Auris' Nasus' Larynx (Tokyo) 18, 17-26 (1991)
A CASE OF EOSINOPHILIC GRANULOMA IN THE TEMPORAL BONE Nobuko
M.D., Yoichi ISHlZUKA, M.D., and Takao YABE, M.D.
WANIFUCHI,
Department 0/ Otolaryngology, Mizonokuchi Hospital, Teikyo University School 0/ Medicine, Kawasaki, Japan
The following case reports a 4-year-old boy with a solitary eosinophilic granuloma in the right temporal bone. The patient complained of an inflammatory tumor in the right external ear canal. The histopathological diagnosis made based on the first specimen of the tumor in the right ear canal was foreign body granuloma. A polyp developed again in the right ear canal with postauricular swelling. Computerized tomography of the skull at that time showed an osteolytic defect in the right temporal bone filled with soft tissue. Diagnosis was established by finding of the presence of Birbeck granules in Langerhans histiocytes by electron microscopy. Eosinophilic granuloma of the bone is a rare benign disease which is characterized by single or multiple osteolytic skeletal lesions. It affects children less than 15 years old and the temporal bone is one of the affected skeletal lesions. The etiology remains unknown. However, its histopathology shows non-neoplastic abnormal proliferation of Langerhans histiocytes, which play an important role in contact dermatitis and tumor immunology. Therefore, an immunological disorder has been suggested for pathogenesis of this disease in recent years. CASE
A 4-year-old boy complained of a tumor following drainage in the right external ear canal. He had suffered a wound on the right posterior meatal wall I week earlier, which occurred during cleaning of the ear. Although the tumor had been removed twice at another clinic, it developed again. The patient was admitted to our clinic for treatment of the tumor. The patient had no other serious diseases and the family history was unremarkable. A white edematous polyp following serous drainage filled the right external ear canal and the eardrum Received for publication June 14, 1990 17
18
N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
was not seen. Chest X-ray and laboratory examinations were all within normal limits. Suspecting an inflammatory polyp, it was removed through the right meatal canal under general anesthesia. The polyp was located on the posterior meatal wall and consisted of granulation tissue invading into subcutaneous area. The eardrum was normal. Histopathological features revealed histiocyte infiltration with a few multinucleated giant cells in fibrous stroma without distinct eosinophil infiltration (Fig. 1). The diagnosis made at that time was foreign body granuloma. In a few weeks after the first operation, a polyp developed again in the right meatal canal following drainage with postauricular swelling. Results of computerized tomography of the skull showed an osteolytic defect in the right temporal bone filled with soft tissue. A mass of soft tissue was also observed in the extracranial mastoid lesion (Fig. 2a). Computerized tomography of the right temporal bone revealed an extensive osteolytic defect filled with soft tissue in the right mastoid and middle ear cavity (Fig. 2b). Angiograms revealed no abnormal tumor staining in the intra- and extracranial lesions. Three months after the first operation, the right mastoid was explored and a large bony defect in the mastoid was observed filled with a dark red, soft material. The dura mater was observed in the tegmen and posterior part of the temporal bone. In the middle ear the facial nerve, chorda tympani, incus, and stapes were enveloped with granulation tissue. Invasion into the labyrinth was not observed. The malleus and eardrum were intact except for partial thickening in the mucosal layer of the eardrum. The tissue was removed and a simple mastoidectomy was performed. Light microscopic histopathological studies using H-E staining revealed remarkable proliferation of histiocytes with abundant eosinophils (Fig. 3a). S-100 protein staining revealed a number of positive stained cells (Fig. 3b). In the transmission electron microscopic specimens, Birbeck granules were observed in the cell cyto-
Fig. 1. Photomicrograph of specimen in the right external ear canal at first operation. Histiocytes infiltrate following poly nucleated giant cells. Eosinophil infiltration is not remarkable (H-E stain, original x 100).
EOSINOPHILIC GRANULOMA
Fig. 2. a: Computerized tomography of the skul!. An osteolytic defect in the right tern· poral bone filled with soft tissue and a mass of soft tissue in the extracranial temporal bone are demonstrated. b: Computerized tomography of the temporal bone. An osteolytic defect in the right mastoid filled with soft tissue expanding into external ear canal (left: normal side).
Fig. 3. a: Photomicrograph of specimen in the right mastoid at second operation. Distinct proliferation of histiocytes following numerous eosinophils is demonstrated (H·E stain, original x 100). b: Photomicrograph of specimen in the right mastoid. Specimen stained with S-IOO protein shows numerous positive stained histiocytes (immunoperoxidase stain with S-IOO protein, original x 200). c: Photoelectron micrograph : Specific Birbeck granule ( ... ) in cytoplasm identifies the cell as Langerhans histiocyte (original x 30,000).
