Radiographic abnormalities retinoblastoma and other

British Journal of OphthAimology, 1978, 62, 365-372

Radiographic abnormalities in eyes withretinoblastoma and other disordersGORDON K. KLINTWORTHFrom the Departments of Pathology and Ophthalmology, Duke University Medical Center, Durham,North Carolina, USA

SUMMARY The importance of radiographic examinations of pathological ocular material is stressed.Characteristic ocular radiodensities are observed with retinoblastomas, calcified cataracts, senilescleral plaques, intraocular ossification, and a variety of radiodense foreign bodies. Radiographssupplement other techniques for the documentation of ocular abnormalities and in certain instancesmay be the ideal method. They also permit the precise localisation of radiodense foreign bodies thatneed to be removed prior to the processing of tissue for microscopic examination. In certain situationsvaluable data can be obtained by x-ray examinations of embedded material. Retinoblastomas havean extremely high incidence of radiodensities with a characteristic appearance. This finding stressesthe clinical importance of utilising and developing clinically applicable techniques for the detectionof calcification in patients with suspected retinoblastomas.

Roentgenography has entrenched itself as a valuablediagnostic procedure in clinical ophthalmology andin medicine in general. Several texts are specificallydevoted to applications of x-ray examinations ofinterest to ophthalmologists (Hartmann and Gilles,1959; Guillot et al., 1966; Lombardi, 1967). On theother hand scant attention has been paid to radio-graphic examinations of excised pathological oculartissues despite the fact that such investigations offereven more opportunity for evaluation as the limi-tations imposed by the bony orbit are absent. Thisreport reviews experience with radiographic exami-nations on approximately 200 selected eyes.

Materials and methods

Since 1969 x-ray examinations have been performedat Duke University Medical Center on approxi-mately 200 selected eyes with a wide variety ofabnormalities. These included phthisis bulbi, uvealmelanomas, panophthalmitis, endopthalmitis, cata-racts, glaucoma of several types, gunshot wounds,known or suspected foreign bodies, detached retinas,retinoblastomas, Coats's disease, segmental retinalgliosis, retrolental fibroplasia, senile scleral plaques,and microphthalmos. Some eyes had encirclingbands for detached retinas or implants of radio-

Address for reprints: Dr Gordon K. Klintworth, Departmentof Pathology, Duke University Medical Center, Durham,North Carolina, USA

opaque materials. Eyes from individuals of variousages with no apparent ocular disease were alsostudied. Radiographs of all enucleated eyes withretinoblastomas between 1969 and 1977 (24 cases)were obtained. In addition to these cases x-rayexaminations were performed on portions of otherembedded globes (17 Paraplast, 21 paraffin, and 4celloidin) with retinoblastomas. In all instances theeyes were examined microscopically.

X-ray examinations were performed with equip-ment designed to give high resolution radiographsof small to medium sized objects while operating offan ordinary 1 0-V, 50/60 cycle ac line. Most of theroentgenography was carried out with a Picker110-kV Hotshot portable x-ray unit designed pri-marily for the industrial radiography of light metal.The equipment was mounted on a light metalquadrupod and consisted of a self-contained trans-former tubehead equipped with a 0*5-mm thickberyllium window and possessed a 0 5-mm focalspot tube for finest detail sensitivity. The totalfiltration of the x-ray beam through the berylliumwindow ensured a high radiation output within ashort time at low kV. Lead shielding was installedbetween the tube head and an underlying rectangularcabinet (27-9 x 26-7 x 53-3 cm) with 14-mm-thicklead walls. The joints between them were lined with2-mm-thick sheets of lead to provide additionalprotection. X-ray examinations were performed byplacing specimens on a shelf in the radiation-

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Figs. 1-3 The calcifications in retinoblastomas are readily visualised in roentgenographsof enucleated eyes

Fig. 1 Uncut eye with retinoblastoma

Fig. 2 Celloidin-embedded eye with retinoblastoma andtypical radiodensities

Fig. 3 Paraffin-embedded eye with exophyticretinoblastoma and detached retina

shielded cabinet with the x-ray beam directedvertically toward the specimen, which was placedon Kodak industrial x-ray film type M. Radiographsof eyes were taken at 20 to 24 kV and 6 mA withexposure time of 1 minute. After x-ray exposure thephotographic film was developed for 5 minutes.Recently comparable radiographs have been ob-tained with a Faxitron x-ray System (Model43805N) (Hewlett Packard, Oregon) with thecapability of selecting the optimum kVp and deter-

mining correct exposure time. This equipment hasan 0 25-mm-thick beryllium window.

