent bone lesion does not become evident until a pathologic fracture occurs. Long bones and membranous bones are equally and randomly affected. The calvarium is very frequently involved, showing characteristic "punched out" lesions on x-rays (Figure 2).
Isolated osteolytic defects, usually of the multicystic variety, may be present in the long bones, giving the syndrome of "eosinophilic granuloma of bone" when there is no involvement of other organ systems. The vertebral bodies are often affected, with formation of "vertebra plana" and possible danger to the spinal cord. Entire ribs may be infiltrated, resulting in their disappearance on x-ray examination (Figure 3). Facial bones, especially the orbit and the alveolar bone of maxillae and mandible, are frequently affected; involvement of facial bones results in proptosis and painful "floating" teeth and sometimes leads to their extrusion (Figure 4). The mastoids may also become invaded, with possible damage to the facial nerve.
Skin. This is most often affected, especially in the younger patient. Neonatal histiocytosis may manifest itself as a generalized varicelliform eruption. In infancy, an unusually resistant "cradle cap" may prove to be the seborrhea-like dermatitis of histiocytosis. The most typical skin lesions consist of a fine, discrete, dry, scaly, petechial rash, axially distributed on the upper trunk anteriorly and posteriorly (Figure 5). The rash frequently appears on the face, the lower trunk, and the body folds. The scalp involvement may vary from a mild "dandruff to a weeping, matted, bleeding diffuse dermatitis (Figure 6).
Figure 2. Skull x-rays of a child with histiocytosis. Top: Note "punched-out" skull defects. Bottom: X-ray of same child is normal two years later.
The perianal region and the vulva may be subject to an erythematous itchy rash due to the histiocytosis infiltrate. In terminal stages of the diffuse disease it is not unusual to see infiltrates in the periungual tissues, wth abnormalities of the nails (Figure 7). Bright orange or tan skin xanthomas may appear in a random distribution (Figure 8). The ear canals may have a dry and scaly or a weeping dermatitis, providing media favoring superimposed infections. Smears from scrapings of these skin lesions usually show large numbers of typical histiocytes, which may help in the diagnosis.
Figura 3. Rib infiltration. Top: X-ray indicates rib is "absent," because of massive replacement by the histiocytosis infiltrate (arrow). Bottom: X-ray taken two years later of same patient, showing partial osseous reconstitution of rib previously "absent."
Figure 4. "Floating tooth" (arrow in x-ray at top) follows alveolar bone destruction in young child with histiocytosis. Bottom: Same patient has healthy gums and deciduous teeth one year later, folowing radiotherapy and chemotherapy. The upper right lateral incisor tooth had been extruded.
Mucous membranes. Hstiocytosis has a predilection for the gums, which become dark purple and hypertrophic. The gum infiltrates, along with the alveolar-bone invasion, contribute to the "floating" teeth and tooth buds and their eventual loss. The vulva, as mentioned earlier, can be infiltrated with an erythematous rash or may show a boggy, dark purple discoloration.
Lymph nodes. In some cases, lymph nodes may be the only site of invasion by histiocytosis, often with bilateral massive cervical involvement giving a "bull neck" appearance. In the absence of other signs of the disease, the lymph-node biopsy will establish the diagnosis by showing the characteristic infiltrate. Generalized or patchy adenopathy, usually not of massive size, accompanies the clinical picture, with multiple-organ involvement.
Central nervous system. Diabetes insipidus may be the first manifestation of histiocytosis, or it may develop after the diagnosis has been established from skin or bone lesions. Deficiency of growth-hormone release has also been described. The lack of antidiuretic hormone and absence of somatotropin commonly, but not always, coexist, while deficiency of other pituitary hormones is extremely rare.2 A hypothalamic lesion could explain the deficiency of both hormones, with sparing of other anterior pituitary hormones. Histiocytosis can also affect the cerebellum, with debilitating truncal ataxia and dysarthria. The pyramidal tracts and the cranial nerves can also be invaded.3
Figure 5. Skin involvement. Note axial distribution of the fine, scaly, petechial rash characteristic of histiocytosis.
Figure 6. Skin involvement. Scalp problems may range from a mild dandruff to the severe, weeping, crusted, hemorrhagic dermatitis shown here.
Figure 7. Nail abnormalities. Periungual infiltrates with nail disruption in an infant in the terminal stages of histiocytosis.
Figure 8. Xanthoma in a child with histiocytosis.
Lungs. Pulmonary involvement may either accompany other manifestations of the disease or precede them. It is usually asymptomatic in children. Pulmonary involvement is diagnosed by the radiologic appearance of the lungs, which show either a fine granular infiltration, punctate nodular lesions, or diffuse cystic changes. Lung biopsy demonstrates the characteristic histiocytosis infiltrate. Spontaneous pneumothorax, progressive respiratory failure, and cor pulmonale are possible complications, especially in adults.4
Liver and spleen. These organs are most often affected in infants and in children below three years of age who have widely disseminated disease. Hepatosplenomegaly due to histiocytosis often indicates poor prognosis, especially in the presence of hepatic dysfunction.
