Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

British Journal ofOphthalnology, 1982, 66, 695-704

Uveal melanomas presenting during pregnancy and the investigation of oestrogen receptors in melanomas

JOHANNA M. SEDDON,' DAVID T. MACLAUGHLIN,2 DANIEL M. ALBERT,' EVANGELOS S. GRAGOUDAS,' AND MICHAEL FERENCE III3 From the 'Retina Service and Howe Laboratory, Departnent of Ophthalmology, Harvard Medical School, Massachusetts and EarInfirmary, Boston, MA; the 2VincentResearch Laboratory, DepartmentofObstetrics and Gynecology, Massachusetts General Hospital, Boston, MA; and the 3Leahey Eye Clinic Inc., Lowell, MA, USA

SUMMARY We observed a young woman who showed growth of a choroidal melanoma over the course of 2 pregnancies, with subsequent enucleation of the eye. This is the first such documented case. In addition 4 other women with uveal malignant melanomas presented during pregnancy. This observed number of pregnancies (5) was greater than the expected number (2-1) among women of childbearing age who underwent enucleation with subsequent analysis in our pathology laboratory. However, this difference was not statistically significant. Further, more females 44 years of age or younger underwent enucleation for malignant melanoma than men of comparable age. Evaluation of these cases led us to propose that there is a subset of patients whose ocular melanomas are hormonally responsive. We therefore analysed and choroidal copyright. tissue from 7 patients, including one of the pregnant women, for the presence of oestrogen receptors. No specific oestrogen binding was found. The possibilities that other hormones are involved or an immunological mechanism is operative are discussed.

Endocrine influences on cutaneous malignant mela- On the other hand some epidemiological studies http://bjo.bmj.com/ noma have been explored for many years. "-16 In con- reveal a higher incidence and mortality for cutaneous trast, the effect of endocrine factors on ocular mela- melanoma inwomen ofreproductive and menopausal nomas has received little attention. A few anecdotal age than in men."I 12 Similarly, other reports suggest references3 1718 and case reports'922 of uveal mela- an unfavourable effect on prognosis when melanomas nomas occurring during pregnancy could be found in are exacerbated during pregnancy'3 or when stage II the literature. However, no one has reported whether melanomas are related to pregnapcy. 1" Activation of or not growth of a uveal melanoma occurs during naevi or melanomas with use of birth control pills,'5 on September 29, 2021 by guest. Protected pregnancy or explored hormonal aspects of ocular during pregnancy,'6 and after oestrogen administra- melanoma or uveal tissue. tion'2 has been observed. Furthermore some animal Studies of cutaneous melanoma on differences in studies imply changing growth patterns of skin mela- incidence and mortality according to sex yield con- noma in animals of differing hormonal status.'3232' tradictory results.'' The association between cu- Such cli-nical findings arouse the suspicion thatsome taneous melanoma and pregnancy or hormonal status patients with cutaneous melanoma may respond to among women is also equivocal. 7'6 Some report a hormonal stimuli. Since uveal and skin melanocytes better prognosis in women than in men3 orinpregnant both derive from the neural crest, it is reasonable to than in nonpregnant women.' However, a few find no propose that similar mechanisms may play a role in significant differences in outcome according to sex,' ocular melanoma. pregnancy,' 5-7 marriage status,8 9 or use of oral con- Steroid hormone receptors have also been studied traceptives.'0 in an effort to understand honnonal influences on Correspondence to Johanna Seddon, MD, Retina Service, Massa- malignancies. The presence of steroid receptors ir chusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA the cytoplasm of cells is characteristic of endocrine 02114, USA. responsive tissue. Oestrogen bindingactivity hasbeen 695 Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

