0oumal ofNeurology, Neurosurgery, and Psychiaty 1993;56:1008-1012

SHORT REPORT

A clinico-pathological study of adult histiocytosisX involving the brain

K Hasegawa, T Mitomi, H Kowa, T Motoori, S Yagisita

AbtractAdult histiocytosis X involving the CNScaused progressive spastic paraparesis.The diagnosis was made by immuno-reactive anti-S100 protein antibodystaining and from the presence ofBirbeck granules in biopsy specimens ofskin lesions. Neuropathological examina-tion showed massive proliferation andinfiltration of S-100 containing histio-cyte-like cells and reactive astrocytesthroughout the CNS.

(J Neurol Neurosurg Psychiatry 1993;56:1008-1012)

The conditions which produce progressivespastic paraparesis without apparent spinalcord lesions include familial spastic paraple-gia, adrenoleukodystrophy, and HTLV-Iassociated myelopathy (HAM). HistiocytosisX usually occurs in childhood and is rare inadults.' 2 Most patients with this diseasedevelop masses and/or osteolytic lesions, andit is also known as an important cause of dia-betes insipidus (DI) in adults.We present a rare case of progressive

spastic paraparesis due to histiocytosis X.

Department ofNeurology andDepartment ofPathology, KitasatoUniversity School ofMedicine, JapanK HasegawaT MitomiH KowaT MotooriDivision ofPathology,KanagawaRehabilitation Centre,Sagamihara-shi,Kanagawa, JapanS YagisitaCorrespondence to:Dr Hasegawa, Departmentof Neurology, KitasatoUniversity School ofMedicine, 1-15-1 Kitasato,Sagamihara, Kanagawa 228,Japan.Received 7 August 1992and in revised form3 November 1992.Accepted 6 November 1992

Case reportA male engineer, aged 45 years, had an awk-ward gait for six years. His gait disturbancebecame progressively worse, so that by theage of 41 years (in 1984) he could not walkwithout assistance. At the same time, heoccasionally had difficulty in skilful handmovements. At the age of 42, dysarthria anddysphagia also developed, and he could notwalk without using two sticks, his gait havingbeen reduced to a scissors-type motionbecause of severe spasticity.A year later, skilful hand movements had

deteriorated, and all extremities had becomealmost completely paralysed. Dysphagia was

also aggravated,, and he was referred to our

hospital at the age of 44. There was no rele-vant past or family history.On admission xanthoma-like lesions were

observed on the head and face, and a papularerythematous rash was observed over thechest. Both skin lesions were already presentat the onset of gait disturbance and had grad-ually enlarged. He appeared malnourished

and dehydrated because of dysphagia. Thesuperficial lymph nodes were not palpableand no hepato-splenomegaly was noted.There were no abnormalities of cardiac orpulmonary function.

Neurologically, slight disorientation anddementia were noted. His dysarthria wasregarded as being both pseudobulbar andcerebellar in nature. Ophthalmological exami-nation revealed anisocoria, a rapid lightreflex, and a slight restriction of vertical gaze.Horizontal movements were normal and hori-zontal gaze nystagmus was also observed.Moreover, the smooth pursuit eye move-ments showed a staircase pattern. Palatalmyoclonus was noted. Projection of thetongue was impossible, although no lingualatrophy was observed. The pharyngeal reflexwas normal.

Spastic tetraplegia in extension wasdemonstrated. All deep tendon reflexes wereexaggerated and pathological reflexes, suchas, the snout, sucking, grasp, Babinski,Chaddock, Hoffman and Troemner reflexes,were all positive.

It was impossible to properly examine thesensory, the extrapyramidal or the cerebellarsystems, but no apparent abnormalities werenoted.No abnormalities were noted on haemato-

logical, biochemical, endocrinological, orimmunological examinations. The CSF wasnormal, as were the lysozomal enzymalactivities.

In electroencephalography, the basicrhythm was found to be slow a with some 0waves. There were no sharp waves, spikes, orasymmetry. The electronystagmographyrevealed downbeat nystagmus in all eye posi-tions. The caloric test was normal. Auditoryevoked potentials showed no potentials butwave I. The latency of all somatosensoryevoked potentials appearing subsequent tothe Ni wave was prolonged. Electro-myography and nerve conduction velocitystudies showed no abnormal findings. Theblink reflex test revealed slight prolongationof the left Ri latency time.

