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Diagnostic and Differential Diagnostic Aspects in Histiocytosis X Diseases
Path. Res. Pract. 166, 59-71 (1979) Departments of Pathology and Radiology, University of Gottingen, FRG
Diagnostic and Differential Diagnostic Aspects in Histiocytosis X Diseases M. BERGHOLZ, A. SCHAUER, and H. POPPE
Summary Diagnostic and differential diagnostic aspects of the known manifestations of histiocytosis X are discussed with respect to our own findings. It is our considered opinion that the term "histiocytosis X" should not be employed in isolation for diagnostic purposes. Rather, one should make an effort to designate the disease exactly 10 stating the prognosis for a particular patient. Both clinical and morphologic parameters must be considered in making this exact diagnosis.
Introduction The nosological unity of disease entities summarized under the headline "histiocytosis X" is still controversial today. Nonetheless this concept is employed more and more as a diagnosis without further qualification. The use of cytostatic drugs and the critical evaluation of their effectiveness, however, have made the discussion of diagnostic criteria for delimiting various subcategories of histiocytosis X highly relevant to modern medical practice (Newton and Hamoudi, 1973; Komp et aI., 1978). The knowledge of the clinical spectrum of this disease group has broadened on the basis of reports on unusual organ manifestations and natural histories of the disease. This widened perspective of the disease, however, has also enlarged its differential diagnosis. In this report, we shall illustrate and discuss diagnostic and differential diagnostic aspects of histiocytosis X diseases using several cases.
1. Eosinophilic Granuloma of the Bone Clinical and radiographic data: The peak ages among our patients lay between five and ten years old, our oldest patient being 32 years old. The polyostotic form was present in about one fifth of cases. The clinical course was determined for the most part by local symptoms.
60 . M. Bergholz, A. Schauer, and H. Poppe
The radiographic signs of eosinophilic granuloma are essentially characterized by rapidity of onset and localization in flat (calvaria, vertebrae) and tubular bones. In the description and differential diagnosis, the often rapid development within a few weeks to months is valuable. Uehlinger (1963) published a case history in which a 2 em bony focus in the ilium at the time of initial discovery had extended into the entire ala of the iliac bone over a period of 15 months. The origin of eosinophilic granuloma in the marrow space of the bone and its central-expansive development also determine its radiographic pattern of destruction. As a rule one sees punched out osteolytic zones, occasionally surrounded by a narrow zone of sclerosis. When disease is localized in the cranial cap, involvement in the external table is greater than that in the internal table as a rule. Computerized axial tomograms thus show an "amputation" pattern in the laminograms which is almost characteristic for eosinophilic granuloma. Localization of such foci in the region of the frontal bone (Fig. 1) and -less often - in the parietal bone region may provide differential diagnostic clues as contrasted to the radiographic appearance of multiple myeloma, especially in conjunction with the age of the patient. In tubular bones one finds bean-sized to plum-sized osteolytic foci in bone situated in the marrow space of the dia-metaphysis at the time of initial discovery. Occasionally a focus located in a central-eccentric position may
Fig. 1. Characteristic radiographic appearance of eosinophilic granuloma in the frontal bone, with amputation-like defects at the edges of the external and internal tables.
Histiocytosis X . 61
Fig. 2. Olive-sized eosinophilic granuloma in the proximal femoral diaphysis, with lateral-eccentric highlighting and spindled, partially lamellar periosteal reaction.
lead to a lamellar periosteal reaction (Fig. 2). Locations of initial involvement of eosinophilic granuloma seldom lead to spontaneous fractures at the time of initial discovery. However, the manifestations of eosinophilic granuloma in the vertebral column are less often osteolytic foci in the vertebral bodies or arches as they are characteristic pathologic fractures seen as wedge-shaped vertebral compression, which may progress to the level of the flattened form, or "vertebra plana". In the great majority of observations, the vertebral arches and articular processes are spared, a situation which accounts for the very rare occurrence of gibbus formation in eosinophilic granuloma. For reasons which remain unclear, eosinophilic granulomas which are located in the clavicular region and in the ribs are characterized by a natural course in which the bone develops reactive potential over the course of time. In this situation we frequently find spindle-shaped, sclerotic bony outgrowths, which are virtually pathognomonic for eosinophilic granuloma when they appear on the clavicle (Fig. 3). Pathologic Anatomy: The histologic appearance is characterized by an ordered granuloma structure with centrally located histiocyte aggregations and peripheral zones of organization. The histiocytes are largely isomorphic, and the edge shows brisk formation of giant cells with erythrophagocytosis and deposition of iron and fat (Fig. 4). Since it is occasionally the case that the first observed lesion in malignant histiocytosis (Rappaport, 1966) is osteolysis, it should be included in our
62 . M. Bergholz, A. Schauer, and H. Poppe
Fig. 3. Eosinophilic granuloma of bone in the left clavicle with a spindled swelling.
Fig. 4. Eosinophilic granuloma of bone with numerous histiocytic giant cells (H & E, 100 x).
Fig. 5. Malignant histiocytosis of bone in a 12 year old male: dense, polymorphic histiocytic infiltrare with increased mitotic activity (H & E, 160 x). We wish to thank Prof. Dr. D. Harms, Department of Pathology, University of Kiel, for this picture.
