Multiple system Erdheim—Chester disease with massive hypothalamic—sellar involvement and hypopituitarism

Case report and review of the literature

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✓ Erdheim—Chester disease (ECD) is a rare multiple system histiocytosis that is characterized pathologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The diagnosis is often confirmed by biopsy of bone or of orbital or retroperitoneal soft tissue. Intracranial involvement is rare. The authors report a case of ECD in which the diagnosis was made after biopsy of a hypothalamic mass. The mass had been discovered during a workup for panhypopituitarism in a 55-year-old man with urological and bone disease. Aside from diabetes insipidus, other features of pituitary insufficiency have seldom been reported and no patients have presented with a hypothalamic tumor. The endocrinological and neurological aspects of ECD are discussed, as is its differential diagnosis. Reported cases of the disorder associated with hypopituitarism or found during biopsy of central nervous system structures are also reviewed.

Abstract

✓ Erdheim—Chester disease (ECD) is a rare multiple system histiocytosis that is characterized pathologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The diagnosis is often confirmed by biopsy of bone or of orbital or retroperitoneal soft tissue. Intracranial involvement is rare. The authors report a case of ECD in which the diagnosis was made after biopsy of a hypothalamic mass. The mass had been discovered during a workup for panhypopituitarism in a 55-year-old man with urological and bone disease. Aside from diabetes insipidus, other features of pituitary insufficiency have seldom been reported and no patients have presented with a hypothalamic tumor. The endocrinological and neurological aspects of ECD are discussed, as is its differential diagnosis. Reported cases of the disorder associated with hypopituitarism or found during biopsy of central nervous system structures are also reviewed.

Erdheim—Chester disease is a multiple organ histiocytosis that is characterized pathologically by xanthogranulomatous infiltrates and is defined clinically and radiologically by bone involvement. Symmetrical sclerosis of bones is a constant and pathognomic finding. Increased uptake of tracer on bone scans is also characteristic. Visceral involvement varies, but is observed in more than half of the cases. Sites commonly affected include the retroperitoneum, kidneys, orbits, skin, pericardium, and lungs. Involvement of the CNS takes the form of dural and parenchymal infiltrates. Diffuse or localized, the latter tend to involve the cerebellum, brainstem, region of the hypothalamus/pituitary, and cerebrum. Histopathological verification of a diagnosis of ECD usually involves biopsy of bone, skin, and orbital or retroperitoneal lesions.

Neurological involvement usually produces DI or cerebellar—brainstem symptoms. Less frequent signs are unifocal or multifocal deficits in cerebral function. Computerized tomography and MR imaging typically demonstrate CNS abnormalities. Postmortem studies are few.1,4,7,13

Neurosurgical biopsies have seldom been documented and none in the setting of a hypothalamic tumor and hypopituitarism. In this paper we report the case of a 55-year-old man with a 7-year history of DI, in whom panhypopituitarism and hyperprolactinemia developed as well as progressive retroperitoneal and bone disease. The diagnosis of ECD was made on biopsy of a hypothalamic mass. A retrospective review of bone radiographs and neuroimages confirmed the diagnosis.

Case Report
History

This 55-year-old retired Chinese businessman presented in June 1999 with the complaint of months of lethargy, 1 year of episodic low-grade fevers, and 2 years of bone pain. He had experienced polyuria and polydipsia due to DI for 7 years and had responded well to desmopressin treatment. In 1994 a head CT scan had been performed and the results were reportedly normal. In 1995, the patient began to experience progressive renal impairment and hydronephrosis, leading to the necessity of intermittent ureteric stenting and, over the past year, peritoneal dialysis.

In 1998, the patient first noted bilateral hip and thigh pain in addition to decreased libido, impotence, lethargy, and weight loss. Hypopituitarism was confirmed by laboratory findings, including the following concentrations of hormones: thyroxine at 3.3 µg/dl (normal 4.5–12 µg/dl), TSH at 1.45 mIU/L (normal 0.4–4.7 mIU/L), FSH at 0.9 IU/L (normal 1–12 IU/L), LH less than 0.1 IU/L (normal 1–12 IU/L), testosterone at 0.2 nmol/L (normal 8.4–28.7 nmol/L), serum hormone-binding globulin at 34 nmol/L (normal 17–57 nmol/L), and a free androgen index of 0.6 (normal 18–210). The patient's serum prolactin level was increased to 41.1 µg/L (normal 1.6–18.8 µg/L). Correlating with the low-grade fever (38°C) was a markedly elevated erythrocyte sedimentation rate of 137 mm/hour.

The patient's symptoms were relieved by medical treatment consisting of hormone replacement therapy (cortisone acetate 12.5 mg twice daily and thyroxine 0.1 mg once daily).

Examination

When the patient presented to us in 1999, he was thin with a sallow complexion and minimal body hair. Ophthalmological examination yielded normal findings, but bitemporal hemianopsia was noted during visual field testing. The patient's neurological examination was unremarkable. His prostate was small, as were his testes (6 cm3 each).

Laboratory abnormalities included anemia with a hemoglobin level of 10 g/dl (normal 13–18 g/dl) and elevated serum levels of creatinine at 168 µmol/L (normal 88–132 µmol/L) and uric acid at 14.9 mg/dl (normal 4.3–8 mg/dl). Urea, sodium, potassium, and glucose levels were normal. Pituitary insufficiency was again documented, with concentrations of LH lower than 0.07 mIU/ml (normal 1.5–9.3 mIU/ml), FSH at 0.7 mIU/ml (normal 1.4–18.1 mIU/ml), ACTH lower than 10 mIU/L (normal 10–46 mIU/L), GH lower than 0.13 mIU/L (normal 0.16–13 mIU/L), TSH at 0.06 mIU/ml (normal 0.47–5.01 mIU/ml), thyroxine at 81 nmol/L (normal 57–141 nmol/L), and testosterone at 0.1 ng/ml (normal 2.7–10.7 ng/ml). Again the serum prolactin level was elevated to 39.2 ng/ml (normal 2.1–17.7 ng/ml). Central DI was also confirmed by an elevated serum osmolality of 318 mmol/kg (normal 275–295 mmol/kg), and an overnight water deprivation test revealed persistent diuresis (200 ml/hour) at an osmolality of 140 mmol/kg in the face of a plasma osmolality of 310 mmol/kg.

