spontaneousregression ofbilateral retinoblastomaof any report of a growing, viable retinoblastoma...

British Journal ofOphthalmology, 1982, 66, 685-690

Spontaneous regression of bilateral retinoblastomaGEORGE E. SANBORN,* JAMES J. AUGSBURGER, AND JERRY A. SHIELDS

From the Oncology Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University,Philadelphia, Pennsylvania, USA

SUMMARY A 24-year-old black man was found to have bilateral, spontaneously regressed retino-blastoma that had previously been misdiagnosed as post-traumatic chorioretinal scarring. His son

and half-brother both had bilateral viable retinoblastoma. The ophthalmoscopic and fluoresceinangiographic features of this patient's fundus lesions included a calcified, whitish mass locatedcentrally in one of the scars and a fine residual vascularity in another of the fundus lesions. Theauthors review the pertinent literature on spontaneous regression of retinoblastoma.

Spontaneous regression is an uncommon but well-described feature of retinoblastoma,' which is esti-mated to occur in approximately 2 of every 100tumours.2 Clinical diagnosis of spontaneous regres-sion can be made with relative certainty only inpatients having viable retinoblastoma in the same orthe opposite eye or in patients with a pathologicallyconfirmed family history of retinoblastoma.

Unilateral, unifocal spontaneous regression ofretinoblastoma is uncommon; bilateral multifocalspontaneous regression of retinoblastoma is evenrarer. Yet several cases of this type have beenreported.3-'3 In many of the previously reported casesthe eye (or eyes) containing the spontaneouslyregressed tumour has been phthisical and blind.67 12-17Only a few reports describe preservation of the eyesand retention of useful vision in both eyes.3'57 1 Evenfewer of these cases have been well illustrated photo-graphically.

This paper describes the case of a man with bi-lateral, spontaneously regressed retinoblastoma whoretained useful vision in both eyes. The appearance ofthese lesions is illustrated with clinical photographsand fluorescein angiograms.

Case report

A 24-year-old black man (patient Ilb in Fig. 1) wasseen when his son was examined (patient ITlb in Fig.1). He was found to have 3 lesions in the left fundus

Correspondence to Dr James J. Augsburger, Oncology Service,Wills Eye Hospital, 9th and Walnut Streets, Philadelphia,Pennsylvania 19107, USA.*Present address: Division of Ophthalmology, University of UtahMedical Center, Salt Lake City, Utah, USA.

and one lesion in the right fundus. The son (patientIlIb) had just been found to have bilateral viableretinoblastoma. Inquiries into the family history re-vealed that the patient's half-brother (patient Ila inFig. 1) had also had bilateral retinoblastoma and hadpreviously undergone enucleation of one eye andphotocoagulation and cryotherapy of a peripherallesion in the opposite eye. Histopathological exami-nation of the enucleated eye demonstrated a well-differentiated retinoblastoma.

Patient lIb reported having had poor vision sincechildhood in his left eye. A previous ophthalmicexamination performed elsewhere had revealedexotropia, for which the patient had undergone hori-zontal rectus muscle surgery 5 years before our firstexamination. A macular lesion had been noted in thepatient's left eye prior to this surgery, but it wasdiagnosed as a post-traumatic chorioretinal scar re-sulting from unrecalled ocular trauma. The patient'sfamily history was negative at that time.

Ocular examination on the Oncology Service at

Fig ARetinoblastma family pedIagIbe

IIIbi

Fig. I Retinoblastoma family pedigree.685

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George E. Sanborn, James J. Augsburger, and Jerry A. Shields

Fig. 2A Fig. 2BFig. 2 Fundus drawings ofrightfundus (A) and leftfundus (B) ofpatient fIb.