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N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
cell cytoplasm (Fig. 3c). Based on this, the histiocytes were identified as Langerhans cells. Diagnosis was established to be eosinophilic granuloma. Following diagnosis, the patient was treated with 1 mg of betamethasone and 600 mg of AMPC daily. He appeared moon-faced approximately 1 month after beginning of treatment. Following that time, he has been observed without medication. COMMENTS AND DISCUSSION
Histiocytosis X. Following considerable observation, there emerged in 1940 a provisional new concept of the conditions previously designated as eosinophilic granuloma of the bone, Letterer-Siwe disease and Hand-Schuller-Christian disease, in which these conditions were revealed to be interrelated expressions of the same malady. LICHTENSTEIN (1953) gave the name Histiocytosis X to these three diseases in all of which the abnormal proliferation of histiocytes appears. He and many other pathologists believed that the three conditions appear at different stages of one disease, that being a distinctive and specific non-neoplastic histiocytosis whatever the etiologic agent may ultimately be proved to be. Eosinophilic granuloma of the bone is characterized as a solitary or mUltiple osteolytic skeletal lesion. LICHTENSTEIN and JAFFE (1940) reported a solitary tumor in the femur which they referred to as eosinophilic granuloma of the bone. In the same year, OTANI and EHRLICH (1940) described solitary granuloma of the bone in four cases located in the rib and scapula. Hand-Schuller-Christian disease originally referred to the classic triad of a bony defect in the skull, exophthalmous and diabetes inspidus, which is caused by thalamus invasion. HAND (1921) reported the case of a 3-year-old child with hepatomegaly, splenomegaly, lymphadenopathy, exophthalmous, polyuria, bony defect in the skull. SCHULLER (1915) and CHRISTIAN (1919) also reported similar cases. SIWE (1933) referred to the disease, which was characterized by the classic triad, as Hand-Schuller-Christian disease. In the Histiocytosis X grouped by Lichtenstein, the disease is characterized by invasion of multiple organs including both skeletal and extraskeletal lesions. In addition, the classic triad appears in less than 10% (HUDSON and KENAN, 1969). As multiple organs are invaded at various times, a chronic course appears. It affects both children and young adults and the mortality rate is 15-30% (HUDSON and KENAN, 1969). Mortality rate is dependent upon low age and the affected organs such as the lung, liver, blood, as well as infections. Histopathology reveals proliferation of histiocytes with foam cells which are lipidated histiocytes. As a result, Hand-SchUller-Christian disease is occasionally referred to as xanthogranuloma. In Letterer-Siwe disease, systemic proliferation of histiocytes appears in acute or subacute course distinctively in infants or children, especially those under the age of three, and usually has a fatal outcome. LETTERER (1924) reported the case of a 6-year-old child with fever, purulent otitis, lymphadenopathy, hepato-
EOSINOPHILIC GRANULOMA
21
splenomegaly, and general bleeding, who expired rapidly. SIWE (1933) described similar conditions in a 16-year-old child. ABT (1936) believed that these conditions were a new disease with unknown etiology and gave it the name of LettererSiwe disease. The systemic course of the disease, which involves bone destruction, lymphadenopathy, hepatosplenomegaly, skin lesions, diffuse pulmonary involvement, thrombocytopenia, and anemia, proceeds dramatically. Histopathology reveals distinct proliferation of histiocytes, including Letterer cells, which are large histiocytes. Etiology of Histiocytosis X. The term Histiocytosis X for the three diseases is accepted even now as a disease which presents with similar histopathology (i.e. non-neoplastic proliferation of histiocytes) even though there have been numerous papers in opposition to the same pathogenesis because both their clinical and histopathological features are so different. This is especially true in the case of eosinophilic granuloma and Letterer-Siwe disease. Whether or not the three diseases have the same etiology remains unclear even at present. These histiocytes that proliferate in Histiocytosis X are identified as Langerhans cells after BASSET and TURIAF (1965) demonstrated Birbeck granules in the histiocytes of pulmonary eosinophilic granuloma. Therefore, the disease is also called Langerhans cell histiocytosis. Langerhans cells were first described in the skin by LANGERHANS (1868). Their role was long obscure. However, the immunological function of these cells has been greatly elucidated over the past 10 years. Langerhans cells are lineaged from macrophage-monocytes and play a major role in immunoregulation during contact allergies in the skin (SILBERBERG, 1971). They are bone marrow derived cells and are found in the skin, lymph nodes, thyroid, mucosa, and vagina. Most patients with disseminated Histiocytosis X exhibit an increased T-Iymphocyte helper (T4) to suppressor (T8) ratio due to deficiency of circulating suppressor lymphocytes . In addition, abnormal changes in thymic biopsies have also been reported in malignant tumors. The role of Langerhans cells in malignant tumors is thought to be similar to the role they have in T-cell activation against human tumors. Due to the tumor proliferation of Langerhans histiocytes related to immunoreaction and the non-neoplastic histopathological appearance, the pathogenesis of Histiocytosis X is thought to be an immunological disorder or immunological response to uncertain stimulations. Eosinophilic granuloma. Eosinophilic granuloma affects young children. SBARBARO (1961) reported 34 % were younger than the age of 4 and 74 % were younger than the age of 20 years in 50 patients . In addition, many papers have reported that the disease indicates male predominance (2: I). Our patient was also a 4-year-old boy. The skull, temporal bone, and mandible are the affecting skeletal lesions in head and neck, and bones of extremities, ribs and pelvis are also affected in the body. The disease also occurs in soft tissue. Isolated cases of eosinophilic
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N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
