Jourmd ol the %'urolo,,,ical Sciences 1982, 53:359 375 359 Elsevier Biomedical Press NEOPLASTIC ANGIOENDOTHELIOSIS M. FLINT BEAL and C. MILLER FISHER NcurolocLr Service, Massachusetts General Ho,spital, Bo.v:on. MA (12114 : U.S.A. ) (Received 6 July, 1981) (Accepted 21 July. 19bll) SUMMARY We add two cases of neoplastic angioendotheliosis to the previous 13 with central nervous system manifestations. This unusual neoplastic phenomenon is thought to represent a diffuse malignant proliferation of endothelial cells. A man aged 58 first had transient ischemic attacks followed by a subacute profound dementia with psychomotor retardation. Remision followed steroid therapy, Abulia recurred along with a gradually progressive paraplegia leading to death 16 months after onset of symptoms. Pathologic examination showed tumor masses in the basal ganglia and widespread patchy cerebral int:arction. The spinal cord below the midthoracic level was destroyed. Microscopically small mononuclear tumor cells were widespread within and largely confined to the lumens of small cerebral blood vessels which showed varying degrees of occlusion and recanalization. Factor 8 antigen, a specific endothelial cell marker, was not present on the surl;ace of the malignant cells. Another man aged 61 developed subacute dementia with frontal lobe signs, dysphasia and impairment of memory. Computerized tomography showed multiple infarcts. A brief respite followed steroid therapy but progressive deterioration led to death in 15 weeks, Frontal lobe biopsy revealed the same neoplastic vascular process. The hallmark of the illness is a progressive subacute lobar dementia. Transient spells may occur. Hemiparesis is unusual and seizures do not occur except terminally. Angiography is normal. Supported in part by a grant from the Freed Foundation, Washington, DC and the Departments of Neurology and Neuropathology, Massachuselts General Hospital and Harvard Medical School, Boston, MA 02114. Address correspondence to: M. Flint Beal, M.D.. Massachusetts General Hospital. Neurolog_~ Service, Boston. MA 02114, U.S.A. 0022-510X/82,,0000-0000, $02 75 © Elsevier Biomedical Press 360 INTRODUCTION Neoplastic angioendothetiosis, although well established as a clinicopathologic entity remains relatively unknown, Only 13 cases with predominantly neurologic involvement have been described. The neurologic features in brief consist of transient ischemic attacks, a subacute apathetic dementia and in some cases progressive paraparesis In the present 2 cases the clinical and pathological findings are available and in addition an attempt was made to identify the nature of the tumor cells using the immunoperoxidase technique to stain for factor VIII antigen. CASE R E P O R T S Case l A 58-year-old m a n experienced a five-minute episode of numbness and weakness of the right hand during which he was unable to pick up a pencil. Three days later while typing Ire developed n u m b n e s s and difficulty controlling the fingers of the right hand. The n u m b n e s s spread to the right forearm and his speech was slurred and contained some wrong words. The episode resolved after one hour. He was admitted to another hospital where he had some fifteen further spells in the next two weeks involving either hand and usually lasting about five minutes. Evaluation with computerized tomography (CT) a n d bilateral carotid angiography was normal. Cerebrospinat fluid {CSF) showed 10 mononuclear cells m m 3 and a protein o f 102 mg/dt. During the next 2 weeks he became progressively more confused, disoriented and greatly slowed in movement and speech. On psychometric testing an oral I.Q. was 50-60 and written 40-50 whereas he had previously been a successful executive. When transferred to the Massachusetts General Hospital 5 weeks after the onset, he was alerl and cooperative but slow. quiet, unanimated, disinterested, emotionally flat and devoid o f initiauve. He disclaimed depression. Normally he was t h e d o m i n a n t figure in the family a n d had a quiet temper. He had absolutely no insight into his illness. Do you feel sick? "No, I feel sick only because of what 1 have. the hands feel sick and it is transferred to my body". Are you a patient here? ~'I don't know, ask my wife", He said it was February 18, 1978 rather than March, He thought he was in Worcester. Counting backwards from 30 or 10 was impossible; from 10: 14321473. Proverbs were interpreted concretely and he was unable to write his name or copy line