Results

Numerous distinct radiographic appearances weredetected (Figs. 1-14). Of particular importance wasthe high incidence of characteristic radiodensitiesin retinoblastomas. These were discrete and rela-tively uniformly sized (about 1 mm in diameter)

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Radiographic abnormalities in eyes with retinoblastoma and other disorders

Figs. 4-7 Radiographs of eyes

Fig. 4 Central callotte of sectioned phthiscal eye withcalcified cataract and bone

Fig. 6 Extensive ossification in phthisis bulbi

(Figs. 1-3). In parts of some tumours they wereabundant, often closely packed and not discerniblefrom each other. Such eyes, nevertheless, still con-tained smaller discrete opacities (Fig. 3). All 24non-embedded complete eyes with retinoblastomashad this characteristic radiograph. When onlyportions of embedded eyes were studied the fre-quency of positive results varied being 5/5 (100%),16/18 (89 %), 12/21 (57 %) with celloidin, Paraplast,and paraffin embedded tissue respectively. Theoverall incidence of the typical roentgenographic

Fig. 5 Calcified cataractous lens and intraocular bonein phthisis bulbi

Fig. 7 Intraocular bone and plastic cyclodialysis tubeimplant

appearance was 840%. All eyes with characteristicradiographic densities contained foci of calcificationin tissue sections, but in some instances the calcificdeposits were not always present in random sec-tions through the tumour. Radiographs indicatedthe appropriate region for histological examinationwhich invariably contained calcific deposits. Calci-fication was not observed in the choroid, opticnerve, or in extraocular extensions of retinoblasto-mas.A review of tissue sections of tumours that did

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Fig. 8 Siliconised rubber (Silastic implant) withinscleral shell of eviscerated eye

F ig. IO BB pellet and bone in eye of child

not show radiographic abnormalities disclosed thatonly small fragments of tumour were present inmost instances. Some of these retinoblastomas haddistinct characteristics. One tumour had destroyedall recognisable ocular components and extendedextensively into the periocular tissues, another hadmuch necrosis but no calcification, and 2 othersdespite massive invasion of the choroid did notmanifest zones of necrosis. Additional retinoblas-tomas were well differentiated with neither necroticnor calcific foci or small with minimum cellulardebris. Three non-radiographically detectable retino-

Fig. 9 Encircling band around eye with retinal detachment

Fig. 11 Metallic Joreign body in eye

blastomas contained numerous haematoxyphilicdeposits which did not stain with histochemicalmethods for calcium (alizarin red, von Kossa), orDNA (Feulgen) but stained positively for RNAwith methyl green pyronin.

Siliconised rubber (Silastic) and plastic materialsused in treatment as in implants of eviscerated eyes,encircling bands for retinal detachment, and cyclo-dialysis implants dissolved during the normalpreparation of tissue sections. They were, however,readily demonstrated by radiographs which formeda permanent record of their presence (Figs. 7-9).

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Radiographic abnormalities in eyes with retilnoblastmna alid othili disorders


Fig. 12 Itntraoc ulcar itront wire

Fig. 13 Calcified scleiral plaques at sites of inser-tioni ofmedial and lateral r-ectus miiuscles

Fig. 14 Radioclelnsity ini vitreous of'glauconmatous eye ofpatient wit/h sarcoidosis

Surprisingly many eyes, especially of elderly indi-viduals, showed an increased radiodensity of thevitreous (Fig. 14). This did not persist after theglobes were sectioned and the vitreous merged withthe fixative. In some instances it was accompaniedby a diffuse but non-radiographically detectablecalcification of the sclera or calcific deposits in theciliary body or ocular lesions. Four cases were

associated with glaucoma, but the radiodensity ofthe vitreous did not reflect increased intraocularpressure. It was almost always found in eyes withnormal intraocular pressure, and most glaucomatouseyes did not show this change.