Histiocytosis X . 63
differential diagnosis (Fig. 5). The most important differential diagnostic consideration, however, is osteomyelitis with an atypical radiographic appearance. Likewise, one should always think of histiocytosis X (and especially eosinophilic granuloma) in every questionable case of osteomyelitis. Here it is helpful to note that eosinophilic granuloma shows a monotonous histiocytic proliferation with associated eosinophils, while osteomyelitis shows a polymorphic inflammatory picture eventually with marked involvement of plasma cells, and bony sequestrations may be demonstrable. Therapy: Basically, the therapy for eosinophilic granuloma should take into consideration its tendency toward spontaneous regression. The wellknown "radiosensitivity" of eosinophilic granuloma justifies the attempt at primary radiotherapeutic management, where radiation dose should be calibrated to avoid osseous necrosis. Doses in the range of 900 to 1100 rads are usually sufficient to provoke the tendency toward regression of eosinophilic granuloma in our experience with 91 bony foci. Higher doses are subject to the danger of late, radiation-induced damage of the bone (Fig. 6). The initial discovery of a vertebra plana should not lead to immediate therapeutic measures, such as operative intervention and correction and/or
a
b Fig. 6. a) Almond-sized eosinophilic granuloma of bone in the distal radial metaphysis, b) Inappropriate treatment of eosinophilic granuloma, eleven years after radiation therapy (dose 3500 rads): radiation-induced growth disturbance in the carpal bones in combination with osteoradiodystrophy and necrosis.
64 . M. Bergholz, A. Schauer, and H. Poppe
Fig. 7. a) Eosinophilic granuloma of bone in the 12th thoracic vertebra, with wedge-like deformation of the vertebra, b) Spontaneous recovery of the 12th thoracic vertebra without radiotherapeutic measures, 12 years after initial observation.
local radiation therapy. Even with high-grade development of a vertebra plana at the time of initial discovery (Fig. 7), one may possibly achieve regrowth of the vertebra without active therapeutic measures over the course of years or decades. A retrospective study of 71 long term cases has shown that radiotherapeutic treatment of local osseous foci leads to healing without "osseous scars" in three times as high a percentage of cases as does surgical intervention.
Histiocytosis X . 65
2. Pulmonary Histiocytosis and other Isolated Organ Manifestations Isolated histiocytosis of the lung occurs predominantly in young adults. The early stage is characterized radiographically by a perihilar, butterflyshaped shadow (Weber et ai, 1969). Symmetric reticular and miliary shadows serve as correlates of interstitial eosinophilic granulomas (Radenbach et ai, 1977). Spontaneous healing is not infrequent, and stabilization or remission is achieved with cortisone. Progression of the disease, however, leads to fibrosis with honeycomb structure. In contrast to sarcoidosis (Boeck's disease), the hilar lymph nodes in pulmonary histiocytosis are not appreciably enlarged. Occasionally histiocytosis X appears as an isolated disease of the skin, oral or anal mucosa, central nervous system, or lymph nodes. Whenever fibroblastrich, foam celled local lesions are observed, one must consider classification into the group of so-called xanthofibrogranulomatoses as part of the differential diagnosis (Kastendieck and Hiisselmann, 1978).
3. Chronic Multicentric Histiocytosis Histiocytosis involving multiple organ systems with the entire spectrum of the Hand-Schuller-Christian triad (map-like skull, exophthalmos, diabetes insipidus) appears relatively infrequently. Osteolytic lesions are the predomi nant feature, and the sellar region is often radiographically unremarkable despite endocrinologic disturbances. The lesions usually arise from the highly vascularized basal meninges; however, foci may also form in the hypothalamus and cerebellum. The majority of patients are preschool and school-aged children . The active phase of the disease usually lasts no longer than 5 years. Skin eruptions such as those seen in Letterer-Siwe disease are not uncommon in the early age groups; temporary the disease may progress with hepatosplenomegaly, lymph node enlargement, and lung densities. Adults most often exhibit skeletal and pulmonary involvement; here, the course of the disease is often substantially longer; occasionally exacerbations may recur after many years. The differential diagnostic distinction between eosinophilic granuloma and Hand-Schuller-Christian disease is not possible on radiographic and histomorphologic grounds alone (Figs. 8 and 9). In polytopic manifestations of Hand-Schuller-Christian disease, radiographically we see more marked local bony changes in the area of destruction than in eosinophilic granuloma. Nonetheless it is not possible to render unquestionable prognostic statements for the individual case on the basis of radiographic findings. The following case studies serve to demonstrate, among other things, the variable clinical course of the disease. In particular, it should be pointed out that cytostatic agents were not used in either case. 5 Path. Res. Pract, Vol. 166
66 . M. Bergholz, A. Schauer, and H. Poppe
b Fig. 8. a) Focus of osteolysis in Hand-SchullerChristian histiocytosis in the distal femoral metadiaphysis (suspected radiographic diagnosis: osteomyelitis), b) Focus of osteolysis in Hand-Schiiller-Christian disease in the ala of the right iliac bone.
Fig. 9. Hand -Schiiller-Christian disease (bone marrow): predominantly histiocytic infiltrate. (Giemsa, 100 x).
