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Purpose: To evaluate the efficacy of topical mitomycin C in treating conjunctival and corneal epithelial dysplasia and neoplasia., Methods: Seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia were treated with one drop of topical mitomycin C 0.04% four times a day for 7 days in alternate weeks. The patients' charts were reviewed retrospectively. Patients with either multiple recurrences or extensive ocular surface involvement were treated. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy. Patients were examined at least every 14 days during treatment and examined at intervals after completion of treatment., Results: With topical mitomycin C, six eyes of seven patients had complete clinical regression of their conjunctival and corneal epithelial dysplasia and neoplasia. One eye of one patient had partial clinical regression of conjunctival and corneal epithelial dysplasia. Follow-up after completion of topical mitomycin C therapy and excision of residual disease ranged from 2 to 16 months (mean, 9 months; SD, 4.3 months) and was without clinical sign of recurrence. Topical mitomycin C therapy was associated with transitory ocular discomfort, conjunctival injection, tearing, photophobia, and punctate epithelial keratopathy., Conclusion: In this small series of eyes, topical mitomycin C was effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia.

Objective: To determine the visual anatomical results and survival after combined chemotherapy and whole eye radiotherapy for patients with bilateral Reese-Ellsworth group V retinoblastoma., Setting: A national referral center for retinoblastoma., Patients: Fourteen patients with bilateral Reese-Ellsworth group V retinoblastoma seen between March 1, 1989, and April 30, 1995, were treated., Interventions: Patients were treated with chemotherapy (using carboplatin, etoposide, and vincristine) and whole eye radiotherapy (40-44 Gy in 20-22 equivalent fractions). A medical record review was performed to determine outcomes., Main Outcome Measures: Survival, eye preservation rate, and visual acuity., Results: Two patients died, 1 from a primitive neuroectodermal tumor and the other from the meningeal spread of retinoblastoma. Four eyes were enucleated primarily because of severe disease at presentation. Of the remaining 20 eyes, 6 required enucleation. The disease recurred in 4 of those patients, and neovascular glaucoma developed in 2 patients. Of the 12 surviving children, 5 have a visual acuity better than l/60 in at least 1 eye., Conclusion: Although most of the treated group V eyes could be salvaged with chemotherapy plus radiotherapy, the resultant visual acuity was often poor.

Most melanomas in the orbital region are primary tumours. The uveal tract is the commonest site though the skin of the eyelids, the conjunctiva and, very occasionally, the orbit itself may be involved. Direct spread may cause the tumour to present in an adjacent structure so that a uveal tract melanoma with an extrascleral nodule may appear to arise in the conjunctiva or in the orbit whilst a conjunctival melanoma may first be apparent in the adjacent eyelid skin. Metastatic deposits from cutaneous melanoma may occasionally present in the eye or ocular adnexa.

Two children presenting with sporadic unilateral retinoblastoma and exhibiting a high degree of chromosome breakage were noted to have unusual facies, microcephaly and abnormal skin pigmentation. In the first child the pattern of both spontaneous and mitomycin-C-induced chromosome breakage was characteristic of Fanconi's anaemia although the degree of breakage was extreme. She also exhibited a striking increase in X-ray-induced chromosomal damage in G0 lymphocytes as measured by dicentric formation and increase in chromatid-type aberrations. She had a number of typical clinical features, including cafe-au-lait patches and abnormalities involving the kidney; however, she demonstrated neither the hypoplasia of radius and thumb nor the typical aplastic phase of this disorder. At age 22 months the child became anaemic with trilineage myelodysplasia, which was rapidly followed by the development of acute myeloblastic leukaemia. The early onset (at age 4 months) of retinoblastoma may have been associated with the underlying genomic instability. The second child exhibited a pattern of chromosome breakage characteristic of Bloom's syndrome, in addition to a moderate increase in damage induced by mytomycin-C. She had the typical stunted growth and malar hypoplasia of Bloom's syndrome although she did not demonstrate the frequently described erythematous 'butterfly rash' Although patients with Fanconi's anaemia and Bloom's syndrome are recognised to be at an increased risk of cancer, retinoblastoma has not previously been described in patients with either condition. We suggest that underlying recessive chromosome breakage syndromes may be underdiagnosed in paediatric cancer patients, with important implications for prognosis and genetic counselling.