Roentgenographic abnormalities were conspicu-ously absent in certain ocular disorders, including

endophthalmitis, panophthalmitis, segmental retinalgliosis, uveal melanomas, and most eyes withglaucoma.

Discussion

This study, in which highly sensitive x-ray equip-ment was used, stresses the practical value of roent-genographic examinations in ophthalmic pathology.By means of this technique radiodense foreignbodies can be localised precisely. This greatlyfacilitates their removal from the eye prior to itsprocessing for microscopic examination. Markedlycalcified lesions such as bone, cataracts and scleralplaques, which might create difficulties when tissue

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Table 1 Incidence of calcification in retinoblastornas

Method of detecting calcification

Samnple Roentgenographic calcification Calcification insize Orbits Globes tissue sections

20 15 (75%)

10 8 (80%)

Chemical analyses ofashed tissue bocks Remyiarks

Roentgenographic examination ofportions of enucleated globes

Calcification detected roentgeno-graphically before enucleationand in enucleated globe

4 3 (75 %)

Merriam (1950) 8 4 (50%)

Swan and Hyman(1952)

Zeiter (1962)

Bullock et al. (1977)

23 18 (78 %)

10

16 3 (19%)

Cases that eventually fatal andhaving necropsy

7 (70%)

Standard roentgenograms. Onepatient had negative skull viewbut positive orbital view

8 (100%)

40

37

38 (95 %)

26 (70%)

Present study:Non-embedded

complete globesPortions ofembedded globesParaplastParaffinCelloidin

24 (100%)

16 (89%)12 (57%)5 (100%)57 (84%) Limited amount of tissue

available for study in eyeswithout detectable calcification

is sectioned, can be detected and decalcified beforethe eye is embedded. Another virtue of x-ray exami-nations is that radiographs permit the documenta-tion of certain ocular abnormalities better thanphotographs or tissue sections. For example, some

radiopaque materials used in therapeutic proceduresdissolve during the routine processing of the tissue.The tendency of retinoblastomas to calcify,

particularly in necrotic portions, has attracted con-

siderable attention. For more than a centurycalcareous concretions have been recognised in thisneoplasm (Knapp, 1869). Depending upon themethod of detection, the reported incidence ofcalcification within retinoblastomas varies con-

siderably (Pfeiffer, 1936; Fulton, 1950; Merriam,1950; Swan and Hyman, 1952; Zeiter, 1962;Bullock et al., 1977) (Table 1). Bullock et al. (1977)reported radiodensities in only 19% of cases onstandard preoperative roentgenograms, but in ashedtissue blocks with 8 retinoblastomas they foundthe calcium content in all instances to be muchhigher than in 4 normal eyes. These investigators

found that the quantity of calcium in retinoblasto-mas with histologically and roentgenographicallydetectable calcification did not differ from thoseeyes in which one or both of these techniques failedto detect it. The diagnostic importance of thesedeposits has been emphasised.

Characteristic white flecks are evident to some

degree in virtually all retinoblastomas, and inendophytic and some exophytic neoplasms the areas

of calcification are evident ophthalmoscopically.Their clinical appearance is modified by the depthof the pearly or chalk white calcific deposits.Superficial flecks appear discrete, while deeperdeposits have more poorly demarcated borders.They are considered to be the most important clinicalcharacteristic of the tumour, and their detectioncan be decisive in difficult diagnostic cases (Reese,1976). That retinoblastomas contain areas of calci-fication of sufficient density and size to be detectedby roentgenographic examination is well estab-lished (Pfeiffer, 1936; Fulton, 1950; Bullock et al.,1977). In 1936 Pfeiffer drew attention to the practical

Study

Pfeiffer (1936)

Fulton (1950)

24

18215

68 59 (87 %)

