Vitreous relapse following primary chemotherapy for retinoblastoma: is adjuvant diode laser a risk factor?

AIMS: To evaluate rates of vitreous relapse among retinoblastoma patients treated with primary chemotherapy and assess diode laser as a potential risk factor for relapse. METHODS: Retrospective review of all patients treated with primary chemotherapy at a large ocular oncology centre. Eyes that developed vitreous relapse were coded with regard to Reese-Ellsworth Group, laterality, time to relapse, type of relapse (vitreous base or non-vitreous base relapse), treatments used (including adjuvant diode laser), and ocular preservation. Individual tumour foci treated with laser hyperthermia were also coded for laser parameters including power settings, number of treatments, and concomitant administration of systemic chemotherapy (chemothermotherapy). RESULTS: 15 of 106 eyes (14.15%) developed vitreous relapse over a 6 year period. Mean time to relapse was 7.2 months after chemotherapy was completed. Five cases (33%) were of the vitreous base variety. Ocular salvage was attempted in 11 cases using a variety of methods; one patient was lost to follow up. Six of the remaining 10 eyes (60%) were salvaged. Eight of 38 eyes (21%) treated with systemic chemotherapy and laser hyperthermia developed vitreous relapse compared with seven of 68 eyes (10%) treated with primary chemotherapy alone (p<0.005). Laser settings, number of hyperthermia treatments, and the concomitant use of systemic chemotherapy (chemothermotherapy) were not associated with higher rates of vitreous relapse. CONCLUSION: Nearly one in seven eyes with retinoblastoma treated with primary chemotherapy may develop vitreous relapse. The administration of diode laser hyperthermia appears to increase this risk. Despite additional therapy a number of these eyes succumb to enucleation.

Microvessel count predicts survival in uveal melanoma.

Microvessel density has become established as an important prognostic indicator for many tumor types. This study investigates the microvessel density as a prognostic factor for survival in patients with uveal melanoma, which is the commonest intraocular tumor and has a clear tendency for metastatic spread to the liver. Factor VIII-related antigen was identified immunohistochemically in bleached sections from 123 tumors. Maximum blood vessel density in an area of 0.25 mm2 was recorded, along with other accepted prognostic information. Microvessel density was the single most important prognostic factor on univariate testing, and in a Cox proportional hazard model, tumor size was the only other variable to be entered. No other accepted prognostic factor entered the model. We conclude that microvessel density is an important prognostic factor for survival in patients with uveal melanoma and allows the identification of high-risk patients for whom adjuvant therapy should be considered.

Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.

Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.

Ocular radioimmunoscintigraphy: sensitivity and practical considerations.

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.

Familial aggressive nevi of the iris in childhood.

We report the occurrence of amelanotic melanocytic tumors of the iris arising in the second decade of life in two successive generations. Clinically, both tumors enlarged rapidly, with subsequent enucleation of the eye in one patient. In both cases, histologic examination revealed an aggressive iris nevus composed of spindle A cells. Both lesions had similar argyrophilic nucleolar organizing region counts, which may be of prognostic significance. A possible autosomal-dominant pattern of inheritance for this rare tumor is discussed.

Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma.

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.

Oestrogen receptors in conjunctival malignant melanoma: immunocytochemical study using formalin fixed paraffin wax sections.

In a group of 15 women with conjunctival malignant melanoma six cases (40%) were shown to have oestrogen receptor positivity using a monoclonal antibody to oestrogen receptor related antigen (ER-D5, Amersham RPN.710) on formalin fixed, paraffin wax sections. Receptors were also present in the epithelium of these six cases but not in controls and cases without ER-D5 positivity in their tumours. A subset of these aggressive, intractable unilateral tumours may therefore be amenable to hormone treatment.

Five cases of coexistent primary ocular and cutaneous melanoma.

BACKGROUND: Patients with the atypical mole syndrome are prone to cutaneous melanoma, but their risk of ocular melanoma has not been established. We studied the skin of 207 consecutive patients with eye melanoma referred to Moorfields Hospital in London, England, in an attempt to determine what percentage of these patients had the atypical mole syndrome phenotype. OBSERVATIONS: Five patients were seen who had primary melanomas of both the eye and the skin. In three of these patients, the cutaneous melanomas were discovered only as a result of this study. The number of cutaneous melanomas expected in this cohort of patients with eye melanomas was no more than 0.4 on the basis of the United Kingdom incidence of both tumors. This difference was highly significant. CONCLUSIONS: The occurrence of primary cutaneous melanoma in five patients from a cohort of 207 patients with eye melanoma (or the premalignant melanocytic lesion of the conjunctiva called "primary acquired melanosis") provides strong evidence of an association between cutaneous and ocular melanoma. Three of the five patients also had the atypical mole syndrome phenotype, suggesting that the atypical mole syndrome predisposes to both types of melanoma.

Pigmentation of the eyelid margin accompanying conjunctival melanoma.

In a review of patients with histologically verified malignant melanoma of the conjunctiva, we found 17 patients who had heavy pigmentation of the ipsilateral eyelid margin that was visible on external examination. Among nine patients in whom the histologic characteristics of the skin pigmentation could be studied, the features ranged from an increase in pigmentation of melanocytes within the basal layer to invasive malignant melanoma. The presence of heavy skin pigmentation in association with conjunctival melanoma appeared to be an ominous sign, even when the eyelid did not show histologic features of malignancy. Twelve of the 17 patients (70%) died of metastases after histologic verification of the conjunctival melanoma.

