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Vitiligo in patients with metastatic melanoma: A good prognostic sign
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Vitfiigo in patients with metastatic melanoma: A good prognostic sign J a m e s J Nordlund M D , John M Klrkwood, M D , Bernadette M Forget, R N , M S N , G e r a r d M f l t o n , MD D a m e l M Albert, M D , a n d A a r o n B Lemer, M D
,
West Haven and New Haven, CT, and Sydney, Austpaha We have identified and studied twenty-seven patients with melanoma who also had Vltthgo Four patients had vttthgo before the diagnosis of melanoma, and twenty-three developed dep~gmentatton after the dmgnosJs of mahgnancy We also have revmwed pubhshed reports about twenty-four other patients with melanoma who developed Vltthgo The chmcal course of the melanoma m the fifty-one patients was remarkably similar Thirty-seven had a melanoma arlsmg at a site whmh tends to carry a poor prognosis, for example, on the trunk, under the nml, or on the mucous membranes Forty-nine patients had metastases In regional lymph nodes or at distal s~tes Thirty-three patmnts survived 5 year,;, and twenty-five survived l0 years These data suggest that the appearance of vmhgo m patients w~th metastatic melanoma portends a longer survival than expected The patients with vitdtgo are not necessarily cured and eventually may succumb to metastatic disease We were unable to detem~me whether the vltthgo caused retardation of tumor growth or whether the melanoma caused vmhgo (J AM ACAD DERMATOL 9 689-696, 1983 )
Patmnts w~th m e l a n o m a s have been observed to develop vxtdlgo or d e p l g m e n t e d spots on the skin ~-J4 M e l a n o m a and vxtdigo also have been observed together m a m m a l s , e g , Arabian horses ~ and Sinclair swine ~ The association of the two d~sorders m humans and tn other m a m m a l s suggests that the two d~seases are related not merely by chance The associat|on In some ways ~s a
From the Department of Dermatology West Haven VA Medical Center West Haven Dep',mments of Medicine and Dermatology Yale Umverslty School of Medicine New Haven and the De partment of Surgery Sydney Hospital Sydney Supported m par~ by flmds from the West Haven VA Medmal Center Natmnal Institutes of Health grant AM 25252 CA 08341 the General Chmcal Research Center RR 00125 and the Intematmnal Umon Against Cancer Accepted for pubhcatmn Feb 8 1983 Reprmt requests to Dr James J Nordlund Deparlment ol Dermatology, University of Cmcum,m College of Medicine Cmcm nat,, OH 45216
paradox because m e l a n o m a is an uncontrolled prohferatlon of m a h g n a n t m e l a n o c y t e s , vltfltgo is the result o f destrucnon o f normal p i g m e n t cells Most m v e s n g a t o r s h a v e c o n c l u d e d that the dep~gmentatlon observed in patmnts with m e l a n o m a s is indeed vltlhgo, ~-~ ,~t although not all investigators concur on th~s point tt H o w e v e r , whether or not the d e v e l o p m e n t o f v m h g o in a patient w~th a m e l a n o m a has any p r o g n o s t m s~gmficance has been e x a m i n e d in only t w o studms to ,a Tile results of one study suggested that vttdtgo had little ~mpact on the course of a p a t m n t ' s m e l a n o m a t l Others observers m suggest that vital|go is associated with visceral m e t a s t a s e s and carries a gr~m prognosis H o w e v e r , we h a v e suggested that v~tdlgo heralds prolonged survival, although not necessarily a cure, for patients w~th metastatic m e l a n o m a tv To learn more about the ~lgmficance o f the assocxatmn, we have e x a m i n e d the cllmcal course o f
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T a b l e I. Patients with vitiligo and melanoma Source of patients
Published reports Sydney Melanoma Unit Yale New Haven Hospital Total
I
Nure- Age range bet (yr)
Male-~male ratio
24 8
24-75 48-88
13:11 5:3
19
30-70
9:10
51
24-88
Published cases. The French and English literature about patients with melanoma and vitiligo was identified with the help of Cumulated Index Medicus and a MEDLARS computerized search. Citations which omitted data on patient survival were excluded. D e f i n i t i o n o f vitiligo
27:24 (1.1:I)
