Conjunctival and uveal melanoma in the dysplastic nevus syndrome

SURVEY

OF OPHTHALMOLOGY

CLINICAL

VOLUME 37. NUMBER 5 - MARCH-APRIL 1993

PATHOLOGICAL

REVIEW

DAVID APPLE AND MILTON BONIUK, EDITORS

Conjunctival and Uveal Melanoma in the Dysplastic Nevus Syndrome J. MARTIN MCCARTHY, M.D.,’ JACK ROOTMAN, M.D., F.R.C.S. (C),‘*’ DOUGLAS HORSMAN, M.D., F.R.C.P. (C), ’ AND VALERIE A. WHITE, M.D., F.R.C.P. (C)‘q*

Departments of ‘Pathology and ‘Ophthalmology, Valtcouver General Hospital, British Colwnhia Cancer Agency and the University of British Columbia, Vancouver, BC, Canada

Abstract. The dysplastic

nevus syndrome was conceptualized in the late 197Os, and the proposal ofa genetic relationship with ocular melanoma has stimulated debate in the literature which remains unresolved. We present the case of a 60-year-old man with

subsequent

histologically proven sporadic dysplasic nevus syndrome and a prior history of nine cutaneous melanomas, who developed a large, exophytic melanoma of the cornea and limbal conjunctiva. Cytogenetic analysis of this melanoma revealed a clonal 1; 14 translocation. We believe this is the first reported case to use cytogenetic techniques in the analysis of conjunctival melanoma, either associated with dysplastic nevus syndrome or in isolation. We review the clinical literature as well as the cytogenetic and molecular genetic data related to the possible association of cutaneous melanoma, conjunctival and uveal melanoma and the dysplastic nevus syndrome. (SUIT Ophthalmol 37:377-386, 1993)

Key words. conjunctival melanoma dysplastic nevus syndrome hereditary neoplasm uveal melanoma l

l

cutaneous disorders

melanoma melanoma

l

l

cytogenetics

l

l

l

Primary ocular melanoma is uncommon, and its association with primary cutaneous melanoma is rare. This association occurs almost exclusively in the setting of familial or sporadic dysplastic nevus syndrome (DNS),‘~“~“5~“”suggesting a linkage of these abnormal melanocytic proliferations.

I. Dysplastic News

Syndrome

DNS was simultaneously conceptualized by Clark et al’“,” and Lynch’“,‘” in the late 197Os, and was alternately labelled the BK mole syndrome”’ and familial atypical multiple molemelanoma syndrome.2g,‘6,4” Considerable controversy has surrounded this syndrome, with debate focusing on the histopathologic definition

and the minimal clinical of dysplastic nevl ‘15.9~.T,L’ criteria required for inclusion of individuals or families within the syndrome.“.‘“,“” In general, DNS is characterized by increased numbers of both typical and clinically and histologically dysplastic nevi,“’ which develop at an early age, usually appearing in adolescence and increasing in number throughout adult life. In addition to the usual sun-exposed areas, dysplastic nevi are found on the covered areas, including the scalp, buttocks and female breast. Dysplastic nevi in this setting are both precursors’.“’ and markers’,:%i,“:~ of an increased risk of cutaneous melanoma, which appears at an earlier age in this group than is typically seen in the general population. The syndrome is thought to affect

378

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37 (5) March-April

MCCARTHY ET AL

1993

1

TABLE Clnssifiicntion Tvpe

Classification

A

Sporadic

B

Familial

C D D1 D2

Sporadic Familial Familial Familial

qf Sporadic

and Familinl Dysplastic Nexus Sydromu Descrintion

Individual with DNS phenotype and no personal or family history ofcutaneous melanoma or family history of DNS More than one family member with the DNS phenotype but no personal or family history of cutaneous melanoma Individual with DNS phenotype and a personal history of cutaneous melanoma Familial DNS with cutaneous melanoma occurring in member(s) not having dysplastic nevi Familial DNS with one member having both dysplastic nevi and cutaneous melanoma Familial DNS with two or more members with dysplastic nevi and cutaneous melanoma

approximately 30,000 individuals in the United States.“” The critical factor in the classification of DNS is whether the phenotype is present sporadically or in two or more members of a kindred. Subclassification is dependent upon the presence or absence of a personal or family history of cutaneous melanoma.‘“‘.4’ Familial DNS is inherited in an autosomal dominant manner.x.36,4’ The modification of Greene’s classification”0 system proposed by Kraemer et a144is summarized in Table 1. We will apply this classification system when discussing previously reported cases of ocular melanoma and DNS in an attempt to make consistent comparisons.

