INTRACRANIAL RING ENHANCING LESIONS IN DOGS: A CORRELATIVE CT SCANNING AND NEUROPATHOLOGIC STUDY

MICHAEL WOLF, DR. VET. MED.,* VINCE PEDROIA, DVM,’F ROBERT J. HIGGINS, BVSc, PHD,I PHILIP D. KOBLIK, DVM, MS,§ JANE M. TURREL, DVM, MS,ll JERRY M. OWENS, DVM#

This retrospective analysis of 15 dogs with postcontrast ring enhancing brain lesions, each detected by a single Computed Tomography [CT] examination, searched for any association between their CT appearance and the pathologic diagnosis. In a subgroup of these dogs [n = 71 necropsied within 2 days of the last CT scan, we evaluated whether there was any anatomic correlation between the ring zone and the histopathologic features of the lesions. Our study consisted of eight dogs with primary brain tumors [3 meningiomas, 3 astrocytomas, 1 mixed glioma, 1 oligodendroglioma], 4 with metastatic brain tumors [2 fibrosarcomas, 1 mammary carcinoma, 1 melanoma] and 3 with non-neoplastic brain lesions [2 intraparenchymal hemorrhages, 1 pyogranulomatous meningoencephalitis]. The overall size and shape of the contrast enhancing CT lesions, as well as the thickness, surface texture and degree of enhance- ment of the ring were subjectively evaluated. No association was found between the CT lesion char- acteristics and the pathologic diagnosis. In the sub-group of dogs euthanatized within 2 days of the CT examination, distinct histologic features which anatomically correlated with the zone of ring enhance- ment were found in 3 of 7 lesions. The findings of this study are consistent with those of ring-enhancing lesions in people, and indicates that CT ring enhancement is a non-specific phenomenon which can occur in a variety of neoplastic and non-neoplastic lesions in the dog. Veterinary Radiology & Ultra- sound, Vol. 36, No. I , 1995, p p 16-20.

Key words: dog, computed tomography, ring enhancement, brain, neuropathology.

Introduction OMPUTED tomography [CT] has proven to be a highly C effective imaging technique to identify the presence,

location, size and anatomic relationship of intracranial le- sions in people. ’ The general principles of interpretation of such lesions include the primary features demonstrated in pre- and post-contrast studies as well as any secondary ef- fects associated with space-occupying lesions. After con- trast medium administration, lesions may enhance either uniformly, heterogeneously, in a ring-like pattern [“blush”], or not change. In contrast-enhanced CT studies in people, ring patterns are not an uncommon finding in various types of intracranial space-occupying lesions. 2-7 Such ring en- hancement has been seen in 20% of a series of 2,500 intra- cranial human neoplasms, including both primary and met- astatic lesion^.^^^^^ Ring enhancement has also been re-

From the Departments of Surgery and Radiology*,§, and Pathology,$ School Veterinary Medicine, University of Califomia-Davis, Davis, CA. 95616; Animal Care Center,? Rohnert Park, CA. 94928; Veterinary On- cology Specialties,lI Pacifica, CA. 94044 and Special Veterinary Ser- vices,# Berkeley, CA, 94707. USA.

Address correspondence and reprint requests to Robert J Higgins, BVSc MS PhD, Dept Veterinary Pathology, School Veterinary Medicine, Uni- versity Califomia-Davis, Davis, CA, 95616, USA.

Received September 28, 1993; accepted for publication January 10, 1993.

ported in a variety of non-neoplastic brain conditions in man, including brain abscesses, fungal granulomas, herpes virus encephalitis, multiple sclerosis, infarcts, hematomas, vascular anomalies, parasitic and congenital cysts, postra- diation necrosis and post surgical cerebral injury .273,7-10 In people, this pattern of CT enhancement is regarded as a non-specific phenomenon and therefore generally of mini- mal diagnostic usefulness.

In contrast, there are only 6 dogs reported with patho- logically confirmed, ring enhancing, intra-cranial tumors; a meningioma, an astrocytoma, an anaplastic glioma, an oli- godendroglioma, a gliosarcoma, and a metastatic mammary tumor. 12,13,16 A few non-neoplastic ring enhancing lesions have also been reported in the dog and include one cerebral arteriovenous malformation, l4 two patients with granulo- matous meningoencephalitis, one pug-dog encephalitis and one patient with canine distemper virus associated necro- sis.I6 Ring enhancement has also been described in dogs that developed brain necrosis following experimental inter- stitial Iz5I irradiation. l5

In people, histopathologic studies of lesions with ring enhancement suggest that the ring is created by a zone of blood vessels, reactive astrocytes and fibroblasts which sur- round a central core containing necrotic tumor cells, edema, hemorrhage or liquefactive necrosis from various causes, Thus the ring effect has been suggested to result from either

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VOL. 36, No. 1 CANINE INTRACRANIAL CT RING ENHANCING LESIONS 17

a defective blood brain barrier in this zone with massive interstitial leakage and/or retention of contrast medium in abnormal vascular tissue due to loss of autoregulation.24’8 Similar CT-pathological studies of this phenomenon in dogs have not been reported.

