ACTA O P H T H A LMOLOG I CA 71 (1993) 846-849

CASE REPORT

PUVA treatment and choroidal malignant melanoma

Gulhanim Haciyakupoglul, llter Varinlil, Hamdi R. Memi$ogluz, Seyhan Varinli3, Nihal Demircanl and Gul Denli2

Departments of Ophthalmologyl, Dermatology2 and Pathology3, Cukurova University, Adana Turkey

Abstract. Choroidal malign melanoma showing rapid progression in a boy 17 years old is presented. The patient was under therapy with methoxy psoralen + Ultraviolet A (PUVA)* for psoriasis vulgaris. He had undergone com- plete ophthalmologic examinations with three-month in- tervals from the beginning of this therapy. The tumor was detected in the seventh month, rapidly enlarging within the next twenty days, and eventually leading to enuclea- tion. PUVA is known to be a risk factor for cutaneous ma- lign melanoma. However, there is no reported incidence of choroidal malign melanoma in PUVA treated patients. To our knowledge, this is the only case showing the possible role of PUVA therapy as a predisposing factor in the development of uveal malign melanoma.

Key words: 8 methoxy psoralen - Ultraviolet A - psoriasis - uveal malign melanoma.

Case report The patient diagnosed as having psoriasis vulgaris had, upon referral to the Ckurova University De-

* PUVA is a method of photochemotherapy in which fu- rocumarin compound psoralen is used in conjunction with Ultraviolet A (UVA). It is used in the treatment of psoriasis and various other skin diseases (McEvoy & Stern 1987). P W A therapy has systemic, cutaneous, and ocular side effects. In clinical and experimental studies it has been shown that the induction of cataract can be related t o P W A therapy(Wooetal.l985).Theriskofretinal tox- icity, particularly for young and aphakic patients, has been reported. In literature there are a few cases of cuta- neous malign melanoma, but here are no patients develo- ping ocular malign melanoma during PUVA therapy (Man et al. 1983; Cox et al. 1987).

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partment of Dermatology, undergone conven- tional therapy consisting of systemic steroids, which was not found to be effective during the 4 years of follow-up. He was then subjected to PUVA therapy. According to the predetermined proto- col, written consent was obtained from the patient after he was informed about the progress of the disease and the potential complications of the pro- posed treatment. PUVA sessions four times per week were started.

In each session, two hours after the ingestion of 0.6 mg/kg 8 methoxypsoralen (MOP), Ultraviolet A (UVA) was applied in the PUVA 8001 cabin ac- cording to the predetermined minimum photo- toxicity dose (MDP). His eyes were shielded with wrap-around sunglasses during UVA application and until 12 h thereafter. An improvement of the lesions was observed after a dose of 2?’9joule/cm2 UVA in 54 sessions. The patient was then subjected to a maintenance treatment once in a week.

Before and during the PUVA therapy ophthal- mologic examination was performed on the pa- tient with 3-month intervals. No ocular pathology was dectected in the first three examinations. 7 months after the beginning of the therapy the pa- tient was referred to the hospital with a complaint of visual loss in the right eye.

Visual acuity in his right eye was at the level of finger counting. Anterior segment was normal. A nontransilluminating solid mass in the lower tem- poral quadrant, extending to the macula, was ob- served on fundus examination. There was a shal- low retinal detachment between 3 and 5 o’clock ex- tending to the macula. IOP was 11 mmHg appl. The left eye was entirely normal.

B scan ultrasound revealed serous retinal de- tachment in the lower temporal quadrant and a mass with 2.261 cm3 of volume, covering the whole right temporal quadrant and extending behind the lens. In computed orbital tomography this mass was found to be 2 X 1 cm in size and appeared to originate from the choroid. The bone scinti- graphy, abdominal ultrasound, tomography, and peritoneoscopy did not indicate systemic meta- stasis. The laboratory findings were in accordance with the increased cytotoxic cell activity.

The right eye was enucleated under general an- esthesia. Histopathological examination showed a malign neoplastic lesion of the choroid consisting of atypical cells with centrally localized, hyper- chromatic nuclei and melanin-laden cytoplasm. Vortex veins were intact. Histopathological diag- nosis was reported as choroideal pigmented ma- lign melanoma of mixed cellular type.

The patient was followed with monthly intervals postoperatively. No metastases were detected in the follow-up period of 12 months.

Discussion

The significant role of UV radiation in the pa- thogenesis of some corneal and cunjunctival pa- thologies, cataract, and retinal phototoxic lesions are well known. PUVA, which was found to be an effective method in the treatment of various skin diseases, including psoriasis (Panish et al. 1974; Henseler et al. 1981), is a kind of photochemothe- rapy, and therefore is apt to cause some adverse ef- fects on the eye.