II. Ocular Melanoma Melanoma, including uveal melanoma and conjunctival melanoma, is the most common primary malignant neoplasm of the eye, with an incidence of 0.7/100,000.4y Uveal melanoma involving the choroid, ciliary body and iris, account for 95% of ocular melanoma, while only 5% are conjunctival in origin.4” Caucasians, particularly those with lightly pigmented irides and hair, are at greatest risk.‘7 Several cases of uveal melanoma and conjunctival melanoma associated with DNS have been reported in the literature. We report another case in which conjunctival melanoma occurred in an individual with sporadic DNS and a prior history of multiple cutaneous melanomas. The conjunctival melanoma was analyzed cytogenetitally and revealed a clonal abnormality. We believe this to be the first case of cytogenetic investieither melanoma, gation of conjunctival associated with DNS or in isolation. We review the previous cases of ocular melanoma reported in association with DNS and the arguments for and against this association. The genetic data

which might support or refute an association tween these disorders is also discussed.

be-

III. Case Report A. CLINICAL

COURSE

A 60-year-old man was referred with a large epibulbar tumor. A cerebrovascular accident four years earlier resulted in inability to close the left eye and the development of unremitting exposure keratitis. Treatment with topical preparations and bandage soft contact lenses over a two-year period were inadequate in controlling these problems, but resolution occurred with tarsorrhaphy performed two years prior to presentation. The patient was lost to follow-up for the next two years, at which time he returned to his primary ophthalmologist with copious amounts of purulent discharge through the lid closure. Examinat.ion revealed conjunctivitis and an occult epibulbar mass which prompted referral to the Ocular Oncology service of the University of British Columbia. Significant past history included hypertension, insulin dependent diabetes mellitus and DNS. Medications included cefoxitin and insulin. DNS had first appeared in childhood and worsened in adolescence with increasing numbers of expanding irregular nevi developing in sun-exposed and covered areas (Fig. 1). These lesions were observed until age 55, when two cutaneous melanomas of the superficial spreading type were removed. The numerous remaining lesions were observed regularly and frequently for suspicious changes and excised as required. In total, seven more cutaneous melanomas and fifteen dysplastic nevi (Fig. 2) were removed prior to the development of the conjunctival mass. Examination of the right eye was unremarkable. Visual acuity was 20125. Examination of the

OCULAR

MELANOMA

AND DYSPLASTIC

NEWS

left eye was limited by lid closure, but showed a large, firm, telangiectatic, epibulbar mass marginally exposed through the tarsorrhaphy. There was no light perception. Multiple cutaneous nevi and an expressive aphasia were apparent on systemic evaluation. Metastatic evaluation, including liver function tests, abdominal ultrasonography, chest X-ray and bone scan, was unremarkable. Computerized tomography of the head was consistent with prior cerebrovascular accident. Abnormalities of orbital tomography were limited to a soft tissue mass arising on the nasal conjunctiva and cornea (Fig. 3). Examination at the time of division of tarsorrhaphy and biopsy showed a 2.2 x 2.0 cm epibulbar tumor involving large portions of the cornea and limbal conjunctiva (Fig. 4). On biopsy, the mass proved to be a conjunctival melanoma and

subtotal

year later

exenteration

the patient

was performed.

One

SYNDROME

Fig. 1. Numerous pigmented lesions on patients’ hack displaying clinical characteristics of dysplastic nrvi, including large size, asymmerry, irregular margins and variable pigmentation. Note multiple scars f’rorn prcviorls cxcisional biopsies.

is free of local and metastat-

ic ocular disease; however, a cutaneous squamous cell carcinoma, a dysplastic nevus, and a lentigo maligna melanoma have been excised. B. PATHOLOGY

The biopsy specimen showed predominantly epithelioid cells with large oval nuclei, prominent nucleoli and numerous mitotic figures (Fig. 5). Fine melanin pigmentation was present in occasional cells. By indirect immunoperoxidase staining, the lesion was positive for S- 100 protein (Research Development Corporation, Toronto, ON, polyclonal) and with HMB-45 (Enzo Diagnostics, NY, NY, monoclonal). The resection specimen consisted of a subtotal exenteration

Fig. 2. Photomicrograph of excisional skin hiopsy showing bridging of adjacent nests of melanocytes, lenti$nous melanocytic proliferation and cytologic atypia, characteristic of histologically dysplastic nevi. (H&E:. x 100)

with a large polypoid cornea1 and limbal mass (Fig. 6). Microscopic examination showed this to be predominantly anterior to Bowman’s layer with stromal invasion through small, focal breaks. The tumor was covered by a thinned and focally ulcerated epithelium. Intraocular extension was not present. The cytologic appearance was similar to that seen in the biopsy specimen. A lymphocytic inflammatory infiltrate and foci of necrosis were present within the tumor. There was no evidence of primary acquired melanosis in the surrounding conjunctival epithelium. Resection margins and vascular and lymphatic channels were not involved. Focal nerve fiber

380

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37 (5) March-April

1993

MCCARTHY ET AL

Fig. 4. Division of the tarsorrhaphy exposed a pale mass measuring 2.2 x 2.0 cm and involving the superiFig. 3. CT scan showing a prominent soft tissue mass arising on the anterior and nasal aspect of the left globe

or, nasal, and inferior aspects of the limbus and cornea. Only the lateral cornea was free of tumor. Note the area of previous wedge biopsy of the inferior portion of the lesion (arrow).