granuloma have also been reported in the lung, thyroid, skin, gastrointestinal tract, lymph nodes, thymus, and bladder. However, such cases are extremely rare. A disease that is occasionally reported as eosinophilic granuloma of soft tissue such as the parotid gland or lymph nodes, and presents with lymph follicular formation and eosinophilic infiltration is different from the eosinophilic granuloma in Histiocytosis X. The disease is named Kimura disease. Although the etiology of this disease also remains unclear, close correlation with allergy-I is suggested with eosinophils and IgE often increasing in the peripheral blood. In lesions of the skull, the incidence of eosinophilic granuloma following trauma was reported to be 38 % (CHARLES, LA WLINGS, ROBERT, and WILKINS, 1984). However, there have been no papers published relating to trauma in the temporal bone. In our case, there was trauma in the canal wall 1 week prior to the occurrence of the tumor. As pathogenesis is thought to be related to immunological reaction, the possibility that trauma acted as a triggering factor for eosinophilic granuloma cannot be overlooked. Temporal bone is one of the affected skeletal lesions. Bilateral temporal bone involvement also occurs. TOOHILL, KIDDER, and EBY (1973) reported a unifocallesion in 11 and bilateral involvement in 5 out of 15 cases of eosinophilic granuloma in the temporal bone. Hand-Schuller-Christian disease often occurs at first in a solitary skeletal lesion and therefore is diagnosed as eosinophilic granuloma. Later other organs are invaded, and then the diagnosis of HandSchuller-Christian disease is established. ApPLING (1983) reported that 7 out of 22 cases (32 %) appeared with multiple lesions 1-5 months after the first diagnosis of solitary eosinophilic granuloma. TOOHILL et al. (1973) described that the incidence of solitary eosinophilic granuloma appearing later with general dissemination or multiple lesions is 30-35 %. WILLIAM and CHARLES (1988) described that the differential diagnosis between unifocal and multi focal presentation is determined by an initial bone scan and by the presence or absence of new lesions over a 12-month period. The incidence of aural and temporal bone involvement in Hand-Schuller-Christian disease has been found to be relatively high at 20-40 %. In the review (Tos, 1966), 61 % of the 500 cases of the disease demonstrated aural and temporal bone manifestations. Also in LettererSiwe disease, temporal bone is one of the systemic lesions that is frequently affected, appearing as otitis media. HUDSON and KENAN (1969) reported the case of a lO-month-old male who initially complained of bilateral draining from ears with granulation tissue on the right external canal. This rapidly developed into systemic involvement. Symptoms of eosinophilic granuloma. In eosinophilic granuloma of the bone, skeletal lesions begin in the marrow, gradually erode the cortex, and then expand into the surrounding soft tissue. The most common symptom which the patient first presents with is localized bone pain. In the temporal bone, the disease first occurs in the mastoid. The osteolytic course then proceeds without pain
EOSINOPHILIC GRANULOMA
23
except for infections. Therefore, the first presenting symptoms are ear polyps, repeated otorrhea, subcutaneous swelling in the mastoid lesion, and hearing impairment. When secondary infections occur, acute mastoiditis is a first picture. Hudson described that despite extensive temporal bone destruction, involvement of the labyrinth is rare, suggesting that the bony labyrinth is extremely resistant to invasion by granulation tissue. However, Van Baade reported a 35-year-old male with a positive fistula sign. Peripheral facial nerve palsy was noted in only 2.4 % of the 500 cases of Hand-Schtiller-Christian disease reviewed by Tos, despite the fact that the nerve was frequently noted during surgery to be exposed and surrounded by the histiocyte proliferation. Our case presented a tumor in the external ear canal without facial nerve palsy, despite noting the facial nerve during surgery. Diagnosis of eosinophilic granuloma. During diagnosis of the pathological feature, that being proliferation of histiocytes, consideration of clinical features is important. In particular, finding the proliferation of Langerhans histiocytes will establish the diagnosis. When Langerhans cells are stained with S-100 immunoreactive protein, positive staining strongly suggests Langerhans cells. As melanocytes, glial cells, and other normal or tumor cells contain S-100 protein, this is not specific for Langerhans cells. Electron microscopy is the most effective in identifying specific granules, those being Birbeck granules, in the cytoplasm of Langerhans cells. When the disease is present in the temporal bone of adults, it is important to differentiate it from cholesteatoma. MAEDA and KODAMA (1980) reported a case of eosinophilic granuloma in the temporal bone with maxillary and mandibular lesion in addition to a lung lesion in a 24-year-old male. In order to differentiate from cholesteatoma and as evidence of eosinophilic granuloma, he pointed out the appearance of granulation tissue in the posterior wall of the external canal, the absence of a perforated eardrum, the absence of a history of otitis media, and the presence of an osteolytic defect without reactive sclerosis in X ray of the temporal bone. X ray provides us with very important information pertaining to the diagnosis of eosinophilic granuloma of the bone. This is because the disease appears in the characteristic form of punched-out lesions in the bone. In the case we examined, the only information we had at the first operation was the histopathological finding because we did not suspect eosinophilic granuloma. Therefore, X ray of neither the skull nor temporal bone was examined. In addition, bone scintigraphy is also helpful in providing information as to the presence of other skeletal lesions. At present, computerized tomography is the best means of conducting imaging examination of the site for surgery. Treatment and prognosis of eosinophilic granuloma. As therapy for eosinophilic granuloma, surgical removal is often selected first in the case of a solitary skeletal lesion, due to the adverse side effects of radiation and chemotherapy such as vinblastin sulfate, prednisolone, methotrexate, or topical nitrogen mustard. Twenty-nine cases of solitary eosinophilic granuloma in the temporal bone re-
24
N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
Table 1.
Treatment for solitary eosinophilic granuloma in the temporal bone of 29 cases. Age
Sex
Presenting symptoms
Therapy
Year
23
M
mastoidectomy+Co 16 Gy
1955
2 3 4 5
7 9 2 45
M M M F
mastoidectomy + Co 10 Gy mastoidectomy + Co 18 Gy mastoidectomy + Co 8 Gy Co 10 Gy
1959 1959 1963 1965
6 7 8 9 10 11 12 13 14
9 7 3 4 2.6 2 4 5 3
F M M F M M M M F
Co 30 Gy Co 40 Gy Co 25 Gy mastoidectomy mastoidectomy+Co 10 Gy mastoidectomy + Co 10 Gy mastoidectomy mastoidectomy mastoidecomy + Co 10 Gy
1966 1966 1968 1968 1971 1971 1973 1973 1974
IS
16
35 1.4
M F
mastoidectomy+Co 20 Gy mastoidectomy + Co 40 Gy
1976 1977
17 18
0.11 24
F M
mastoidectomy mastoidectomy+Co 38 Gy
1977 1979
betamethasone p.o. mastoidectomy+Co 10 Gy
1982 1983
mastoidectomy + Co 14 Gy mastoidectomy + prednisolone injected into the cavity mastoidectomy + prednisolone sodium injected into the cavity mastoidectomy + prednisolone sodium injected into the cavity mastoidectomy + Co 10 Gy + steroid, antihistamine Co 16 Gy
1983 1985
mastoidectomy
1988
mastoidectomy+Co 16 Gy + betamethasone, prednisolone mastoidectomy + betamethasone p.o.