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Radiographic abnormalities in eyes with retinoblastoma and other disorders

use of this attribute in the clinical evaluation ofpatients with leucokoria, and stressed the need forroentgenograms of good quality and describedtechnical details of several methods. He recommen-ded stereoscopic films and exposure of the orbitwith the patient under general anaesthesia in theCaldwell position as for examination of the sinuses.Other radiographic techniques have been used(Fulton, 1950), but standard radiographs are notreliable in detecting the calcification in retinoblasto-mas even when it is present (Shields et al., 1976;Bullock et al., 1977). Roentgenographic examinationsin young children pose difficulties, and, as a con-stant success is not obtained, many ophthalmolo-gists unfortunately no longer consider it a usefuldiagnostic aid.The high frequency of the radiodensities in

retinoblastomas detected in the present studyunderscores the fact that the vast majority ofretinoblastomas not only calcify but have a charac-teristic radiographic pattern. When present thehighly characteristic roentgenograms of retino-blastomas permit the diagnosis to be confirmed withapparent certainty within a few minutes of enuclea-tion without even cutting the globe. The possibilityof other calcified lesions being confused withretinoblastomas needs to be considered. Fortu-nately, most intraocular calcific deposits occur at adifferent age to retinoblastoma and do not causeconfusion clinically. The multiple stippled radio-densities that typify retinoblastomas have not beenobserved in other entities. In the present study alleyes which were erronously enucleated for suspectedretinoblastoma lacked detectable calcification. Otherinvestigators have also not found radiodensitiesearly in life in eyes with lesions that are commonlyconfused with retinoblastoma (Pfeiffer, 1936;Bullock et al., 1977). However, spotty calcificationhas been observed in tissue sections of eyes withlarval granulomatosis (Howard and Ellsworth,1965).Massive gliosis of the retina is unlikely to be

confused with retinoblastoma clinically, as it rarelyoccurs in the same age group. Also, when it isaccompanied by calcification, foci of ossificationusually coexist (Yanoff et al., 1971). The retinalastrocytic hamartomas of tuberous sclerosis cancontain numerous calcospherites, but these too arenot abundant early in life. Radiographs of eyeswith the aforementioned conditions have not beenstudied, but because of their histopathologicalfeatures one is led to suspect that the pattern ofradiodensities would differ from that of retino-blastomas. Time will tell whether the characteristicradiographic pattern of retinoblastomas is or is notdistinctive for this condition. With retrolental

fibroplasia, which has been mistaken clinically forretinoblastoma, the calcification does not occurearly in life and is a late manifestation and anexpression of ossification in phthisis bulbi. Tayebi(1956) observed roentgenographic evidence of calci-fication in 14 of 22 eyes with retrolental fibroplasiain children over the age of 4. It was not found inchildren under 4 years of age. The present studyincluded phthisical eyes with retrolental fibroplasiafrom 2 individuals over the age of 20. Both hadradiographic and histological evidence of calcifiedcataracts and intraocular bone. In neither case didthe radiograph resemble that found in retinoblasto-mas.

In the present study characteristic radiographswere obtained with all 24 retinoblastomas in whichthe entire eye was x-rayed. Negative findings withthis tumour were only obtained with x-ray exami-nations performed on portions of eyes. As thecalcifications in some retinoblastomas is not uni-formly distributed throughout the tumour mass,many of these eyes would probably have containedit if more tissue had been studied. Nevertheless,the possibility that some retinoblastomas may notbe detectable by techniques that demonstrate calci-fication seems highly likely. Experience with portionsof embedded globes with retinoblastomas that lackedradiodensities suggests that an absence of radio-graphically detectable calcium may occur withretinoblastomas that are small or markedly ana-plastic. The absence of radiographically detectablecalcium clearly is not an indicator of prognosis inindividual cases. Calcification was absent in portionsof highly invasive anaplastic retinoblastomas aswell as in small localised well differentiated tumoursthat were cured by enucleation. It was likewisealso present in retinoblastomas with favourable orunfavourable outcomes.The clinical diagnosis of retinoblastoma has

improved considerably since this potentially lethalintraocular neoplasm first became recognised.Nevertheless, eyes enucleated with suspected retino-blastomas frequently do not harbour a malignancy(Howard, 1969; Kogan and Boniuk, 1962), andeven today such errors still occur. Refinements inthe clinical distinction between retinoblastomas andother binding conditions of infancy and childhoodis clearly of more than academic interest. Unneces-sary enucleations during this critical period oforbital development need to be minimised.