(arrow).

layer infarction and cytoid bodies were present in the retina. The eyelid structures and remainder of the ocular and orbital contents were unremarkable.

ma1 metaphases, with the t( 1;14) being the only abnormality common to each abnormal metaphase.

C. CYTOGENETICS

The risk of cutaneous melanoma is known to be increased within the setting of DNS and is thought to increase from Type A through Type D2 DNS. Affected family members have a cumulative lifetime risk of cutaneous melanoma approaching loo%,“” a risk at least 100 times that of the general population.““s9” In those individuals with type D2 DNS (two or more family members with dysplastic nevi and cutaneous melanoma),

Fresh tumor tissue from the exenteration specimen was submitted for cytogenetic analysis using routine culture methods. The tumor tissue was disaggregated and subjected to shortterm tissue culture by standard methods. Karyotype analysis revealed: 45-46, X, -Y, t(1;14)(p36;ql l), -15[cp4]/46,XY[lO]“” (Fig. 7). There was evidence of cell-to-cell variation between the abnor-

Fig. 5 Biopsy specimen showing predominantly epithelioid cells with large oval nuclei, prominent nucleoli and moderate numbers of mitotic figures. Similar histologic features were seen on examination of the exenteration specimen, (H&E, x 400)

IV.

Discussion

OCULAR

MELANOMA

AND DYSPLASTIC

NEWS

Kraemer et al”” estimated the risk to be 395 times that of the unaffected population. In a prospective study of 452 white patients with dysplastic nevi, Rigel et al”” found that these patients exceeded the lifetime risk for cutaneous melanoma in only two years of follow-up and suggested longterm surveillance would reduce mortality. Similar surveillance for ocular melanoma patients has been proposed, but is controversial;i,“l.“(i.3~.‘l.iIt is unclear whether a risk relationship exists between sporadic and familial DNS and ocular melanoma, although evidence suggesting an association has been presented. I.:i.4.I I.!!4.4i.tll.5H.t,‘,5 A. PREVIOUS MELANOMA

CASES

SYNDROME

381

i

OF OCULAR

ASSOCIATED

WITH

DNS

The primary evidence for an association between DNS and ocular melanoma are the thirteen previously reported cases of conjunctival and uveal melanomas occurring in the context of familial and sporadic DNS. These are summarized as cases 1 to 13 in Table 2. Another case, reported by Greenel”l.“‘.‘” to be among this group, is excluded, as no relationship existed between the ocular melanoma patient and the DNS blood line. In order to apply the classification of Kraemer et al”’ we have tabulated these individuals and families, focusing on the ocular melanoma patient, who is not necessarily the originally reported “proband.” This classification requires clinical examination of all family members and so is clinically cumbersome and difficult to use in a retrospective fashion. Such

Fig. 7. Representative karyotype demonstrating the rearranged 1 and 14 resulting chromosome from the t( 1: 14)(p36;qll) (arrows). Also evident in this metaphase: ? ins (1Oq). - 15, + marker (arrowheads).

Kg. 6. Vertical pupil-optic nerve plane of section through the exenteration specimen showing a large exophytic mass involving the superior and inferior cornea and limbus. The uveal tract is ft-ec of tumor. (H&E, x 4)

problems are exemplified by cases 6 and 10, in which the family histories appeared to be incomplete, making categorization unclear. Misclassification is common in the absence of complete skin examinations of all first degree relatives with possible familial cases being mislabelled as sporadic (types A and C).” Although numbers are small, it is interesting to note that while CoM accounts for only 5% of all ocul?r melanoma, it represents four of the thir-

382

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37 (5) March-April

MCCARTHY ET AL

1993 TABLE

Conjunctival Report

Personal history of OM patient

1

M,61

CoM,CM,DNS**

neg

C

1990

2 3 4 5 6

F,16 M,28 F,68 F,71 M,59

CoM,DNS** UM,DNS* UM,CM,DNSns UM,DNSneg CoM,DNSns

DNS* DNS* CM,DNS** CM,DNS* CM,DNS***

B B D D Dl orC

1987

7

M,7 months

UM,DNS

neg

A

1987

Case

1992

Vink (62)

Jensen

case

(40)

Friedman Albert Greene Lynch

(24)

(4) (32) (43)

Abramson Bellet Gilbert

(1)

(11) (28)

Korting

(41a)