Wills Eye Hospital revealed his best corrected visualacuities to be 6/5 in the right eye and 6/60 in the left.Intraocular pressures, measured by applanationtonometry, were normal. External examination dis-closed conjunctival scars over the horizontal rectusmuscles of the left eye. Slit-lamp biomicroscopy re-vealed no anterior segment abnormalities. Fundusexamination of the right eye (Fig. 2A) showed a 3x2mm minimally elevated grey-white lesion locatedabout 9 mm superior to the fovea (Fig. 3A). Thefluorescein angiogram of this lesion showed retinalpigment epithelial window defects (Fig. 3B). Theoverlying retinal circulation was intact, and there wasno indication of a specific tumour circulation. The leftfundus (Fig. 2B) contained 3 lesions. A 7T5x6 mmirregularly pigmented grey-to-black lesion was pre-sent in the macula (Fig. 4A). Near the centre of thislesion was an irregular, whitish, slightly elevated mass.There was an associated loss of the papillomacularnerve fibre layer. Fluorescein angiography demon-strated retinal pigment epithelial window defectswithout a retinal tumour vessel pattern (Fig. 4B). Thesecond lesion in the left eye (Fig. 2B) was an 8x7 mmwhitish-grey, gliotic-appearing, slightly elevated masslocated about 5 disc diameters inferior to the fovea(Fig. SA). The fluorescein angiogram of this lesionshowed small, relatively discrete retinal pigment

epithelial window defects as well as a finely branchingpattern of small retinal tumour vessels (Fig. SB). Thethird lesion was a very small, calcific nodule adjacentto the ora serrata at the 6:15-o'clock meridian (Fig.2B).A plasma carcinoembryonic antigen (CEA) test on

patient lIb was slightly elevated at 3-7 ng/ml (normalrange 02-5 ng/ml); the half-brother, patient Ila, hada plasma CEA of 6-8 ng/ml. (SI conversion: ng/ml=,ug/l.) The parents of patients hIa and Ilb were ex-amined ophthalmoscopically and were found to haveno fundus lesions. Patient I', the father of bothpatients hIa and IIb, had a normal plasma CEA level.

Discussion

A number ofwell-documented cases ofspontaneouslyregressed retinoblastoma have been reported in theliterature. Many of the unilateral cases have beendiagnosed on the basis of histopathological findings inpatients with unilateral -phthisis bulbi of unknownaetiology.'5 The characteristic histopathological fea-tures of spontaneously regressed retinoblastoma insuch eyes include calcified tumour cell nests andnecrosis of the surrounding retina.'5 Some patientswith spontaneous tumour regression in a phthisical

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Spontaneous regression of bilateral retinoblastoma

rig. SA rig. 3BFig. 3 A. Atrophic chorioretinal lesion in rightfundus ofpatient fIb. B. Venous phase offluorescein angiogram showingretinal pigment epithelial window defects.

eye have been found to have viable retinoblastoma inthe fellow eye.6 14-17 A rare patient has even beenfound to have bilateral spontaneous tumour regres-sion presenting as nontraumatic phthisis bulbi duringchildhood. 12

Spontaneously regressed retinoblastomas in other-wise normal eyes have also been reported. Many suchcases were diagnosed on the basis of a positive familyhistory of retinoblastoma or the histopathologicalidentification of retinoblastoma in the fellow

Fig. 4A Fig. 4BFig. 4 A. Macular lesion in left eye ofpatient lib. Note calcific retinalfoci centrally within lesion. B. Recirculation phasefluorescein angiogram ofmacular lesion, which demonstrates retinal pigment epithelial window defects without tumourvessels.

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Fig. 5A Fig. 5BFig. 5 A. Inferior lesion in left eve ofpatient flb. B. Venous phasefluorescein angiogram of lesion showingfine retinaltumour vessels.

eye.4-7 9 Other cases have been diagnosed byophthalmoscopic observation of characteristic lesionsin the fundi of patients with no family history ofretinoblastoma.2"23 The diagnosis of retinoblastomamust be considered presumptive in these cases.The typical ophthalmoscopic appearance of spon-

taneously regressed tumours is generally described interms ofstandard postirradiation regression patterns .8The macular lesion in our patient's left eye was consis-tent with a type I regression pattern with pronouncedretinal-pigment epithelial alterations, and the inferiormidperipheral lesion in this eye was similar to the typeII regression pattern. The small, far peripheral in-ferior lesion in the left fundus appeared to be anentirely calcified type I lesion, but the small lesion inthe right eye showed persistent fine tumour vessels.This observation is consistent with our findings inpreviously irradiated eyes with type I and type II