Chest x-ray films appeared normal, aside from an old fracture of the right seventh rib. Although an intravenous urogram showed bilateral hydronephrosis with poor excretion from the left kidney, there was good clearance of contrast agent following intravenous administration of Lasix (40 mg). A CT scan of the abdomen revealed an extensive abnormality of the perirenal spaces and paraaortic regions, wherein the ureters were encased by ill-defined tissue of increased density. This was interpreted as retroperitoneal fibrosis. The cytological findings of a specimen obtained by fine-needle aspiration of the perirenal space were nondiagnostic. Radiographs revealed extensive sclerosis of both femoral necks without an associated periosteal or soft-tissue abnormality. Lytic lesions were also noted in the neck of the right femur. The heads of both femurs and the lumbar vertebrae were unremarkable. The possibility of a metabolic bone disease was raised when an isotopic bone scan showed increased uptake of tracer in the patient's shoulders, hips, and knees bilaterally.

Magnetic resonance imaging of the head (Fig. 1) revealed a homogeneously enhancing suprasellar mass measuring approximately 18 mm, which displayed intermediate signal intensity on T2-weighted images. The mass extended from the infundibulum to the hypothalamus, superiorly displacing the floor of the third ventricle. It also extended anterolaterally, resulting in enlargement and enhancement of the optic nerves and chiasm. The pituitary fossa appeared normal. The remainder of the brain was unremarkable. Leading diagnostic considerations included a granulomatous disease, such as sarcoidosis or tuberculosis, and tumor, particularly LC histiocytosis or lymphoma.

Fig. 1.
Fig. 1.

Preoperative contrast-enhanced MR images revealing a discrete, bosselated intra- and suprasellar tumor that is enhancing.

Operation

A right pterional craniotomy with complete resection of the suprasellar tumor was performed. Supplied by branches of the internal carotid artery, the tumor was well defined, soft, and yellow.

Postoperative Course

Displaying no deterioration of neurological function, the patient was discharged 1 week after surgery. Hormone replacement included cortisone acetate (25 mg every morning and 12.5 mg every night), thyroxine (0.1 mg daily), desmopressin (0.1 mg daily), and testosterone esters (250 mg delivered by injection monthly).

Because no reported treatment strategies, including steroid medications, chemotherapy, or radiotherapy, had resulted in more than temporary or minimum relief of symptoms, our patient chose not to undergo further treatment. At his most recent follow-up examination, performed 16 months following the craniotomy, he complained of progressive bone pain. Although an MR image of the head revealed no residual or recurrent mass in the hypothalamic region, new, diffuse enhancing infiltrates of the meninges developed (Fig. 2). Absence of the normally bright signal of the posterior pituitary was also noted. Fully 8 years after onset of DI, our patient is alive and receiving hormone replacement therapy.

Fig. 2.
Fig. 2.

Follow-up contrast-enhanced MR images demonstrating no regrowth of residual sellar disease. Nonetheless, new, diffuse, enhancing meningeal lesions became apparent.

Pathological Findings

Macroscopically, the tumor consisted of a soft, tannish yellow, 1.7-cm lobulated tissue fragment. Histologically, it was composed of sheets of foamy histiocytes with abundant cytoplasms demonstrating variable lipidization and small, round nuclei lacking grooves or atypia. Scattered multinuclear Touton-type giant cells were also noted, as were aggregates of mature lymphocytes and rare eosinophils (Fig. 3). Fibrosis and gliosis were focally noted.

Fig. 3.
Fig. 3.

Photomicrographs. Upper: Histologically, the somewhat lobular infiltrate consists of mononuclear and scattered multinuclear histiocytes accompanied by patchy lymphocytic inflammation. H & E, original magnification × 160. Lower: At a higher magnification, the histiocytes feature uniform, round-to-oval and somewhat hyperchromatic nuclei, as well as cytoplasms that centrally are granular to hyaline and peripherally pale. H & E, original magnification × 400.

Immunostains confirmed the histiocytic nature of the mono- and multinuclear cells, which stained strongly and diffusely for CD68 (Fig. 4). Both S-100 protein (polyclonal, dilution 1:800; Dako Corp, Carpinteria, CA) and CD1a (monoclonal, dilution 1:5; Immunotech/Coulter, Westbrook, ME), markers of LCs, were negative. The cells also proved to be negative for CD30 (monoclonal, dilution 1:150), CD20 (monoclonal, dilution 1:60), ALK-1 (monoclonal, dilution 1:20), myeloperoxidase (polyclonal, dilution 1:5000), and glial fibrillary acidic protein (polyclonal, dilution 1:800; all antibodies purchased from Dako Corp.). Neurofilament protein staining highlighted the expansive rather than infiltrative nature of the lesion: the axons were displaced to the periphery of the lesion. No organisms were noted on methenamine-silver stains for fungi or on acid-fast and auramine—rhodamine stains for tubercle bacilli.

Fig. 4.
Fig. 4.

Photomicrograph showing widespread staining of both mono- and multinuclear histiocytes. Immunostains for CD68 (KP-1), original magnification × 250.

Ultrastructural examination confirmed the presence of mono- and multinuclear cells with features of histiocytes (Fig. 5). The cytoplasm contained a small quantity of lysosomes as well as lipid droplets. Intermediate filaments were occasionally seen dispersed in whorls. No characteristic inclusions were noted to suggest a specific storage disease. Birbeck granules were lacking.