A case-control study was set up to assess the risk of eye melanoma in relation to the number and type of cutaneous melanocytic naevi and pigmented lesions of the iris. Cases comprised 211 unselected ocular melanoma patients attending the Ocular Oncology Clinic at Moorfields Eye Hospital, London, during November 1990 to October 1991 and diagnosed after August 1986. Hospital and general practice controls (416) were recruited in the North East Thames Region of the UK. Cutaneous naevi greater than or equal to 2 mm in diameter were counted on the skin. Clinically atypical and congenital naevi were recorded separately. Pigmented lesions of the iris were counted. The relative risk for ocular melanoma increased with numbers of atypical naevi and numbers of common naevi. Ten percent of cases but 3% of controls had at least 100 naevi of 2 mm or greater diameter. Seven percent of cases and 0.4% of controls had 4 or more atypical naevi. Pigmented lesions of the iris were significantly more common in cases than controls. Nine percent of cases had the Atypical Mole syndrome (AMS) phenotype compared with 1% of controls. Six cases had concurrent cutaneous melanoma primaries. We conclude that atypical and iris naevi are important risk factors for eye melanoma and that patients with eye melanoma are at increased risk of cutaneous melanoma. Dermatological examination for the AMS phenotype and cutaneous melanoma should be recommended in eye melanoma patients with large numbers of pigmented lesions of the skin or family history of melanoma.

A retrospective analysis has been performed of the results of external beam radiotherapy for retinoblastoma using a whole eye technique. Local tumour control has been assessed in a consecutive series of 175 eyes in 142 children all of whom received external beam radiotherapy as the primary treatment for retinoblastoma. Follow up ranged from 2 to 17 years (median 9 years). Tumour control rates have been analysed with respect to the Reese Ellsworth classification and the series includes eyes in groups I to V. Focal salvage therapy was given for persistent, recurrent, or new tumours after radiotherapy. Following whole eye radiotherapy alone, the overall ocular cure rate was 57%, though with salvage therapy 80% of eyes could be preserved.

A retrospective analysis is presented of the results of external beam radiotherapy for retinoblastoma utilising an accurate lens sparing technique. Local tumour control has been assessed in a consecutive series of 67 eyes in 53 children all of whom received external beam radiotherapy as the primary treatment of retinoblastoma. Follow up ranged from 12 to 82 months (median 35 months) with 76% of the children followed for more than 2 years. Tumour control rates have been analysed with respect to the Reese-Ellsworth classification. The role of adjuvant and salvage focal therapy is emphasised. Following lens sparing radiotherapy with prior adjuvant treatment of anterior tumours, where appropriate, the overall ocular cure rate was 72%. With salvage therapy of persistent, recurrent, or new tumours, 93% of eyes could be preserved in this series which includes mainly eyes classified in Reese-Ellsworth groups I-III. These results compare favourably with those of whole eye external beam radiotherapy for comparable tumours, and with those of lens and anterior segment sparing using other techniques. They were achieved without the ocular morbidity associated with whole eye external beam radiotherapy.

Malignant melanomas may arise in the uveal tract, the conjunctiva, the skin of the eyelid, or the orbit. Risk factors so far identified include pre-existing choroidal naevi for uveal melanomas, primary acquired melanosis (PAM) for conjunctival tumours, and ocular and oculodermal melanocytosis for uveal and orbital lesions. The atypical mole syndrome (AMS) is associated with uveal and conjunctival melanomas, especially when the ocular lesions are multiple or familial. AMS patients should be screened for ocular melanomas. Conjunctival melanomas are managed by excision with or without adjunctive beta-irradiation. Circumscribed tumours have a better prognosis than diffuse and multifocal lesions arising in acquired melanosis and attempts should be made to limit the progress of the latter variant of the disease by treating PAM with cryotherapy. The most significant prognostic factor in uveal melanoma is the size of the tumour at presentation. Early dissemination is the rule and every effort should be made to distinguish a melanoma from a naevus as soon as possible. Small and medium-sized melanomas respond well to focal treatments chosen according to the size and location of the tumour. The techniques employed include photocoagulation, radioactive plaque therapy, proton beam radiotherapy and surgical resection.

A retrospective analysis has been conducted of regression patterns following treatment of retinoblastoma by external beam irradiation. There were 180 tumours in 105 eyes of 83 patients. Type I regression was found to be the commonest pattern and occurred in 50% of cases. Initial tumour size was found to be the only statistically significant determinant of regression pattern (p < 0.01). Thirteen tumours (7%) recurred within a median interval to recurrence of 12 months. All recurrences occurred within 40 months of completion of treatment and none occurred after age 4 years. No tumour less than 6 mm in diameter recurred. Although 10 out of 13 recurrences were of Type I, Cox model regression analysis showed initial tumour size to be the only independent predictor of recurrence (p < 0.01).