696 Johanna M. Seddon, D. T. MacLaughlin, D. M. Albert, E. S. Gragoudas, and M. Ference III found in 12 to 46% of cutaneous melanomas indepen- Follow-up procedures on the 4 living patients in- dent of the patient's sex or age.2"28 Since steroid volved personal contact with the patients as well as hormones may be involved in the pathophysiology of documentation of their status from their ophthalmol- various human malignancies or may be useful as thera- ogists and internists. Two patients died, and discharge peutic regimens, as in breast cancer, looking for recep- summaries and slides of biopsies were examined to tors in cancer tissue makes good biochemical sense.2' confirm the cause of death. We herein report 5 cases of young women who The age and sex distributions of patients who had presented with uveal malignant melanomas during an enucleation for uveal malignant melanoma with pregnancy, one of whom is the only well documented subsequent pathology analysis at the MEEI over the case in the literature of growth of ocular melanoma same time period as the 5 cases were evaluated. Fe- associated with pregnancy. The possibility that there male and male ratios for patients 44 years of age or might be a subset of patients whose ocular mela- younger were calculated. Birth rates for all women in nomas are hormonally responsive was raised. Since the United States adjusted for age and year of birth32 oestrogens are the major trophic hormone of preg- were then used to calculate the cumulative probability nancy, a biological response of uveal tissue to of being pregnant for each woman 44 years of age or oestrogens was proposed. To test this hypothesis, we younger. These probabilities were then added to analysed uveal melanomas and adjacent uveal tissue obtain the expected number of pregnancies among after enucleation for the presence of oestrogen recep- women in this age group. The significance of the tors, and, as will be discussed, none were found. difference between the observed and expected num- ber of pregnancies was then determined by the Subjects and methods Poisson distribution.

CASES OESTROGEN RECEPTOR ANALYSIS We recently observed 2 patients with ocular mela- Uveal melanoma tissue (at least 2 mm3) was collected noma presenting during pregnancy. This led us to under sterile conditions from 5 cases as soon as pos-

review our series ofmelanomas in the Pathology Lab- sible after enucleation and frozen in liquid nitrogen. copyright. oratory at the Massachusetts Eye and Ear Infirmary One of these specimens was from the eye of a preg- (MEEI) from 1953 through 1973 and we identified nant young woman discussed in this report (case 1). specimens from 3 other pregnant women with ocular At the same time normal choroid was collected from melanoma. Paraffin embedded, formalin fixed tissue an area adjacent to the tumours to serve as control was processed forlight microscopy. Slides were stained tissue. Delays of 4 and 7 hours in processing tissue with haematoxylin and eosin or periodic acid-Schiff, were encountered in two other cases (one necropsy and potassium permanganate treated (bleached) sec- and one from a distant institution), and these cases tions, when indicated, were obtained. We examined were analysed as negative controls. the slides, verified the diagnosis, and describedcharac- Oestrogen receptor assays were carried out on the http://bjo.bmj.com/ teristics of the tumours in each case. A specimen from tumour and choroidal tissue cytosols according to the tumour which grew during 2 pregnancies (case 1) methods used for the analysis of oestrogen receptors was studied by electron microscopy by techniques in human breast cancers in the laboratory performing previously described.303' breast receptor assays for the Massachusetts General

Table 1 Clinical andpathological data on S cases ofuveal melanomas presenting duringpregnancy on September 29, 2021 by guest. Protected Patient Age Month Presenting Melanoma Outcome (accession race of complaint number) pregnancy Location Size Cell type 1 27 7 (1st) Ocular pain OS Choroid Medium Mixed Normal delivery (E80-923) W 6 (2nd) for 2 days dead due to metastatic melanoma 2 33 Blurred vision Choroid Small Spindle B Normnal delivery (E80-1275) W 7 OD for 2 days alive and well 3 35 Blurred vision Choroid Small Spindle B Normal delivery (E56-341) W 5 ODfor2weeks alive and well 4 22 Blurred vision Choroid Large Spindle B Normal delivery (E69-746) W 6 OS for 4 days dead due to metastatic melanoma 5 29 Injection OS, , Small Spindle B C-section (E61-497) W 4 history ofglaucoma ciliary body alive and well and 'cyst' OS Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

Uveal melanomas presenting duringpregnancy and the investigation ofoestrogen receptors in melanomas 697

Fig. IA Fig. lB copyright. http://bjo.bmj.com/ Fig. 1C Fig. ID Fig 1 Case 1. (A) Pigmented mass involving the macula OS during herfirstpregnancy, November 1978. (B) Edge ofthe lesion in November 1978, showing retinal detachment (RD). Bifurcation ofvessel (B) used as a landmarkfor comparison in Fig. IB and Fig. IC. (C) Edge ofthe mass in between her2 pregnancies showing a decrease in the subretinalfluid (*) with straighteningofthe vessels. (D) Tumoursurroundingthe opticdisc as seen immediatelyfollowingdelivery ofhersecond child in June 1980. on September 29, 2021 by guest. Protected