Fig. 5.
Fig. 5.

Electron micrograph demonstrating that both mono- and multinuclear histiocytes are filled with lysosomes. There are few intermediate filaments (arrows) and no Birbeck granules. Original magnification × 25,000.

Given the pathological features of the brain biopsy, the patient's clinical history, and the radiographic features of the long-bone lesions, a firm diagnosis of ECD was established. Nevertheless, other xanthogranulomatous processes were considered in the differential diagnosis. Although usually diseases of children, these included juvenile xanthogranuloma, multiple system reticulohistiocytosis, and hemophagocytic lymphohistiocytosis. Rosai—Dorfman disease was also considered, but was excluded because of the lack of emperipolesis and S-100 protein immunostaining. In light of the patient's clinical history, strong consideration was given to LC histiocytosis; however, this was excluded because of the lack of the histological, immunocytochemical, and ultrastructural findings.

Discussion

The two earliest cases of ECD were described by Chester in 1930 as “lipoid granulomatosis.”5 Since then, a number of reports have been published. Although most have been case reports or very small series, a literature review of 59 patients was recently published by Veyssier-Belot, et al.24

To date, the literature contains more than 60 cases of this sporadically occurring, systemic form of non-LC histiocytosis. The median age of patients with ECD is in the sixth decade and there is a slight male preponderance. By definition, bone involvement is always present; whether asymptomatic or causing pain, it is the cardinal feature of ECD. Radiographically, characteristics of the disease include symmetrical sclerosis of long bones with diaphyseal or metaphyseal involvement and epiphyseal sparing. Additional lytic lesions are present in 30% of the cases. Bone scans reveal increased radionuclide uptake, particularly at the ends of long bones. Our patient suffered from bone pain, accompanied by typical radiographic and scintigraphic findings. In addition to bone disease, involvement of the retroperitoneal space and renal dysfunction, with or without hydronephrosis, has been observed in more than 25% of patients. All were features in the present case. Infiltration of orbital and retroorbital soft tissue with resulting exophthalmus is also a frequent presentation. Involvement of the lungs and heart, although less common and not a feature of our case, is a major contributor to mortality in these patients.

Diabetes insipidus attributed to infiltration of the pituitary—hypothalamic axis follows bone pain in frequency. Although it often precedes arrival at the diagnosis of ECD by a decade or longer, neuroimaging rarely detects abnormalities. When present, findings range from thickening of the pituitary stalk to a rare tumorlike mass, as was seen in our patient. Absence of the normal high signal of the posterior pituitary on T1-weighted MR images has been reported in a few cases. This is not specific to ECD, however, because it also occurs in DI from other causes, including LC histiocytosis.

Although DI is common in patients with ECD, anterior pituitary dysfunction has seldom been documented. Table 1 provides a summary of four previously reported cases;9,14,21,23 our case constitutes the fifth reported case. In three of these patients, including ours, low serum gonadotropin levels were detected and in two instances decreased libido and impotence were noted. A fourth patient presented with decreased libido; a low serum testosterone level was documented, but LH and FSH levels were reportedly normal.

TABLE 1

Literature review of cases of ECD with anterior pituitary dysfunction*

Authors & YearPatient Age (yrs), SexNeuroendocrinological SymptomsMR/CT Imaging Findings in Brain, Hypothalamus, & PituitaryLaboratory FindingsOther Symptoms/SignsTreatment/Outcome
Miller, et al.,44, Mcentral DIbrain scan initially normal; several yrsnormal levels of T4, cortisol,intermittentvinblastine & prednisone
 1986 for 10 yrs later, head CT scan normal, but sector GH, & PRL, but decreased fever; bone given, but
 followed scan of orbits revealed massive levels of LH, FSH, & testosterone; pain, weight no improvement;
 by impotence infiltrates surrounding length of both biopsies on bone loss, & rash hemibody radiation
 optic nerves from posterior surface & skin therapy w/
 of the globe to orbital apices subjective improvement
Tien, et al.,30, Mcentral DInormal imaging followed by enlargementnormal serum levels of PRL, T4,characteristicimprovement after
 1990 followed of pituitary stalk (7 mm); partially FSH, LH, cortisol, & TSH; bone changes testosterone theraphy
 by decreased empty sella; pituitary stalk thickness decreased levels of GH & on radiographs
 subsequently decreased to 4 mm; absence testosterone; biopsy of bone
 libido of normal high signal intensity on
 T1-weighted images of posterior lobe
Globerman,7, Mcentral DI;CT & MR imaging revealed no brain orinadequate peak GH responseslesions in neck,medical treatment
 et al., short stature pituitary abnormalities; skeletal radiographic to insulin-induced hypoglycemia mediastinum, of DI, asymptomatic
 1991 (2.7 survey & scans demonstrated & to clonidine; 2 random &retroperitoneum; at 2.5 yrs
 SDs below multifocal skull & long-bone lesions somatomedin levels below biopsy
 mean); skeletal low baseline; hyperprolactinemia, revealed bone,
 etal age 4.5 hyperresponsive to TRH; neck mass, &
 yrs normal responses of TSH to mediastinum
 TRH & of cortisol to hypoglycemia
 & metapyrone test
Tritos, et al.,58, Fcentral DI,MR imaging revealed cerebellar atrophy;normal levels of TSH, free T4,bilat eyelid xanthomas;died of aspiration
 1998 cerebellar diffuse leptomeningeal enhancement; total T4, & cortisol; decreased retroperitoneal pneumonia
 dysfunction no focal parenchymal or mass lesions, levels of LH, FSH, & IGF-1;
 but normal bright signal of posterior increased levels of PRL, serum mass; low hemoglobin
 pituitary lacking sodium, & osmolality &
 platelet count

IGF-1 = insulin-like growth factor—1; PRL = prolactin; SD = standard deviation; TRH = thyrotropin-releasing hormone; T4 = thyroxine.