Bone marrow. Mild degrees of anemia and thrombocytopenia are not unusual when there is widespread histiocytosis in an infant or young child. In these patients the marrow might not show an increased number of histiocytes. However, definite invasion of the marrow by histiocytic cells, seen on aspiration or on marrow biopsy, is usually part of the terminal picture of the disease (Figure 9). Such bone-marrow invasion leads to progressive replacement of the normal marrow population by histiocytes and results in profound pancytopenia.
Gastrointestinal tract. Infiltration of the gastrointestinal mucosa is associated with a malabsorption syndrome. This occurs most frequently in severely ill infants with the disseminated form of the disease. Vigorous support with parenteral nutrition may be given to these patients in anticipation of the therapeutic effect of chemotherapy.
Eosinophilic granuloma of bone. Lesions are confined to the skeleton, usually appearing as one, isolated, "solitary" osteolytic lesion. It occurs almost exclusively in older children, over five years of age. Eosinophilic granuloma of bone is the most benign form of histiocytosis and responds to local treatment with low-dose radiation, with complete resolution and filling of the defect. It does not require systemic chemotherapy. Rarely is more than one bone affected, in which case the patient should be followed closely, since other bones or organ systems may become involved as well.
Figure 9. Bone-marrow aspirate from child with terminal histiocytosis. Note absence of normal marrow cells and replacement with sheets of histiocytes (Wright stain).
Hand-Schuller-Christian or Schuller-Christian syndrome. This is characterized by multiple and varied osseous lesions, coupled with infiltrates in other organ systems, usually of mild to moderate severity. It has a chronic, indolent course and appears in children above two or three years of age. The skin infiltrates wax and wane; xanthomas may appear and involute over several months. The bone lesions appear in bouts and cause the highest morbidity. There is greatest morbidity when the lesions occupy weight-bearing bones, the vertebral bodies, the orbits, and the alveolar bones. Hypothalamic-pituitary lesions may cause a deficiency of antidiuretic hormone and somatotropin (growth hormone), with resultant diabetes insipidus and growth retardation. Other CNS lesions may affect the pyramidal tracts, the cranial nerves, and the cerebellum. Occasionally the Schüller-Christian syndrome may assume a more aggressive course, with multiorgan involvement resembling the Letterer-Siwe syndrome.
Letterer-Siwe syndrome. This is the most virulent form of the disease. It may start with severe involvement of several organs, or it may become severe after some months of an indolent course resembling the HandSchüller-Christian syndrome. It usually begins in infancy and early childhood, up to two or three years of age. Skin and mucous membranes are almost always affected, bone lesions are common, and lung infiltration ma> be present. Anemia and moderate thrombocytopenia may occur even though the bone marrow may not show histiocytic infiltration. Hypersplenism may be a prominent feature. Localized or generalized lymphadenopathy of varius degrees is usually present. Centralnervous-system lesions may occur. The child may be febrile, irritable, and obviously ill. In fulminant cases or in severe stages of the disease, hepatosplenomegaly may occur and the liver and spleen may reach enormous size. In terminal stages there may be bone-marrow replacement by histiocytes, leading to pancytopenia, infection, and death.
Pulmonary syndrome. Some patients may present with histiocytosis affecting the lungs almost exclusively. In such cases there may be isolated lesions having a benign clinical course or there may be severe diffuse infiltration leading to impaired pulmonary function or pneumothorax. Generalized disease may follow. This syndrome occurs mostly in teenagers, but there have been reports of cases in younger children, even in one nine-month-old infant.5
Nodal syndrome. A small group of patients show only localized lymph-node involvement, such as massive enlargement of cervical lymph nodes, without other evidence of histiocytosis.
The histologic picture of biopsied material is characteristic and necessary for the diagnosis. The bone defects may also have the characteristic "punched out" appearance on x-rays, which helps in the diagnosis. The bone scan may be useful, in conjunction with x-rays, in demonstrating active bone lesions.
There are no specific diagnostic blood tests. Blood levels of lipids and cholesterol are normal. Immunoglobulins are normal or increased, especially IgG. Peripheral blood lymphocyte studies have shown normal T-cell populations, with normal or increased B-cell percentage. Phytohemagglutinin stimulation indices are normal or increased.6,7 The karyotype is normal. Persisting low urine specific gravity will suggest the presence of diabetes insipidus. In these cases, serial urine and blood osmolarity during dehydration and after subcutaneous injection of aqueous vasopressin will confirm the diagnosis.
Chemotherapy is the treatment of choice. Radiotherapy may be necessary in specific circumstances.