2

in the Dysplastic Neuus Syndrome

OM Case

Year

Current

and Uveal Melanoma

Family history

DNS category

8

F,29

CoM,DNS**

neg

A

1985

9

M,78

UM,DNS

CM,DNS*

Dl

1983

10

M,60

UM

CM,DNS***

Dl orC

1981

11

M,57

UM-bilateral CM,DNS**

CM,DNS

D2

1980

12

M,51

UM,CM,DNS*

DNS*

Dl

1980

13

M,54

UM,CM,DNS**

neg

C

neg

na

1987

14

F,56

UM,CM

1983

15

neg

M,41

UM,CM

neg

na

Augsburger

(6)

1982

16

M,64

UM,CM

ns

ns

Oosterhuis

(45)

1982

17

M,52

UM,CM

ns

ns

Legend OM = ocular melanoma, UM = uveal melanoma, CoM = conjunctival melanoma, DNS = dysplastic nevus syndrome DNS category: modification by Kraemer et al of Green’s nomenclature (21,28) neg = negative for finding or syndrome, na = not applicable, ns = not specified *clinically suggestive of DNS, not histologically verified, **histologically verified family member examined.

cases (31%) of either conjunctival or uveal melanoma reported in association with DNS (cases 1, 2, 6, 8). One may speculate that this finding results from an intrinsic difference in uveal and conjunctival melanocytes or from variable exposure to potential carcinogenic influences, such as ultraviolet light.‘” Taylor”’ has suggested that conjunctival melanocytes have a closer relationship with cutaneous melanocytes than with uveal melanocytes. It is possible that conjunctival and uveal melanomas have distinct and independent associations with DNS. teen

B. FURTHER EVIDENCE FOR AN ASSOCIATION BETWEEN OCULAR MELANOMA AND DNS Further evidence for a relationship between ocular melanoma and DNS are the nine cases in which

ocular

melanoma

ma occur as independent

and

cutaneous

melano-

primary malignancies

CM = cutaneous

melanoma,

DNS, ***DNS

in only other

in a single patient. These are summarized as cases 1, 4, 11-17 in Table 2. Three additional cases of ocular and cutaneous melanomas reported as double primaries are excluded from this group because, in one, the choroidal melanoma was later considered to be a nevus.““‘.‘” and in two cases of “primary eyelid and primary conjunctival malignant melanoma,0’g as the authors pointed out, the melanomas were likely single, contiguous lesions involving both skin and conjunctiva. In 1984 Kodrigues-Sains noted that all individuals developing both cutaneous and ocular melanomas did so within sporadic or familial DNSb8 Gilbert’* and Korting4” have published exceptions to this finding (cases 14, 15). In two cases reported early in the evolution of DNS (cases 16, 17), the status of DNS could not be determined from the information presented. Using an age-adjusted yearly incidence for cuta-

OCULAR MELANOMA

AND DYSPLASTIC

NEWS

neous melanoma of 6 per 100,000 and of ocular melanoma of‘ 0.7 per 100,000 and a lifetime chance ofthese malignancies of l/250 and l/400, Rodriguez-Sains estimated the coincidental lifetime chance of this combination occurring to be 1/400,000.““~“” ‘I‘he significance of this very snxs!! number is unclear. Determining the actual incidence of‘ ocular melanoma in DNS populations by tongterm follow-up of large numbers of patients would be difficult and to date has not been carried out. Not only would this require following patients fen- extended periods, but would also require consensus on the diagnostic criteria for DNS; to date, this has not been reached. However, the almost exclusive occurrence of combined ocular and cutaneous melanoma in DNS is suggestive of a non-random relationship. Further evidence fi)r an association between ocular melanoma and DNS is that a significantly greater percentage of patients with DNS were fimnd to have conjunctival, iris and choroidat nevi as compared to a control poputation.‘x Similarly, a significantly greater percentage of individuals with cutaneous melanoma were found to have iris nevi.” ‘l‘he number of iris nevi was also fi)und to be greater, although not at a statistically signiticant level. Uvea!, conjunctival and cutaneous metanocytes have a ~01rlnw11 neural crest heritage and dermal alld ocular metallomas exhibit common itrliiluilogenicity.‘” KodriguezSains suggested that this common lineage and i~nmuilogenicity might imply COI~I~OI~ behavior, suggesting that increased ocular nevi might be markers of increased ocular melanoma risk just as increased numbers of’cutaneous nevi are associated with increased cutaneous ~netanoma risk,.ii.b~X

C. EVIDENCE AGAINST AN ASSOCIATION BETWEEN OCULAR MELANOMA AND DNS ‘l.wo main reports have been sited as evidence against a genetic relationship between ocular melanoma and DNS. (Greene et a!“” examined two kindreds presenting as familial DNS with ocular and cutaneous melanomas. ‘I’he authors suggested that the proposed association between the DNS and ocular melanoma was coincidental on the basis of detailed neuro-ophthalmologic examinations performed on 26 patients with the DNS or hereditary cutaneous melanoma. ‘I’his report has been criticized for several reasons. As the authors stated in their paper, the family examined in detail was not a kindred with ocular melanoma associated with the DNS. -rhe DNS was in the paternal blood line and the isolated