Histiocytosis X . 67
Between his second and fifth years of life, a boy suffered from a stormy and at times life-threatening disease course. The disease began with chronic otitis media, multiple cranial foci, moderate anemia, and elevated blood sedimentation rate. Following a transient remission, the child developed massive, generalized lymphomas, fever, yellowish-brown skin papules on the trunk, mild bilateral bulbar protrusion, distinct hepatosplenomegaly, additional new osteolyses in the skull, pelvis, and right fibula, and diffuse finepatchy lung densities. With reappearance of the moderate anemia and elevation of sedimentation rate, the patient developed dyspnea. The child showed only moderate regression of disease manifestations under treatment with antibiotics therapy in use at that time, nonetheless the child subsequently recovered, and when last seen at the age of five in the ambulatory clinic he had no pathologic findings. A male patient developed multiple osteolytic lesions in skull, vertebrae, ribs, pelvis, and femur over the period between 18 and 21 years of age. Clinically the patient early suffered from multiple infections having poor general condition. There was moderate anemia and elevated sedimentation rate. The skin at first showed indistinct eruptions, then xanthomas on the trunk and extremities and xanthelasmas on the eyelids. Blood lipids were normal. Diabetes insipidus was present from the onset of the disease, and by its third year there were reticular, fine-patchy lung densities. The lung densities remained unchanged, but lung function was not affected essentially. The bony foci healed within a period of four and a half years without radiologic therapy.
4. Letterer-Siwe Disease The characteristic findings are acute and usually simultaneous onset of skin eruptions, anemia, hepatosplenomegaly, and pulmonary densities in the period of infancy. Bony lesions are often first discovered at autopsy. Our patients died during the first year of life. In a recently observed case, we also considered juvenile xanthogranulomatosis of the skin in the differential diagnosis, but autopsy confirmed the diagnosis of Letterer-Siwe disease with disseminated, destructive histiocytosis of the internal organs and soft tissue (Fig. 10). We could not demonstrate Langerhans granules in spite of multiple electron microscopic investigations. The morphologic appearance of lymph nodes in our cases varied between unremarkable sinus histiocytosis and destructive infiltration by polymorphic cells. The infiltration arose from the medullary and cortical sinuses, while the follicles initially remained uninvolved. Proliferations arose from papillary bodies in the skin and progressed focally to the epidermis. Lung infiltrates
68 . M. Bergholz, A. Schauer, and H. Poppe
Fig. 10. Letterer-Siwe disease with histiocytic skin infiltrate (H & E, 100 x).
were present predominantly in the peribronchial interstitium, in the liver the portal fields were mostly affected arid -in the spleen the parafollicular zones. Desmoplasia, giant cells, eosinophilic granulocytes, foam cells, and erythrophagocytosis varied in different regions. Areas of predilection included the submucosa of the digestive tract and serous sufaces. Bone marrow , fat tissue, and musculature were in part "phlegmonously infiltrated". In addition, there were also fiber-rich, nodular foci without the typical architecture of eosinophilic granuloma.
Discussion Examination of the morphologic appearance and natural history of histiocytosis gives the following breakdown: Chronic Granulomatous-focal Histiocytosis:
localized:
multicentric (in more than one organs):
eosinophilic granuloma of bone (monostotic and polyostotic), pulmonary histiocytosis, and other isolated organ manifestations. Hand-Schuller-Christian Disease.
Acute Disseminated Histiocytosis: Letterer-Siwe Disease
Letterer-Siwe disease appears almost exclusively in infancy, and is most comparable to acute leukemia in its clinical course. Chronic multicentric histiocytosis attacks mostly pre-school and early school-age children, but may
Histiocytosis X . 69
appear at any time of life. In general, the older the patient, the more organspecific and more slowly the disease progresses. In contrast to Letterer-Siwe disease, the other forms of histiocytosis X have the character of a granulomatosis with a tendency toward spontaneous healing. Occasionally eosinophilic granuloma of the digestive tract and familial hemophagocytic reticulosis (Farquhar) are wrongly taken as histiocytosis X diseases. There are no further morphologic similarities to the former condition than simply the presence of eosinophil-rich fibrohistiocytic, inflammatory granulomas in the stomach and intestines. Farquhar's disease shows a lymphocytic organ infiltrate (Bergholz et al, 1978). Further conditions which must be distinguished from histiocytosis X include: multicentric giant cell histiocytosis of the skin and joints in older women (lipid dermatoarthritis), sinus histiocytosis with massive lymphadenopathy, sea-blue histiocytoses and other lipid storage diseases, and concomitant histiocytoses in infection, immune deficiency diseases, and after immunization. . The morphologist can only provide clues with respect to specificdiseases in histiocytosis X from biopsy material. Since the degree of cellular atypia varies in Letterer-Siwe disease, skin biopsies in particular often do not permit a distinction to be made from phenotypically similar Hand-Schiiller-Christian disease and sometimes even from juvenile skin xanthogranulomatosis (Newton and Hamoudi, 1973; Wolff et al, 1975). Although the histiocytic infiltrate in Letterer-Siwe disease, with its occasional bizarre nuclear forms, is usually more