Hospital (Vincent Research Laboratories and delivered full-term normal infants. Two of them sub- DT)33 34 sequently died of metastatic malignant melanoma. Since the tumour samples were small (tumour average net weight 98 mg, choroid average weight 61 CASE 1 mg), duplicate single saturating dose assays at 2 nM3H This 27-year-old white female was first seen on 30 oestradiol in the absence and presence of 250-fold October 1978, with the complaint of pain in the left molar excess of unlabelled diethylstilbestrol were eye of 2 days' duration followed by oedema and red- performed. ness of the and decreased vision. At this time she was 7 months pregnant. There was no significant Results past ocular history. She had been on birth control pills from about March 1977 to March 1978. Family history Five white women ranging in age from 22 to 35 pre- revealed that her mother died of stomach cancer. sented during their fourth to seventh months of preg- Her last ocular examination, in April 1973 by an opto- nancy with uveal malignant melanoma (Table 1). All metrist, revealed normal visual acuity in both . Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

698 Johanna M. Seddon, D. T. MacLaughlin, D. M. Albert, E. S. Gragoudas, and M. Ference III

There was minimal conjunctival injection and the was tender to palpation. There were amoderate number of cells in the anterior vitreous OS. The pigmented lesion in the left eye was slightly larger, extending superior and inferior to the disc with ir- regular margins. There was a bullous retinal detach- ment extending from 2.00 to 9.00. There did not appear to be an increase in height. Again, because of her pregnancy, further testing was not performed. She was delivered of a normal son at term on 27 May 1980. In June her visual acuity was counting fingers at 5 feet (150 cm) OS. Fundus examination revealed that the pigmented tumour was even larger than before, andit surrounded the opticdisc (Fig. 1D). was performed and re- vealed several hyperfluorescent areas in the early and middle phases of the angiogram which progressed during the transit and leaked, consistent with vascular Fig. 2 Case 1. Fluorescein angiogram ofthe mass OS areas seen in melanomas (Fig. 2). Ultrasonography during arteriovenous phase showing hyperfluorescent areas. revealed a solid lesionwith some suggestion ofacoustic shadowing in the . Choroidal excavation was not definitely seen. A clinical diagnosis of malignant melanoma was Ocular examination of the right eye was normal. made. Because the lesion had grown and her visual Visual acuity OS was counting fingers at 1 foot (30 acuity was poor, enucleation was advised. Liver func- cm). Visual field examination revealed a central scot- tion tests including bilirubin, alkaline phosphatase, copyright. oma, almost complete loss of the superonasal quad- and SGOT were normal. Enucleation of the left eye rant, with marked constriction superotemporally. She was performed on 28 July 1980. had moderate oedema and erythema of the lids, with She remained well until January 1982, when biopsy- minimal conjunctival injection and chemosis. There proved liver metastases developed. Chemotherapy was an afferent pupillary defect. Ocular motility was was initiated, but she died in April 1982 ofwidespread normal. Slit-lamp examination of the and metastases. anterior chamber was unremarkable. Applanation Pathological examination. On gross examination of intraocular pressures were 15 mmHg, 10 mmHg OS. the eye a pigmented choroidal tumour was seen sur- http://bjo.bmj.com/ In the fundus of the left eye was a dark lesion measur- rounding the optic nerve. It extended 10 mm tempor- ing about 3 x4 disc diameters located 11/2 disc dia- ally from the disc atid 2 mm nasally. The temporal meters temporal to the disc involving the macula aspect of the tumour was a circumscribed mass (Fig. 1A). There was some pigment proliferation and elevated 3 mm, while the remainder of the tumour mottling at the temporal border of the lesion. A large had a more flat, diffuse configuration with an serous detachment extended from 2.30 to 8.00 o'clock. elevation of 1-2 mm (Fig. 3A). The retina was totally Ultrasonography revealed a lesion 2 mm in height detached. with no choroidal excavation. Histologically the tumour contained areas of dense on September 29, 2021 by guest. Protected The differential diagnosis at this time was subretinal connective tissue (Fig. 3B). Spindle A, spindle B, and pigment epithelial haemorrhage or malignant mela- epithelioid cells were present, with a diagnosis of noma. It was decided that because of her pregnancy, mixed cell type.35 There were nests of naevus-like further testing would be delayed. The lesion remained cells at the edge of the tumour adjacent to the optic stable during the latter part of her pregnancy. nerve. Tumour cells were seen invading the optic She was then delivered of a normal daughter on 29 nerve anterior to the lamina cribrosa and scleral emis- January 1979. She did not resume birth control pills sary canals (Fig. 3C). Bruch's membrane was not and again became pregnant in August 1979. During ruptured. A moderate amount of chronic non- this interval between pregnancies the subretinal fluid granulomatous inflammation was present within the decreased (Figs. 1B,C). tumour. The retina was detached, and areas of associ- Suddenly on 1 February 1980, 6 months into her ated retinal pigment epithelium had undergone fibrous second pregnancy, she had a recurrence of the ocular metaplasia. The cornea, anterior chamber, lens, iris, pain and irritation OS similar to herexperience during and ciliary body appeared normal. Electron micro- herfirst pregnancy. Hervisual acuity had not changed. scopy of this melanoma revealed bundles of collagen Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