SYNDROME

383

ocular melanoma occurred in the maternal blood tine.‘” E’otberg pointed out the inadequate sample size and the tack of longterm follow-up in this study.21 Second is the investigation in which ‘l‘aylor et at”’ postulated that if an etiologic relationship exists between DNS and ocular melanoma, dysplastic nevi should occur with greater frequency in ocular melanoma populations. In this study the prevalence of dysplastic nevi in patients with ocular melanoma was 4.5?%, significantly less than the 41%, prevalence of dysplastic nevi in patients with nonfamilial cutaneous melanoma. From these findings the authors concluded that no significant relationship exists between DNS and ocular melanoma. However, to test the proposed relationship between ocular melanoma and DNS, a search for the syndrome, both sporadic and familial, rather than isolated dysplastic nevi would be helpftlt. As previously noted, this would require detailed family histories and dermatotogic examinations. It was noted that 13 patients had family histories ofunusual nevi, which could mean that there were 13 cases of familial DNS in the 44 cases of ocular melanoma studied.”

D. REVIEW OF RELEVANT CYTOGENETIC AND MOLECULAR GENETIC LITERATURE ‘l‘he genetic information available concerning ocular melanoma and DNS may also be examined in an attempt to determine if a ralationship between the two disorders exists. Cytogenetic studies of cutaneous melanoma performed mainly on metastases, has revealed that losses 01 rearrangements of chromosomes 1, 6, and 7 occur most frequently (83, 66 and cil’%, respectively) with chromosomes 9, 3, 2, 1 1 and 10 showing changes in 44-29% of cases.““.“‘,“” ‘I‘he area of chromosome 1 which is most frequently involved is 1 pl 1-~22. Dracopoti et a!‘!’ have presented evidence suggesting that changes on chromosome 1 occur late in rnelanorna progression. More recently an attempt has been made to determine the primary chromosomat changes in melanoma by the examination of precusor lesions, benign and dysplastic nevi, as wet! as multiple metastases from the same patient. Losses or rearrangements ofchromosome 9 were the most frequent.“,“” In tight of the frequent involvement of the p arm of chromosome 1 in cutaneous melanoma and evidence of a weak linkage between the Kh locus’” (also on 1p) and DNS, an attempt has been made by several groups to further characterize the association. Hale et al7 reported a linkage between

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1993

DNS and loci which mapped to 1~36 at the distal end of the short arm of chromosome 1. However, this linkage has not been confirmed by other groups. ‘2.4’,64 Evidence for chromosomal instability in DNS has been presented.‘“,“’ Genetic examination of uveal melanoma has lagged behind that for cutaneous melanoma. However, in recent years a large enough series of tumors has been reported to determine that the most frequent cytogenetic abnormalities are the loss of a whole chromosome 3 and duplication of the q arm of chromosome 8.9x~5’,6”Deletions of 6q, similar to those in cutaneous melanoma are also seen, but less frequently than abnormalities of chromosomes 3 and 8, and almost exclusively associated with complex karotypes suggesting that it is a late change, as postulated for CM.” There may be some heterogeneity in uveal melanoma, as abnormalities of 3 and 8 are seen more frequently in tumors involving the ciliary body than those confined to the choroid.‘rx.“” Abnormalities of a variety of other chromosomes are also seen, but with less frequency than changes in 3, 6 and 8. We have seen abnormalities of chromosome 1 in approximately one third of our cases of uveal melanoma. Usually the proximal portion of the p arm is involved, but in two of twenty four cases, the distal portion (1~35 and 1~36) was involved (unpublished observations of authors DEH and VAW). To our knowledge, there has been no previous report of cytogenetic investigation of conjunctival melanoma, either isolated or in association with DNS. This may be due to the small size of these lesions and the requirement that all of the tissue be used for histopathology. We were able to obtain sufficient tissue for cytogenetic examination in the present case, due to the large size of the melanoma which grew unobserved under the tarsorrhaphy. This case showed a translocation between chromosomes 1 and 14 in which the breakpoint at 1~36 was in the region found to be linked to DNS by Bale et al.’ Structural rearrangements of chromosome 1, especially lq, are detected in a wide variety of hematopoietic malignancies and solid tumors, but usually are secondary changes.47 The t(1;14) in this case appears to be the primary karyotypic abnormality, as it was observed in all cells examined, which suggests that a breakpoint site at 1~36 or 14 qll may be etiologic in this tumor type. Additional cytogenetic studies confirming involvement of either of these sites in conjunctival melanoma are required. Therefore, the available genetic information does not establish an association between