1988
Case
19 20
4 2
F M
21 22
7 5
M M
otorrhea, positive fistula sign pain behind rt. ear, vertigo It. otorrhea rt. otorrhea It. otorrhea, swell behind It. ear mass behind It. ear facial N. palsy mass behind rt. ear swelling behind It. ear rt. otorrhea, dizziness rt. otorrhea, ear pain rt. otorrhea, ear pain rt. otorrhea, ear pain It. otorrhea, swell behind It. ear vertigo mass behind rt. ear, olorrhea, ear pain mass behind rt. ear rt. ear pain, otorrhea, vertigo rt. ex. ear tumor acute mastoiditis, It. otorrhea pain behind rt. ear mass behind rt. ear
23
2
M
rt. ear otorrhea
24
1.6
M
swelling behind rt. ear
25
1.2
F
26
9
F
27
9
F
28
10
M
29 (our case)
4
M
swelling behind rt. ear, otorrhea swelling behind It. ear, repeated otitis rt. hearing impairment, otorrhea It. ear pain, otorrhea, hearing impairment, facial N. palsy rt. otorrhea, ex. ear tumor
1985
1985
1986 1986
1989
EOSINOPHILIC GRANULOMA
25
ported in the literature (TAKIMOTO, NAGAYAMA, MURATA, ISHIBASHI, FURUKAWA, and UMEDA, 1982; FRADlS, PODOSHlN, BEN-DAVID, and GRISHKAN, 1985; SAKUMOTO, FURUKAWA, KAMIIDE, MIYA, and UMEDA, 1988; KAKI, ARISHlGE, NODA, and AKAMIZU, 1988) together with our case were listed up in order to examine the treatment (Table 1). These included single mastoidectomy in 5 cases, single radiation therapy after biopsy in 5 cases, single steroid therapy after biopsy in 1 case, radiation following mastoidectomy in 11 cases, steroid therapy after mastoidectomy in 4 cases including our case, and radiation and steroid therapy after mastoidectomy in 3 cases. No other drugs, such as vinblastin, were used for chemotherapy other than steroids. There was no recurrence in any of the 29 cases following treatment. Mastoidectomy was performed in 23 out of 29 cases. In our case eight months after the second operation, developing granulation was not observed in the right mastoid and the general condition of the patient was satisfactory. In those cases that involve multiple lesions including the temporal bone, there are numerous reports of radiation and chemotherapy being employed following mastoidectomy. In addition, other chemotherapy drugs such as vinblastin and methotrexate are used in combination with steroids, employing methods similar to those used in the treatment of leukemia. The prognosis of solitary eosinophilic granuloma of the bone is favorable, demonstrating a good response to the treatment. However, there is also occasional mUltiple organ involvement in short periods of time. HARTMAN (1980) determined that the recurrence rate for monostatic eosinophilic granuloma is 16 %. Therefore, long-term following of the patient at least for 5 years is considered to be important in cases of eosinophilic granuloma. CONCLUSION
A case of a 4-year-old boy with solitary eosinophilic granuloma in the temporal bone was described. Solitary eosinophilic granuloma of the bone is a rare disease. However, the temporal bone is an affected lesion. Computerized tomography showed destruction of the temporal bone. Histopathological studies revealed histiocytes proliferation and eosinophil infiltration. Birbeck granules were found in the histiocytes under electron microscopy and therefore, the established diagnosis of eosinophilic granuloma, that is Langerhans cell histiocytosis, was made. REFERENCES ABT, A. F.: Letterer-Siwe's disease. Splenohepatomegaly associated with widespread hyperplasia of non lipoid-storing macro phages; discussion of the so-called reticuloendothelioses. Am. J. Dis. Child. 51: 499, 1936. ApPLING, K.: Eosinophilic granuloma in the temporal bone and skull. DlalarYl/gal. Head Neck
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N. WANIFUCHI, Y.lSHIZUKA, and T. YABE
Surg. 91: 358-365, 1983. BASSET, F., and TURIAF, F.: Identification par la microscopie electronique de particules de nature probablement virale dans les lesions granulomateuses dune histiocitose X pulmonaire. Cr. A cad. Sci. 261: 3701-3703, 1965. CHARLES, E., LAWLINGS, IlL, ROBERT, H., and WILKINS.: Solitary eosinophilic granuloma of the skull. Neurosurgery 15: 155-161,1984. CHRISTIAN, H. A.: Defects in membranous bone, exophthalmous and diabetes inspidus; an unusual syndrome of dyspituitalism. Med. Clin. North. Alii. 3: 849, 1919. FRADIS, M., PODOSHIN, BEN-DAVID, J., and GRISHKAN, A.: Clinical records. Eosinophilic granuloma of the temporal bone. J. Laryngol. Otol. 99: 475-479, 1985. HAND, A.: Defects of membranous bones, exophthalmos and polyuria in childhood. Is it dyspituitarism? Am. J. Med. Sci. 162: 509, 1921. HARTMAN, K. S.: Histiocytosis X: a review of 114 cases with oral involvement. Oral SIII·g. Oral Med. Oral Pathol. 49: 38-53, 1980. HUDSON, W. R., and KENAN, P. D.: Otologic manifestations of histiocytosis X. Laryngoscope 25: 678-693, 1969. KAKI, 0., ARISHlGE, S., NODA, M., and AKAMIZU, H.: A case of eosinophilic granuloma of the temporal bone. Pract. Otol. Kyoto 27: 77-82, 1988. LANGERHANS, P.: aber die Nerven der mensch lichen Haut. Virchiws Arch. 44: 325, 1868. LETTERER, E.: Aleukaemische Retikulose. Frank Z. Pathol. 30: 377, 1924. LICHTENSTEIN, L.: Histiocytosis X. Arch. POlhol. 56: 84-102, 1953. LICHTENSTEIN, L., and JAFFE, H. L.: Eosinophilic granuloma of bone; with report of a case. Am. J. Pathol. 16: 595-607, 1940. MAEDA, H., and KODAMA, A.: Diagnosis and treatment of histiocytosis-X of the temporal bone-A case report. J. Otolaryngol. Jpn. 52: 659-665, 1980. OTANI, S., and EHRLICH, J.: Solitary granuloma of bone; simulating primary neoplasm. Alii. J. Palhol. 16: 479-490, 1940. SAKUMOTO, M., FURUKAWA, M., KAMIlDE, M., HIYA, W., and UMEDA, R.: Two cases ofgranulorna with eosinophilic infiltration. O.R.L. Tokyo 31: 695-701, 1988. SBARBARO, J. L., and FRANCIS, K. c.: Eosinophilic granuloma of bone. JAMA 178: 706-710, 1961. SCHULLER, A.: aber eigenartige Schadeldefekte im Jugendalter. Fortschr. Roentgenstr. 23: 12-18, 1915. SILBERBERG, I.: Ultrastructural studies of Langerhans cells in contact sensitive and primary irritant reactions to mercuric chloride. Clill. Res. 19: 715, 1971. SIWE, S. S.: Die Retikuloendotheliose-eine neues krankheitsbild unter den Hepatosplenomegalien. Z. Kinderheilkd. 55: 212, 1933. TAKIMOTO, T., NAGAYAMA, 1., MURATA, S., ISHIBASHI, Y., FURUKAWA, M., and UMEDA, P.: Eosinophilic granuloma of the temporal bone. O.R.L. Tokyo 25: 41-45, 1982. TOOHILL, R. J., KIDDER, T. M., and EBY, L. G.: Eosinophilic granuloma of the temporal bone. Laryngoscope 83: 877-889, 1973. Tos, M.: A Survey of Hand-Schuller Christian disease in otolaryngology. Acta Ololaryngol. 62: 217-228, 1966. WILLIAM, K., and CHARLES, P.: Eosinophilic granuloma. Oral Surg. 65: 736-741, 1988.
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Dr. N. Wanifuchi, Department of Otolaryngology, Mizonokuchi Hospital, Teikyo University School of Medicine, 74 Mizonokuchi, Takatsu-ku, Kawasaki, Kanagawa 213, Japan
A CASE OF EOSINOPHILIC GRANULOMA IN THE TEMPORAL BONE Nobuko
M.D., Yoichi ISHlZUKA, M.D., and Takao YABE, M.D.