twenty-seven patients in our clinics who had both a melanoma and vitiligo. In addition, we have reviewed published reports about twenty-four other patients with both diseases. The results of studies on these fifty-one patients confirm that vitiligo is associated with a relatively good prognosis for patients with metastatic melanoma. METHODS Patients Yale N e w Haven Hospital ( Y N t t l i ) . All patients cared for in the melanoma and/or oncology clinic at Yale New Haven Hospital from 1971 to the present have been examined frequently with a Wood's lamp for evidence of vitiligo. Between the years 1971 and 1981, 386 patients were entered in the melanoma registry at YNIM-I. At the time of this study, 200 of these 386 patients with melanoma were cared for in the melanoma/oncology clinic at YNHH. The remainder had either died or returned to the care of their private physicians. Sydney M e l a n o m a Unit. Two-hundred ninety-six Caucasian patients followed and cared for in the melanoma unit in Sydney Hospital, Sydney, Australia, were examined with a Wood's lamp for evidence of vitiligo. Patients were chosen randomly from 1,500 patients followed by physicians at that hospital. In addition, I00 randomly chosen Caucasian control patients without melanoma who were hospitalized at the Sydney Hospital and forty-five volunteer men, incarcerated at a local prison, were also examined with a Wood's lamp for the presence of vitiligo or halo nevi. Control patients were similar in age to those patients with melanomas. The mean and median ages of the 296 patients with melanoma were 49 and 50 years, respectively. For the control, the mean and median ages were 46 and 49 years (p > 0.05). However, more of the control subjects were male (66%) than the melanoma patients (51%). The patients and controls were all Caucasians and of English, Welsh, or Celtic ancestry.
Patients with vitiligo have acquired spreading depigmentation and exhibit large segments of depigmented skin. Only those patients with clear-cut vitiligo were included in this study. Pronounced early graying of hair and halo nevi may represent subsets of vitiligo. At times, they occur alone and at other times they are accompanied by loss of pigment in the skin. Patients with only gray hair, halo nevi, or halo metastases were not included in the analyses of survival unless they also had vitiligo. Many patients with melanomas have a sun-induced, nonspecific poikiloderma.X'a This type of depigmentation is differentiated from vitiligo by its nonprogressive course and by the mottled hyperpigmentation and depigmentation limited exclusively to the sun-exposed skin. Patients with only actinic poikiloderma were also excluded from this study. RESULTS YNHH. Nineteen patients with vitiligo and melanoma were identified between the years 1971 and 1981. Not all of the 386 patients with melanoma, registered at YNHH, were examined. Some patients were followed by other physicians after the initial diagnosis of a melanoma was made, although their names are permanently entered on the registry. They have not been seen since the initial diagnosis. Thus, at YNHH a 5% prevalence of vitiligo in patients with melanoma (19 of 386) is a minimal estimate. Sydney M e l a n o m a U n i t . Two hundred ninetysix patients with melanoma were examined by us. These patients were in all stages of disease progression, stages I-III. Eight (2.7%) were found to have vitiligo. Many others had actinic poikiloderma. Four (2.8%) of the 145 control subjects without melanoma had vitiligo. Published reports, Twenty-four patients who had both melanoma and vitiligo were identified in the English and French medical literature. 1-7,9.t' A number of other reports indicated that many other patients had the two diseases, s,lt.13.1q,~s-'2~ However, the reports did not provide sufficient information so that we could determine the course
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691
Table II. Site of primary tumor
I +r.~
Extremities
Historical Sydney Yale Total
4 5 5 14
I .+adn k
6 1 5 12
I cra'len",'.o I
Other
6 0 2 8
3 0 0 3
0 1 4 5
]
No primary 5 1 3 9
Table III. Level of primary and stage at diagnosis
Clark
Historical Sydney Yale Total
,,I
,,,
1
NA* 1 4
Clinical stage
Breslow (ram)
I ,v NA 1 2
[ v NA 2 2
0.75-1.49 NA 0 1
I
1.5-4.0 [ >4.0 NA 3 1
NA 3 3
11111111 10 3 8 21
14 5 10 29
0 0 1 1