Growth hormone levels were decreased in four patients, including ours. In a 7-year-old boy, the only child with ECD reported on in the literature,9 the disease was symptomatic and led to short stature (Table 1).

Our patient is the first in whom panhypopituitarism was documented, in addition to low serum levels of TSH, thyroxine, and ACTH. Hypothyroidism may have contributed to our patient's lethargy, because this symptom improved in response to hormone replacement therapy.

Interestingly, in the case we describe and in two previously published cases,9,23 hyperprolactinemia was documented. This is likely due to a stalk section effect, that is, the mechanical disruption of the hypothalamic dopaminergic pathway that normally inhibits secretion of prolactin.

In all reported cases featuring anterior pituitary hypofunction, the presence of posterior pituitary dysfunction, that is, DI, had preceded it for years. Furthermore, DI has always occurred in the setting of multiple organ involvement. The actual incidence of anterior pituitary dysfunction may be higher than reported, because there is no doubt that there have been asymptomatic cases in which measurement of hormone levels was never undertaken.

In the four reported cases of ECD wherein CT and/or MR imaging of the hypothalamic—pituitary region was performed,9,14,22,23 results varied from the absence of detectable changes in three patients9,14,23 to thickening of the pituitary stalk in one.22 Orbital and meningeal involvement were detected in two different cases.4,7 Histological confirmation of hypothalamic involvement has not been previously reported. Involvement was assumed on the basis of laboratory and imaging findings, and the diagnosis was made on the basis of biopsies of extraneural disease. None of the previously published cases of ECD, in which there was dysfunction of both the anterior and posterior pituitary, was associated with a detectable mass. It is only in our patient that MR imaging detected a homogeneously enhancing suprasellar mass.

Because in our case the disease was not clinically suspected and a retroperitoneal fine-needle aspiration failed to obtain diagnostic tissue, histological examination of the hypothalamic mass became a necessity. Before craniotomy and in light of the retroperitoneal and bone disease, the differential diagnosis included tumor (LC histiocytosis, lymphoma, or metastases) and granulomatous disease (tuberculosis or sarcoidosis). Resection of the tumor revealed it to be a xanthogranulomatous lesion. Cytologically, the features of the histiocytes were dissimilar from those of LCs. Their foamy cytoplasm, round nuclei with smooth contours, small nucleoli, and lack of nuclear grooves were distinguishing features, as was the lack of eosinophils and Birbeck granules viewed ultrastructurally. Rosai—Dorfman disease also entered into the differential diagnosis; however, lack of emperipolesis, a distinctive histological feature, as well as lack of immunoreactivity for S-100 protein did not support this diagnosis. Last, no specific ultrastructural features indicative of a storage disease were noted.

Although neurological involvement has been apparent in several reported cases of ECD, histological confirmation of the diagnosis has rarely relied on brain biopsy. Central nervous system involvement usually has been suspected on the basis of neurological symptoms in the setting of histologically and/or radiologically proven ECD. Cerebellar symptoms have followed DI in frequency.1,7,8,16,27 Focal neurological deficits indicative of cerebral or spinal lesions have only rarely been encountered.2,4 Computerized tomography and/or MR images have been used to confirm the clinical diagnosis. Regarding the lesion, most have been diffuse and meningeal based,4,27 although some have been more localized and caused mass effects.2,15 Intraparenchymal involvement is very uncommon and is evident on MR images as multifocal, diffuse, or infiltrative lesions mimicking granulomas, infarcts, or demyelinating disease.11,19 On CT scans, typical lesions have appeared hypodense and displayed contrast enhancement. On MR images, they have appeared isotense; enhancement has persisted for prolonged periods in some instances2,8,11,16,19,22,27 and up to 23 days in one case.12 Laboratory tests usually have provided nonspecific findings. The presence of histiocytes in cerebrospinal fluid was noted in one case.19

Although only performed in occasional cases,1,4,15 autopsies have provided a complete picture of CNS involvement in patients with ECD, including those who were neurologically asymptomatic.1 Meningeal lesions, in particular, exhibit the typical xanthogranulomatous infiltrates observed in other organs. Involvement of various arteries, such as the vertebral and basilar, has also been documented. Intraparenchymal lesions are typically infiltrative and feature a perivascular distribution.1 Occasionally histiocytes have been few and lacked the distinctive cytological characteristics of foam cells.7 Nonetheless, CD68 staining is a regular feature. Scant S-100 protein staining of histiocytes has been noted, but CD1a stains have been negative and ultrastructural studies have shown Birbeck granules to be lacking. In one report7 the associated reactive gliosis was prominent and simulated infiltrative glioma. Rosenthal fibers may also be seen.1,7

Because ECD is a multiple system process, establishment of a tissue-based diagnosis seldom depends on examination of CNS tissue. As a result, neurosurgical reports of this disease are rare, when compared with those in the pathology, radiology, and neurology literature. The literature contains only six cases in which neurosurgical biopsies were performed (Table 2). In those cases, a CNS biopsy was the first step toward establishing the diagnosis. In three cases, including the present one, symptoms indicated systemic involvement as well. As in our case, characteristic bone involvement was not generally recognized at the time of CNS biopsy.