The first aim of this retrospective study of 15 dogs was to search for any association between the computed tomo- graphic features of ring enhancement of intracranial lesions on a post-contrast CT examination and the neuropathologic diagnosis. The second aim was to determine, in a subgroup of these dogs [n = 71 which underwent necropsy within 2 days after the CT examination, whether any histopathologic features of the lesions might correlate with the ring-like zone on the CT images.

Material and Methods Fifteen dogs which had both a ring enhancing lesion in

the brain on contrast enhanced CT images and a subsequent neuropathologic examination of the lesion were retrospec- tively selected from dogs examined at four veterinary clin- ics in the period between 1979 and 1991.

All CT images were acquired while the dogs were under general anesthesia and positioned in sternal recumbency. Transverse images were acquired as a series of contiguous 3-5 mm slices from the level of the cribriform plate to the level of the foramen magnum. CT studies were performed at three different clinics using 4 different scanners and three different protocols for administration of contrast medium. CT images were recorded on X-ray film using a multiformat camera. Window level and width were within the range of 20-30 and 150-250 Hounsefield units respectively. The CT features of ring-enhancement were qualitatively evaluated using the following criteria [see Table 11: degree of en- hancement [minimal, moderate or marked], ring shape [cir- cular or irregular], definition of inner and outer ring mar- gins [smooth or rough], ring thickness [uniform or non- uniform] and opacity of the central core [iso- or hypodense].

A complete necropsy was done on 13 dogs, including the removal and gross examination of the brain, which was then immersion-fixed in 10% buffered formal saline. The size, location and type of any gross lesion on external examina- tion of the brain was recorded. After fixation, 3 mm thick transverse sections of the brain were examined and each section which corresponded to those CT images with ring enhancing lesions was submitted for subsequent routine his- tologic processing in paraffin.

Then, 6um thick sections were cut, stained with haema- toxylin and eosin [H&E] and neuropathologically evalu- ated. In two dogs [#3, 71 similar neuropathological evalu- ation of the lesions was done from tissue submitted from a surgical biopsy procedure. Both dogs eventually died but complete necropsies were not permitted by their owners. When appropriate, selected sections were also stained with Masson’s trichrome, Gomorri’s reticulin, Brown and Brenn’s gram, Gomorri’s methenamine silver, Luxol-fast blue [LFBI-cresyl Echt violet and LFB-Bodian stains for a more detailed histologic evaluation. A routine streptavidin- biotin-peroxidase procedure employing rabbit anti-human Von Willebrand factor VIII antibody at 1:400 [Dako Corp., Carpintaria, CAI was used for visualisation of endothelial cells. This procedure was also used for demonstration of glial fibrillary acidic protein [GFAP] using rabbit anti-cow GFAP antibody [Dako Corp., Carpintaria, CAI at 1:2000.

Results

CT Findings and Neuropathological Diagnosis

The characteristics of the zone of ring enhancement and the neuropathologic diagnosis of brain lesions in the 15 dogs is summarized in Table 1. The interval between the CT examination and necropsy of these dogs ranged from im- mediately up to 150 days, except in one dog at 350 days [case # 51.

TABLE 1. Pathological Diagnosis and CT Characteristics of Ring Enhancing Lesions in the 15 Dogs

Dog # 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5

Pathologic diagnosis*$ M M M A A A MG 0 MF MF MC MM CH AH PG Location of lesiont C C F F O L F F T T T F T T P TH CT-FINDINGS Ring shape11 c I c c I c c I I c c c I c c

Uniformity of thickness** + - - - - + + + - + + - + + + Degree of contrast enhancement5 MO MA MA MA MA MA MO MA MA MA MO MA MO MO MO Margin of innerlouter ring# SIS SIS RIR RIR SIR SIS SIS RIS SIS RIR SIS SIS RIR SIR WR

Central Opacitytt HO IS HO HO HO IS HO HO IS HO HO IS IS IS IS

*Tumors: M = Meningioma; A = Astrocytoma; MG = Mixed glioma; 0 = Oligodendroglioma; MF= Metastatic fibrosarcoma; MC = mammary

TLocation: C = Cerebellum, F = Frontal lobe, H = Hypothalamic, 0 = Olfactory lobe, P = Parietal lobe, T = Temporal lobe, TH = Thalamus. $Other: AH = acute and CH = chronic hemorrhage; PG = pyogranulomatous encephalitis. §Degree of contrast enhancement: MO = moderate, MA = marked. ]]Ring enhancement shape: C = circular, I = irregular. #Ring margin appearance [innerlouter borders]: R = rough, S = smooth. **Uniformity of ring thickness: + = uniform, - = non-uniform. ttCentral core of ring: IS = isodense; HO = hypodense.

carcinoma; MM = Metastatic melanoma.