*NA:Not available. of disease for the patients. These cases are not included in this study. Demographic characteristics There were nineteen patients from YNHH, eight patients from Sydney Hospital, and twenty-four patients identified in the published reports, a total of fifty-one patients with both vitiligo and melanoma. These fifty-one patients had an age range from 28 to 88 years. Fifty-three percent were male; 47% were female (ratio 1.1:1). The ages, sex, and sites of primary tumors were similar for the three groups of patients (Table I). General characteristics of m e l a n o m a s Fourteen (27%) of the fifty-one melanomas arose on an extremity, a site which carries a better prognosis. Thirty-seven (73%) tumors arose at unfavorable sites (Table II). Eight patients had acral ]entiginous tumors, some of which were massive. :~'6 Seventeen (33%) of the fifty-one melanomas arose on the head and neck or trunk. The remainder developed in the eye or on mucosal surfaces. Nine (17%) of the patients had no known primary tumor, i.e., the diagnosis was made by a biopsy of enlarged lymph nodes. The Clark and Breslow levels were unknown for five of the twenty-nine melanomas (Table III) from the Yale and Australian patients and for all of the patients reported in the literature. A few of the
tumors reported in the literature were massive, 3"6 Statistical analysis of the available data for the thickness of the tumors in the Australian and Yale patients indicated a positive correlation between thickness of the tumors and development of vitiligo (p < 0.04). Twenty-one (41%) of the fiftyone patients were clinical stage I at the time of diagnosis, and thirty patients (59%) were clinical stage II or HI. Forty-nine of the fifty-one patients had metastases at the time of diagnosis or developed local, regional, or distant metastases later (Table IV). Three patients had pulmonary lesions which regressed during the course of the disease. One patient (Patient 5, Table V) had brain metastasis at the time of diagnosis, received radiation to the brain, and the tumor disappeared simultaneously with the onset of vitiligo. Onset of vitiligo The onset of vitiligo in all patients recorded in published reports occurred after the diagnosis of melanoma was made. One patient o f the eight from the Sydney Melanoma Unit and four of nineteen from Yale New Haven Hospital had vitiligo prior to developing melanomas (Table V); i.e., at Yale New Haven Hospital, 4/386, or 1.0% of the patients with a melanoma had preexisting vitiligo. The prevalence of vitiligo in patients with melanoma was 5%. The prevalence of vitiligo in 296 Australian pa-
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Nordlund et al
Table IV. Course of disease 9o x~.
8C -1
Historical Australia Yale Total
;'(l
6a
z uJ o
4o
uJ o.
Jo
Ih
=4
,~ do ~ "a'* g ~6s c~ ~,I, MONTHSFROUmAGN0SlS
%
Fig. I. Life table analysis of survival for fifty-one pa-
tients with vitiligo and melanoma. The twenty-seven Yale and Australian (Y + A) patients and twenty-four historical (H) were analyzed separately and together (fifty-one patients--Y + A + H ) . Seventy percent of the fifty-one patients survived 60 months. Survival for these fifty-one patients was substantially better than that for large groups of patients with melanoma in stages I and II published by others (CL, reference 13; E, reference 22; B, reference 23; CH, reference 24; V, reference 25). Even at 120 months, half the patients at risk were still alive. tients with melanoma was 2.7% (8/'296 patients); in the 145 control subjects, the prevalence was 2.8%. Each patient was carefully examined for white spots with fluorescent lights. Hypopigmented halos around nevocellular nevi were observed by Wood's lamp examination in thirty patients (10%) with melanoma and in fifteen control subjects (10%). A few of these hypopigmented rings were visible around nevi when the patients were re-examined under fluorescent lamps. No biopsies were obtained from these lesions. Most patients (46/51) developed vitiligo after a diagnosis of melanoma was confirmed histologically, Of the forty-six patients, fourteen developed vitiligo after the diagnosis of melanoma but before metastases were noted. Thirty-two patients developed metastases first and vitiligo later. Survival
No. and % dead*
No. and % alive*
23 8 18 49
11 (46) 1 (12) 12 (63) 24 47
13 (54) 7 (88) 7 (37) 27 53
* Numbers in parentheses indicate percent dead or alive as recorded in published report or at time study was completed.