TABLE 2

Literature review of cases of ECD in which neurosurgical biopsy was performed*

Authors & YearPatient Age (yrs), SexNeurological/Endocrinological SymptomsMR/CT Imaging Findings in Brain, Hypothalamus, & PituitaryOperative FindingsOther Symptoms/SignsTreatment/Outcome
Tien,54, Morbital masses resultingCT scan revealed multiplecraniotomy included subtotalcharacteristic signsno changes in neurological
 et al., in visual enhancing intraconal masses; resection of a 4-cm parasagittal, on bone radiological status
 1989 loss & diplopia; multiple low attenuation, gray-yellow, & friable studies noted
 gait disturbance but intensely enhancing, falcine mass; no involvement after brain biopsy
 & lack of coordination parasagittal masses of sagittal sinus
Miyachi,42, Mbilat exophthalmus;orbital lesions followed by developmentorbital exenteration; subsequentretroperitoneal massrecovered postop, but
 et al., visual disturbance of a large CT—non-enhancing, craniotomy disclosed firm, died of pleural effusion
 1990 followed by vomiting low-density tentorial xanthomatous mass, demarked w/in 3 mos;
 & altered neurological mass extending to rt posterior from brain w/ no autopsy showed
 status, fossa w/ resultant obstructive leptomeningeal attachment; regrowth of dural
 but no focal deficits hydrocephalus; low Torkildsen shunt placed tumor
 signal intensity of mass on T1-
 & T2-weighted MR images;
 angiogram revealed avascular
 tentorial mass
Sandrock,54, M2 yrs of bilat proptosisCT scan revealed bilat orbitalbiopsy revealed exclusion of anperhaps familialradiotherapy to orbits
 et al., & orbital masses that increased in size orbital & 1 of 3 CNS brainstem, angioneurotic (35 Gy), but no objective
 1990 pain; recent loss after 2-yr interval; MR imaging cerebellum, & cerebral edema improvement;
 of balance, lack revealed 3 intracerebral masses stable on
 of coordination, masses; IVP showed hydronephrosis; regimen of prednisone;
 headaches MR imaging revealed new white
 renal medullary infiltrates, matter infiltrate,
 ureter obstruction; but no neurological
 echocardiogram demonstrated symptoms during
 pericardial mass & effusion; follow-up exams
 bone scan abnormalities
Smith,58, Minitial lack of handMR images revealed multifocalstereotactic biopsy of frontalno other symptoms;prednisone & azathioprine
 et al., coordination, impaired hyperintensity in midbrain, lobe enhancing lesion CSF held increased ineffective;
 1993 tandem gait, cerebellar peduncles, & lt levels of WBRT led to
 diminished dysarthria, occipital region on T2-weighted protein & albumin; improvement of
 dysphagia, images & confluent enhancement no oligoclonal symptoms in 6 wks
 & hemisensory in abnormal areas on T1- bands; histiocytes & decrease in
 deficit weighted images present lesion size in 6 mos
Babu,22, Mstiffness of gait followedMR image revealed enhancingdecompressive laminectomy ofcharacteristicrecurrent dural mass
 et al., by paraparesis spinal epidural mass at T5–11; T5–12; thick, white, rubbery signs on bone at 8–18 mos;
 1997 & reduced 6 mos later periorbital masses densely adherent to radiological studies; patient alive 4 yrs
 T-6 sensory level swelling developed; CT scan dura mater; 2nd biopsy of periorbital after 2nd decompressive
 revealed bilat intracranial orbital tissue swelling & proptosis laminectomy
 infiltrative mass
Wright,42, Fcentral DI; progressiveMR images initially normal;lt suboccipital craniotomylt knee pain; characteristicquestionable transient
 et al., gait disturbance; 2 yrs later, patchy, enhancing showed fullness of brainstem signs postop improvement
 1999 mild ataxic pontine lesions, w/ abnormalities above CN VII–VIII & inferior on bone radiological in
 dysarthria; headache extending to medulla to CN V; fibrous 1.5- to 2-cm studies; slight speech & gait w/
 & cerebellar peduncles seen mass indenting brainstem beneath exophthalmus oral prednisone
 on T2-weighted images CN V; mass removed & chemosis treatment

CN = cranial nerve; CSF = cerebrospinal fluid; IVP = intravenous pyelogram; WBRT = whole-brain radiation therapy.

Radiological and neurosurgical awareness of ECD may initiate a systemic review, including long-bone imaging studies. Some clinical features of the disease overlap with those of LC histiocytosis, but others are distinct. Although both diseases share a frequent occurrence of DI, bone pain, and exophthalmus, these are more often seen in cases of LC histiocytosis. On the other hand, cerebellar and cerebral involvement is more common in cases of ECD. And although LC histiocytosis is primarily a disease of children and young adults, only one pediatric case of ECD has been reported.9 Both conditions feature involvement of bone, but the osseous lesions of LC histiocytosis are typically lytic and more often involve flat bones, including the skull. When lytic lesions do occur in patients with ECD, the lesions are invariably accompanied by symmetrical sclerosis of long bones.

When ECD is suspected, histological confirmation is necessary. Tissue samples may be obtained more easily from bone or other organs than by CNS biopsy. Nevertheless, in our patient as well as in one with a spinal epidural mass2 and another with obstructive hydrocephalus requiring shunt placement,15 a neurosurgical approach is occasionally needed to reduce mass effects and provide symptomatic relief. In most reported cases, however, brain involvement has been sufficiently generalized and removal of the tumor has not been feasible. Furthermore, although debulking can provide temporary relief, the lesion may rapidly regrow to its original size.15 Postoperatively, patients may report symptomatic improvement, including abatement of fever and weight loss, as well as better control of the DI. Nonetheless, no therapies, including a regimen of steroid medication, chemotherapy, or radiotherapy, have resulted in more than temporary relief of symptoms or abatement of disease.

Although the initial course of ECD may be asymptomatic or slowly progressive over a period of years, rapid deterioration occurs at some point in most cases. The eventual, high mortality rate is attributed to lung or pericardial involvement and, occasionally, to renal failure.

In summary, we have reported a case of ECD in a patient presenting with hypothalamic—infundibular involvement and panhypopituitarism. It is the first reported case in the neurosurgical literature in which the diagnosis was first established by CNS biopsy. Although ECD is currently considered a distinct, progressive form of non-LC histiocytosis,10,17 there are reports of mixed or simultaneous occurrence of both diseases1,3,20,25,26 and of overlapping imaging and pathological findings.16 The possibility that these two diseases represent a disease spectrum is still under debate. The cause of ECD is unknown. No causative infectious agents or familial or genetic predisposition has been reported. Whether ECD is a metabolic disease or a neoplastic clonal disorder similar to LC histiocytosis6 has yet to be determined.