polymorphic, still giant cells, foam cells, erythrophagocytosis, and eosinophilic granulocytes are often present and exhibit no certain criteria for differentiation. In the bone marrow and internal organs, desmoplastic activity varies from focus to focus. However, an ordered focus architecture such as seen in eosinophilic granuloma would argue against the diagnosis of Letterer-Siwe disease. Changes in lymph nodes, spleen, and liver and in the organ interstitium (particularly in the sumucosa of the digestive tract) may partially imitate reactive histiocytosis. Sometimes even autopsy fails to reveal pathologic findings in lymph node groups, liver, and spleen (Daneshbod and Kissane, 1978). All in all, changes in the so-called reticulo-endothelial system are expressed in varying degrees, and the autopsy findings as a whole most strongly suggest a hematogenous distribution to areas of predilection. We conclude from these observations that prognostic judgments in the individual case must take the clinical picture into account. In addition to fever and weight loss, anemia, lung densities, and signs of liver dysfunction most strongly suggest a malignant clinical course. The relatively rare cases of Letterer-Siwe disease, in particular, should be studied electron microscopically in order to determine the diagnostic and nosologic value of Langerhans granulas. A nosologic relationship between
70 . M. Bergholz, A. Schauer, and H. Poppe
histiocytosis X, juvenile xanthogranuloma and malignant histiocytosis is a matter of controversy. As has been discussed, juvenile xanthogranuloma may sometimes appear as a disseminated disease (Wolff et al, 1975). Malignant histiocytosis is described predominantly but not exclusively in adults (Nezeloff and Jaubert, 1978; Rappaport, 1966). This disease does not progress in such a stereotyped manner as Letterer-Siwe disease. However, osteolytic lesions and involvement of skin, mucosal and even serosal surfaces (in addition to the obligatory changes in the lymphohematopoietic system) are not rare. The histologic appearance has at least some similarities with respect to the character of infiltrate (histiocytic medullary reticulosis), variation in cellular atypia, and the variable presence of eosinophilic granulocytes, giant cells, and erythropagocytosis. Langerhans granules have been described (Wolfson et al, 1976). Lichtenstein's "histiocytosis X" is a mixture of diseases with both benign and malignant clinical courses, in which so-called transitions between these two extremes appear at most in early childhood. Letterer-Siwe disease should be included into the histiocytosis X-group reservedly. In favor of its classification as a tumor and against its classification as a histiocytosis X disease, there are congenital (Kiichemann, 1974) and leukemic (Frisch et al, 1974; Nyholm, 1971) forms in early childhood, as well as discrepancies with respect to the other histiocytosis X diseases in its sensitivity to cytostatic agents (Komp et al., 1978), and finally the neoplastic character of the autopsy findings taken as a whole. A unified concept of histiocytosis X diseasesshould not influence the prognostic evaluation and therapy of the individual patient. It is clear that clinicians and morphologists must continue their vigilance in distinguishing among the several histiocytosis X diseases.
References Amiradjazil, Z., Esca, S.-A., Konrad, K.: Histiocytosis X in an adult with skin and uncommen central nervons system involvement. Dermatologica 155, 283-291 (1977) Bergholz, M., Rahlf, G., Doering, K.-M.: Familial hemophagocytic reticulosis (Farquhar). Path. Res. Pract. 163,267-280 (1978) Daneshbod, K., Kissane, J. M.: Idiopathic differentiated histiocytosis. Amer. J. Clin. Path. 70, 381-389 (1978) Frisch, H., Gotz, M., Radaszkiewicz, R., Rosenmayr, F.: Histiozytose X im Kindesalter, Klin. Padiatr, 186, 336-345 (1974) Huhn, D., Meister, P.: Malignant Histiocytosis. Cancer 42, 1341-1349 (1978). Kastendieck, H., Hiisselmann, H.: Zur Pathologie der Xanthofibrogranulomatose. Virchows Arch. A. Path. Anat. HlstOI. 380, 237-259 (1978) Komp, D. M., Silva-Sosa, M., Miale, T., Sexauer, CH., Herson, J.: Evaluation of a mopp-type regimen in histiocytosis X. Cancer Treat. Rep. 61, 855-859 (1977)
Histiocytosis X . 71 Komp, D. M., Herson, J., Starling, K. A., Vietti, T. J., Hvizdala, E.: Prognostic variables in Histiocytosis X. Proc. Amer. Ass. Cancer Res. and Amer, Soc. Clin. Onco!. 19, 390, abst.
C-335, (1978) Kiichemann, K.: Congenital Letterer-Siwe disease, Beitr. Path. 151,405-411 (1974) Newton, W. A., Hamoudi, A. B.: Histiocytosis: A histologic classification with clinical correlation. Perspect. Pediatr. Path. Chicago 1,251-283 (1973) Nezelof, Jaubert, F.: Histiocytic and/or reticulum cell neoplasias. In: Recent Results in Cancer Research 64. Lymphoid Neoplasias 1, 118-124 (1978) Nyholm, K.: Eosinophilic xanthomatous granulomatosis and Letterer-Siwe's disease. Act. path. mikrobio!. scand. A Supplement No. 216 (1971) Radenbach, K. 1., Brandt, J. J., Freise, G., LIebig, S., Preussler, H.: Diagnostische und therapeutische Besonderheiten bei zwolf Fallen von pulmonaler Histiozytosis X. Z. Erkr. Atmungsorg. 147,26-40 (1977) Rappaport, H.: Tumors of the hematopoetic system. Atlas of tumor pathology Section III Fascicle 8, Armed Forces Institute of Pathology (1966) Starling, K. A., Donaldson, M. H., Haggard, M. E., Vietti, T. J., Sutow, W. W.: Therapy of histiocytosis X with vincristine, vinblastine and cyclophosphamide. Amer. J. Dis. Child 123,
c.,
105-108 (1972) Uehlinger, E.: Das eosinophile Knochengranulom. Handbuch d. ges, Harnatol. Band IV, Teil 2,
56-87 (1963) Weber, W. N., Margolin, F. R., Nielsen, S. 1.: Pulmonary histiocytosis X. Am. J. Roentgeno!.