drawings. He ate his m e a t with his fingers. Memory was surprisingly good in that after 24 hours he spontaneously recalled 9½ poinls o f a simple 10 point story he was given to remember. How long have y o u been sick? "5 weeks". There was ao dysphasia. Brisk tendon reflexes, bilateral grasp reflexes, and slight tip pursing were noted. Rapid alternating m o v e m e n t s were impaired in the right hand and forearm. The remainder o f the neurologic examination was normal. A n electroencephalogram (EEG) revealed diffuse delta slowing. Body-computerized tomography revealed bilaterally enlarged adrenal glands, Percutaneous biopsy of the left adrenal revealed an undifferentiated small cell tumor. The transient spells o f n u m b n e s s a n d weakness ceased without specific therapy aJ~d the cortical deficits present on admission improved. He began to faint u p o n arismg from bed a n d w h e n found to be Addisonian was started on replacement therapy. Further studies revealed no other deposits of metastatic disease. He was begun on cytoxan, hydroxyurea, vincristine and prednisone chemotherapy While on 100 mg of prednisone daily as part of chemotherapy his apathy diminished further and initiative increased. At the time of discharge, 2 m o n t h s after admission, his wife felt that his reactions and personality were close to normal. When seen one m o n t h later he felt "'great" and could rapidly do serial sevens. Three m o n t h s after discharge slowness, apathy and loss o f spontaneity reappeared. His wife reported. "'He looks good but he is blank, the look in his eyes is g o n e . " W h a t are you thinking about? " N o t h i n g ' . Haven't you anything to think about? " N o " . "All day tong he just sits or pitches horseshoes. He walks and talks in stow motion". W h e n his son was aecidently injured he showed no reaction t o the news. Memory was relatively preserved. A repeat body-computerized tomography showed resolution of the adrenal enlargement. Five m o n t h s after discharge he was either incontinent or urinated in inappropriate places such as a wastebasket. His appetite was excessive. He received chemotherapy m o n t h l y for 6 months. Seven 361 months after discharge lumbar back pain began and over the next 2 months the patient gradually developed a flaccid paraplegia and fecal incontinence. He became somnolent. On readmission 9 m o n t h s after discharge he was apathetic but recalled a 6-point verbal test story after 1½ hours and counted backwards from 10 but not from 20. Examination of the cranial nerves and upper extremities was normal except for the presence of marked grasping and sucking reflexes. There was a sensory level to all modalities at the inguinal ligament bilaterally. The only lower extremity movement was slight flexion of the left hip. The tendon reflexes and plantar responses were absent. Three cerebrospinal fluid examinations showed normal pressures, protein levels of 139 240 mg/dl and 6 32 mononuclear cells/mm 3. Cytologic examinations were negative. Computerized tomography of the head was normal, A myelogram showed questionable widening of the conus medullaris but no block. Biopsy by way of T i r L E laminectomy revealed necrotic spinal cord tissue but no tumor. The postoperative survival of 2 months was complicated by lever, increasing disorientation, stupor, recurrent seizures and p s e u d o m o n a s bacteremia. A repeat computerized tomography scan revealed non-enhancing symmetrical low density areas in the basal ganglia consistent with tumor masses. Death occurred 16 months after his initial symptoms. Pathological examination Undifferentiated tumor involved the adrenal glands, kidneys and liver. On microscopic examination small hyperchromatic tumor cells were confined to blood vessel lumens except ira the adrenals wherc there were small perivascular accumulations. Ira some areas blood vessels showed intimal thickening with occasional thrombosis. In the kidneys tumor cells showed a predilection for small veins adjaccm to the glomeruli and in the adrenals they were largely confined to the medullary sinusoids. Sections of spleen, bone marrow and lung were uninvolved. Muscular arteries were spared. The brain which was grossly swollen weighed 1360 g and showed bilateral uncal hcrniatiom right greater than left. On coronal sectioning widespread extensive patchy areas of bland and hemorrhagic infarction were seen throughout the hemispheres sparing the frontal and occipital poles. On each side a discrete tan-white tumor mass about 3 cm in diameter extended from the globus pallidus into the lateral thalamus (Fig. 1). The mid brain was elongated longitudinally and petecehial hemorrhages were seen ira the right pontine tegmentum, The spinal cord from the mid-thoracic region caudall, ~,as shrunken and soft (Fig. 2). Fig. 1. Coronal section o1" the brain showing multiple patches of bland and hemorrhagic infarction. bilateral tumor masses in the region o|" the globus pallidus and bilateral tmcal herniation. 