Biopsies were performed of the facialxanthomas and the papular erythematousrash on the chest. The chest skin biopsy spec-imens showed histiocyte-like cell infiltrationbelow the epidermis. These infiltrating cellswere stained positive by anti-S 100 protein

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A clinico-pathological study of adult histiocytosis X involving the brain

Figure 1 Pathologicalfindings in skin biopsies.(A) Many histiocyte-likecells are seen in the upperdennis. About half of theinfiltrating cells areimmunoreactive; precordialskin biopsy (SlOO proteinimmunostain x 200);(B) Three Birbeckgranules are seen in a partof the cytoplasm ofahistiocyte-like cell onelectron microscopy(x 100,000).

antibody (fig 1A). Ultrastructurally, histio-cyte-like cells contained characteristic ofBirbeck granules (fig 1B). The biopsy fromthe facial xanthomas showed similar findings,and so the facial eruptions were also causedby histiocytosis X, but exhibited a differentexpression of the same disease. The patholog-ical findings in the skin closely resembledthose of Abt-Letterer-Siwe disease.A Cranial CT scan on admission revealed

disproportionate cerebral atrophy for thepatient's age. In the peri-lateral ventricularregion, MRI showed a mass lesion which wasconsidered to be either a tumour or ademyelinating focus. Disseminated smallhigh-intensity areas were noted deep in thewhite matter of the cerebrum. In addition,high-intensity areas were observed in the ven-tral pons in Tl-weighted images. However,the nature of the pontine lesions was notassessed.

It was strongly suspected that a disease ofthe CNS had been induced by histiocytosisX. The main lesions in the CNS were consid-ered to be located in the pons and uppermedulla since palatal myoclonus, downbeatnystagmus in all eye positions, and spastictetrariplegia were cardinal clinical features.

After the tentative diagnosis of histiocytosisX, in order to treat the disease and prevent itsspread from the ventral part of the pons toother parts of the CNS, we tried y-interferontherapy, which has recently been reported tobe effective against malignant lymphoma andpoorly differentiated malignant tumours,because conventional chemotherapies are atpresent usually considered ineffective againstthis disease. The chest and the facial xan-thomas were transiently reduced after twomonths of y-interferon therapy.

In 1988, however, when the patient was 45

years old, his level of consciousness deterio-rated, and abnormal eye movements, such as,ocular bobbing developed, accompanied bybilateral lateral gaze palsy.A high-intensity area mainly situated in

the pons but extending to the midbrain, cere-bellar peduncles and medulla, was seen onTi-weighted MRI (fig 2). The top of thislesion was thought to have reached the thala-mus. Moreover, a round mass was also foundin the left caudate nucleus, protruding intothe lateral ventricle, and disseminated small

Figure 2 MRlfindings of the brain. Tl-weighted MRIimage (parasagittal plane). The high-intensity area in thepons is seen extending into the cerebellum.

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Figure 3 Macroscopic findings in the CNS. (A) Markedswelling of the brainstem, especially the pons. Prominentlesions extendfrom the medulla to the diencephalon. (B)Disseminated masses involving the pons to spinal cord.

high-intensity foci were also noted in thecerebral white matter on T2-weighted MRI.

Diabetes insipidus and optic neuritis devel-oped later. Electrophysiological and radiolog-ical findings suggested that the brainstemlesion had grown into the thalamus, hypo-thalamus and optic nerves. The patient's con-dition deteriorated and in 1988 he died.

Pathological findingsNo gross abnormalities other than the skinlesions were revealed by general pathologicalexamination. There was no macroscopic

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Figure 4 Microscopic findings in the pons. Marked proliferation of homogeneouseosinophilic tumour cells is shown. Some degenerating or morphologically normal nervecells are also present in between. (HE x 125).

tumour infiltration into the visceral organs orthe bones. On microscopic examination, his-tiocytosis X tumour cells were found to haveinvaded the base of the skull and the spleen.The brain weighed 1440g. Marked

swelling of the brainstem, especially of thepons, was noted (Fig 3A). The optic nerves,medulla, and cerebellar hemispheres werealso grossly swollen. Some tumefactions wereobserved in the spinal nerve roots, especiallyat the cauda equina. In cross sections, anumber of tumorous lesions were alsoobserved from the basal ganglia to the cere-bellum and spinal cord (fig 3B). A tumourmass was revealed in the left caudate nucleus.It was 1 cm in diameter and protruded intothe lateral ventricle.

Microscopically, most tumour cells hadabundant homogeneous eosinophilic cyto-plasms, and presumably originated from thereticuloendothelial -system, infiltrated thebrainstem diffusely, accompanied by reactiveastrocytosis (GFAP positive) and Langerhanstype giant cells (fig 4). There were bothdegenerating and normal appearing nervecells together with the tumour cells as a situa-

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tion also seen in pontine gliomas. Thesetumour cells were found throughout the CNSand the spinal nerve roots, including the cere-bral hemispheres, basal ganglia, optic nerves,brainstem, cerebellum, spinal cord, andspinal nerve roots. In addition, small malacicfoci that were probably due to circulatory dis-turbances secondary to compression by thetumours were found in the globus pallidusand the mammillary bodies. The tumour cellswere immunoreactive to anti-S 100 protein,but failed to show Birbeck granules on elec-tron microscopy. Although the skull base was

slightly invaded by histiocyte-like cells, thistumour could, on the basis of the clinicalfindings, be considered a direct invasion fromthe pons rather than the base of the skull.

