phthisis bulbi in retinoblastoma

Original Articleceo_2426 105..110

Phthisis bulbi in retinoblastomaSeema Kashyap MD,1,3,6 Rachna Meel MS,2,3,6 Neelam Pushker MD,2,3,6 Seema Sen MD,1,3,6

Sameer Bakhshi MD,4,5,6 Mandeep S Bajaj MD,2,3,6 Bhavna Chawla MS,2,3,6 Sumita Sethi MS,2,3,6

Supriyo Ghose MD2,3,6 and Mahesh Chandra MS2,3,6

1Ocular Pathology Services, 2Oculoplastics & orbit Services, 3Dr. Rajendra Prasad Centre for Ophthalmic Sciences, 4Departmentof Medical oncology and 5Dr. BR Ambedkar International Rotary Cancer Hospital, 6All India Institute of Medical Sciences,New Delhi, India

ABSTRACT

Background: Phthisis bulbi is a relatively uncommonand atypical clinical presentation of retinoblastoma.

Design: Retrospective study conducted at a tertiarycare hospital.

Participants: Eighteen consecutive retinoblastomapatients with primary phthisis bulbi.

Methods: Retrospective analysis of clinical, imagingand histopathological features of all retinoblastomapatients with primary phthisis bulbi, treated at ourcentre between January 2005 and December 2009.

Main outcome Measure: Clinical and histopathologyfeatures.

Results: Eighteen (3.5%) retinoblastoma patientsdeveloped primary phthisis bulbi. The median age ofpresentation was 1.5 years. The median duration ofsymptoms before presentation was 6 months. Intotal, 15 out of 18 (83%) cases had bilateral disease.Among these, 80% (12/15) had advanced intraocu-lar disease in the fellow eye. Most common firstsymptom was white reflex. History of orbital inflam-mation was present in 12/18 cases. Computed tomo-graphic scan of orbit showed intraocular mass withcalcific densities in 16 eyes. In two cases, hyperdensemass was seen without any calcification. On histo-pathology, residual viable tumour cells with charac-teristics of poorly differentiated retinoblastoma werefound in 67% (12/18) eyes. High-risk factors were

present in six cases with microscopic residual diseasein three cases.

Conclusions: This is the largest case series of retino-blastoma patients with primary phthisis bulbi. Phthi-sis bulbi in retinoblastoma may be associated withbilateral disease in most cases and advancedintraocular disease in the fellow eye in a significantnumber of cases. Regression is incomplete in major-ity of these cases; therefore, enucleation must defi-nitely be done in all cases of retinoblastomapresenting with phthisis bulbi.

Key words: histopathology, imaging, phthisis bulbi, ret-inoblastoma, treatment.

INTRODUCTION

A small but significant number of eyes with retino-blastoma become phthiscal. Few reports have analy-sed this presentation of retinoblastoma specific-ally.1–4 Herein, we report clinical, radiological andhistopathological features in 18 cases of retinoblas-toma who presented with or developed primaryphthisis bulbi.

METHODS

We retrospectively reviewed medical records of allretinoblastoma patients with primary phthisis bulbi,treated at our centre between January 2005 andDecember 2009. Demographic profile, clinicalhistory, radiology details and histopathology find-ings were analysed in these cases.

� Correspondence: Dr Rachna Meel, Oculoplastic and oncolgy Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of

Medical Sciences, New Delhi 110 029, India. Email: [email protected]; [email protected]

Received 10 May 2010; accepted 22 August 2010.

Clinical and Experimental Ophthalmology 2011; 39: 105–110 doi: 10.1111/j.1442-9071.2010.02426.x

© 2011 The AuthorsClinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists

Phthisis bulbi was clinically defined as a soft,shrunken, hypotonus globe with a flattened andopaque cornea and no vision. Radiological criteriacomprised of a small globe with disruption of iden-tifiable structures of the eye and/or thickening ofocular coats with/without calcification of ocularcontents.

Radiology findings were assessed for presence ofintraocular mass with or without calcification in thephthisical eye and overt orbital disease, that is,extraocular mass and/or optic nerve thickening. His-topathology slides were reviewed and assessed forpresence of viable tumour cells, necrosis, calcifica-tion and inflammatory cells/macrophages. Presenceof high-risk factors, that is, involvement of anteriorchamber, uveal tissue, optic nerve (short of resectedmargin) and sclera by viable tumour cells; andmicroscopic residual disease, that is, involvement ofextrascleral tissue or optic nerve cut end by viabletumour cells was also noted. At our centre, theroutine systemic workup for retinoblastoma patientsincludes magnetic resonance imaging (MRI) brain inall cases, and bone marrow biopsy and cerebrospinalfluid cytology in cases with histopathological high-risk factors, microscopic residual, overt orbital ormetastatic disease. Bone scan is additionally done incases with locally advanced and/or metastaticdisease. The results of these tests were also noted.