IllV 9 CL 110
mB
o
Metastases
and mortality
Vitiligo and metastases did not invariably presage an imminent death (Tables I V a n d V) (Fig. 1). Fourteen (52%) of the twenty-seven patients cared
for by us at YNHH or examined by us at Sydney Melanoma Unit were still alive at the time of this writing. The duration of survival for these fourteen living patients was 5 to 241 months. The patients who succumbed to the disease survived for 36 to 234 months after diagnosis. Thirteen of the twenty-four patients in published reports were alive and well at the time of publication. The duration of survival of the patients reported as alive in these reports was 36 to more than 144 months; the patients dying from their disease survived 24 to 108 months after diagnosis. Fourteen of fifty-one (27%) patients died within 12 months o f the onset of vitiligo regardless of whether vitiligo developed before or after metastases were identified. Although all but two patients had metastatic disease either in regional lymph nodes or in distal sites, a life table analysis (Fig. 1) revealed that 67% survived 5 years and 50% of the total sample survived 10 years. All deaths were attributed to metastatic disease. DISCUSSION We have identified twenty-seven of our own patients and twenty-four patients recorded in the literature who had both vitiligo and melanoma. Many other observers have reported patients with halo metastases or halo nevi. m.v~.21,'-'2 We have excluded these subjects with only perilesional depigmentation from our study. Patients reported here had large areas of skin which were totally depigmented. We have studied depigmented skin specimens from three patients by light and electron microscopy and have confirmed almost complete loss of epidermal pigment cells. Others have observed a partial loss of epidermal melanocytes.~' 11 That vitiligo and melanoma are frequently as-
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Vitiligo in metastatic melanoma
693
Table V. Clinical characteristics of YNHH patients t Clark/Breslow Stage at Dx
Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 I5 16 17 18 19
55 42 57 46 60 65 30 56 42 50 70 51 61 32 33 64 60 70 42
F M F M M F F M M F M F F F F M M F M
IV / Unknown Ill / 10 NP NP IV / IlI/ Unknown HI/2.6 NP Unknown Unknown V/12 III / 1.04 Unknown NP V/12 NP II /
1 1 1 2 3 2 1 Unknown 1 2 2 2 2 1 1 2 2 2 1
Primary site
Leg Leg Toe None None Trunk Arm Neck Head Head Trunk Thigh Foot Trunk Trunk Head Arm None Back
Months from dlagnosist o : ~ Metastasis I
6 2 24 0 0 0 120 192 60 0 0 0 0 11 92 0 0 0 None
Vitiligo
33 36 36 48"t" 11 4 140 216 Chitdhood[ 0 Childhoodt 34 32 22 70 12 12 20* 0
Temporal sequence of I ~ a t h [ melanoma, Rx and Vit
81 46 51 26 147 232 67 90 38 36 18 29 15
M-S-S-Im-Ch-Vit M-S-Ra-Ch-Vit-Ch M-S-Im-Ch- Vit Vit-M-S-Ch M-Ra-S- Vit-Ch M-S-Im-Vit M-S-Ra-Ch-Im-Vit M-S-S- Vit-Ch Vit-M-S-Ra-Ch M-Vit-S-Im Vit-M-S-Ch M-S-Ch-Im-Ra-Vit M-S-Ch-Vit M-S-Ch-hn-Vit M-S-Vit M-Ra-S- Vit-Ch M-S-Ch-Vit Vit-M-S-Ra-Ch M-S-Vit
Ch: Chemotherapy; lm: immunotherapy, either injections of BCG or MER; M: melanoma; NP: no primary tumor found; Ra: radiation; S: surgery; Rx: therapy; Vit: vitiligo. *Age at diagnosis. tVitiligo antedated development of melanoma.