Psoralen covalently binds to DNA, forming monofunctional single strand photoadducts with thymine bases and interstrand cross links (bifunc- tional adducts) between opposite pyrimidine base pairs. The formation of these photoadducts of pso- ralen and pyrimidines presumably leads to inhibi- tion of DNA synthesis. This inhibition of epider- mal DNA synthesis is the rationale for the use of psoralens in the treatment of psoriasis (Stolk & Siddiqui 1985).

The incidence of overall phototoxicity of PUVA in 1125 patients was found to be 6% in those older than 45 years (Stern et al. 1980a). Erythema, pruri- tus, vomiting, headache, and dizziness were re- ported as the short-term side effects of the treat- ment. The long-term complications were reported

as basal cell carcinoma, bullous pemphigoid, Lupus Erythematosus, and PUVA lentigines (Ler- man 1980; Woo et al. 1985; Lerman et al. 1980; Marxet al. 1983; Coxet al. 1987; Farber et al. 1983). Because of its long-term side effects it should not be applied in children (Segal et al. 1978).

Cataract is one of the ocular side effects of PUVA therapy. According to Lerman (1980) and Woo et al. (1985) 10 hours following oral ingestion protein bound 8 MOP retains; photoproducts accumulate in the lens and cause nuclear or posterior capsular opacities following repeated therapy. Experiments have demonstrated that 8 MOP can be detected in human lens for at least 12 h after oral ingestion of a single therapeutic dose. The drug can also be found in the rat lens after intraperitoneal injec- tion (Lerman 1980). If UVA is not applied, 8 MOP tends to diffuse out of the lens within 12 to 24 h. On the other hand, we also know that UV radiation above 300 nm is in itself capable of generating cataract. This is the rationale for shielding the eyes during the sessions. In our case the lenses were found to be normal in the 12-month follow-up period after PUVA treatment.

Another ocular side effect of PUVA, especially in young and aphakic patients, is the retinal photo- chemical reaction undetectable in standard eye examinations (Lerman 1980). Stern and colleagues (1985) could not demonstrate an increased risk of ocular phototoxicity in the follow-up period of 5 years in 1299 patients receiving PWA therapy. Moreover, Cox and colleagues (1987) found no sig- nificant change in retinal function tests in an 8-year follow-up study.

The question of the greatest concern is whether there is any increased incidence of skin cancer after PUVA treatment. Reports of follow-up studies addressing this question indicate increase not in melanotic but in non-melanotic skin cancer incidences. A 2.4-fold increase in squamous cell carcinoma was reported after PUVA therapy of high cumulative doses (Stern et al. 1980 b, 1985 b). The development of cutaneous carcinoma during PUVA could be related to risk factors such as ion- izing radiation therapy, inorganic arsenic inges- tion, skin type 1-2, cutaneous carcinoma, and his- tory of skin carcinoma.

PUVA has been considered a risk factor for ma- lign melanoma by Marx and colleagues (1983). Widespread lentigines in normal skin, repigmen- tation in depigmented areas of vitiligo, or histopa-

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thological changes in nevus can be observed in PUVA treated patients. Therefore, PUVA should especially not be applied to the patients who have hereditary tendency to develop nevus. Abnormal mitochondria, swollen and distorted endoplasmic reticulum, and large lysosomes in the melanocytes were observed in 50-70% of PUVA treated skin biopsies (Heidbreder & Henseler 1980; Zelickson et al. 1979; Niemi et al. 1983; Abel et al. 1985).

This patient is the first reported case of uveal malign melanoma developing during PUVA treat- ment. Some postulations could be made to explain the possible relation of this entity with the treat- ment in this particular patient:

1. PUVA treatment may have promoted a rapid development of a choroidal malign melanoma that was pre-existing.

2. PUVA therapy initiated the development of the melanoma.

3. This observation can be coincidental.

The average incidence of uveal malign melanoma is known to be 2-6/10000 of all eye patients. The very low incidence in the second decade, reported to be Y00.1-0.6 of overall malign melanoma cases by Duke Elder (1960), suggests that a predisposing factor is likely in our patient. Tumor development may not be attributed solely to UV light because there were no signs of cataract or other effects on the eye. Moreover, the necessary protection was apparently practised. Our patient received a total of 279 joulekm2 UVA dose in 54 sessions which should not bring him into a risk group for tumor development. Considering the unusual age of our patient, the well known effects of PUVA on mela- nocyte stimulation, and the high rate of growth of the tumor, this therapy could be suggested among the predisposing factors for uveal malign mela- noma.

Acknowledgments

This study was presented at the Internal Society of Oph- thalmic Pathology (ISOP) third meeting in Brussels, May 1992.

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Received on December 12th. 1992.

Corresponding author:

Dr. Giilhanim Haciyakupoglu, CU Tip Fakiiltesi, Balcali Hastanesi, Goz Hast ABD, Adana, Turkey.

54 Acta Ophthal. 71.6 849