107, 280-289 (1969) Wolff, H. H" Vigl, E., Braun-Falco, 0.: Juveniles Xanthogranulom und Organmanifestationen. Hautarzt 26, 268-272 (1975) Wolfson, W. 1., Gossett, T., Pagani, J.: Systemic giant-cell histiocytosis. Cancer 38, 2529-2537
(1976)
Received February 22, 1979 . Accepted February 26, 1979
Key words: Histiocytosis X - Eosinophilic granuloma - Hand-SchidlerChristian Disease - Letterer-Siwe Disease - Diagnosis - Pathology Dr. Michael Bergholz and Prof. Dr. A. Schauer, Department of Pathology, University G6ttingen, Roberr-Koch-Strafse 40 3400 G6ttingen, FRG Prof. Dr. H. Poppe, Department of Radiology, University G6ttingen, Robert-Koch-Strafse 40 3400 G6ttingen, FRG
Diagnostic and Differential Diagnostic Aspects in Histiocytosis X Diseases M. BERGHOLZ, A. SCHAUER, and H. POPPE
Summary Diagnostic and differential diagnostic aspects of the known manifestations of histiocytosis X are discussed with respect to our own findings. It is our considered opinion that the term "histiocytosis X" should not be employed in isolation for diagnostic purposes. Rather, one should make an effort to designate the disease exactly 10 stating the prognosis for a particular patient. Both clinical and morphologic parameters must be considered in making this exact diagnosis.
Introduction The nosological unity of disease entities summarized under the headline "histiocytosis X" is still controversial today. Nonetheless this concept is employed more and more as a diagnosis without further qualification. The use of cytostatic drugs and the critical evaluation of their effectiveness, however, have made the discussion of diagnostic criteria for delimiting various subcategories of histiocytosis X highly relevant to modern medical practice (Newton and Hamoudi, 1973; Komp et aI., 1978). The knowledge of the clinical spectrum of this disease group has broadened on the basis of reports on unusual organ manifestations and natural histories of the disease. This widened perspective of the disease, however, has also enlarged its differential diagnosis. In this report, we shall illustrate and discuss diagnostic and differential diagnostic aspects of histiocytosis X diseases using several cases.
1. Eosinophilic Granuloma of the Bone Clinical and radiographic data: The peak ages among our patients lay between five and ten years old, our oldest patient being 32 years old. The polyostotic form was present in about one fifth of cases. The clinical course was determined for the most part by local symptoms.
60 . M. Bergholz, A. Schauer, and H. Poppe
The radiographic signs of eosinophilic granuloma are essentially characterized by rapidity of onset and localization in flat (calvaria, vertebrae) and tubular bones. In the description and differential diagnosis, the often rapid development within a few weeks to months is valuable. Uehlinger (1963) published a case history in which a 2 em bony focus in the ilium at the time of initial discovery had extended into the entire ala of the iliac bone over a period of 15 months. The origin of eosinophilic granuloma in the marrow space of the bone and its central-expansive development also determine its radiographic pattern of destruction. As a rule one sees punched out osteolytic zones, occasionally surrounded by a narrow zone of sclerosis. When disease is localized in the cranial cap, involvement in the external table is greater than that in the internal table as a rule. Computerized axial tomograms thus show an "amputation" pattern in the laminograms which is almost characteristic for eosinophilic granuloma. Localization of such foci in the region of the frontal bone (Fig. 1) and -less often - in the parietal bone region may provide differential diagnostic clues as contrasted to the radiographic appearance of multiple myeloma, especially in conjunction with the age of the patient. In tubular bones one finds bean-sized to plum-sized osteolytic foci in bone situated in the marrow space of the dia-metaphysis at the time of initial discovery. Occasionally a focus located in a central-eccentric position may
Fig. 1. Characteristic radiographic appearance of eosinophilic granuloma in the frontal bone, with amputation-like defects at the edges of the external and internal tables.
Histiocytosis X . 61
Fig. 2. Olive-sized eosinophilic granuloma in the proximal femoral diaphysis, with lateral-eccentric highlighting and spindled, partially lamellar periosteal reaction.
lead to a lamellar periosteal reaction (Fig. 2). Locations of initial involvement of eosinophilic granuloma seldom lead to spontaneous fractures at the time of initial discovery. However, the manifestations of eosinophilic granuloma in the vertebral column are less often osteolytic foci in the vertebral bodies or arches as they are characteristic pathologic fractures seen as wedge-shaped vertebral compression, which may progress to the level of the flattened form, or "vertebra plana". In the great majority of observations, the vertebral arches and articular processes are spared, a situation which accounts for the very rare occurrence of gibbus formation in eosinophilic granuloma. For reasons which remain unclear, eosinophilic granulomas which are located in the clavicular region and in the ribs are characterized by a natural course in which the bone develops reactive potential over the course of time. In this situation we frequently find spindle-shaped, sclerotic bony outgrowths, which are virtually pathognomonic for eosinophilic granuloma when they appear on the clavicle (Fig. 3). Pathologic Anatomy: The histologic appearance is characterized by an ordered granuloma structure with centrally located histiocyte aggregations and peripheral zones of organization. The histiocytes are largely isomorphic, and the edge shows brisk formation of giant cells with erythrophagocytosis and deposition of iron and fat (Fig. 4). Since it is occasionally the case that the first observed lesion in malignant histiocytosis (Rappaport, 1966) is osteolysis, it should be included in our
62 . M. Bergholz, A. Schauer, and H. Poppe
Fig. 3. Eosinophilic granuloma of bone in the left clavicle with a spindled swelling.
Fig. 4. Eosinophilic granuloma of bone with numerous histiocytic giant cells (H & E, 100 x).
Fig. 5. Malignant histiocytosis of bone in a 12 year old male: dense, polymorphic histiocytic infiltrare with increased mitotic activity (H & E, 160 x). We wish to thank Prof. Dr. D. Harms, Department of Pathology, University of Kiel, for this picture.