sociated is emphasized by the occurrence of the two diseases in other mammalians, e.g., Sinclair swine 1~ and a variety of horses, i.e., Arabian, Lippinzaner, and Percheron breeds. "~ However, the onset and course of depigmentation in patients with melanoma differ from classical vitiligo not associated with melanoma. In the latter, depigmentation most often begins on the hands, face, and feet and spreads centripetally to the trunk, in patients with melanoma, depigmentation begins more commonly on the trunk and spreads centrifugally to involve the neck, face, and extremities. The patterns of spread may differ because the mechanism of pigment cell destruction is different in the two groups of patients. On the other hand, the mechanism of pigment cell destruction may be the same but the route of exposure to the inciting agent, e.g., an antigen or a melanocytotoxin such as tyrosine-dopa by-product, may differ. Regardless of the mechanism, the destruction of pigment cells suggests that this depigmentation is true vitiligo. The important question to be answered is,
"What is the biologic significance of this association?" The main conclusion of this study is that patients with melanomas and vitiligo usually have metastases at least to regional lymph nodes but are capable of surviving with the tumor for longer periods of time than expected. We attempted to find an appropriate control population for the fifty-one patients with vitiligo and melanoma. We can identify many other patients with melanomas who do not have vitiligo but who have similar clinical findings, i.e,, the same age, sex, site of tumor, stage of tumor, and thickness of the primary tumor. Control patients with melanomas without vitiligo sometimes survived a few months; others survived for long periods o f time. Ideal controls are not yet available. Most of the patients with vitiligo had melanomas arising at sites which carry a poor prognosis, e.g., the tmnk, head, neck, eyes, or mucous membranes. Most (59%) had stage II disease at the time of diagnosis. Metastases occurred in forty-nine of fifty-one patients. In other reports, ~:1'''~,~:~-'~ less than 50% of patients with
694
N o r d h m d et al
thick stage I or stage I[ melanomas survived 5 years. Sixty-five percent of our patients survived 5 years and 50% survived 10 years (Fig. 1). We have observed many other patients who have survived for many years with metastasis who did not develop vitiligo. Thus, not all patients who survive for prolonged periods of time develop vitiligo, but its presence seems to be a good prognostic sign. One investigator j'3 studied a group of patients with halo metastasis, vitiligo, or nonspecific depigmentation, He concluded that depigmentation had no significance or effect on the patients' survival. However, the author studied only four patients with vitiligo and many others with actinic poikiloderma. Thus, the results and conclusions of his study cannot be compared to ours in which only those patients with obvious and widespread vitiligo were included. O r t o n n e l~ reported four patients with generalized depigmentation associated with melanoma. All four died from metastasis within 12 months after the onset of depigmentation. Two patients at the time of diagnosis were in Stage If; one was in stage III. One patient with stage II disease refused surgical therapy and died about 2 years after the onset of disease. The patient with stage III disease died shortly after diagnosis, but the duration of survival from the onset of tumor was unknown. The other two patients both survived 4 years. These observations are consistent with those reported here. We found that fourteen of the fifty-one patients died within 12 months after the onset of vitiligo. The survival of our patients is comparable to that of patients reported by Ortonne. However, the data from this larger group of fifty-one patients indicate that patients with a melanoma who get vitiligo will survive longer than generally expected. Destruction and proliferation of pigment cells would not be expected to occur together. We have asked whether one disorder causes the other. It is not clear from the findings of this or any other study that vitiligo has an influence on the course of melanoma or that melanoma causes vitiligo. It is tempting to speculate that the immune response against melanoma destroys normal epidermal pigment cells. Lymphocytes, cytotoxic to al-