362 Fig. 2. Lower spinal cord and cauda equina showing shrunken and softened cortl Microscopic sections through multiple areas of cortex revealed areas of bland and hemorrhagic infarction. Numerous small vessels in the subarachnoid space and corte;~ were tilled with hyperchromatic tumor cells. Vessels involved were thin-walled veins and capillaries and smatl .~rleries with a tunica media more than 4 cells thick were spared (Figs. 3 and 4). In many areas the vessel walls were necrotic and small extravasatlons of blood had occurred. The globus pallidus, inlern~d capsule and adjacent lateral thalamus bilaterally were replaced by sheets of small hyperchromatic qaononuclet~J Fig. 3. Cortical arteriole of 40 ~m diameter filled with hyperchromatic mononuclear lum~,r cells showing clumped chromatin. Luxol fast blue. hematoxylin and eosin. ~ 620. 363 q Q B 51 0 P 8 ! O 0 I O Fig. 4. Small arteriole with mononuclear tumor cells in the lumen and a few in the perivascular space. [.uxol fasl blue, hemaloxylin and eosin, x 320. Fig. 5. Section through the globus pallidus showing difl'use infiltration of hyperchromatic mononuclcar tumor cells and palisading around small blood vessels. Luxol fast blue, hematoxylin and cosin, × I(~0. 364 tumor cells with clumped chromatin and scant cytoplasm. The cells were tdenticat w~th those ~,ccta within vessel lumens. They infiltrated diffusely into the surrounding tissue and showed some congregatio~ around vessels (Fig. 5). The pons showed several small hemorrhages in the right lateral pontmc tegmentum and numerous small arteries containing tumor cells. The basilar artery was spared There was complete necrosis of the spinal cord from the mid-thoracic region caudally. The spinal cord had an extraordinary appearance in that the white matter was trabeculated and ~he only clearl~ recognizable structures were the anterior septum and surrounding meninges (Fig 6~. The meninges and anterior septum contained numerous greatly thickened occluded blood vessels in varying stages of organization and recanalization. Fibrinoid necrosis was common. In the anterior septum there wa~ neovascularization (Fig. 7). Many small arteries, capillaries and veins contained tumor cells which were confined to the vessel lumens and in some instances arranged in discontinuous loci (Fig~ ~ and 9~ In the lumbosacral region the anterior and posterior roots were necrouc At cervical levels there w~s secondary demyelination in the fascictllus gracilis. The peroxidase-antiperoxidase technique (Taylor and Mason 1974: Ta31or 1')7~ wa~ utilized for the detection of factor VIII antigen on the surface of the malignant cells. Unstained sections of cerebral cortex, globus pallidus and spinal cord were deparaffinized with xylene and 100" ethanol Endogenous peroxidase was blocked with 0.6% H202 followed by l0 rain incubation, in I : 2 swtne serum. The slides were then incubated in I : ]0 rabbit antihuma~ factor VIII for 45 m~t~tLtes, washed with buffer, then incubated with ] : 20 swine anti-rabbit IgG for 30 min. The~ were washed mid incubated for 30 min with t: 40 rabbit peroxidase-anti-peroxidase and stained with diaminobenzidme lbr 5 n~m followed by bematoxylin counter stare. The procedure was also performed with rabbit anti-kappas. anti-lambda, anti-lgA, anti-lgG and anti-lgM in place of anti-human factor VIII Positive staining for factor VIII antigen on the endothelial cells of both control~ a~td the patient was demonstrated by the presence of a red-brown precipitate. Malignant cel[~ both in the globus paltidus and in vessel lumens showed no factor VIII staining. The malignam cells showed nt~ ~,~anlNlg l~l" light chains or lmmunoglobulins IgA. IgG and lgM. Fig. 6. Lumbar spinal cord showing destruction all cord elements except the anterior septum and surrounding meninges. The white matter has a loosetrabecutated appearance Luxol fast blue hematoxylin and eosin. × 4. Fig. 7. Higher power view of the anterior septum of the spinal cord from Fig. 6 showing marked intimal proliferation, fibrinoid necrosis of vessel walls and neovascularization. Luxol lilst blue. hemaloxvlin and eosin, x lO0. Fig. 8. Spinal meningeal artery containing hyperchromatic rnononuclear lumor cells und showing fihrinoid necrosis o[" the vessel wall. Luxol filst blue, hematoxylin and eosin, × 256. 