Uveal melanomas presenting during pregnancy and the investigation ofoestrogen receptors in melanomas 699

Fig. 3A

-1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~O

3 Case 1. Choroidal

Fig. (A) copyright. tumour with diffuse configuration. (Haematoxylin and eosin, xS-8). (B) Dense connective tissue within the tumour. (Haematoxylin and eosin, x42). (C) Peripapillary tumour with invasion ofthe optic nerve (arrow). (Haematoxylin and eosin, x26-5). http://bjo.bmj.com/ Fig. 3I on September 29, 2021 by guest. Protected

Fig. 3C Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

700 Johanna M. Seddon, D. T. MacLaughlin, D. M. Albert, E. S. Gragoudas, and M. Ference III

ocular pressures were 18 mmHg OU. Fundus exami- nation of the right eye revealed a pigmented lesion 5 mm in diameter, 2 mm elevated located 3 to 4 disc diameters superior to the disc OD (Fig. 4). A second- ary serous detachment involving the macula was pre- sent. The fundus of the left eye was normal. A number of consultants agreed that the lesion was a malignant melanoma. Various treatment possibili- ties including observation for evidence of growth, enucleation, and alternative methods, such as proton beam irradiation, were discussed. When the patient learned that she had a tumour in her eye she insisted on prompt enucleation and would not consider alter- native therapies. Her alkaline phosphatase level was normal. Enucleation was then performed on 14 October 1980. The size of the tumour was too small to warrant sampling for oestrogen-receptor analysis. The patient did well subsequent to her enucleation and was delivered of a normal son on 12 December Fig. 4 Case 2. Wide angle photograph ofpigmented mass 1980. Thus far she and her son have remained in good superior to the disc OD. health with no systemic medical problems. fibrils amid tumour cells in areas of connective tissue seen on light microscopy. copyright. CASE 2 This 33-year-old woman presented in her seventh month of pregnancy with a 2-day history of her vision being obstructed by a 'veil' OD. Her last reported visual acuity was 20/20 OU in November 1977, when she was treated for an allergic conjunctivitis. There was no other significant past ocular history. Her visual acuity was 20/100 OD and 20/20 OS. External and anterior segment examination was en- http://bjo.bmj.com/ tirely within normal limits OU. Applanation intra- Fig. 5A

Fig. 5 Case2. (A) Tumourarising from the choroid in the posterior pole seen on gross examination (x5-5). (B) Melanoma consisting

ofspindle A and spindle B cells. on September 29, 2021 by guest. Protected (Haematoxylin and eosin, x265).