WANIFUCHI,
Department 0/ Otolaryngology, Mizonokuchi Hospital, Teikyo University School 0/ Medicine, Kawasaki, Japan
The following case reports a 4-year-old boy with a solitary eosinophilic granuloma in the right temporal bone. The patient complained of an inflammatory tumor in the right external ear canal. The histopathological diagnosis made based on the first specimen of the tumor in the right ear canal was foreign body granuloma. A polyp developed again in the right ear canal with postauricular swelling. Computerized tomography of the skull at that time showed an osteolytic defect in the right temporal bone filled with soft tissue. Diagnosis was established by finding of the presence of Birbeck granules in Langerhans histiocytes by electron microscopy. Eosinophilic granuloma of the bone is a rare benign disease which is characterized by single or multiple osteolytic skeletal lesions. It affects children less than 15 years old and the temporal bone is one of the affected skeletal lesions. The etiology remains unknown. However, its histopathology shows non-neoplastic abnormal proliferation of Langerhans histiocytes, which play an important role in contact dermatitis and tumor immunology. Therefore, an immunological disorder has been suggested for pathogenesis of this disease in recent years. CASE
A 4-year-old boy complained of a tumor following drainage in the right external ear canal. He had suffered a wound on the right posterior meatal wall I week earlier, which occurred during cleaning of the ear. Although the tumor had been removed twice at another clinic, it developed again. The patient was admitted to our clinic for treatment of the tumor. The patient had no other serious diseases and the family history was unremarkable. A white edematous polyp following serous drainage filled the right external ear canal and the eardrum Received for publication June 14, 1990 17
18
N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
was not seen. Chest X-ray and laboratory examinations were all within normal limits. Suspecting an inflammatory polyp, it was removed through the right meatal canal under general anesthesia. The polyp was located on the posterior meatal wall and consisted of granulation tissue invading into subcutaneous area. The eardrum was normal. Histopathological features revealed histiocyte infiltration with a few multinucleated giant cells in fibrous stroma without distinct eosinophil infiltration (Fig. 1). The diagnosis made at that time was foreign body granuloma. In a few weeks after the first operation, a polyp developed again in the right meatal canal following drainage with postauricular swelling. Results of computerized tomography of the skull showed an osteolytic defect in the right temporal bone filled with soft tissue. A mass of soft tissue was also observed in the extracranial mastoid lesion (Fig. 2a). Computerized tomography of the right temporal bone revealed an extensive osteolytic defect filled with soft tissue in the right mastoid and middle ear cavity (Fig. 2b). Angiograms revealed no abnormal tumor staining in the intra- and extracranial lesions. Three months after the first operation, the right mastoid was explored and a large bony defect in the mastoid was observed filled with a dark red, soft material. The dura mater was observed in the tegmen and posterior part of the temporal bone. In the middle ear the facial nerve, chorda tympani, incus, and stapes were enveloped with granulation tissue. Invasion into the labyrinth was not observed. The malleus and eardrum were intact except for partial thickening in the mucosal layer of the eardrum. The tissue was removed and a simple mastoidectomy was performed. Light microscopic histopathological studies using H-E staining revealed remarkable proliferation of histiocytes with abundant eosinophils (Fig. 3a). S-100 protein staining revealed a number of positive stained cells (Fig. 3b). In the transmission electron microscopic specimens, Birbeck granules were observed in the cell cyto-
Fig. 1. Photomicrograph of specimen in the right external ear canal at first operation. Histiocytes infiltrate following poly nucleated giant cells. Eosinophil infiltration is not remarkable (H-E stain, original x 100).
EOSINOPHILIC GRANULOMA
Fig. 2. a: Computerized tomography of the skul!. An osteolytic defect in the right tern· poral bone filled with soft tissue and a mass of soft tissue in the extracranial temporal bone are demonstrated. b: Computerized tomography of the temporal bone. An osteolytic defect in the right mastoid filled with soft tissue expanding into external ear canal (left: normal side).
Fig. 3. a: Photomicrograph of specimen in the right mastoid at second operation. Distinct proliferation of histiocytes following numerous eosinophils is demonstrated (H·E stain, original x 100). b: Photomicrograph of specimen in the right mastoid. Specimen stained with S-IOO protein shows numerous positive stained histiocytes (immunoperoxidase stain with S-IOO protein, original x 200). c: Photoelectron micrograph : Specific Birbeck granule ( ... ) in cytoplasm identifies the cell as Langerhans histiocyte (original x 30,000).