RESULTS

A total of 514 retinoblastoma patients were treated atour centre during the study period (5 years). Eigh-teen (3.5%) of these presented with or developedphthisis bulbi (Fig. 1). In total, 17 out of 18 caseshad phthisis bulbi at presentation and 1 case (Case13) developed phthisis during the course ofinvestigation. There were 13 male and 5 femalepatients. The median age of presentation was1.5 years (range: 8 months–6 years). The median lagperiod that is the time interval between firstsymptom and the commencement of treatmentwas 6 months, as reported by the parents (range:

1 month–1.5 years). One patient had family historyof retinoblastoma. In 12/18 (67%) cases there washistory consistent with orbital inflammation preced-ing the onset of phthisis bulbi that is ocular pain,watering, eyelid swelling, corneal haze and propto-sis with or without fever and/or vomiting. The inter-val between the onset of these symptoms andshrinkage of globe ranged from 15 days to 2 months.The severity of inflammatory symptoms was vari-able, as some cases required systemic therapy andothers could be managed with topical medicationsalone. The most common first symptom was whitereflex followed by redness and pain. Clinical andtreatment details are described in Table 1.

In total, 15 out of 18 (83 %) cases had bilateraldisease. In 12 out of 15 cases (80 %), the other eyehad advanced intraocular disease, that is, group C–E(group C in 1, group D in 8 and group E in 3) as perthe International classification for retinoblastoma.5

According to the Reese-Ellseworth classification 6 ofthese 12 cases were in group Va and 5/12 were ingroup Vb. Case 9 presented with phthisis bulbi onright and leucocoria, proptosis and eyelid swellingon left side.

On imaging, phthisis bulbi was evident in 12cases at presentation. Case 13 presented with buph-thalmos and later developed phthisis bulbi after aperiod of 4 weeks. Case 2 and case 14 showed hyper-dense mass in a shrunken globe without any calcifi-cation (Fig. 2a,b). Intraocular mass with calcificdensities was seen in 16 eyes (Fig. 2c,d). In Case 9,computed tomographic (CT) scan orbit showed pres-ence of intraocular mass and calcification in ashrunken globe bilaterally, with possible retrobul-bar extension on left side. Systemic work up waswithin normal limits in all cases.

Seventeen cases underwent enucleation for thephthisical eye with retinoblastoma. Exenterationwas done in case 9 in view of orbital extension sug-gested by imaging.

The histopathology findings are described inTable 2. Viable tumour cells were found in 67% (12/18) phthisical eyes (Figs 3b,c). All 12 cases hadpoorly differentiated retinoblastoma. Uveal tract wasdisorganised in all cases so that iris, ciliary body andchoroid could not be demarcated from one another.However, uveal tract was identified by the presenceof melanin pigment. Sclera was markedly thickenedin all the cases on gross as well as microscopicexamination (Fig. 3a). Necrosis was identified in14/18 cases. Calcification was seen in 15/18 cases(Fig. 3c). In one case no viable tumour cells, necrosisor calcification was found, however the other eye hadgroup D retinoblastoma (Case 14).

Histopathological high-risk factors were presentin six cases (Table 2). Among these, three also hadmicroscopic residual disease (optic nerve transection

Figure 1. Clinical photograph of a retinoblastoma patient pre-senting with primary phthisis bulbi on right side.

106 Kashyap et al.


involvement in two and extrascleral involvement inone). Chronic inflammatory cells were seen in five,macrophages in six and giant cells in one case. Opticnerve was atrophic in three cases. Cholesterol crys-tals and lipofuscin pigment were found in one andtwo cases, respectively.

Seven patients were lost to follow-up after surgery.The median follow-up, in the remaining 10 patients,was 9 months (mean follow-up: 13.7 months). Tenpatients received chemotherapy for chemoreductionof tumour in other eye and/or chemoprophylaxis

in view of high-risk factors in the enucleatedeye. Three patients were also administered externalbeam radiotherapy (EBRT). Case 10 received EBRTunilaterally for progressive intraocular disease inthe fellow eye, and cases 12 and 13 were adminis-tered EBRT bilaterally for microscopic residualdisease after enucleation of phthisical eye on oneside and progressive intraocular disease in thefellow eye. The EBRT was delivered using mega-voltage cobalt-60 beam using lens sparing tech-nique, with immobilization under short sedation.