Histiocytosis X . 63
differential diagnosis (Fig. 5). The most important differential diagnostic consideration, however, is osteomyelitis with an atypical radiographic appearance. Likewise, one should always think of histiocytosis X (and especially eosinophilic granuloma) in every questionable case of osteomyelitis. Here it is helpful to note that eosinophilic granuloma shows a monotonous histiocytic proliferation with associated eosinophils, while osteomyelitis shows a polymorphic inflammatory picture eventually with marked involvement of plasma cells, and bony sequestrations may be demonstrable. Therapy: Basically, the therapy for eosinophilic granuloma should take into consideration its tendency toward spontaneous regression. The wellknown "radiosensitivity" of eosinophilic granuloma justifies the attempt at primary radiotherapeutic management, where radiation dose should be calibrated to avoid osseous necrosis. Doses in the range of 900 to 1100 rads are usually sufficient to provoke the tendency toward regression of eosinophilic granuloma in our experience with 91 bony foci. Higher doses are subject to the danger of late, radiation-induced damage of the bone (Fig. 6). The initial discovery of a vertebra plana should not lead to immediate therapeutic measures, such as operative intervention and correction and/or
a
b Fig. 6. a) Almond-sized eosinophilic granuloma of bone in the distal radial metaphysis, b) Inappropriate treatment of eosinophilic granuloma, eleven years after radiation therapy (dose 3500 rads): radiation-induced growth disturbance in the carpal bones in combination with osteoradiodystrophy and necrosis.
64 . M. Bergholz, A. Schauer, and H. Poppe
Fig. 7. a) Eosinophilic granuloma of bone in the 12th thoracic vertebra, with wedge-like deformation of the vertebra, b) Spontaneous recovery of the 12th thoracic vertebra without radiotherapeutic measures, 12 years after initial observation.
local radiation therapy. Even with high-grade development of a vertebra plana at the time of initial discovery (Fig. 7), one may possibly achieve regrowth of the vertebra without active therapeutic measures over the course of years or decades. A retrospective study of 71 long term cases has shown that radiotherapeutic treatment of local osseous foci leads to healing without "osseous scars" in three times as high a percentage of cases as does surgical intervention.
Histiocytosis X . 65
2. Pulmonary Histiocytosis and other Isolated Organ Manifestations Isolated histiocytosis of the lung occurs predominantly in young adults. The early stage is characterized radiographically by a perihilar, butterflyshaped shadow (Weber et ai, 1969). Symmetric reticular and miliary shadows serve as correlates of interstitial eosinophilic granulomas (Radenbach et ai, 1977). Spontaneous healing is not infrequent, and stabilization or remission is achieved with cortisone. Progression of the disease, however, leads to fibrosis with honeycomb structure. In contrast to sarcoidosis (Boeck's disease), the hilar lymph nodes in pulmonary histiocytosis are not appreciably enlarged. Occasionally histiocytosis X appears as an isolated disease of the skin, oral or anal mucosa, central nervous system, or lymph nodes. Whenever fibroblastrich, foam celled local lesions are observed, one must consider classification into the group of so-called xanthofibrogranulomatoses as part of the differential diagnosis (Kastendieck and Hiisselmann, 1978).
3. Chronic Multicentric Histiocytosis Histiocytosis involving multiple organ systems with the entire spectrum of the Hand-Schuller-Christian triad (map-like skull, exophthalmos, diabetes insipidus) appears relatively infrequently. Osteolytic lesions are the predomi nant feature, and the sellar region is often radiographically unremarkable despite endocrinologic disturbances. The lesions usually arise from the highly vascularized basal meninges; however, foci may also form in the hypothalamus and cerebellum. The majority of patients are preschool and school-aged children . The active phase of the disease usually lasts no longer than 5 years. Skin eruptions such as those seen in Letterer-Siwe disease are not uncommon in the early age groups; temporary the disease may progress with hepatosplenomegaly, lymph node enlargement, and lung densities. Adults most often exhibit skeletal and pulmonary involvement; here, the course of the disease is often substantially longer; occasionally exacerbations may recur after many years. The differential diagnostic distinction between eosinophilic granuloma and Hand-Schuller-Christian disease is not possible on radiographic and histomorphologic grounds alone (Figs. 8 and 9). In polytopic manifestations of Hand-Schuller-Christian disease, radiographically we see more marked local bony changes in the area of destruction than in eosinophilic granuloma. Nonetheless it is not possible to render unquestionable prognostic statements for the individual case on the basis of radiographic findings. The following case studies serve to demonstrate, among other things, the variable clinical course of the disease. In particular, it should be pointed out that cytostatic agents were not used in either case. 5 Path. Res. Pract, Vol. 166
66 . M. Bergholz, A. Schauer, and H. Poppe
b Fig. 8. a) Focus of osteolysis in Hand-SchullerChristian histiocytosis in the distal femoral metadiaphysis (suspected radiographic diagnosis: osteomyelitis), b) Focus of osteolysis in Hand-Schiiller-Christian disease in the ala of the right iliac bone.
Fig. 9. Hand -Schiiller-Christian disease (bone marrow): predominantly histiocytic infiltrate. (Giemsa, 100 x).