DiscussionThe term "histiocytosis X" was proposed byLichtenstein' to serve as a unifying name for a

group of pathological conditions. The basicpathological feature of this disease is to formtumour masses or granulomatosis withdestruction of the surrounding tissues.Histiocytosis X may be associated with CNSinvolvement, which is usually limited to thehypothalamus or posterior pituitary gland.While granulomatous lesions have beenreported in the brainstem, spinal cord, spinalnerve roots and cauda equina, the most com-mon site for extradiencephalic involvementappears to be the cerebellum.34 The table liststhe reported cases with no symptoms of eitherdiabetes insipidus nor exophthalmos.

This case was characterised by the confine-ment of symptoms and signs to the motorsystem and the skin for the first seven years.Gradually, in the late stage, pontine neuro-

logical symptoms and signs became apparent.And diffuse swelling in the brainstem wasobserved at the same time without radiologi-

cal evidence of mass formation. It is rare formass formation not to occur in histiocytosisX. Only three cases are reported with a

pathology similar to our case: Feigin's case 2,5the case reported by both Hirai at al,8 andYamaguchi et al,9 and case 3 of Kepes et al.'0The neuropathology of these cases and ofours was granulomatosis of the brainstemwith invasion of the cerebellum and dien-cephalon. We believe that a brainstem variantof histiocytosis X should be recognised.

Although there was no pathological conti-nuity between the skin lesions and the CNSlesions, it is reasonable to consider that theywere another expression of the same diseaseprocess. Unfortunately, we could not demon-strate Birbeck granules in the tumour cells inthe CNS, but only two cases with Birbeckgranules have been reported.'3 14 The skinlesions in our case were histologically similarto those in Letterer-Siwe disease, whosepathological process is thought to be infiltra-tive and destructive, and the tumours we

found in the CNS were also infiltrative.Moreover, fatty degeneration of the neoplas-tic cells was observed in the brainstem in thiscase, so it is plausible that the tumour cellsare less mature histiocytes than are usuallyseen. This also supports our notion that theskin and CNS involvement were differentexpressions of the same disease. Histo-logically, eosinophilic plasma-rich monocytesand giant cells tend to proliferate in histio-cytic granulomatosis. In addition, normalappearing nerve cells were also sporadicallyobserved. These remaining neurons suggestthat the neurological symptoms should havebeen relatively mild.

In our case, symptoms other than the neu-

rological ones, particularly the papular ery-thematous rash in the precordial region,served as keys to the diagnosis. If a definitediagnosis of the disease had not been made

Summary of atypical reported cases of histiocytosis X without diabetes insipidus or exophthalmus

Author Age of onset Duration Clinical symptoms Osteolysis Neuropathology

Feigin5 case 2 11 Years ? fever, quadriplegia - brainstem granulomatosisRube6 case 1 20 Months ? ICPt+ leptomeningeal granulomatosis

case 2 30 Months ? ICP T + leptomeningeal granulomatosiscase 3 36 Months ? lymphadenopathy rash - leptomeningeal granulomatosis

Elian7 37 Years 4-5 Years ataxia + multiple dural massspastic paraplegia

Hiral' and 31 Years 3 Years epilepsy, xanthomas + brainstem granulomatosisYamaguchi' cerebellar signsKepes'" case 1 12 Years ? ICP T ? temporal mass

case 2 11 Years 6 Weeks ICP T, hemiparesis ? temporal masscase 3 9 5 Years ? ICP T ? temporal masscase 4 26 Years 1 Year hemiparesis, ICP T ? frontal mass

cerebellar massSalcman" 7 Years ? paraparesis, lymphadenopathy + spinal epidural massHewlett'2 47 Years ? paraparesis + spinal dural massSivalingam" 9 Years 18 Months epilepsy - temporal massCerda-Nicolas'4 35 Years ? epilepsy - frontal mass

hemiparesisGreenhood"5 14 Years 2 Years epilepsy, ICP T temporal mass

cerebellar signsCamilleri"6 47 Years ? paraparesis + brainstem granulomatosis

cervical tumourWaldrom'7 34 Years ? epilepsy, ICP T + frontal mass

tenderness of occipital areaGeoffray'8 2 Years 6 Months fever, otitis media - multiple massYamak"9 7 Years ? epilepsy, ICP T + dural massAl-Rodhan20 1 Year ? paraparesis, fever, lymphadenopathy? spinal tumourDrolshagen2' 12 Months ? hemiparesis - cervical tumourPresent case 39 Years ? quadriplegia, pontine - brainstem granulomatosis

syndrome, rash spinal tumour

ICP, intracranial pressure.

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on the basis of the skin biopsies, diagnosisfrom the postmortem histology alone wouldhave been very difficult. Thus patients withspastic paraplegia of unknown cause shouldbe suspected of having this disease. Evenminor organic lesions warrant careful attention.The author thanks Assistant Professor Mikio Masuzawa,Department of Dermatology, Kitasato University School ofMedicine, for supplying y-interferon and for his valuableadvice.

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