Table 1. Clinical features and treatment details of retinoblastoma patients with phthisis bulbi

Cases Age/ Sex Phthisicaleye

Other eye classification Firstsymptom

Lag period History ofinflammation

Treatment Follow-up

R–E ICRB

1 1 year/ M L Va D WR 11 months - Chemo PD; 5 months2 2 years/ M R Va E Squint 6 months - NA LFU3 10 months/ F L IIb B WR 8 months + Chemo CR; 24 months4 1.5 years/ M L Va E WR 6 months - NA LFU5 10 months/ M L Nil Nil Redness 8 months + NA LFU6 1.5 years/ F R Vb D DV 15 months + NA LFU7 5 years/ M R Nil Nil WR 3 months - Chemo NED; 21 months8 2 years/ F L Va E WR 6 months + NA LFU9 1.5 years/ M BL - - WR 16 months + NA LFU

10 8 months/ M R Vb D Redness 1 month + Chemo + EBRT CR; 10 months11 1.5 years/ M R Va D Squint 16 months + Chemo PR; 9 months12 4 years/ M L Vb C WR 2 months + Chemo + EBRT PR; 9 months13 11 months/ F L Va D WR 1 month + Chemo + EBRT PR; 9 months14 4 years/ M R Vb D Redness 18 months + Chemo PR; 7 months15 9 months/ M L Vb D WR 4 months + Chemo PR; 5 months16 1 year/ F L IIb B WR 2 months + Chemo CR; 36 months17 1 year/ M R IIb B WR 3 months - Chemo CR; 16 months18 6 year/ M L Nil Nil DV 12 months - NA LFU

BL, bilateral; Chemo, chemotherapy; CR, complete remission; DV, diminution of vision; EBRT, external beam radiotherapy; F, female;ICRB, International classification for retinoblastoma; L, left; LFU, lost to follow-up; M, male; NA, not available; NED, no evidence of disease;PD, progressive disease; PR, partial response; R, right; R-E, Reese Ellseworth Classification; WR, white reflex; +, present; -, absent.

(a) (b)

(c) (d)

Figure 2. (a) Magnetic reso-nance imaging orbit (axial, T2weighted image) showing intraocu-lar mass on left side and anextremely shrunken, disorganizedglobe on right side (case 14). (b)Computed tomographic (CT) scan(axial cut) of the same patientshowing absence of any intrao-cular calcification. (c) CT scanorbit (axial cut) showing bilateralintraocular masses with calcifi-cation with a shrunken globe onleft side. (d) CT scan orbit (axialcut) showing small globe on leftside with intraocular mass andcalcification.

Phthisis bulbi in retinoblastoma 107


Both the cases who received EBRT after enucleationwere able to retain prosthetic eye with good cos-mesis at last follow-up

At last follow-up, 6/11 patients were in completeremission and 5 had partial response which wasdefined as a greater than 50% reduction in tumoursize, vitreous and subretinal seeds. One case (case 1)had progressive disease at 5 months of follow-upand thereafter, was lost to follow-up.

DISCUSSION

The incidence of primary phthisis bulbi among ret-inoblastoma patients was 3.5%, in our study, whichis within the reported range of 0.5–5.3%.1–4 Themedian age of presentation was 18 months. Previ-ously, this has been reported to be 14 and 4 monthsin two different studies.2,4 The median lag periodthat is the duration between the first symptom andtreatment, was 6 months.

In three case series on primary phthisis bulbiin retinoblastoma patients, reported in literature,50–86% patients had bilateral disease.1,2,4 Most casereports of retinoblastoma patients presenting withphthisis bulbi also report bilateral disease.6–12 Soviket al. reported retinoblastoma in six siblings, three ofwhom had phthisis bulbi with bilateral disease.6 Atotal of 83% (15/18) patients in our series hadbilateral retinoblastoma. Therefore, phthisis bulbiappears to be associated with bilateral disease inmajority of the cases. However, it is possible thatdifficulty in making the diagnosis in non-familial,

unilateral cases of retinoblastoma that presentwith phthisis bulbi, may partly account for thisobservation.