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  • 8.

    Fukazawa TTsukishima ESasaki Het al: Erdheim-Chester disease and slowly progressive cerebellar dysfunction. J Neurol Neurosurg Psychiatry 58:2382401995Fukazawa T Tsukishima E Sasaki H et al: Erdheim-Chester disease and slowly progressive cerebellar dysfunction. J Neurol Neurosurg Psychiatry 58:238–240 1995

  • 9.

    Globerman HBurstein SGirardina PJet al: A xanthogranulomatous histiocytosis in a child presenting with short stature. Am J Pediatr Hematol Oncol 13:42461991Globerman H Burstein S Girardina PJ et al: A xanthogranulomatous histiocytosis in a child presenting with short stature. Am J Pediatr Hematol Oncol 13:42–46 1991

  • 10.

    Kenn WEck MAllolio Bet al: Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol 31:7347392000Kenn W Eck M Allolio B et al: Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol 31:734–739 2000

  • 11.

    Kujat CJunk BHermes Met al: Zerebrale manifestationen der Erdheim-Chester-Krankheit. Radiologe 31:3073091991Kujat C Junk B Hermes M et al: Zerebrale manifestationen der Erdheim-Chester-Krankheit. Radiologe 31:307–309 1991

  • 12.

    Martinez R: Erdheim-Chester disease: MR of intraaxial and extraaxial brain stem lesions. AJNR 16:178717901995Martinez R: Erdheim-Chester disease: MR of intraaxial and extraaxial brain stem lesions. AJNR 16:1787–1790 1995

  • 13.

    Mergancova JKubes LElleder M: A xanthogranulomatous process encircling large blood vessels (Erdheim-Chester disease?). Czech Med 11:57641988Mergancova J Kubes L Elleder M: A xanthogranulomatous process encircling large blood vessels (Erdheim-Chester disease?). Czech Med 11:57–64 1988

  • 14.

    Miller RLSheeler LRBauer TWet al: Erdheim-Chester disease. Case report and review of the literature. Am J Med 80:123012361986Miller RL Sheeler LR Bauer TW et al: Erdheim-Chester disease. Case report and review of the literature. Am J Med 80:1230–1236 1986

  • 15.

    Miyachi SKobayashi TTakahashi Tet al: An intracranial mass lesion in systemic xanthogranulomatosis: case report. Neurosurgery 27:8228261990Miyachi S Kobayashi T Takahashi T et al: An intracranial mass lesion in systemic xanthogranulomatosis: case report. Neurosurgery 27:822–826 1990

  • 16.

    Pautas ECherin PPelletier Set al: Cerebral Erdheim-Chester disease: report of two cases with progressive cerebellar syndrome with dentate abnormalities on magnetic resonance imaging. J Neurol Neurosurg Psychiatry 65:5975991998Pautas E Cherin P Pelletier S et al: Cerebral Erdheim-Chester disease: report of two cases with progressive cerebellar syndrome with dentate abnormalities on magnetic resonance imaging. J Neurol Neurosurg Psychiatry 65:597–599 1998

  • 17.

    Pertuiset ELaredo JDLioté Det al: Erdheim-Chester disease: report of a case, review of the literature, and discussion of relationships with Langerhans cell histiocytosis. Rev Rheum 60:5045111993Pertuiset E Laredo JD Lioté D et al: Erdheim-Chester disease: report of a case review of the literature and discussion of relationships with Langerhans cell histiocytosis. Rev Rheum 60:504–511 1993

  • 18.

    Sandrock DMerino MJScheffknecht BHet al: Scintigraphic findings and follow up in Erdheim-Chester disease. Eur J Nucl Med 16:55601990Sandrock D Merino MJ Scheffknecht BH et al: Scintigraphic findings and follow up in Erdheim-Chester disease. Eur J Nucl Med 16:55–60 1990

  • 19.

    Smith MEKatz DAHarris JOet al: Systemic histiocytosis presenting as multiple sclerosis. Ann Neurol 33:5495541993Smith ME Katz DA Harris JO et al: Systemic histiocytosis presenting as multiple sclerosis. Ann Neurol 33:549–554 1993

  • 20.

    Strouse PJEllis BIShifrin LZet al: Case report 710: symmetrical eosinophilic granuloma of the lower extremities (proven) and Erdheim-Chester disease (probable). Skeletal Radiol 21:64671992Strouse PJ Ellis BI Shifrin LZ et al: Case report 710: symmetrical eosinophilic granuloma of the lower extremities (proven) and Erdheim-Chester disease (probable). Skeletal Radiol 21:64–67 1992

  • 21.

    Tien RKucharczyk JNewton THet al: MR of diabetes insipidus in a patient with Erdheim-Chester Disease: case report. AJNR 11:126712701990Tien R Kucharczyk J Newton TH et al: MR of diabetes insipidus in a patient with Erdheim-Chester Disease: case report. AJNR 11:1267–1270 1990

  • 22.

    Tien RDBrasch RCJackson DEet al: Cerebral Erdheim-Chester disease: persistent enhancement with Gd-DTPA on MR images. Radiology 172:7917921989Tien RD Brasch RC Jackson DE et al: Cerebral Erdheim-Chester disease: persistent enhancement with Gd-DTPA on MR images. Radiology 172:791–792 1989

  • 23.

    Tritos NAWeinrib SKaye TB: Endocrine manifestations of Erdheim-Chester disease (a distinct form of histiocytosis). J Intern Med 244:5295351998Tritos NA Weinrib S Kaye TB: Endocrine manifestations of Erdheim-Chester disease (a distinct form of histiocytosis). J Intern Med 244:529–535 1998

  • 24.