Histiocytosis X . 67
Between his second and fifth years of life, a boy suffered from a stormy and at times life-threatening disease course. The disease began with chronic otitis media, multiple cranial foci, moderate anemia, and elevated blood sedimentation rate. Following a transient remission, the child developed massive, generalized lymphomas, fever, yellowish-brown skin papules on the trunk, mild bilateral bulbar protrusion, distinct hepatosplenomegaly, additional new osteolyses in the skull, pelvis, and right fibula, and diffuse finepatchy lung densities. With reappearance of the moderate anemia and elevation of sedimentation rate, the patient developed dyspnea. The child showed only moderate regression of disease manifestations under treatment with antibiotics therapy in use at that time, nonetheless the child subsequently recovered, and when last seen at the age of five in the ambulatory clinic he had no pathologic findings. A male patient developed multiple osteolytic lesions in skull, vertebrae, ribs, pelvis, and femur over the period between 18 and 21 years of age. Clinically the patient early suffered from multiple infections having poor general condition. There was moderate anemia and elevated sedimentation rate. The skin at first showed indistinct eruptions, then xanthomas on the trunk and extremities and xanthelasmas on the eyelids. Blood lipids were normal. Diabetes insipidus was present from the onset of the disease, and by its third year there were reticular, fine-patchy lung densities. The lung densities remained unchanged, but lung function was not affected essentially. The bony foci healed within a period of four and a half years without radiologic therapy.
4. Letterer-Siwe Disease The characteristic findings are acute and usually simultaneous onset of skin eruptions, anemia, hepatosplenomegaly, and pulmonary densities in the period of infancy. Bony lesions are often first discovered at autopsy. Our patients died during the first year of life. In a recently observed case, we also considered juvenile xanthogranulomatosis of the skin in the differential diagnosis, but autopsy confirmed the diagnosis of Letterer-Siwe disease with disseminated, destructive histiocytosis of the internal organs and soft tissue (Fig. 10). We could not demonstrate Langerhans granules in spite of multiple electron microscopic investigations. The morphologic appearance of lymph nodes in our cases varied between unremarkable sinus histiocytosis and destructive infiltration by polymorphic cells. The infiltration arose from the medullary and cortical sinuses, while the follicles initially remained uninvolved. Proliferations arose from papillary bodies in the skin and progressed focally to the epidermis. Lung infiltrates
68 . M. Bergholz, A. Schauer, and H. Poppe
Fig. 10. Letterer-Siwe disease with histiocytic skin infiltrate (H & E, 100 x).
were present predominantly in the peribronchial interstitium, in the liver the portal fields were mostly affected arid -in the spleen the parafollicular zones. Desmoplasia, giant cells, eosinophilic granulocytes, foam cells, and erythrophagocytosis varied in different regions. Areas of predilection included the submucosa of the digestive tract and serous sufaces. Bone marrow , fat tissue, and musculature were in part "phlegmonously infiltrated". In addition, there were also fiber-rich, nodular foci without the typical architecture of eosinophilic granuloma.
Discussion Examination of the morphologic appearance and natural history of histiocytosis gives the following breakdown: Chronic Granulomatous-focal Histiocytosis:
localized:
multicentric (in more than one organs):
eosinophilic granuloma of bone (monostotic and polyostotic), pulmonary histiocytosis, and other isolated organ manifestations. Hand-Schuller-Christian Disease.
Acute Disseminated Histiocytosis: Letterer-Siwe Disease
Letterer-Siwe disease appears almost exclusively in infancy, and is most comparable to acute leukemia in its clinical course. Chronic multicentric histiocytosis attacks mostly pre-school and early school-age children, but may
Histiocytosis X . 69
appear at any time of life. In general, the older the patient, the more organspecific and more slowly the disease progresses. In contrast to Letterer-Siwe disease, the other forms of histiocytosis X have the character of a granulomatosis with a tendency toward spontaneous healing. Occasionally eosinophilic granuloma of the digestive tract and familial hemophagocytic reticulosis (Farquhar) are wrongly taken as histiocytosis X diseases. There are no further morphologic similarities to the former condition than simply the presence of eosinophil-rich fibrohistiocytic, inflammatory granulomas in the stomach and intestines. Farquhar's disease shows a lymphocytic organ infiltrate (Bergholz et al, 1978). Further conditions which must be distinguished from histiocytosis X include: multicentric giant cell histiocytosis of the skin and joints in older women (lipid dermatoarthritis), sinus histiocytosis with massive lymphadenopathy, sea-blue histiocytoses and other lipid storage diseases, and concomitant histiocytoses in infection, immune deficiency diseases, and after immunization. . The morphologist can only provide clues with respect to specificdiseases in histiocytosis X from biopsy material. Since the degree of cellular atypia varies in Letterer-Siwe disease, skin biopsies in particular often do not permit a distinction to be made from phenotypically similar Hand-Schiiller-Christian disease and sometimes even from juvenile skin xanthogranulomatosis (Newton and Hamoudi, 1973; Wolff et al, 1975). Although the histiocytic infiltrate in Letterer-Siwe disease, with its occasional bizarre nuclear forms, is usually more polymorphic, still giant cells, foam cells, erythrophagocytosis, and