366 Fig. 9. R e c a n a l i z e d small spinal cord a r t e r y c o n t a i n i n g numerott,,, d i s c o n t i n u o u s foc~ - tuct~ur ceils within the r e c a n a l i z e d lumens. Luxol last blue. h e m a [ o x v l i n and costa ~ 16(t Comment on Case 1 After initially presenting with transient ischemic attacks, apparenlly of cerebrovascular origin, the patient developed a subacute profound dementia leaturing mainly a frontal lobe psychomotor retardation with relative sparing o f memory function. Investigation revealed an undifferentiated small cell tumor mass in each adrenal. Improvement in the above symptoms occurred spontaneously but particularly after chemotherapy when the patient's mentality returned almost to normal and the adrenal masses disappeared. Respite was brief and in a few months marked abulia returned. After 7 months a gradually progressive paraplegia developed from which the patient died. Pathological examination showed discrete tumor masses in the basal ganglia and widespread patchy infarction o f the cerebral hemispheres and brainstem. The spinal cord below the mid-thoracic level was destroyed. Microscopically the special finding was the widespread presence of tumor cells within and largely restricted to the lumens of small blood vessels produchag various degrees of occlusion and recanalizatton. The clinical presentation was puzzling in particular the mechanism by which an undifferentiated small celt tumor gave rise to transient ischemic attacks and dementia The computerized tomography scan and cerebrospinal fluid cytology were both negative. The early spontaneous improvement was unexplained. Later the pathological basis for the progressive paraplegia was not evident in life even with the help of surgical biopsy, 367 The patient, a 61-year-old man was well until 2 months before admission to the Massachusetts General Hospital. The first symptoms were fatigue and aching in tile legs. At about the same time. he was no longer interested in the news and his wife would find him lying on his bed in the dark with his clothes on. He fell asleep after meals. Oil a Sunday, about 10 days later, he drove away in his car, returning 10 minutes later. He said he thought the day was Sunday. When told it really was Sunday lie replied, "'1 thought today was Sunday." When asked what month it was he said "'It's the fourth month i/l" the year, April". (It was July). The year'7 ""74 or "75". (1979). The next day he was disoriented and ctid not go to work. fie put pipe tobacco in the palm of his hand and asked for a match as if he werc going to light it. He could not manage to fill his pipe. "'His hand wouldn't do what he wanted it to". He was taken to his physician the next day and did not dress properly. "He looked a mess" whereas he normally was vain about his appearance. After the examination he put his pants on inside out and back to front. When the error was pointed out he was hostile and asked to be left alone. Two weeks from the onset he was admitted to his local hospital where he gave answers that made no sense. He asked for a cigarette although he had not smoked them for I0 years. His language was borrowed from earlier years of" his life and when asking for a cigarette he would say "'Do you have a butt ?" He had to be restrained because of instability of gait and liiilure to stay in bed. A C T scan shovl agaul few m i n u t e s later he said "9. 8 . 6 . 5th. 4. 5th. 4. 5th, 4 . 4 . 5. 5th'" He gave his age as 4 0 : 0 1 , ,\re vo~ m a r r i e d ? "'Oh, y e a h " . H o w m a n y children'? "'Four" ttwot. Are they all girls? " Y e s " rru, The a c c u r a c y of his responses fluctuated. At his best he gave the year ~1 9 7 9 / a n d the ~i~ iBoston W h e n a s k e d w h a t he w a n t e d he said "1 need sex. t h a t ' s all". W h e n ~tsked to write hi', haunt" ll~.e I h u n l b o f the left h a n d b e c a m e c a u g h t on a b a r o f the siderail of the bed a n d at first he was u n a b l e ~o t,xtrlcate it. W i t h the right h a n d h o l d i n g the pen he reached 5 or 6 inches past Ihe top of the ~hect tac was to write on a n d when the left h a n d b e c a m e free lae crushed the paper. With the right hand !le m a d e