    Veyssier-Belot CCacoub PCaparros-Lefebvre Det al: Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine 75:1571691996Veyssier-Belot C Cacoub P Caparros-Lefebvre D et al: Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine 75:157–169 1996

  • 25.

    Vital CBioulac-Sage PTison Fet al: Brain stem infiltration by mixed Langerhans cell histiocytosis and Chester-Erdheim disease: more than just an isolated case? Clin Exp Pathol 47:71761999Vital C Bioulac-Sage P Tison F et al: Brain stem infiltration by mixed Langerhans cell histiocytosis and Chester-Erdheim disease: more than just an isolated case? Clin Exp Pathol 47:71–76 1999

  • 26.

    Waite RJDoherty PWLiepman Met al: Langerhans cell histiocytosis with the radiographic findings of Erdheim-Chester disease. AJR 150:8698711988Waite RJ Doherty PW Liepman M et al: Langerhans cell histiocytosis with the radiographic findings of Erdheim-Chester disease. AJR 150:869–871 1988

  • 27.

    Wright RAHermann RCParisi JE: Neurological manifestations of Erdheim-Chester disease. J Neurol Neurosurg Psychiatry 66:72751999Wright RA Hermann RC Parisi JE: Neurological manifestations of Erdheim-Chester disease. J Neurol Neurosurg Psychiatry 66:72–75 1999

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Article Information

Address reprint requests to: Bernd W. Scheithauer, M.D., Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Preoperative contrast-enhanced MR images revealing a discrete, bosselated intra- and suprasellar tumor that is enhancing.

  • View in gallery

    Follow-up contrast-enhanced MR images demonstrating no regrowth of residual sellar disease. Nonetheless, new, diffuse, enhancing meningeal lesions became apparent.

  • View in gallery

    Photomicrographs. Upper: Histologically, the somewhat lobular infiltrate consists of mononuclear and scattered multinuclear histiocytes accompanied by patchy lymphocytic inflammation. H & E, original magnification × 160. Lower: At a higher magnification, the histiocytes feature uniform, round-to-oval and somewhat hyperchromatic nuclei, as well as cytoplasms that centrally are granular to hyaline and peripherally pale. H & E, original magnification × 400.

  • View in gallery

    Photomicrograph showing widespread staining of both mono- and multinuclear histiocytes. Immunostains for CD68 (KP-1), original magnification × 250.

  • View in gallery

    Electron micrograph demonstrating that both mono- and multinuclear histiocytes are filled with lysosomes. There are few intermediate filaments (arrows) and no Birbeck granules. Original magnification × 25,000.

References

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Adle-Biassette HChetritt JBergemer-Fouquet AMet al: Pathology of the central nervous system in Chester-Erdheim disease: report of three cases. J Neuropathol Exp Neurol 56:120712161997Adle-Biassette H Chetritt J Bergemer-Fouquet AM et al: Pathology of the central nervous system in Chester-Erdheim disease: report of three cases. J Neuropathol Exp Neurol 56:1207–1216 1997

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Babu RPLansen TAChadburn Aet al: Erdheim-Chester disease of the central nervous system. Report of two cases. J Neurosurg 86:8888921997Babu RP Lansen TA Chadburn A et al: Erdheim-Chester disease of the central nervous system. Report of two cases. J Neurosurg 86:888–892 1997

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Brower ACWorsham GFDudley AH: Erdheim-Chester disease: a distinct lipoidosis or part of the spectrum of histiocytosis? Radiology 151:35381984Brower AC Worsham GF Dudley AH: Erdheim-Chester disease: a distinct lipoidosis or part of the spectrum of histiocytosis? Radiology 151:35–38 1984

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Caparros-Lefebvre DPruvo JPRemy Met al: Neuroradiologic aspects of Chester-Erdheim disease. AJNR 16:7357401995Caparros-Lefebvre D Pruvo JP Remy M et al: Neuroradiologic aspects of Chester-Erdheim disease. AJNR 16:735–740 1995

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Chester W: Uber lipoidgranulomatose. Virchows Arch Pathol Anat 279:5616021930Chester W: Uber lipoidgranulomatose. Virchows Arch Pathol Anat 279:561–602 1930

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Chetritt JParadis VDargere Det al: Chester-Erdheim disease: a neoplastic disorder. Hum Pathol 30:109310961999Chetritt J Paradis V Dargere D et al: Chester-Erdheim disease: a neoplastic disorder. Hum Pathol 30:1093–1096 1999

7.

Evidente VGHAdler CHGiannini Cet al: Erdheim-Chester disease with extensive intraaxial brain stem lesions presenting as a progressive cerebellar syndrome. Mov Disord 13:5765811998Evidente VGH Adler CH Giannini C et al: Erdheim-Chester disease with extensive intraaxial brain stem lesions presenting as a progressive cerebellar syndrome. Mov Disord 13:576–581 1998

8.

Fukazawa TTsukishima ESasaki Het al: Erdheim-Chester disease and slowly progressive cerebellar dysfunction. J Neurol Neurosurg Psychiatry 58:2382401995Fukazawa T Tsukishima E Sasaki H et al: Erdheim-Chester disease and slowly progressive cerebellar dysfunction. J Neurol Neurosurg Psychiatry 58:238–240 1995

9.

Globerman HBurstein SGirardina PJet al: A xanthogranulomatous histiocytosis in a child presenting with short stature. Am J Pediatr Hematol Oncol 13:42461991Globerman H Burstein S Girardina PJ et al: A xanthogranulomatous histiocytosis in a child presenting with short stature. Am J Pediatr Hematol Oncol 13:42–46 1991

10.

Kenn WEck MAllolio Bet al: Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol 31:7347392000Kenn W Eck M Allolio B et al: Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol 31:734–739 2000

11.