Also we observed that 80% (12/15) of the casesthat presented with bilateral disease had advancedintraocular retinoblastoma in other eye. In some ofthese cases it could be explained by a late presenta-tion (duration of symptoms more than 6 months).But in others, advanced intraocular retinoblastomain fellow eye was observed despite a shorter dura-tion of symptoms. Two infants (8 months and11 months old; case 10 and case 13) who had only1-month history of symptoms had group D disease inother eye. Advanced intraocular disease was foundin the fellow eye of many single cases reported inliterature.6,8–11 Kao et al. in their series on retinoblas-toma with phthisis bulbi, reported advanced diseasein other eye in 50% (3/6) of their cases.4 Two of thesehad metastatic disease (regional lymph nodemetastasis in one and central nervous systemmetastasis in one) and one had overt orbitalinvolvement. Five out of ten cases reported by Mul-laney et al. had bilateral disease but the other eyestatus was not mentioned.2

Ultrasonography (USG) and CT scan of orbitreveal intraocular mass with calcification in mostcases of retinoblastoma presenting with phthisisbulbi. However, in a few cases, calcification may beabsent and it may be difficult to pick up a mass inextremely small and disorganized globes on USG orCT scan. In such cases, presence of lesion in the othereye is helpful in diagnosis. In cases, where other eye

Table 2. Histopathological findings in retinoblastoma patients with phthisis bulbi

Cases Viable cells Necrosis Calcification Macrophages High-risk factors Microscopic residualdiseaseAnterior chamber Choroid Optic nerve Sclera

1 1 1 4 + - - - - -2 4 2 0 - - + + + Extrascleral3 3 0 4 + - - - - -4 1 2 0 - - - - - -5 1 3 3 - - - - - -6 0 2 2 - - - - - -7 1 2 4 + + + - - -8 2 0 4 - - - - - -9 1 4 3 + - - - - -

10 0 1 1 - - - - - -11 0 1 2 - - - - - -12 4 4 2 + - + + + Optic nerve cut end13 1 4 4 - - + + - Optic nerve cut end14 0 0 0 - - - - - -15 1 3 4 - - + - - -16 0 4 2 - - - - - -17 0 0 2 - - - - - -18 1 2 1 + - + + - -

Grading for necrosis and calcification: 0, none; 1, few small areas (less than 25% of tumour); 2, 25–50% of tumour; 3, more than 50% oftumour; 4, almost all of the tumour is necrotic/calcified. Grading for viable cells: 0, none; 1, few viable cells; 2, few small clusters; 3, largeclusters; 4, viable cells all over the tumour. +, present; -, absent.

108 Kashyap et al.


is not involved, MRI should be done to rule outpresence of an intraocular mass. Two of our cases didnot show any calcification on CT scan orbit, but bothhad bilateral disease. As a clear cut evidence of ret-inoblastoma may be missing in a phthisical eye onimaging, so when a child presents with a phthisicaleye because of unexplained etiology, retinoblastomashould be ruled out, and if the doubt persists enucle-ation must be performed.

The exact mechanism of phthisis bulbi is not clear.It is believed that phthisis bulbi is associated withextensive tumour necrosis.13,14 The tumour necroticproducts leach out of the eye producing panoph-thalmitis with orbital cellulitis that often precede theoccurrence of phthisis.2 In our study, there washistory of clinical symptoms suggestive of orbitalinflammation, prior to onset of phthisis bulbi, in67% (12/18) cases. These episodes preceded theonset of phthisis by 15 days to 2 months and werecharacterized by varying combinations of ocularpain, eyelid swelling, proptosis, corneal haze, feverand vomiting. Few of these patients became severelyill, requiring systemic treatment.

In the two case series on phthisis bulbi in retino-blastoma majority of the cases gave history of orbitalinflammation prior to shrinkage of the globe.2,4 Theseverity of these symptoms has been reported to bevariable, and some authors have reported a history ofchild becoming severely ill,1 others report episodesof pain, watering, corneal haze and redness beforeshrinkage of the globe was noted.9 Like in our study,the interval between the commencement of thesesymptoms and occurrence of phthisis has beenreported between 1 and 2 months.2,9,15

Duke-Elder and Reese hypothesized that tumournecrosis occurs when tumour outgrows its bloodsupply.13,14 Some believe that tumour necrosisresults from infarction, which results from tumourclogging blood vessels to the tumour and eye.1,15

However, the objective evidence for this has beenreported rarely.15

Phthisis bulbi is rarely seen in longstanding casesof retinoblastoma despite large intraocular tumours.This together with the fact that in our study 7/10cases with duration of symptoms less than or equalto 6 months and bilateral disease had advanced ret-inoblastoma in the fellow eye, make us speculatewhether phthisis bulbi may be associated with moreaggressive disease in some cases.