A 39-year-old Caucasian woman with a history of recurrent conjunctival melanoma of her right eye developed an intrastromal heavily pigmented malignant melanoma, which involved the whole corneal diameter. The patient was treated by corneoscleral lamellar keratoplasty and there has been no evidence of recurrent neoplasm during 4 years of follow-up. This apparently unique presentation of malignant melanoma of the cornea is illustrated and the differential diagnosis of corneal pigmentation is discussed.

Xeroderma pigmentosum is a rare autosomal recessive dermatosis. The neoplastic changes in sunlight-exposed areas of the skin and eyes may be related to the impaired replication of ultraviolet radiation-damaged DNA. A 38-year-old Greek woman is reported with a mild form of xeroderma pigmentosum and primary acquired melanosis with atypia of her right limbal conjunctiva and cornea. The development of this precursor of conjunctival malignant melanoma in a xeroderma pigmentosum patient may support the putative role of sunlight exposure in malignant transformation of conjunctival melanocytes.

The main characteristics of malignant cells include increased metabolism and capacity for division which are associated with high membrane fluidity. Membrane fluidity is in turn controlled by multiple factors which include the ratio of saturated to unsaturated fatty acids in the cell wall i.e. the Saturation Index (SI). The SI is known to be reduced in neoplastic cells as well as in the circulating erythrocytes of patients with some malignant tumours but not others. It has been suggested that the SI may be useful as a marker of malignancy.

We report an unusual family pedigree segregating the retinoblastoma predisposition gene. Expression of the phenotype in different individuals in this family ranges from asymptomatic gene carriers, regressed tumours, through unifocal to bilateral multifocal lesions. Because of the unusual pattern of inheritance in this family, initial genetic counselling at a local hospital did not take into account the possibility of incomplete penetrance of the gene, and complete ophthalmological examination of unaffected family members was not undertaken. We have used DNA probes from within the retinoblastoma predisposition gene for unequivocal identification of gene carriers. The subsequent demonstration of regressed tumours in founder members of the family confirmed the diagnosis of a dominantly inherited disease. The circumstances of the management of this family emphasises the need for specialist ophthalmic examination of first degree relatives and detailed genetic analysis of all such families with DNA probes.

Restriction fragment length polymorphisms (RFLPs) in 55 families affected by retinoblastoma have been studied using recombinant DNA probes derived from within the retinoblastoma predisposition gene. Only six families were uninformative for any of the DNA polymorphisms. The remaining 49 families can be offered prenatal screening. No obligate recombinations between any of the polymorphic loci and the retinoblastoma phenotype were observed. Four previously unknown cases of non-penetrance were identified. Prenatal testing for the inheritance of mutant alleles was performed in two cases and perinatal screening in two additional cases. One fetus inherited the normal allele from the affected parent and is therefore not at risk of retinoblastoma; the second fetus inherited the mutant allele and will require frequent screening for early detection of retinoblastoma. Both perinatal tests showed the absence of the mutant allele.

Five children with an orbital recurrence of retinoblastoma have been successfully treated by a combination of excision biopsy of the tumour mass, radical orbital radiotherapy, and systemic chemotherapy. Nine previous children, consecutive with the five presented here, died from disseminated retinoblastoma after failure of earlier treatment programmes for orbital recurrence. An aggressive therapeutic approach is justified by this improvement in survival.

It can be difficult to distinguish between various forms of pale intraocular tumour, and in particular between an amelanotic malignant melanoma, a choroidal haemangioma, and a solitary metastasis. If a monoclonal antibody specific for melanoma could be identified, it might be radiolabelled to provide a scanning technique which could distinguish between an ocular melanoma and a similar lesion. This pilot, in vitro study was undertaken to determine if monoclonal antibody against cutaneous melanoma recognises any antigenic similarity in ocular melanomas. Three cutaneous melanoma MoAbs 225.28S, 376.96S, and 763-24T and a non-specific MoAb HMFG2 were studied. Cell impressions were obtained from fresh ocular malignant melanomas. Standard staining techniques with immunofluorescence were used. MoAb 225.28S, 376.96S, and 763.24T were positive in melanomas with a dominant epithelioid cell type and in those with a dominant spindle cell type. It is concluded that MoAb 225.28S, 376.96S, and 763.24T may be suitable for imaging ocular melanomas after labelling with 123I, 111In, or 99mTc.

123I metaiodobenzylguanidine (MIBG) is a radiopharmaceutical used for imaging neural crest tumours. The possibility of using 123I MIBG for imaging retinoblastomas has been assessed in this pilot study. Ten patients were studied, nine with clinically and histologically proved retinoblastomas and one with Coats's disease. 123I MIBG scintigraphy correctly identified the neoplasm in eight patients but gave a negative result in two, one of whom had Coats's disease and the other a retinoblastoma which proved to be extensively necrotic on histological examination. These preliminary results suggest that 123I MIBG scintigraphy may have a role in differentiating retinoblastomas from lesions that simulate them.