Radiotherapy. This is indicated for treatment of the bone lesion in "solitary" esosinophilic granuloma of bone. The dose of radiotherapy given is less than 1,000 rads; usually 600 rads is given, split into two to three doses. This dose of radiotherapy is adequate for cure and is preferable to curettage, which may not result in complete excision of the cellular infiltrate. In the other syndromes, radiotherapy is necessary for lesions of the vertebral bodies in order to achieve a rapid recovery and to prevent cord complications. The same reasoning applies to large bone defects in the femur and tibia, which may result in pathologic fractures due to weight bearing.
Bone defects in other sites may need radiotherapy only if symptomatic. One of these sites may be the alveolar bone of the mandible and maxilla. When these bones are infiltrated, there can be severe pain on eating; these infiltrates may cause extrusion and loss of der ciduous teeth and loss of the tooth buds of the permanent teeth. Infiltrations of the orbital bones causing proptosis usually require radiotherapy. Cases presenting with large localized adenopathy may need radiotherapy as well as chemotherapy. Pituitary-hypothalamic irradiation has been used, but it has no beneficial effect on the diabetes insipidus.8
Chemotherapy. A large number of chemotherapeutic agents are effective in histiocytosis, either when given alone or in combination. These include alkylating agents (chlorambucil, nitrogen mustard, and cyclophosphamide), plant alkaloids (vinblastine and vincristine), antimetabolites (methotrexate and 6-mercaptopurine), the corticosteroids, and procarbazine. The principle in the chemotherapy of histiocytosis is long-term treatment until all evidence of disease disappears and then continuation of chemotherapy for at least six months, sometimes a year or more, after complete remission has been achieved. Remission of all symptoms and signs usually takes several months, especially for lung and bone lesions. Therefore, a longterm commitment to chemotherapy is necessary.
If the disease is minor and is not causing morbidity or organ dysfunction, a single agent might suffice and result in improvement within a few weeks, with the least side effects. In these cases, chlorambucil (0.2 mg./kg. body weight, orally, adjusted so that the white blood cell count remains above 3,000/cu. mm.) has given excellent results in experienced hands for the past two decades.9 Oral daily cyclophosphamide might give the same results, but long-term therapy with this agent should be avoided, since it may have serious delayed side effects.10 Vinblastine given once a week (0.15 to 0.3 mg./kg. per dose, as tolerated in order to maintain the white-cell count above 3,000/cu. mm.) has given excellent results and is among the best agents for this disease.
In cases with wide dissemination of the histiocytosis, it is useful to initially combine vinblastine with an alkylating agent (i.e., one course of nitrogen mustard or pulse doses of cyclophosphamide intravenously) in order to produce a more rapid resolution. Prednisone can also be added to the above, especially in cases of massive involvement. More complex protocols of combination chemotherapy, including the addition of procarbazine,11 may be devised for unusually severe cases. Seemingly hopeless cases - for example, in a young man with the Letterer-Siwe syndrome who had had total bone-marrow replacement by histiocytes and in a young man with massive diffuse pulmonary infiltration - have yielded to prolonged combination chemotherapy including nitrogen mustard, vinblastine, and procarbazine.12 Vincristine, as well as methotrexate and 6-mercaptopurine, has been used in combination with other drugs.12"14 The most effective agents, however, remain vinblastine and the alkylating agents, alone or in combination.
The seborrhea-like dermatitis of the scalp may improve with a selenium-based shampoo used twice a week. When diabetes insipidus occurs, hormonal substitution therapy becomes necessary: vasopressin tannate may be used intramuscularly, as needed, usually every two to four days, or lysine vasopressin may be given by nasal spray two to four times daily. The frequency of the doses will be dictated by the return of polyuria and polydipsia, and parents become quite adept at regulating them under medical supervision. In cases of growth-hormone deficiency, a fair response has been obtained with the administration of this hormone in children.2
The prognosis is usually excellent in cases of solitary eosinophilic granuloma of bone, if the lesion has not caused damage to adjacent vital structures before therapy.
Chemotherapy has improved the prognosis for the other syndromes but has not eliminated the fatalities, especially in the younger group. Score systems have been attempted in order to better classify the various clinical presentations of the disease and to correlate them with prognosis.1*16"18 It appears that younger age at the onset of the disease and evidence of organ dysfunction carry the poorest prognosis; also, dysfunction of organs is more significant than the number of organs affected.
The presence of dysfunction of the lungs, the liver, or the hematopoietic system is a determining factor as to response to chemotherapy. Among 83 patients included in the comparative chemotherapeutic trials of the Children's Cancer Study Group, good responses were seen in 66 per cent of patients without dysfunction, as against 33 per cent in patients who had dysfunction of these vital organs. Of 32 children below three years of age with organ dysfunction, 22, or 66 per cent, died.17
These somber data indicate the seriousness of histiocytosis, especially in the early years of life. An aggressive combination chemotherapy approach is necessary to improve the prognosis in the younger patients and in all patients with dysfunction of vital organs.
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