Gallie et al. reported that 50% (25/50) of phthisicaleyes with retinoblastoma reported in literature hadcomplete tumour regression and the rest had tumourproliferation beyond the boundaries of phthisicaleye or from the other eye resulting in death.1

Although authors have been advocating enucleationof the phthisical eyes in view of possible incompletetumour regression, systematic analysis of the pres-ence of viable residual tumour cells in large series ofpatients has not been possible because of smallnumbers of these patients. In a case series of 10 casesreported by Mullaney et al. authors found well-differentiated residual tumour in all the cases.2 Atotal of 12 out of 18 cases, in our study, revealedpoorly differentiated residual tumour cells. Also sixcases had histopathological high-risk factors, ofwhich three also had microscopic residual disease,

(a)

(b)

(c)

Figure 3. (a) Gross photograph of an enucleated phthisical eyewith retinoblastoma showing dislocated crystalline lens (arrowhead) and a markedly thickened sclera (arrow). (b) Photomicro-graph showing large areas of necrosis and cluster of viabletumour cells (arrow head) abutting the choroid (arrow) (haema-toxylin & eosin stain, magnification ¥ 25). (c) Photomicrographshowing areas of calcification (arrows) and cluster of viabletumour cells (asterisk) (haematoxylin & eosin stain, mag-nification ¥ 100).

Phthisis bulbi in retinoblastoma 109


necessitating chemotherapy and/or EBRT. The histo-pathological documentation of viable tumour in 67%cases in the current study and 100% cases in theprevious study provides objective (histopathologi-cal) proof that tumour is partially regressed in mostcases of phthisis bulbi with retinoblastoma.

In current study, large areas of calcification werefound in six cases on histopathology. There is someevidence in literature that calcium has a toxic effecton retinoblastoma.16,17 However, its role in causingtumour regression and phthisis remains doubtful.Three of our cases did not show any calcification.

To conclude, this is the largest case series of ret-inoblastoma patients with primary phthisis bulbi. Itis associated with bilateral disease in majority of thecases and may be accompanied by advanced diseasein the fellow eye. Regression is incomplete andresidual viable tumour cells are present in most ofthese cases. Hence, enucleation must certainly becarried out in all cases of retinoblastoma presentingwith phthisis bulbi.

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4. Kao LY, Yang ML. Spontaneous regression of retino-blastoma in a Taiwan series. J Pediatr Ophthalmol Stra-bismus 2005; 42: 228–32.

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10. Hadjistilianou T, De Francesco S, Marconcini S,Mastrangelo D, Galluzzi P, Toti P. Phthisis bulbi andbuphthalmos as presenting signs of retinoblastoma:a report of two cases and literature review. Eur JOphthalmol 2006; 16: 465–9.

11. Harrison D, Richards J, Andronikou S, Welman C.Bilateral retinoblastoma presenting with simultaneousphthisis bulbi and buphthalmos. J Pediatr OphthalmolStrabismus 2003; 40: 161–3.

12. Maka E, Csákány B, Tóth J. Bilateral retinoblastomapresenting with unilateral phthisis. J Pediatr OphthalmolStrabismus 2009; 27: 1–4.

13. Duke-Elder WS. Textbook of Ophthalmology. St Louis,MO: Mosby, 1942; 3: 2812–43.

14. Reese AB. Tumours of the Eye. New York: Hoeber, 1951;67–140.

15. Anderson SR, Jensen OA. Retinoblastoma with necro-sis of central retinal artery and vein and partial spon-taneous regression. Acta Ophthalmol 1974; 52: 183–93.

16. Verhoeff FH. Retinoblastoma undergoing spontaneousregression: calcifying agent suggested in the treatmentof retinoblastoma. Am J Ophthalmol 1966; 62: 573–4.

17. Cohen SM, Saulenas AM, Sullivan CR, Albert DM.Further studies of the effect of vitamin D on retinoblas-toma inhibition with 1,25-dihydroxycholecalciferol.Arch Ophthalmol 1988; 106: 541–3.

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phthisis bulbi in retinoblastoma

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