An applicator attached to a 6 MV linear accelerator has been adapted to produce a well defined beam for the treatment of retinoblastoma. By using a contact lens as the reference point on the patient's cornea, the beam edge is aligned to just behind the posterior margin of the crystalline lens, thus sparing the anterior chamber and lens from the radiation field. In addition to basic dosimetric measurements made using an ionisation chamber and film densitometry to quantify the output and dose distribution from the applicator, extensive use was made of thermoluminescent dosemeters and a tissue-equivalent anthropomorphic head phantom. This was designed for detailed dosimetry on the eye and was used to confirm the correct positioning and reproducibility of the clinical set-up. We present data that corroborate and extend the dosimetric analyses documented in an earlier Dutch publication. In addition to the improved dosimetric analysis, other advantages include patient immobilisation, anaesthetic procedure and finer couch control as well as a recommendation on the dose prescription.

Two distinct disease entities are recognisable in retinoblastoma. In the commonest form of the condition a solitary tumour involves only one eye and may be of relatively late onset. Less frequently, multiple tumours are encountered and may involve both eyes. Onset tends to be early and this form of the disease is transmitted in an autosomal dominant fashion. Although in the genetically determined form of retinoblastoma all retinal cells contain abnormal genetic material, only a very few undergo neoplastic change. Individually, the resultant tumours are indistinguishable in terms of clinical appearance and response to treatment from those of non-genetic retinoblastoma. The intriguing similarities of the different forms of the tumour may be explained by a new hypothesis which suggests that retinoblastoma may result from the loss of a pair of suppressor genes. When present, this pair of genes may also have a suppressor effect for other types of tumour. Loss of this suppression for tumours other than retinoblastoma may explain why survivors of genetic disease are highly susceptible to second, non-ocular neoplasms. If the gene can be identified using DNA probes, antenatal diagnosis of those who inherit the retinoblastoma gene may be possible in certain families.

Twelve out of a series of 630 children with retinoblastoma, treated in the ocular oncology units at St Bartholomew's and Moorfields Eye Hospitals during the past 30 years, have developed ectopic intracranial retinoblastoma. The ectopic tumour occurred in the pineal region in eight children and in the suprasellar region in four. Ten patients had bilateral retinoblastoma, one unilateral disease, and one child presented with an isolated suprasellar tumour but no evidence of retinal disease. The interval from the initial diagnosis of retinoblastoma to the development of ectopic intracranial disease ranged from 4 to 70 months, median 34 months. Methods of treatment for the ectopic tumour varied, but all 12 children died with a median survival of only 8 months following the diagnosis of ectopic retinoblastoma. Subsequent spread of tumour to other sites within the central nervous system proved to be the most frequent cause of death. Ectopic intracranial retinoblastoma is a potentially curable neoplasm, but it requires adequate therapy to the whole neuraxis as well as high dose equivalent radiotherapy to the primary tumour.

Forty years of research into retinoblastoma has seen wide-ranging changes in our knowledge of the histogenesis of this childhood tumour and in the treatment of the disease. These changes, and some of the more recent developments in the molecular biology of this tumour are reviewed.

Ocular radioimmunoscintigraphy was performed in 20 patients using 99mTc-labeled monoclonal antibody 225.28S, F(ab')2 fragments. Radioimmunoscintigraphy was positive in 13 patients and the diagnosis of ocular melanoma was confirmed by enucleation of the eye or clinical follow-up. Scintigraphy was positive in one patient with lymph node metastasis from an ocular melanoma. In six patients immunoscintigraphy was negative. Using this technique a sensitivity of 92.8% was achieved for detecting ocular melanomas. Single photon emission tomography helped to separate the lesions situated in the nasal quadrant of the eye from the adjacent nasopharyngeal activity. With appropriate imaging techniques small tumors of the order of 3 x 5 x 3 mm could be detected clearly.

Eleven children with metastatic retinoblastoma diagnosed during the period 1970-1984 were treated with chemotherapy. Short-term complete responses were observed in three children treated with a four-drug combination which included cisplatinum, and in one child treated with vincristine and cyclophosphamide. The median duration of survival of the 11 children receiving chemotherapy was nine months, whilst the median survival of 13 children with metastatic retinoblastoma who were not given chemotherapy was only 2.3 months (p = 0.06). This suggests that retinoblastoma is a chemosensitive tumour and therefore adjuvant chemotherapy may have a role in children with retinoblastoma who at diagnosis are thought to be at high risk of developing metastatic disease.