tumour regression patterns.24Regressed retinal tumours in otherwise normal eyes

have been detected in both unilateral and bilateralcases of retinoblastoma.3-5 7 91 123 Most ofthese eyeshave retained useful vision, and many, containingone or more regressed tumours, have had normalvisual acuity because the lesions were in extramacularlocations. Our patient had normal vision in his righteye, which contained a single totally regressed extra-macular tumour. However, his visual acuity was im-paired in the left eye because of the macular locationof one of the 3 regressed tumours.There are several theories about the pathogenesis

of spontaneous regression of retinoblastoma. One ofthe most popular is that regression occurs because ofvascular insufficiency in a rapidly growingtumour.'2526 According to this theory the tumouroutgrows its blood supply, becomes necrotic, andsubsequently regresses. Another theory suggests thatan immunological mechanism may be responsible forspontaneous tumour regression. Histological depositsfound in some retinoblastomas that have undergonespontaneous necrosis appear to be immune com-plexes,27 and increased levels of circulating immunecomplexes have been found in some retinoblastomapatients.28 Both our patient and his half-brother had

Table I Comparison ofspontaneously regressedretinoblastoma in aphthisical eye andspontaneously arrestedretinoblastoma (retinoma)

Spontaneously Spontaneouslyregressed RB arrested RB

Age at detection Childhood to Adulthoodadulthood

Status of involved eye Phthisis bulbi Useful eyeStatus of other eye 1. Viable RB 1. Viable RB (40% +)

2. Retinoma 2. Retinoma (25%+)3. Normal 3. Normal4. Phthisis bulbi 4. Phthisis bulbi

Mechanism of Obstruction of Mutation of partiallydevelopment central retinal differentiated

artery retinoblast

Table adapted from Gallie et al. II

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elevated CEA, an antigen originally described inpatients with gastrointestinal malignancies.29 Somefamily relations of patients with retinoblastoma havebeen found to have elevated CEA, the 'CEA familysyndrome.'30 Whether there is any relationship be-tween CEA levels and an immunological mechanismis unknown. There is no conclusive evidence thateither the vascular or the immunological theory iscorrect.We believe that the lesions in the patient described

are regressed retinoblastomas, because they shareophthalmoscopic features and patterns known tooccur in retinoblastomas following irradiation. How-ever, 2 other suggestions can be made as to the natureof these fundus lesions. The first is that they arespontaneously arrested rather than spontaneously re-gressed retinoblastomas. " Smith considers that thehistological and ophthalmoscopic appearance of theselesions is different from that found in regressedtumours after irradiation. " However, we do not knowof any report of a growing, viable retinoblastomawhich stopped growing spontaneously and assumedthe appearance shown in his article.The second suggestion is that proposed by Gallie

and coworkers3' (Table 1), who feel that this lesion isa nonprogressive retinoblastoma, a benign tumourwhich they have termed a retinoma. Their hypothesisis that a retinoma results when a genetic mutationoccurs in a partially differentiated retinoblast. Hadthis mutation occurred in an immature cell, it wouldpresumably have resulted in a viable, progressiveretinoblastoma. No experimental or histopathologicalevidence has been presented, however, to show thatthis embryological sequence of events is correct.Our patient had previously been misdiagnosed as

having a post-traumatic chorioretinal scar, presum-ably as a result of a prior unrecalled ocular injury. Thepresence of calcified retinal foci within this macularchorioretinal scar, however, suggested the diagnosisof regressed retinoblastoma. We believe that ophthal-mologists should be familiar with the characteristicappearance of regressed tumours and that they shouldconsider retinoblastoma in the differential diagnosisof patients with typical fundus lesions. Correct iden-tification of retinoblastoma at the time ofour patient'sexamination for strabismus might have stimulatedophthalmoscopic examination of his son and half-brother at an earlier age. Then appropriate therapy32could have been initiated earlier and the chances ofsalvaging the eyes and preserving vision would havebeen better.

This work was supported in part by the Pennsylvania Lions SightConservation and Eye Research Foundation, Inc., the Retina Re-search and Development Foundation, the Ocular Oncology Fund,and the Research Department, Wills Eye Hospital, Philadelphia,Pennsylvania.

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2 Gallie BL, Wong JJY, Ellsworth RM, DuPont B, Good RA.Immunological mechanisms in spontaneous regression ofretinoblastoma. In Silverstein AM, O'Connor GR, eds.Immunology and immunopathology of the eye. New York:Masson, 1979: 190-6.

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