Since calcification is so common in retinoblasto-mas, wider use of x-ray examinations and othertechniques for the demonstration of calcific depositsin the clinical diagnosis of retinoblastomas is clearlyindicated. The development of refined techniquesfor the clinical detection of ocular calcification

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should be strongly encouraged. Ultrasonographyhas proved useful in this regard (Sterns et al., 1974;Shields et al., 1976). Shields et al. (1976) havestressed the value of contact B-scan ultrasonographyin the diagnosis of retinoblastomas in children whoseeyes have opaque media or unusual fundus lesions.Also computerised transaxial tomography, which isintrinsically sensitive to large differences in radio-graphic density even when the structure is small,can detect intraocular calcification and has beensuccessfully used in the diagnosis of retinoblastomas(Trokel, 1977). In addition the radionuclide techne-tium diphosphonate, which has an affinity forhydroxyapatite, is being investigated as a possibleaid in the diagnosis of retinoblastomas (Bullocket al., 1977). In children some of these moderndiagnostic techniques for the detection of calcificdeposits unfortunately require general anaesthesia,but the risk of anaesthesia is small and seemsjustified. Intraocular examinations under anaes-thesia have been customary practice for suspectedretinoblastomas for a long time.

This study was supported in part by Grants IR01-EY00146 and 5R01-CA13603 from the US PublicHealth Service.

References

Bullock, J. D., Campbell, R. J., and Waller, R. R. (1977).Calcification in retinoblastoma. Investigative Ophthal-mology and Visual Science, 16, 252-255.

Fulton, H. (1950). A roentgenographic aid in the diagnosisof retinoblastoma. American Journal of Roentgenology andRadium 7herapy, 64, 735-739.

Guillot, P., Saraux, H., and Sedan, R. (1966). L'explorationNeuroradiologique en Ophtalmologie. Masson: Paris.

Hartmann, E., and Gilles, E. (1959). RoentgenologicDiagnosis in Ophthalnology. Lippincott: Philadelphia.

Howard, G. M. (1969). Erroneous clinical diagnoses ofretinoblastoma and uveal melanoma. Transactions ofAmerican Academny of Ophthalmology and Otolaryngology,73, 199-203.

Howard, G. M., and Ellsworth, R. M. (1965). Differentialdiagnosis of retinoblastoma. A statistical survey of 500

children. I. Relative frequency of lesions which stimulateretinoblastoma. American Journal of Ophthalmology, 60,610-618.

Knapp, H. (1869). In On Intra-ocular tumors, p. 101. WilliamWood: Philadelphia.

Kogan, L., and Boniuk, M. (1962). Causes for enucleationin childhood with special reference to pseudogliomas andunsuspected retinoblastomas. International OphthalmologyClinics, 2, 507-524.

Lombardi, G. (1967). Radiology in Neuro-Ophthallnology.Williams & Wilkins: Baltimore.

Merriam, G. R., Jr. (1950). Retinoblastoma: analysis ofseventeen autopsies. Archives of Ophthalmology, 44, 71-108.

Pfeiffer, R. L. (1936). Roentgenographic diagnosis of retino-blastoma. Archives of Ophthalmology, 15, 811-821.

Reese, A. B. (1976). Tumors of the Eye, 3rd edn. Harper &Row: New York.

Shields, J. A., Leonard, B. C., Michaelson, J. B., and Sarin,L. K. (1976). B-scan ultrasonography in the diagnosis ofatypical retinoblastomas. Canadian Journal of Ophthal-mology, 11, 42-51.

Sterns, G. K., Coleman, D. J., and Ellsworth, R. M. (1974).The ultrasonographic characteristics of retinoblastoma.American Journal of Ophthalmology, 78, 606-611.

Swan, K. C., and Hyman, S. (1952). Experience with tumorsof the retina. Archives of Ophthalmology, 47, 416-424.

Tayebi, H. (1956). Ocular calcification and retrolentalfibroplasia. American Journal of Roentgenology RadiumTherapy and Nuclear Medicine. 76, 583-593.

Trokel, S. L. (1977). Unpublished observations.Yanoff, M., Zimmerman, L. E., and Davis, R. L. (1971).

Massive gliosis of the retina. International OphthalmologyClinics, 2, 211-229.

Zeiter, H. J. (1962). Calcification and ossification in oculartissue. American Journal of Ophthalmology. 53, 265-274.

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Radiographic abnormalities retinoblastoma and other