MCCARTHY ET AL either conjunctival or uveal melanoma and DNS at the present time, but further studies are warranted. E. CLINICAL

RELEVANCE

Previous authors have proposed regular ocular exams for individuals with the DNS and thorough dermatologic evaluation for individuals developing ocular melanoma.4*“~“~24~“XDermatologic evaluation to determine the presence or absence of DNS in patients with ocular melanoma is a simple and relevant aspect of the management of these patients. Longterm follow-up and repeat examinations would not be required; the presence or absence of this syndrome can be determined in a single examination. This screening can be undertaken by the ophthalmologist with referral for specialized review only in questionable situations. We support this concept of dermatologic evaluation to exclude DNS in individuals with ocular melanoma. Conversely, ocular examination of all individuals with DNS is more controversial and potentially more costly in the absence of firm minimal diagnostic criteria for the DNS. The utility of ongoing ocular examination is less obvious and its merits and drawbacks have been previously discussed. Barnhill’ suggested that melanoma risk associated with the DNS is a continuum, rather than an absolute presence or absence, based on persona1 and family history and degree of phenotypic expression. Those with strong expression of the DNS phenotype or family history by virtue of cutaneous melanoma or numerous dysplastic nevi could undergo routine and ongoing ophthalmologic examination looking for ocular melanoma.2” Isolated dysplastic nevi may represent the weakest expression of the DNS’,“” and may suggest a minimal increased risk of cutaneous or ocular melanoma. The most compelling reason for ocular examination in these patients may be to further investigate the relationship of these abnormal melanocytic proliferations. If this approach is contemplated, several factors must be considered. Firstly, for early diagnosis of ocular melanoma, the ocular exams would need to be regular for a patient’s lifetime with a greater frequency in the older population where the incidence is higher.4y Secondly, ocular examination should include indirect ophthalmoscopy to invetigate the largest possible area of the uveal tract.“,99-5X Thirdly, and of greatest importance, is the need to carefully define the criteria for inclusion for any longterm study of this group of patients. Careful and complete evalua-

OCULAR MELANOMA AND DYSPLASTIC NEWS tion of family history and examination of family members would be required. Genetic investigations of tumor and normal patient cells would also provide invaluable information regarding the possible link between cutaneous melanoma, ocular melanoma, and DNS. The lack of minimal diagnostic criteria for the DNS remains problematic and until this issue is resolved, valid comparisons will be difficult.

V. Summary An association of ocular melanoma, cutaneous melanoma and the dysplastic nevus syndrome is suggeted by the embryologic, epidemiologic, and clinical evidence; however, the genetic evidence is inconclusive. In order to more fully elucidate the specifics of this possible linkage, both longterm ocular follow-up of individuals with precisely defined dysplastic nevus syndrome and dermatologic evaluation for dysplastic nevi and dysplastic nevus syndrome in patients with ocular melanoma are necessary. In addition, cytogenetic and molecular genetic evaluation of abnormal and ocular melanocytic cutaneous proliferations are required.

References 1.

Abl-amson DH,

RodriqueL-Sains RS, Rubman R: B-K mole syndrome. Cutaneous and ocular malignant melanoma, ‘4~fh 0~)lhllln/?rIo/ YK:1397-l 399, 1980 2. Albert LS, Rhodes AR, Sober AJ: Dysplastic melanocytic nevi and cutaneous m&moma: markers for increased risk for affected persons and blood relatives.] ,4m ,&rrtf DP,_rnc//o/22:69-7.5, 1990 Albert DM, Sear1 SS. Fox-get B, et al: Uveal findings in patients with cutaneous melanoma. Am J OphPdmof 95:474-479. 1983 Albert DM. Chang MA, Lamping KA, et al: ~f‘he dysplastic ncvus syndrome: a pedigree with primary malignant melanoma\ of the choroid and skin. O~h~hn/molng~ 92: 172x-1734, 19x5 .-, hlbrrt DM, (Ihang MA, Lamping KA. et al: (letter). O+ ~/rn~mo/o~~ Y3: 137L’.1986 fi. Augsburier JJ, Shields Jr\, Mastrangefo MJ, Frank PE: Diffuse primary malignant melanoma after primary cutaneous melanoma. .4rclr O~~hlhnlmolY8:1261-1264, 1980 7. Kale S,J, Dracopoli NC, .l‘ucker MA, et al: Mapping the genes for hereditary cutaneous malignant melanomadysplastic nexus to chromosome Ip. h’ Et& / Mrrl 3x 1:367-l ~ 57’-. I989 H Bale SJ, Chakravarti A, (ireen MH: Cutaneous malignant melanoma and familial dysplastic nevi: evidence for autosomal dominant phenotype. Am ,/ H~trrr Crnr/ 38: I X8-96, 1986 0 Karnhill RI.: Current status ofthe dysplastic melanocytic IICVL,~.,/ (:Uln/r /JUtho/ 18: 147-159, 1991 IO Bxnhill RL. Roush GC: (Correlation ofclinital and histopathologic features in (linically atypical melanocytic 110i. Ccrtr~rr- 67:3157-3164, 1991 11 Bellet KE, Shields JA, Sol1 DB, et al: Primary choroidal atld cutaneous melanomas occurring in a patient with the B-K mole qndromr phenotype. ,4vt J Oph/hnlrnol KY:567-570, 1980 I”. (:allnon-Albright LA, Goldgar DE, Wright EC, et al: Evitlcncr against a linkage of cutaneousmelanoma-dyspla-