Malignant melanomas of the conjunctiva, nasal cavity, and paranasal sinuses.

Four patients had malignant melanoma involving the conjunctiva, nasal cavity, and paranasal sinuses. In each patient, the conjunctival melanoma preceded recognition of the lesion in the nasal cavity by months or years. Each patient had one or more conjunctival biopsy specimens that documented melanoma, and in each patient the melanomas evolved in primary acquired melanosis of the conjunctiva. Histologic examination of the epithelium adjacent to the tumor in the nasal cavity failed to show either atypia or diffuse melanosis. We believe that these melanomas in the nasal cavity and paranasal sinuses are most likely to evolve as regional metastases, although it is possible that they arise de novo or as related foci in accordance with the multicentric characteristics of conjunctival melanoma. If a patient with a conjunctival melanoma has symptoms referable to the nasal cavity or paranasal sinuses, ophthalmologists should refer the patient to an otolaryngologist.

Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia.

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.

Ring melanoma--a rare cause of refractory glaucoma.

BACKGROUND: Ring melanoma of the ciliary body and iris is extremely rare and often has adverse histology. This tumour may cause raised intraocular pressure. METHODS: A review of four cases of ring melanomas with insidious presentations seen in the ocular oncology service over a 12 month period. RESULTS: All four patients presented with unilateral anterior segment abnormalities and refractory glaucoma. The misdiagnoses of the causes of the glaucoma included angle recession from previous blunt trauma (patient 1); iridocorneal endothelial (ICE) syndrome supported by endothelial specular microscopy (patients 2 and 3); and melanocytoma on ciliary body biopsy (patient 4). Two patients were treated by several cyclodiode ciliary body ablation treatments and the other two underwent trabeculectomies and Molteno tubes. Two of the four patients have since died from their disease. CONCLUSION: The ophthalmologist should re-evaluate the diagnosis in patients with anterior segment abnormalities and refractory ipsilateral glaucoma. Endothelial specular microscopy and biopsy of the suspicious lesion may give misleading reassurance. The potential presence of an anterior uveal melanoma must always be considered.

Ectopic intracranial retinoblastoma in childhood.

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.

Multifocal amelanotic conjunctival melanoma and acquired melanosis sine pigmento.

Clinical and histopathological features of four cases of multifocal amelanotic malignant melanoma of the conjunctiva in association with 'acquired melanosis sine pigmento' are reported. The absence of conjunctival pigmentation in this extremely rare combination of lesions prevented early diagnosis and clinical monitoring. As a result orbital exenteration was required in three cases. This multicentric non-pigmented variety of conjunctival malignant melanoma tends to present later than pigmented forms and may require exenteration of the orbit as a primary procedure.

Premalignant melanosis of the conjunctiva and the cornea in xeroderma pigmentosum.

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.

Recurrent malignant melanoma of the corneal stroma: a case of 'black cornea'.

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.

Ocular toxicity of desferrioxamine: light microscopic histochemical and ultrastructural findings.

This study documents for the first time light and electron microscopical changes in the retinal pigment epithelium (RPE) following treatment with high dose desferrioxamine for systemic iron overload. The changes include loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, swelling and calcification of mitochondria, and disorganisation of the plasma membrane. In addition, Bruch's membrane overlying degenerate RPE cells appeared abnormally thickened owing to the accumulation of large amounts of mature elastic fibres, pre-elastic oxytalan, and long spacing collagen. The specificity of these changes and the mechanism of toxicity are discussed.

Radioimmunoscintigraphy of ocular melanoma with 99mTc labelled cutaneous melanoma antibody fragments.

The possibility of using radiolabelled monoclonal antibody fragments to image uveal melanomas has been assessed in a pilot study. 99mTc labelled F(ab')2 fragments of MoAb 225.28S raised against cutaneous melanomas were used. Initially 10 patients were imaged. In five patients the clinical findings were typical of uveal melanoma. Immunoscintigraphy was positive in all five cases. In a further five patients there was doubt about the diagnosis. One was though to have a choroidal haemangioma but failed to respond to treatment and immunoscintigraphy was positive, suggesting a diagnosis of melanoma. Two patients were assigned a diagnosis of choroidal haemangioma, one of melanocytoma or possible retinal pigment epithelium carcinoma, and one of metastasis. Immunoscintigraphy was negative in all these four cases. In combination with established diagnostic tests immunoscintigraphy may have a part to play in differentiating uveal melanoma from other similar tumours.

Choroidal malignant melanoma in an albino.

This is the first report of an amelanotic melanoma arising in the unpigmented choroid of a tyrosinase-positive oculocutaneous albino (TPOCA). Melanosomes within the tumour showed a maturation arrest in the unpigmented type II (premelanosome) phase. Other neural crest derived melanocytes in iris and choroid showed similar limited melanogenesis. The neuroectodermally derived melanocytes of the iris, ciliary body, and retinal pigment epithelium (RPE) contained mature melanosomes, though clinically the RPE was pale. The significance of this tumour arising in an albinotic eye is discussed.

Genetic counselling in retinoblastoma: importance of ocular fundus examination of first degree relatives and linkage analysis.

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.