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N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
cell cytoplasm (Fig. 3c). Based on this, the histiocytes were identified as Langerhans cells. Diagnosis was established to be eosinophilic granuloma. Following diagnosis, the patient was treated with 1 mg of betamethasone and 600 mg of AMPC daily. He appeared moon-faced approximately 1 month after beginning of treatment. Following that time, he has been observed without medication. COMMENTS AND DISCUSSION
Histiocytosis X. Following considerable observation, there emerged in 1940 a provisional new concept of the conditions previously designated as eosinophilic granuloma of the bone, Letterer-Siwe disease and Hand-Schuller-Christian disease, in which these conditions were revealed to be interrelated expressions of the same malady. LICHTENSTEIN (1953) gave the name Histiocytosis X to these three diseases in all of which the abnormal proliferation of histiocytes appears. He and many other pathologists believed that the three conditions appear at different stages of one disease, that being a distinctive and specific non-neoplastic histiocytosis whatever the etiologic agent may ultimately be proved to be. Eosinophilic granuloma of the bone is characterized as a solitary or mUltiple osteolytic skeletal lesion. LICHTENSTEIN and JAFFE (1940) reported a solitary tumor in the femur which they referred to as eosinophilic granuloma of the bone. In the same year, OTANI and EHRLICH (1940) described solitary granuloma of the bone in four cases located in the rib and scapula. Hand-Schuller-Christian disease originally referred to the classic triad of a bony defect in the skull, exophthalmous and diabetes inspidus, which is caused by thalamus invasion. HAND (1921) reported the case of a 3-year-old child with hepatomegaly, splenomegaly, lymphadenopathy, exophthalmous, polyuria, bony defect in the skull. SCHULLER (1915) and CHRISTIAN (1919) also reported similar cases. SIWE (1933) referred to the disease, which was characterized by the classic triad, as Hand-Schuller-Christian disease. In the Histiocytosis X grouped by Lichtenstein, the disease is characterized by invasion of multiple organs including both skeletal and extraskeletal lesions. In addition, the classic triad appears in less than 10% (HUDSON and KENAN, 1969). As multiple organs are invaded at various times, a chronic course appears. It affects both children and young adults and the mortality rate is 15-30% (HUDSON and KENAN, 1969). Mortality rate is dependent upon low age and the affected organs such as the lung, liver, blood, as well as infections. Histopathology reveals proliferation of histiocytes with foam cells which are lipidated histiocytes. As a result, Hand-SchUller-Christian disease is occasionally referred to as xanthogranuloma. In Letterer-Siwe disease, systemic proliferation of histiocytes appears in acute or subacute course distinctively in infants or children, especially those under the age of three, and usually has a fatal outcome. LETTERER (1924) reported the case of a 6-year-old child with fever, purulent otitis, lymphadenopathy, hepato-
EOSINOPHILIC GRANULOMA
21
splenomegaly, and general bleeding, who expired rapidly. SIWE (1933) described similar conditions in a 16-year-old child. ABT (1936) believed that these conditions were a new disease with unknown etiology and gave it the name of LettererSiwe disease. The systemic course of the disease, which involves bone destruction, lymphadenopathy, hepatosplenomegaly, skin lesions, diffuse pulmonary involvement, thrombocytopenia, and anemia, proceeds dramatically. Histopathology reveals distinct proliferation of histiocytes, including Letterer cells, which are large histiocytes. Etiology of Histiocytosis X. The term Histiocytosis X for the three diseases is accepted even now as a disease which presents with similar histopathology (i.e. non-neoplastic proliferation of histiocytes) even though there have been numerous papers in opposition to the same pathogenesis because both their clinical and histopathological features are so different. This is especially true in the case of eosinophilic granuloma and Letterer-Siwe disease. Whether or not the three diseases have the same etiology remains unclear even at present. These histiocytes that proliferate in Histiocytosis X are identified as Langerhans cells after BASSET and TURIAF (1965) demonstrated Birbeck granules in the histiocytes of pulmonary eosinophilic granuloma. Therefore, the disease is also called Langerhans cell histiocytosis. Langerhans cells were first described in the skin by LANGERHANS (1868). Their role was long obscure. However, the immunological function of these cells has been greatly elucidated over the past 10 years. Langerhans cells are lineaged from macrophage-monocytes and play a major role in immunoregulation during contact allergies in the skin (SILBERBERG, 1971). They are bone marrow derived cells and are found in the skin, lymph nodes, thyroid, mucosa, and vagina. Most patients with disseminated Histiocytosis X exhibit an increased T-Iymphocyte helper (T4) to suppressor (T8) ratio due to deficiency of circulating suppressor lymphocytes . In addition, abnormal changes in thymic biopsies have also been reported in malignant tumors. The role of Langerhans cells in malignant tumors is thought to be similar to the role they have in T-cell activation against human tumors. Due to the tumor proliferation of Langerhans histiocytes related to immunoreaction and the non-neoplastic histopathological appearance, the pathogenesis of Histiocytosis X is thought to be an immunological disorder or immunological response to uncertain stimulations. Eosinophilic granuloma. Eosinophilic granuloma affects young children. SBARBARO (1961) reported 34 % were younger than the age of 4 and 74 % were younger than the age of 20 years in 50 patients . In addition, many papers have reported that the disease indicates male predominance (2: I). Our patient was also a 4-year-old boy. The skull, temporal bone, and mandible are the affecting skeletal lesions in head and neck, and bones of extremities, ribs and pelvis are also affected in the body. The disease also occurs in soft tissue. Isolated cases of eosinophilic
22
N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