SYNDROME

13.

14.

15.

16.

17.

18.

19.

385

tic nexus qndrome locus to chromosome 1~36. .4n ,/ f/urn C&v& .x.912-918, 1990 Caporaso N, Greene MH, ‘f‘sai S, et al: Cytogcnctics in hereditary malignant melanoma and dysplastic nevun syndrome: Is dysplastic nexus syndrome a chromosome instability disorder? Cn~rrr Grnr/ C.‘y/og~~/u/Z-1.299-3 14, 19x7
20.

21.

Folbel g R: .l‘hc lamilial occurrence olcutaneous melanoma, intraocular melanoma, and the dysplastic nexus \yndt-ome (letter). .4v1 J 0/~)lhlhn/v~1/ Yh:Xl 5, 1983 22. Fountain JW, Bale SJ, Housman DE. DI-acopoli NC:: Genetics of melanoma. Cn~rur S~r7~rr Y:ti45-67 I, 1990 23.

24.

25.

26. 27.

2x.

29

30

31

32

33

Frichot BC, Lynch H.f‘, Guirgis HA, et al: New cutaneous phenotype in familial malignant melanoma (letter-). I,rr,cCP~1:X64-86.5, 1977 Friedman RJ, Rodriguez-Sains R, Jakobiec F: Ophthalmologic oncology: conjunctival malignant m&moma in association with sporadic dysplastic ncvus syndrome. ,/ Dumnlol Surg Owol 1?:31-34, 1987 Fusaro KM. Lynch H?f‘, Oosterhuis JA, Went LN: ‘f‘he familial occurrence of cutaneous melanoma, intraocular melanoma, and the dysplastic nexus synclrome (letter). Am J O~hthalmol Y7:802-805, 1984 Fusaro RM. I,ynch HT: (letter). O~/&lhn/mo/ Y3: 13711372, 1986
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Vphlhalvnol 96816, 1983 34. Greene MH, Sanders KJ, Clark WH, et al: ‘l‘he familial occurrence ofcutaneous melanoma, intraocular melanoma, and the dysplastic news syndrome (letter). Am J 0phlhabol 97: 115-I 17, 1984 35. Greene MH, Clark WH, ‘l’ucker MA, et al: Acquired precursors of cutaneous malignant melanoma the familial dysplastic nevus syndrome. N Engl,/ Mrrl ?12:91-97, 1985 36. Greene MH, Clark WH, ‘l‘ucker MA, et al: High risk of malignant melanoma in melanoma prone families with dysplastic nevi. A?m In&rn Mrd 102~458-465, 1985 Hecht B: Chromosomal rear37. Hecht F, Kaiser-McCaw rangements in dysplastic nevus syndrome predisposing to malignant melanoma. Cancer GP~PLCylr~g0frl~5:73-78, 1988 DE, Sroka H, Kootman J, White VA: Mono38. Horsman somy 3 and isochromosome 8q in “veal melanoma. CarrTP~ GeneI Cylogenel 45:249-253, 1990 Study Group: Guidrlinrs /oo, 39. ISCN Cancer Cytogenetics

40.

41.

42.

43.

44.

45. 46.

47. 48.

49.

50.

MCCARTHY ET AL 51.

52.

53.

54.

55.

56.

Cancrr Cvlogenelics, Supplevnrnt to un In~ervdional SystvvnJar Human kylogevuzlic Nomenclature. Basel, S Karger, 1991

57.