eosinophilic granulocytes are often present and exhibit no certain criteria for differentiation. In the bone marrow and internal organs, desmoplastic activity varies from focus to focus. However, an ordered focus architecture such as seen in eosinophilic granuloma would argue against the diagnosis of Letterer-Siwe disease. Changes in lymph nodes, spleen, and liver and in the organ interstitium (particularly in the sumucosa of the digestive tract) may partially imitate reactive histiocytosis. Sometimes even autopsy fails to reveal pathologic findings in lymph node groups, liver, and spleen (Daneshbod and Kissane, 1978). All in all, changes in the so-called reticulo-endothelial system are expressed in varying degrees, and the autopsy findings as a whole most strongly suggest a hematogenous distribution to areas of predilection. We conclude from these observations that prognostic judgments in the individual case must take the clinical picture into account. In addition to fever and weight loss, anemia, lung densities, and signs of liver dysfunction most strongly suggest a malignant clinical course. The relatively rare cases of Letterer-Siwe disease, in particular, should be studied electron microscopically in order to determine the diagnostic and nosologic value of Langerhans granulas. A nosologic relationship between
70 . M. Bergholz, A. Schauer, and H. Poppe
histiocytosis X, juvenile xanthogranuloma and malignant histiocytosis is a matter of controversy. As has been discussed, juvenile xanthogranuloma may sometimes appear as a disseminated disease (Wolff et al, 1975). Malignant histiocytosis is described predominantly but not exclusively in adults (Nezeloff and Jaubert, 1978; Rappaport, 1966). This disease does not progress in such a stereotyped manner as Letterer-Siwe disease. However, osteolytic lesions and involvement of skin, mucosal and even serosal surfaces (in addition to the obligatory changes in the lymphohematopoietic system) are not rare. The histologic appearance has at least some similarities with respect to the character of infiltrate (histiocytic medullary reticulosis), variation in cellular atypia, and the variable presence of eosinophilic granulocytes, giant cells, and erythropagocytosis. Langerhans granules have been described (Wolfson et al, 1976). Lichtenstein's "histiocytosis X" is a mixture of diseases with both benign and malignant clinical courses, in which so-called transitions between these two extremes appear at most in early childhood. Letterer-Siwe disease should be included into the histiocytosis X-group reservedly. In favor of its classification as a tumor and against its classification as a histiocytosis X disease, there are congenital (Kiichemann, 1974) and leukemic (Frisch et al, 1974; Nyholm, 1971) forms in early childhood, as well as discrepancies with respect to the other histiocytosis X diseases in its sensitivity to cytostatic agents (Komp et al., 1978), and finally the neoplastic character of the autopsy findings taken as a whole. A unified concept of histiocytosis X diseasesshould not influence the prognostic evaluation and therapy of the individual patient. It is clear that clinicians and morphologists must continue their vigilance in distinguishing among the several histiocytosis X diseases.
References Amiradjazil, Z., Esca, S.-A., Konrad, K.: Histiocytosis X in an adult with skin and uncommen central nervons system involvement. Dermatologica 155, 283-291 (1977) Bergholz, M., Rahlf, G., Doering, K.-M.: Familial hemophagocytic reticulosis (Farquhar). Path. Res. Pract. 163,267-280 (1978) Daneshbod, K., Kissane, J. M.: Idiopathic differentiated histiocytosis. Amer. J. Clin. Path. 70, 381-389 (1978) Frisch, H., Gotz, M., Radaszkiewicz, R., Rosenmayr, F.: Histiozytose X im Kindesalter, Klin. Padiatr, 186, 336-345 (1974) Huhn, D., Meister, P.: Malignant Histiocytosis. Cancer 42, 1341-1349 (1978). Kastendieck, H., Hiisselmann, H.: Zur Pathologie der Xanthofibrogranulomatose. Virchows Arch. A. Path. Anat. HlstOI. 380, 237-259 (1978) Komp, D. M., Silva-Sosa, M., Miale, T., Sexauer, CH., Herson, J.: Evaluation of a mopp-type regimen in histiocytosis X. Cancer Treat. Rep. 61, 855-859 (1977)
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C-335, (1978) Kiichemann, K.: Congenital Letterer-Siwe disease, Beitr. Path. 151,405-411 (1974) Newton, W. A., Hamoudi, A. B.: Histiocytosis: A histologic classification with clinical correlation. Perspect. Pediatr. Path. Chicago 1,251-283 (1973) Nezelof, Jaubert, F.: Histiocytic and/or reticulum cell neoplasias. In: Recent Results in Cancer Research 64. Lymphoid Neoplasias 1, 118-124 (1978) Nyholm, K.: Eosinophilic xanthomatous granulomatosis and Letterer-Siwe's disease. Act. path. mikrobio!. scand. A Supplement No. 216 (1971) Radenbach, K. 1., Brandt, J. J., Freise, G., LIebig, S., Preussler, H.: Diagnostische und therapeutische Besonderheiten bei zwolf Fallen von pulmonaler Histiozytosis X. Z. Erkr. Atmungsorg. 147,26-40 (1977) Rappaport, H.: Tumors of the hematopoetic system. Atlas of tumor pathology Section III Fascicle 8, Armed Forces Institute of Pathology (1966) Starling, K. A., Donaldson, M. H., Haggard, M. E., Vietti, T. J., Sutow, W. W.: Therapy of histiocytosis X with vincristine, vinblastine and cyclophosphamide. Amer. J. Dis. Child 123,
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(1976)
Received February 22, 1979 . Accepted February 26, 1979
Key words: Histiocytosis X - Eosinophilic granuloma - Hand-SchidlerChristian Disease - Letterer-Siwe Disease - Diagnosis - Pathology Dr. Michael Bergholz and Prof. Dr. A. Schauer, Department of Pathology, University G6ttingen, Roberr-Koch-Strafse 40 3400 G6ttingen, FRG Prof. Dr. H. Poppe, Department of Radiology, University G6ttingen, Robert-Koch-Strafse 40 3400 G6ttingen, FRG