Fig. SB Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

Uveal melanomas presenting duringpregnancy and the investigation ofoestrogen receptors in melanomas 701 Pathological examination. A small pigmented retinal detachment at the edges ofthe tumour. Exami- tumour was present arising from the choroid in the nation of the fundus OD was normal. Consultants posterior pole above the optic disc. It measured 41/2 agreed that this was a malignant melanoma OS. The mm in largest diameter and 3 mm in elevation (Fig. left eye was enucleated on 22 September 1969. 5A). The surrounding retina was detached. There She was delivered of a full-term baby in December was no gross extrascleral or optic nerve extension. 1969. Three and a half years later she developed a Histologically the tumour was composed of a mix- carcinoma in situ of the cervix and underwent a total ture of spindle A and spindle B type cells (Fig. 5B). hysterectomy inMay 1973. Slides ofthe cervical lesion No epithelioid cells were seen and Bruch's membrane have been reviewed and the diagnosis has been con- was not ruptured. There were a minimal number of firmed by the authors. In November 1974, she noticed chronic inflammatory cells. A shallow detachment multiple nodules in her right breast which were biop- involving the macula was present. Degeneration of sied and subsequently verified by the authors as photoreceptors and outer nuclear layer of the retina metastatic malignant melanoma of mixed cell type. was seen overlying the tumour. There was superficial Chemotherapy and BCG therapy were started in June involvement of by tumour cells. The anterior 1975. A liver scan was suspicious for early metastatic segment was normal. disease. In September 1976 she developed multiple bone metastases, which were treated with radio- CASE 3 therapy. She later developed extensive subcutaneous This 35-year-old woman presented in her fifth month melanotic nodules. Bone marrow failure developed of pregnancy in July 1956 with a history of blurred due to extensive chemotherapy. She died on 30 April vision OD for 2 weeks. She had no previous ocular 1977 of metastatic malignant melanoma and bone problems. Her best corrected visual acuity was marrow failure. 20/70-2 OD and 20/20 OS. Applanation intraocular Pathological examination. A tumour 14 mm in pressures were 17 mmHg OU. Fundus examination largest diameter and 7 mm in elevation was present revealed an elevated mass inferior to the macula 3 to 4 arising from the choroid. Histologically the tumour disc diameters in its widest dimension. There was consisted almost exclusively ofspindleB cells arranged copyright. macular oedema and a retinal detachment overlying in a fascicular pattern. It was lightly pigmented with the mass. The left eye was normal. She was seen at the minimal chronic inflammation. A retinal detachment MEEI and consultants agreed that the lesion was a was present overlying and surrounding the tumour. malignant melanoma. The right eye was enucleated The pigment epithelium over the lesion had under- on 21 August 1956. gone fibrous metaplasia. Bruch's membrane was rup- She was delivered of a normal daughter on 17 tured and there was invasion of the overlying retina. November 1956. Since then she and her daughter No tumour cells were seen in the vitreous. There was have remained in good health with no systemic invasion of the inner aspect of the sclera but no inva- http://bjo.bmj.com/ problems. sion into the scleral emissary canals. Pathological examination. A minimally pigmented choroidal tumour 6 mm in largest diameter and 2 mm CASE 5 in height was located in the posterior pole involving This 29-year-old nurse presented at the MEEI when 4 the macula. The cell type was classified as spindle B in months pregnant on 25 July 1961. Her visual acuity a fascicular arrangement. Compact spindle cells were was 20/20 OD and no light perception OS. Her right

present at the base of the tumour. Bruch's membrane on September 29, 2021 by guest. Protected was not ruptured. There was minimal invasion of the inner aspect of the sclera.

CASE 4 This 22-year-old woman presented in September 1969 when she was 6 months pregnant with a 4-day history of blurred vision OS. She had no significant past ocular history. Her family history was significant for cancer; her sister died from a central nervous system malignancy at age 16 and a paternal uncle was treated for cutaneous malignant melanoma. Her visual acuity was 20/15 OD and 20/400 OS. Applanation intra- ocular pressures were 16 mmHg OU. A choroidal tumour was seen inferotemporally in the left eye ex- tending from the ora to posterior to the equator with a Fig. 6 Case 5. Tumour involving the iris OS (asterisk). Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