Jensen OA, Movin M, MuellerJ: Malignant melanoma of the choroid in an infant with the dysplastic nevus syndrome. Ada Ophfhalmol 65:91-100, 1987 Jerome L, McCoy JL, Herberman KB: Cell-mediated immunity to melanoma-associated antigens in patients with ocular malignant melanoma. Am J Ophlhal?no/ 79: 812-816, 1975 Kefford RF, Sahnon J, Shaw HM, et al: Variable association with dysplastic nevi and absence of genetic linkage to chromosome 1p. CI~I~T Grnrl (,&~PT~P~ 51:45-55, 1991 Korting HC, Blick U, Hamper1 WD: Coincidence of primary malignant melanoma of skin and eye. Report of a case without B-K mole syndrome but with a further malignancy. Demvndologica 16 7:3 17-32 1, 1983 Kraemer KH, Greene MH, ‘l‘arone R. et al: Dysplastic naevi and cutaneous melanoma risk (letter). Latlcrl I: 1076-1077, 1983 Lynch HI‘, Fusaro KM, Pester J, et al: I‘umor spectrum in the FAMMM syndrome. HrJ Gzrrrrr 44:553-560, 198 1 Lynch HI’, Fusaro KM, Kimberling WJ, et al: Familial atypical multiple mole-melanoma (FAMMM) syndrome: segregation analysis. J Med Gewt 20:342-344, 1983 Mitelman 1:: Calalogur u[ Chrovnosovnnl Abrvw~liovrs in CUP rer. New York, Wiley-Liss, 1991, ed 4 Oosterhuis JA, Went LN, Lynch ‘I‘: Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas. Hrj fIphlhrr/rr& 66:930-299 _. .., 1982 . Osterlind A: Trends in incidence of ocular malignant melanoma in Denmark 1943-82. Iv/l,/ Qtlcrr 40: 15 l164, 1987 Paton D, Thomas LB: Simultaneous occurrence of primary malignant melanomasof the eye and the skin. Arch Ophlhnlvnol 62:645-652, 1959

58.

59.

60.

61.

62. 63.

64.

65.

Prescher G, Bornfeld N, Becher R: Nonrandom chromosomal abnormalities in primary “veal me1anoma.j N&l Co,zc~~, fn.s[ 82: 1765- 1769, 1990 Reimer RR, Clark WH, Greene MH, et al: Precursor lesions in familial melanoma. A new gnetic preneoplastic syndrome. JAMA 239:744-746, 1978 Kigel DS, Kivers JK, Kopf AW, et al: Dysplastic nevi, markers tix increased risk tbr melanoma. Cancer 63: 386-389, 1989 Rhodes AR, Mihm MC, Weinstock MA: Dysplastic melanocytic nevi: a reproducible histologic definition emphasizing cellular morphology. Mod Path01 2:306-3 19, I989 Rodriguez-Sains R: Uveal findings in patients with ocular and cutaneous melanoma (letter). Am J Ophlhalmol 96.~257-258, 1983 Rodriguez-Sains K: ‘l‘he familial occurrence ofcutaneous melanoma, intraocular melanoma, and the dysplastic nevus syndrome (letter). Am J 0phphlhalvnol 97: 114-I 15, 1984 Rodriguez-Sains K: Indirect ophthalmoscopy and ocular melanoma (letter). Hovpild Prnclicr Aprt5-56, 1984 Rodriguez-Sains KS: Ocular findings in patients with dysplastic nevus syndrome. Ophlhalmokogy 9?:661-665. 1986 Roth ME, Grant-Kels JM, Ackerman AB, et al: I‘he histopathology of dysplastic nevi continued controversy. Am J Dwvnalopulhol 13:3X-5 I, 199 1 Sisley K, Rennie I(;, Cottam DW, et al: Cytogenetic findings in six posterior “veal melanomas: involvement of chromosomes 3, ti, and 8. (hw.~ Chromosomes ad Canrer 2:205-209 I 1990 L ‘l‘aylor MR, Guerry D, Bondi EE, et al: Lack of association between intraocular melanoma and cutaneous dysplastic nevi. Am J Ophthalmol Y&:478-482, 1984 ‘l‘rent JM: Cytogenetics of human malignant melanoma. (:(IT~cP~Mcl~r.slasis Kw 10: 103-I 13, 1991 ‘l‘rent JM, Leong St’, Meyskens FL: Chromosome alterations m human malignant melanoma, in Conti CJ, et al (eds): Skirt 7’t~rnor.x Bx,!~ilrrit~~,lvnln/ and Clinical Aspck New York, Raven Press, 1989, pp 165-186 van Haeringen A. Bergman W, Nelen MR, et al: Exclusion of the dysplastic nevus syndrome (DNS) locus from the short arm of chromosome 1 by linkage studies in Dutch families. G~noaks 5:61-64, 1989 Vink J. Crijns MB, Mooy CM, et al: Ocular melanoma in families with dysplastic nevus syndrome.,/ Am Acd Dw mad 23:858-X62. 1990

We are grateful to Dr. Kurt Hein (Lethbridge, Alberta) fol providing clinical information and photographs ofcutaneous lesions and kindly tacilitating our acquisition of skin specimens. Author’s address: Valerie A. White, MD, FRCQC), Department of Pathology, 910 West 10th Avenue, Vancouver, BC, Canada, V5% 1 MY. Keprints are not available.