Kujat CJunk BHermes Met al: Zerebrale manifestationen der Erdheim-Chester-Krankheit. Radiologe 31:3073091991Kujat C Junk B Hermes M et al: Zerebrale manifestationen der Erdheim-Chester-Krankheit. Radiologe 31:307–309 1991

12.

Martinez R: Erdheim-Chester disease: MR of intraaxial and extraaxial brain stem lesions. AJNR 16:178717901995Martinez R: Erdheim-Chester disease: MR of intraaxial and extraaxial brain stem lesions. AJNR 16:1787–1790 1995

13.

Mergancova JKubes LElleder M: A xanthogranulomatous process encircling large blood vessels (Erdheim-Chester disease?). Czech Med 11:57641988Mergancova J Kubes L Elleder M: A xanthogranulomatous process encircling large blood vessels (Erdheim-Chester disease?). Czech Med 11:57–64 1988

14.

Miller RLSheeler LRBauer TWet al: Erdheim-Chester disease. Case report and review of the literature. Am J Med 80:123012361986Miller RL Sheeler LR Bauer TW et al: Erdheim-Chester disease. Case report and review of the literature. Am J Med 80:1230–1236 1986

15.

Miyachi SKobayashi TTakahashi Tet al: An intracranial mass lesion in systemic xanthogranulomatosis: case report. Neurosurgery 27:8228261990Miyachi S Kobayashi T Takahashi T et al: An intracranial mass lesion in systemic xanthogranulomatosis: case report. Neurosurgery 27:822–826 1990

16.

Pautas ECherin PPelletier Set al: Cerebral Erdheim-Chester disease: report of two cases with progressive cerebellar syndrome with dentate abnormalities on magnetic resonance imaging. J Neurol Neurosurg Psychiatry 65:5975991998Pautas E Cherin P Pelletier S et al: Cerebral Erdheim-Chester disease: report of two cases with progressive cerebellar syndrome with dentate abnormalities on magnetic resonance imaging. J Neurol Neurosurg Psychiatry 65:597–599 1998

17.

Pertuiset ELaredo JDLioté Det al: Erdheim-Chester disease: report of a case, review of the literature, and discussion of relationships with Langerhans cell histiocytosis. Rev Rheum 60:5045111993Pertuiset E Laredo JD Lioté D et al: Erdheim-Chester disease: report of a case review of the literature and discussion of relationships with Langerhans cell histiocytosis. Rev Rheum 60:504–511 1993

18.

Sandrock DMerino MJScheffknecht BHet al: Scintigraphic findings and follow up in Erdheim-Chester disease. Eur J Nucl Med 16:55601990Sandrock D Merino MJ Scheffknecht BH et al: Scintigraphic findings and follow up in Erdheim-Chester disease. Eur J Nucl Med 16:55–60 1990

19.

Smith MEKatz DAHarris JOet al: Systemic histiocytosis presenting as multiple sclerosis. Ann Neurol 33:5495541993Smith ME Katz DA Harris JO et al: Systemic histiocytosis presenting as multiple sclerosis. Ann Neurol 33:549–554 1993

20.

Strouse PJEllis BIShifrin LZet al: Case report 710: symmetrical eosinophilic granuloma of the lower extremities (proven) and Erdheim-Chester disease (probable). Skeletal Radiol 21:64671992Strouse PJ Ellis BI Shifrin LZ et al: Case report 710: symmetrical eosinophilic granuloma of the lower extremities (proven) and Erdheim-Chester disease (probable). Skeletal Radiol 21:64–67 1992

21.

Tien RKucharczyk JNewton THet al: MR of diabetes insipidus in a patient with Erdheim-Chester Disease: case report. AJNR 11:126712701990Tien R Kucharczyk J Newton TH et al: MR of diabetes insipidus in a patient with Erdheim-Chester Disease: case report. AJNR 11:1267–1270 1990

22.

Tien RDBrasch RCJackson DEet al: Cerebral Erdheim-Chester disease: persistent enhancement with Gd-DTPA on MR images. Radiology 172:7917921989Tien RD Brasch RC Jackson DE et al: Cerebral Erdheim-Chester disease: persistent enhancement with Gd-DTPA on MR images. Radiology 172:791–792 1989

23.

Tritos NAWeinrib SKaye TB: Endocrine manifestations of Erdheim-Chester disease (a distinct form of histiocytosis). J Intern Med 244:5295351998Tritos NA Weinrib S Kaye TB: Endocrine manifestations of Erdheim-Chester disease (a distinct form of histiocytosis). J Intern Med 244:529–535 1998

24.

Veyssier-Belot CCacoub PCaparros-Lefebvre Det al: Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine 75:1571691996Veyssier-Belot C Cacoub P Caparros-Lefebvre D et al: Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine 75:157–169 1996

25.

Vital CBioulac-Sage PTison Fet al: Brain stem infiltration by mixed Langerhans cell histiocytosis and Chester-Erdheim disease: more than just an isolated case? Clin Exp Pathol 47:71761999Vital C Bioulac-Sage P Tison F et al: Brain stem infiltration by mixed Langerhans cell histiocytosis and Chester-Erdheim disease: more than just an isolated case? Clin Exp Pathol 47:71–76 1999

26.

Waite RJDoherty PWLiepman Met al: Langerhans cell histiocytosis with the radiographic findings of Erdheim-Chester disease. AJR 150:8698711988Waite RJ Doherty PW Liepman M et al: Langerhans cell histiocytosis with the radiographic findings of Erdheim-Chester disease. AJR 150:869–871 1988

27.

Wright RAHermann RCParisi JE: Neurological manifestations of Erdheim-Chester disease. J Neurol Neurosurg Psychiatry 66:72751999Wright RA Hermann RC Parisi JE: Neurological manifestations of Erdheim-Chester disease. J Neurol Neurosurg Psychiatry 66:72–75 1999

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