WOLF ET AL 1995

I . Primary brain tumors. Six of the eight primary brain tumors [2 meningiomas, 3 astrocytomas, 1 oligodendro- glioma] had marked contrast enhancement; the other two primary tumors [ l menigioma, 1 mixed glioma] had mod- erate enhancement. The overall shape of these lesions was evenly divided between circular [n = 4; 2 meningiomas, 1 astrocytoma, 1 mixed glioma] and irregular [n = 4; 1 me- ningioma, 2 astrocytomas, 1 oligodendroglioma] . In half of the dogs [n = 4; 2 meningiomas, 1 astrocytoma, 1 mixed glioma] , the enhancing ring had smooth borders while in the other four lesions [ 1 meningioma, 2 astrocytomas, 1 oligo- dendroglioma] some irregularity was noted to the inner or outer surface of the ring. The ring wall was of uniform thickness in four lesions [l meningioma, 1 astrocytoma, 1 mixed glioma, 1 oligodendroglioma] and non-uniform in the other four lesions [2 meningiomas, 2 astrocytomas]. The central core was isodense in one meningioma and one astrocytoma but in the other tumors was hypodense.

I I . Metastatic tumors. Three of the four metastatic brain tumors [2 fibrosarcomas, 1 melanoma] had marked contrast enhancement; the other metastatic tumor [ 1 mammary car- cinoma] had moderate enhancement. The overall shape of three lesions was circular [ 1 fibrosarcoma, 1 mammary car- cinoma, 1 melanoma] while one lesion was irregular [ l fibrosarcoma]. In three of the four dogs [ 1 fibrosarcoma, 1 mammary carcinoma, 1 melanoma] the enhancing ring had smooth borders while in the other lesion [I fibrosarcoma] the inner and outer borders were irregular. The ring wall was of uniform thickness in two lesions [ 1 fibrosarcoma, 1 mammary carcinoma] and non-uniform in the other two lesions [ 1 fibrosarcoma, 1 melanoma]. The central core was hypodense [ 1 fibrosarcoma and the mammary carcinoma] while the other two tumors appeared isodense.

Ill. Non-neoplastic lesions. All three non-neoplastic brain lesions [ 1 chronic hemorrhage, 1 acute hemorrhage, 1 pyogranulomatous meningoencephalitis] had moderate con- trast enhancement, irregular ring wall surfaces and uniform ring wall thickness. Two of these lesions [ l acute hemor- rhage, 1 pyogranulomatous meningoencephalitis] were cir- cular; the other lesion [ 1 chronic hemorrhage] was irregular in shape. All three lesions in this group had isodense central cores.

Comparison Between CT and Pathologic Findings In the subgroup of seven dogs [case #'s 2, 10, 11, 12,

13, 14, 151 a complete necropsy examination was done within 2 days of the postcontrast CT examination. We de- cided this interval would allow for reliable interpretation of any correlation between the ring effect and pathologic changes. In this group, specific histologic features of the lesions that might have explained the ring enhancement oc- curred in three different lesions [#'s 11, 12, 141. In two dogs with metastatic brain lesions (1 mammary carcinoma, 1 melanoma) well demarcated, uniformly well vascularized

thin rims of viable neoplastic tissue were bordering large, central irregular areas of liquefactive necrosis. For these lesions, there was a close anatomic correlation between the shape and location of the viable, vascularized neoplastic tissue and the ring-enhancement zones on the CT studies. Further, the shape of the central radiolucent areas on the CT images conformed closely to that of the central area of liquefactive tumor necrosis. In the dog with acute focal

A

B FIG. 1. A. Dog# 11. A 5 mm thick contrast enhanced CT image of a ring enhancing metastatic mammary carci- noma in the ventromedial portion of the left frontal lobe. Note the circular shaped ring with thickened ventrolat- era1 walls and smooth internal and external borders. There was marked contrast enhance- ment. B. Macrophotograph of the histologic section at the same level as the CT image. A rim of well vascularized vi- able tumor tissue correspond- ing to the ring zone is present surrounding a central necrotic core. There is minimal mass effect and peritumoral change. H&E stain.