granuloma have also been reported in the lung, thyroid, skin, gastrointestinal tract, lymph nodes, thymus, and bladder. However, such cases are extremely rare. A disease that is occasionally reported as eosinophilic granuloma of soft tissue such as the parotid gland or lymph nodes, and presents with lymph follicular formation and eosinophilic infiltration is different from the eosinophilic granuloma in Histiocytosis X. The disease is named Kimura disease. Although the etiology of this disease also remains unclear, close correlation with allergy-I is suggested with eosinophils and IgE often increasing in the peripheral blood. In lesions of the skull, the incidence of eosinophilic granuloma following trauma was reported to be 38 % (CHARLES, LA WLINGS, ROBERT, and WILKINS, 1984). However, there have been no papers published relating to trauma in the temporal bone. In our case, there was trauma in the canal wall 1 week prior to the occurrence of the tumor. As pathogenesis is thought to be related to immunological reaction, the possibility that trauma acted as a triggering factor for eosinophilic granuloma cannot be overlooked. Temporal bone is one of the affected skeletal lesions. Bilateral temporal bone involvement also occurs. TOOHILL, KIDDER, and EBY (1973) reported a unifocallesion in 11 and bilateral involvement in 5 out of 15 cases of eosinophilic granuloma in the temporal bone. Hand-Schuller-Christian disease often occurs at first in a solitary skeletal lesion and therefore is diagnosed as eosinophilic granuloma. Later other organs are invaded, and then the diagnosis of HandSchuller-Christian disease is established. ApPLING (1983) reported that 7 out of 22 cases (32 %) appeared with multiple lesions 1-5 months after the first diagnosis of solitary eosinophilic granuloma. TOOHILL et al. (1973) described that the incidence of solitary eosinophilic granuloma appearing later with general dissemination or multiple lesions is 30-35 %. WILLIAM and CHARLES (1988) described that the differential diagnosis between unifocal and multi focal presentation is determined by an initial bone scan and by the presence or absence of new lesions over a 12-month period. The incidence of aural and temporal bone involvement in Hand-Schuller-Christian disease has been found to be relatively high at 20-40 %. In the review (Tos, 1966), 61 % of the 500 cases of the disease demonstrated aural and temporal bone manifestations. Also in LettererSiwe disease, temporal bone is one of the systemic lesions that is frequently affected, appearing as otitis media. HUDSON and KENAN (1969) reported the case of a lO-month-old male who initially complained of bilateral draining from ears with granulation tissue on the right external canal. This rapidly developed into systemic involvement. Symptoms of eosinophilic granuloma. In eosinophilic granuloma of the bone, skeletal lesions begin in the marrow, gradually erode the cortex, and then expand into the surrounding soft tissue. The most common symptom which the patient first presents with is localized bone pain. In the temporal bone, the disease first occurs in the mastoid. The osteolytic course then proceeds without pain
EOSINOPHILIC GRANULOMA
23
except for infections. Therefore, the first presenting symptoms are ear polyps, repeated otorrhea, subcutaneous swelling in the mastoid lesion, and hearing impairment. When secondary infections occur, acute mastoiditis is a first picture. Hudson described that despite extensive temporal bone destruction, involvement of the labyrinth is rare, suggesting that the bony labyrinth is extremely resistant to invasion by granulation tissue. However, Van Baade reported a 35-year-old male with a positive fistula sign. Peripheral facial nerve palsy was noted in only 2.4 % of the 500 cases of Hand-Schtiller-Christian disease reviewed by Tos, despite the fact that the nerve was frequently noted during surgery to be exposed and surrounded by the histiocyte proliferation. Our case presented a tumor in the external ear canal without facial nerve palsy, despite noting the facial nerve during surgery. Diagnosis of eosinophilic granuloma. During diagnosis of the pathological feature, that being proliferation of histiocytes, consideration of clinical features is important. In particular, finding the proliferation of Langerhans histiocytes will establish the diagnosis. When Langerhans cells are stained with S-100 immunoreactive protein, positive staining strongly suggests Langerhans cells. As melanocytes, glial cells, and other normal or tumor cells contain S-100 protein, this is not specific for Langerhans cells. Electron microscopy is the most effective in identifying specific granules, those being Birbeck granules, in the cytoplasm of Langerhans cells. When the disease is present in the temporal bone of adults, it is important to differentiate it from cholesteatoma. MAEDA and KODAMA (1980) reported a case of eosinophilic granuloma in the temporal bone with maxillary and mandibular lesion in addition to a lung lesion in a 24-year-old male. In order to differentiate from cholesteatoma and as evidence of eosinophilic granuloma, he pointed out the appearance of granulation tissue in the posterior wall of the external canal, the absence of a perforated eardrum, the absence of a history of otitis media, and the presence of an osteolytic defect without reactive sclerosis in X ray of the temporal bone. X ray provides us with very important information pertaining to the diagnosis of eosinophilic granuloma of the bone. This is because the disease appears in the characteristic form of punched-out lesions in the bone. In the case we examined, the only information we had at the first operation was the histopathological finding because we did not suspect eosinophilic granuloma. Therefore, X ray of neither the skull nor temporal bone was examined. In addition, bone scintigraphy is also helpful in providing information as to the presence of other skeletal lesions. At present, computerized tomography is the best means of conducting imaging examination of the site for surgery. Treatment and prognosis of eosinophilic granuloma. As therapy for eosinophilic granuloma, surgical removal is often selected first in the case of a solitary skeletal lesion, due to the adverse side effects of radiation and chemotherapy such as vinblastin sulfate, prednisolone, methotrexate, or topical nitrogen mustard. Twenty-nine cases of solitary eosinophilic granuloma in the temporal bone re-
24
N. WANIFUCHI, Y. ISHIZUKA, and T. YABE
Table 1.
Treatment for solitary eosinophilic granuloma in the temporal bone of 29 cases. Age
Sex
Presenting symptoms
Therapy
Year
23
M
mastoidectomy+Co 16 Gy
1955
2 3 4 5
7 9 2 45
M M M F
mastoidectomy + Co 10 Gy mastoidectomy + Co 18 Gy mastoidectomy + Co 8 Gy Co 10 Gy
1959 1959 1963 1965
6 7 8 9 10 11 12 13 14
9 7 3 4 2.6 2 4 5 3
F M M F M M M M F
Co 30 Gy Co 40 Gy Co 25 Gy mastoidectomy mastoidectomy+Co 10 Gy mastoidectomy + Co 10 Gy mastoidectomy mastoidectomy mastoidecomy + Co 10 Gy
1966 1966 1968 1968 1971 1971 1973 1973 1974
IS
16
35 1.4
M F
mastoidectomy+Co 20 Gy mastoidectomy + Co 40 Gy
1976 1977
17 18
0.11 24
F M
mastoidectomy mastoidectomy+Co 38 Gy
1977 1979
betamethasone p.o. mastoidectomy+Co 10 Gy
1982 1983
mastoidectomy + Co 14 Gy mastoidectomy + prednisolone injected into the cavity mastoidectomy + prednisolone sodium injected into the cavity mastoidectomy + prednisolone sodium injected into the cavity mastoidectomy + Co 10 Gy + steroid, antihistamine Co 16 Gy
1983 1985
mastoidectomy
1988
mastoidectomy+Co 16 Gy + betamethasone, prednisolone mastoidectomy + betamethasone p.o.