702 Johanna M. Seddon, D. T. MacLaughlin, D. M. Albert, E. S. Gragoudas, and M. Ference III

eye was normal. Herleft eye had minimal conjunctival done which was negative. She has had no further injection. She had a superior peripheral medical problems. OS. A pale vascularised mass was present on the Pathological examination. A tumour consisting anterior surface of the iris inferiorly (Fig. 6). There mostly of spindle B cells was present, replacing the was also a subconjunctival mass at the limbus inferior- inferior aspect of the iris and involving the ciliary ly. The pupil OS was irregular, and the anterior body and the trabecular meshwork. It extended chamber was normal in depth. The lens OS had pig- through the sclera into the subconjunctival space. ment on the capsule. Intraocular pressures were 16 Tumour cells were present within the inner layers mmHg OD and 38 mmHg OS. The disc OS was of the corneal periphery and beneath the comeal atrophic. No masses were seen on dilated fundus epithelium at the limbus. Many large vascular chan- examination. nels were present in the tumour. Pigment clumps The patient's previous ocular history according to were scattered among the tumour cells. The angle was notes obtained in 1961 from her ophthalmologist re- closed inferiorly. The choroid showed no evidence of vealed a normal examination in November 1948, when tumour. Diagnosis was malignant melanoma of the she was 17 years old. Examination one year later spindle B cell type, involving the iris and ciliary body revealed advanced OS with optic atrophy with extraocular extension. and 'marked nasal field loss.' She had an 'iridectomy and sclerectomy' for control of the pressure on 24 STATISTICAL ANALYSIS April 1950. We were unable to obtain slidesofmaterial From 1953 to 1973 there were 27 females and 18 males removed at that time. A cystic, vascularised subcon- 44 years of age or younger who had an enucleation for junctival nodule below the limbus was noted prior to uveal melanoma and pathology examination at the the surgery but not biopsied or resected. No iris lesion Massachusetts Eye and Ear Infirmary with adequate was noted at that time. She was followed up by her follow-up. In 1980 there were 6 females and 2 males in ophthalmologist over the following years, but these the same age range. The female to male ratios were records could not be obtained. An iris lesion had 1 5: 1 and 3: 1 respectively. never been mentioned to the patient. Because of the The expected number of pregnancies among copyright. presence of a tumour in her blind eye when seen at women 44 years of age or younger in our sample was MEEI, an enucleation was performed on 11 October 2-1. Although the observed number (5) was greater 1961. than the expected (2-1), this difference was not statis- She was delivered of her child by caesarian section tically significant (one sided p value = 0-06). on 26 December 1961. Since then she has had two more caesarian sections and a hysterectomy. During OESTROGEN RECEPTOR ANALYSIS abdominal surgery, exploration for metastases was A summary of the findings can be found in Table 2. http://bjo.bmj.com/ Table 2 3H oestradiol binding in uveal melanoma and choroidal tissue Patient Age Sex Race Tissue Wet Assay protein Specific (accession weight (mg) (mg/ml) binding number)

(E80-923) 27 F W Melanoma 116 1-44 0 6 on September 29, 2021 by guest. Protected (B80-1284) 85 M W Melanoma, 110 3-74 0 choroid 25 0 40 0 7 (E80-1334) 54 M W Melanoma, 80 3-27 0 choroid 43 046 0 8 (E80-1430) 40 M W Melanoma, 80 3-87 0 choroid 10 - - 9 (E80-1439) 85 F W Melanoma, 80 4-38 0 choroid 35 - - 10 (E81-25) 65 M W Melanoma, 100 2-15 0 choroid 110 2-68 0 11 (E81-104) 83 M W Melanoma, 120 2-32 0 choroid 140 2%96 0 Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

Uveal melanomaspresenting duringpregnancy and the investigation ofoestrogen receptors in melanomas 703