VOL. 36, No. I

A

B

CANINE INTRACRANIAL CT RING ENHANCING LESIONS 19

FIG. 3. Dog# 15. A post-contrast CT image with a ring enhancing area in the right thalamus associated with focal pyogranulomatous meningoen- cephalitis. The ring was circular with uniformly thick walls but rough borders and with moderate enhancement. There were no histologic features which corresponded to the zone of ring enhancement.

hemorrhage [clinical signs for 7 days], dilated or ruptured blood vessels surrounded the periphery of the main lesion which consisted of a central core of fresh hemorrhage. There was marked dilation of apparently pre-existing blood vessels bordering the lesion with associated mild edema. The size, shape and location of the enhancing ring corre- lated anatomically with this thick peripheral zone of dilated or ruptured vessels. In the dog with focal, chronic hemor- rhage [clinical signs for 21 days] there was marked periph- eral organisation with neovascularisation, dense thick fi- brous capsule, peripheral astrocytosis and hemosiderin- containing macrophages. There were no specific zonally- defined pathologic changes [eg edema, demyelination, neuronal or glial cell degeneration, astrocytosis, neovascu- laisation or inflammation] in the corresponding ring en-

zone in the Other four patients examined.

Discussion The results of this study suggest that in dogs, the occur-

rence of ring enhancement of brain lesions is a non-specific finding seen with a broad range of neoplastic and non-

FIG. 2. A. Dog# 14. A contrast enhanced CT image of a ring enhanc- ing area associated with acute focal hemorrhage in the right parietal lobe. The CT ring is circular with uniformly thick walls that have smooth but irregular borders. There is moderate enhancement. B. Macrophotomicro- graph at same level as the CT image. A thin peripheral zone of blood vessels corresponding to the ring zone surrounds a solid area of acute hemorrhage. H&E stain.

20 WOLF ET AL 1995

neoplastic lesions. Despite limitations imposed by the small number of patients, our observations lead us to believe that there is unlikely to be a clinically useful correlation between CT ring appearance and the pathological diagnosis.

As with most retrospective studies, this study was some- what restricted by several factors beyond our control: 11 the total number of dogs with specific brain diseases included in the study population was small, 21 the dogs were not ex- amined using the same equipment or contrast medium ad- ministration protocol, and 31 pathologic evaluation of the lesions was not immediately available after the CT exami- nation in all dogs. To maximize the number of lesions for this study, material was acquired from three veterinary clin- ics. We were concerned that some of the CT features ex- amined in this study, especially the degree of contrast en- hancement, might have been influenced by both the dose and the timing of contrast medium administration. However, we could find no evidence in this limited number of cases to suggest any linkage between the scan results and either the CT equipment or the contrast enhancement protocol.

We found that in three of seven lesions examined from dogs necropsied within 2 days of the CT examination, the ring enhancing zone seen on CT images was associated with either a rim of prominent vascularization, within viable tu- mor tissue surrounding an area of central liquefactive tumor necrosis, or in a peripheral zone around fresh hemorrhage. However, no association could be made in four other le- sions similarly examined and the findings suggest that a different mechanism for ring enhancement could be oper- ating at different stages of the lesions. Similar conclusions have been reached from correlative CT-pathology studies of ring enhancing lesions in p e ~ p l e . * , ~ . ~ . ’ ~ In dog brains using CT, rate constants for the kinetics of uptake and washout of contrast medium in neoplastic [n = 111 and non-neoplastic [n = 131 lesions have been compared.15 There were dis- tinctly different kinetic patterns of contrast enhancement

between these groups. Further, such analysis could discrim- inate between gliomas and a tumor of neuronal origin.15 From this study, it was concluded that the magnitude and kinetics of contrast enhancement were primarily controlled by the extent of permeability defects in the blood-brain barrier. Thus, the in vivo application of electron-dense or fluorescent-labeled tracers might differentiate between ef- fects due to perturbation of either the vascular tone with luxury perfusion or of the blood-brain barrier permeability in the l e s i o n ~ . ~

In people, a high degree of accuracy is claimed for the diagnosis of intraparenchymal hemorrhage based on the temporal sequence of characteristic CT changes in the na- ture and pattern of the ring enhancement and to a lesser extent on the minimal mass e f f e ~ t . ~ ’ ~ ’ ~ ’ ’ ~ Ba sed on serial examinations, distinctive CT changes in shape, size and density of both the mass and ring zone have been shown to correlate closely with the sequential pathologic stages of resolution of brain hemorrhage, and the ultimate loss of ring enhancement within 2-6 Such sequential CT changes are not seen with intra-tumoral hemorrhage,* brain tumors’”’ or other non-neoplastic lesion^.^-^,^ We found histologic stages of resolution of the acute and chronic hem- orrhage similar to those reported in but no dis- tinctive changes in their CT appearance apart from differ- ences in smoothness of their inner rings. Obviously sequen- tial and comparative studies need to be done on more such cases to establish any similar pattern.

In order to interpret more accurately the conclusions from these findings, it would be necessary to study prospectively the spectrum of ring-like patterns from a larger number of specific lesions, to use a single scanner and a standard pro- tocol for contrast enhancement, to perform multiple CT examinations over the clinical course of the disease, and to explore the promising usefulness of the kinetics of contrast medium washin-washout studies using CT. l5

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