1988
Case
19 20
4 2
F M
21 22
7 5
M M
otorrhea, positive fistula sign pain behind rt. ear, vertigo It. otorrhea rt. otorrhea It. otorrhea, swell behind It. ear mass behind It. ear facial N. palsy mass behind rt. ear swelling behind It. ear rt. otorrhea, dizziness rt. otorrhea, ear pain rt. otorrhea, ear pain rt. otorrhea, ear pain It. otorrhea, swell behind It. ear vertigo mass behind rt. ear, olorrhea, ear pain mass behind rt. ear rt. ear pain, otorrhea, vertigo rt. ex. ear tumor acute mastoiditis, It. otorrhea pain behind rt. ear mass behind rt. ear
23
2
M
rt. ear otorrhea
24
1.6
M
swelling behind rt. ear
25
1.2
F
26
9
F
27
9
F
28
10
M
29 (our case)
4
M
swelling behind rt. ear, otorrhea swelling behind It. ear, repeated otitis rt. hearing impairment, otorrhea It. ear pain, otorrhea, hearing impairment, facial N. palsy rt. otorrhea, ex. ear tumor
1985
1985
1986 1986
1989
EOSINOPHILIC GRANULOMA
25
ported in the literature (TAKIMOTO, NAGAYAMA, MURATA, ISHIBASHI, FURUKAWA, and UMEDA, 1982; FRADlS, PODOSHlN, BEN-DAVID, and GRISHKAN, 1985; SAKUMOTO, FURUKAWA, KAMIIDE, MIYA, and UMEDA, 1988; KAKI, ARISHlGE, NODA, and AKAMIZU, 1988) together with our case were listed up in order to examine the treatment (Table 1). These included single mastoidectomy in 5 cases, single radiation therapy after biopsy in 5 cases, single steroid therapy after biopsy in 1 case, radiation following mastoidectomy in 11 cases, steroid therapy after mastoidectomy in 4 cases including our case, and radiation and steroid therapy after mastoidectomy in 3 cases. No other drugs, such as vinblastin, were used for chemotherapy other than steroids. There was no recurrence in any of the 29 cases following treatment. Mastoidectomy was performed in 23 out of 29 cases. In our case eight months after the second operation, developing granulation was not observed in the right mastoid and the general condition of the patient was satisfactory. In those cases that involve multiple lesions including the temporal bone, there are numerous reports of radiation and chemotherapy being employed following mastoidectomy. In addition, other chemotherapy drugs such as vinblastin and methotrexate are used in combination with steroids, employing methods similar to those used in the treatment of leukemia. The prognosis of solitary eosinophilic granuloma of the bone is favorable, demonstrating a good response to the treatment. However, there is also occasional mUltiple organ involvement in short periods of time. HARTMAN (1980) determined that the recurrence rate for monostatic eosinophilic granuloma is 16 %. Therefore, long-term following of the patient at least for 5 years is considered to be important in cases of eosinophilic granuloma. CONCLUSION
A case of a 4-year-old boy with solitary eosinophilic granuloma in the temporal bone was described. Solitary eosinophilic granuloma of the bone is a rare disease. However, the temporal bone is an affected lesion. Computerized tomography showed destruction of the temporal bone. Histopathological studies revealed histiocytes proliferation and eosinophil infiltration. Birbeck granules were found in the histiocytes under electron microscopy and therefore, the established diagnosis of eosinophilic granuloma, that is Langerhans cell histiocytosis, was made. REFERENCES ABT, A. F.: Letterer-Siwe's disease. Splenohepatomegaly associated with widespread hyperplasia of non lipoid-storing macro phages; discussion of the so-called reticuloendothelioses. Am. J. Dis. Child. 51: 499, 1936. ApPLING, K.: Eosinophilic granuloma in the temporal bone and skull. DlalarYl/gal. Head Neck
26
N. WANIFUCHI, Y.lSHIZUKA, and T. YABE
Surg. 91: 358-365, 1983. BASSET, F., and TURIAF, F.: Identification par la microscopie electronique de particules de nature probablement virale dans les lesions granulomateuses dune histiocitose X pulmonaire. Cr. A cad. Sci. 261: 3701-3703, 1965. CHARLES, E., LAWLINGS, IlL, ROBERT, H., and WILKINS.: Solitary eosinophilic granuloma of the skull. Neurosurgery 15: 155-161,1984. CHRISTIAN, H. A.: Defects in membranous bone, exophthalmous and diabetes inspidus; an unusual syndrome of dyspituitalism. Med. Clin. North. Alii. 3: 849, 1919. FRADIS, M., PODOSHIN, BEN-DAVID, J., and GRISHKAN, A.: Clinical records. Eosinophilic granuloma of the temporal bone. J. Laryngol. Otol. 99: 475-479, 1985. HAND, A.: Defects of membranous bones, exophthalmos and polyuria in childhood. Is it dyspituitarism? Am. J. Med. Sci. 162: 509, 1921. HARTMAN, K. S.: Histiocytosis X: a review of 114 cases with oral involvement. Oral SIII·g. Oral Med. Oral Pathol. 49: 38-53, 1980. HUDSON, W. R., and KENAN, P. D.: Otologic manifestations of histiocytosis X. Laryngoscope 25: 678-693, 1969. KAKI, 0., ARISHlGE, S., NODA, M., and AKAMIZU, H.: A case of eosinophilic granuloma of the temporal bone. Pract. Otol. Kyoto 27: 77-82, 1988. LANGERHANS, P.: aber die Nerven der mensch lichen Haut. Virchiws Arch. 44: 325, 1868. LETTERER, E.: Aleukaemische Retikulose. Frank Z. Pathol. 30: 377, 1924. LICHTENSTEIN, L.: Histiocytosis X. Arch. POlhol. 56: 84-102, 1953. LICHTENSTEIN, L., and JAFFE, H. L.: Eosinophilic granuloma of bone; with report of a case. Am. J. Pathol. 16: 595-607, 1940. MAEDA, H., and KODAMA, A.: Diagnosis and treatment of histiocytosis-X of the temporal bone-A case report. J. Otolaryngol. Jpn. 52: 659-665, 1980. OTANI, S., and EHRLICH, J.: Solitary granuloma of bone; simulating primary neoplasm. Alii. J. Palhol. 16: 479-490, 1940. SAKUMOTO, M., FURUKAWA, M., KAMIlDE, M., HIYA, W., and UMEDA, R.: Two cases ofgranulorna with eosinophilic infiltration. O.R.L. Tokyo 31: 695-701, 1988. SBARBARO, J. L., and FRANCIS, K. c.: Eosinophilic granuloma of bone. JAMA 178: 706-710, 1961. SCHULLER, A.: aber eigenartige Schadeldefekte im Jugendalter. Fortschr. Roentgenstr. 23: 12-18, 1915. SILBERBERG, I.: Ultrastructural studies of Langerhans cells in contact sensitive and primary irritant reactions to mercuric chloride. Clill. Res. 19: 715, 1971. SIWE, S. S.: Die Retikuloendotheliose-eine neues krankheitsbild unter den Hepatosplenomegalien. Z. Kinderheilkd. 55: 212, 1933. TAKIMOTO, T., NAGAYAMA, 1., MURATA, S., ISHIBASHI, Y., FURUKAWA, M., and UMEDA, P.: Eosinophilic granuloma of the temporal bone. O.R.L. Tokyo 25: 41-45, 1982. TOOHILL, R. J., KIDDER, T. M., and EBY, L. G.: Eosinophilic granuloma of the temporal bone. Laryngoscope 83: 877-889, 1973. Tos, M.: A Survey of Hand-Schuller Christian disease in otolaryngology. Acta Ololaryngol. 62: 217-228, 1966. WILLIAM, K., and CHARLES, P.: Eosinophilic granuloma. Oral Surg. 65: 736-741, 1988.
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Dr. N. Wanifuchi, Department of Otolaryngology, Mizonokuchi Hospital, Teikyo University School of Medicine, 74 Mizonokuchi, Takatsu-ku, Kawasaki, Kanagawa 213, Japan