One of the specimens studied was a melanoma from a tor, or that they may exert an indirect effect via the pregnant woman (case 1) in which no oestrogen re- regulation of other hormones or factors that directly ceptor was detected. The remaining uveal melanomas affect the melanoma. Other possibilities for hormone and normal choroidal tissues that were studied were control other than oestrogens include a direct effect also negative. of melanocyte stimulating hormone,3 androgens,' or other trophic factors. Discussion Anotherpossible mechanism is that pregnancy may be associated with decrease of a systemic inhibitor It is difficult to ascertain the natural history of mela- allowing stimulation of growth. An immunological nomas prior to their discovery. In case 1, however, rather than hormonal mechanism consistent with this there is no question that her symptoms of discomfort theory is the recent evidence that fetal suppressor and injection began during the latter half of each of cells are present which affect maternal adult lympho- her two pregnancies and that the melanoma grew to cytes and alter the mother's immunological reactivity, ultimately surround the optic nerve while she was preventing rejection of the fetal allograft.' Moreover pregnant. Reasons for her ocular pain and oedema at proteins produced by the mother4' or a reduction in similar times during herpregnancy remain speculative levels of maternal helper T cells42 may partly explain but may be related to growth of the melanoma. The survival of the fetus. Changes in cellular and humoral decrease in sub-retinal fluid and change in the appear- immunity43 occur during pregnancy and are thought ance of the edges of the mass suggested a remission or to be responsible for the diminution during pregnancy regression between pregnancies.36 This case and the of such autoimmune diseases as systemic lupus ery- others discussed in this report led us to question a thematosus or rheumatoid arthritis. Pregnancy has possible influence of hormones or other mechanisms also been found to exert a beneficial effect on involved in pregnancy and the premenopausal period. the Vogt-Koyanagi-Harada syndrome.45 Similarly, This hypothesis is corroborated by our finding of an perhaps an increase in immunosuppression-related increased female to male ratio in cases 44 years of age problems could occur which, for example, would allow or younger. We also found a higher than expected development or growth of a pre-existing slow growing copyright. number of pregnancies amongwomen of childbearing melanoma in the eye. Immunodeficiency states are age in our sample; however, this was not statistically associated with an increased incidence of neoplasia,46 significant., Since our patients are not necessarily but this has not been explored in the pregnant state. representative of all cases of uveal melanoma in the To evoke an immunological mechanism there source population, and the sample size issmall, results should be evidence that melanoma is an antigenic are suggestive and warrant further investigation. tumour. Virus-induced tumours are almost always The present study represents the first investigation antigenic, and there is suggestive evidence that at in the literature for the presence of oestrogen recep- least some ocular melanomas contain virus.47 More- http://bjo.bmj.com/ tors in ocular melanoma and choroidal tissue. over, evidence of immunological effects in melanoma Oestrogen receptors were not found, suggesting that patients has been demonstrated.48 oestrogen receptor activity may not be involved in the Our clinical observations pose the following ques- presentation or growth of ocular melanomas. This tions: (1) Do pregnancy and other hormonal changes assumption is consistent with the finding that cu- influence the occurrence of uveal melanomas? (2) taneous melanomas show a poor response to Does pregnancy affect the course and prognosis of endocrine therapy37 and that the putative responses uveal melanomas, and if so, by what mechanism? A on September 29, 2021 by guest. Protected to hormone therapy in cutaneous melanoma have no case control study would be helpful in answeringthese correlation with the presence of receptor.38 Our re- questions. Ideally, a prospective follow-up of mela- ceptor test group was small, with only one a melanoma noma patients in a national registry would be estab- of pregnancy, so a larger number of this relatively lished to determine differences in occurrence as well rare condition needs to be examined before the statis- as outcome in women of differing hormonal status tical significance of the findings can be established. controlling for histological and other prognostic fac- Questions that remain unanswered include: are uveal tors. Such investigations may provide insight into the melanomas of pregnancy different from tumours in patho-physiology or therapeutic management of a nonpregnant age-matched cases with respect to re- subset of patients with ocular melanoma. ceptor frequency and concentration? Are there sig- nificant receptor differences between males and We thank Dr Philip Lavin forhissuggestionsconcerningthe statistical females, and do values change with age? analysis and Ingrid Von Saltza for her help with translations. Also we The absence of oestrogen receptor, however, does would like to thank JoAnne Taschler and Diane Mahoney forhelping to prepare this manuscript. not rule out the possibility that oestrogens may in- This study was supported in part by Research Grant I F32 fluence tissue by a mechanism not involving a recep- EY05507-01 from the National Eye Institute (Dr Seddon). Br J Ophthalmol: first published as 10.1136/bjo.66.11.695 on 1 November 1982. Downloaded from

704 Johanna M. Seddon, D. T. MacLaughlin, D. M. Albert, E. S. Gragoudas, and M. Ference III

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