Journal of the American Academyof Dermatology logeneic melanoma cells, and antimelanoma antibodies can be identified in the blood of patients with melanomas 26.27 or halo nevi 27 but not in the blood of patients with vitiligo only. 2~ Antimelanoma antibodies have been identified in the blood of patients with mucocutaneous candidiasis, some of whom have vitiligo ~,2:~ but none has melanoma? ~ The antibodies did not seem to be cytotoxic to pigment cells.28 A melanoma-specific protein has been isolated from the urine of patients with melanoma or with vitiligo, a' However, its presence does not confirm or negate a role for the immune response in vitiligo or in the destruction of tumor cells. The clinical course of several patients suggests that the vitiligo could be mediated by an immune response. One patient (Patient 5, Table V) cared for at YNHH had documented metastases to the lung, brain, and kidney soon after the diagnosis of cancer was made. He received radiation therapy to the brain. Shortly thereafter all known deposits of tumor disappeared and he developed widespread vitiligo. He survived for over 4 years. Similar observations were made of patients receiving injections of bacillus Calmette-Gudrin (BCG) for treatment of parenchymal metastases. 6 It is possible that the sudden destruction of tumor may release antigens which boost the immune response that destroys normal epidermal pigment cells. On the other hand, the destroyed tumor may also release toxic tyrosine-melanin precursors or byproducts which destroy pigment cells. All fifty-one patients had the melanoma excised. Many received additional treatments, including a variety of chemotherapeutic agents, injections of BCG, or radiation. No common factors were found in the type of treatment or in the response to treatment by patients to explain the onset of vitiligo (Table V). One other point is worth noting. Some patients were known to have vitiligo several years before the onset of melanoma. Four of 386 patients recorded in the Yale melanoma registry had vitiligo prior to the onset of melanoma. The prevalence of preexisting vitiligo in this group of patients with melanoma was 1.0%. This is the expected prevalence for vitiligo in the United States. Overall, 8/296 (2.7%) Australian patients had
Volume 9 Number 5 November, 1983
vitiligo. Four (2.8%) of 145 control subjects in Sydney Hospital and prison who did not have melanoma had vitiligo. The prevalence of vitiligo in the patient and control samples was identical. Patients with total vitiligo cannot be susceptible to developing cutaneous m e l a n o m a since the cell of origin, the epidermal p i g m e n t cell, is not present in the skin. H o w e v e r , most patients with vitiligo have only partial depigmentation. From our limited series, it would s e e m that patients with vitiligo are as susceptible to acquiring a m e l a n o m a as patients without the disease. In the Australian population, the n u m b e r of patients with melanoma who acquired vitiligo after their m e l a n o m a s (2.7%) is identical to the n u m b e r without melanoma (2.8%). This prevalence is higher than those recorded in most other countries. Equally of interest is that h y p o p i g m e n t e d halos were observed around nevi in 10% o f 296 patients with treated m e l a n o m a and in 10% of 145 control subjects. Some of the halos around nevi were visible only by careful examination with a W o o d ' s lamp and not under fluorescent illumination. Are these lesions halo nevi? A separate study must be carried out to determine the nature of halos around any kind of papule as c o m p a r e d with those around nevi. Do the pigment cells around nevi respond to sunlight differently f r o m pigment cells in other locations? How do these faint halos found in 10% of the patients and controls c o m p a r e with true halo nevi with respect to histologic and immunologic parameters? We hope that further studies will answer these questions. In conclusion, we find that the association of the two diseases does presage a good prognosis for patients with metastatic m e l a n o m a . Possibly the induction of vitiligo in patients with high-risk m e l a n o m a s will delay recurrence o f the disease. A trial testing this hypothesis is in progress. REFERENCES
I. Balabanov K, Andreev VC, Tchemozemsky 1: Malignant melanoma and vitiligo. Dermatologica 139:211219, 1968. 2. Cohen Y. Haim S, Bartal A, et al: Vitiligo associated with BCG-methanol extraction residue in malignant melanoma. Dermatologica 158:8-12, 1979. 3. Frenk E: Depigmentations vitiligineuses chez des patients atteints de melanomes malins. Dcrmatologica 139:84-91, 1969.
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4. Nirankari MS, Khanna KK, Mathur RP: Uveal malignant melanoma with leucoderma. J All-India Ophthalmol Soc 16:63-66, 1968. 5. Milton GW, McCarthy WH, Carlon A: Malignant melanoma and vitiligo. Australas J Demaatol 12:131-142, 1971. 6. Donaldson RC, Canaan SA, McLean RB, et al: Uveitis and vitiligo associated with BCG treatment for malignant melanoma. Surgery 76:771-778, 1974. 7. Gregor RT: Vitiligo and malignant melanoma: A significant association? S Afr Med J 70:1447-1449. 1976. 8. Ortonne JP, Perrot H: Giant melanin granules in vitiliginous achromia with malignant melanoma. Acta Derm Venereol (Stockh) 58:475-480, 1978. 9. Sober A J, Haynes HA: Uveitis. poliosis, hypomelanosis, and alopecia in a patient with malignant melanoma. Arch Dermatol 114:439-441, 1978. 10. Ortonne JP, Gauthier Y, Guillet G, et al: Depigmentation cutanee associee au melanome malin. Ann Dermatol Venereol 105:1043-1052, 1978. 1I. Takahashi M, Sober AJ, Mosher DB, et al: Vitiligo-like leukoderma in patients with metastatic malignant melanoma. Pigment Cell 5:73-87, 1979. 12. Albert DM, Todes-Taylor N, Wagoner M, et al: Vitiligo or halo nevi occurring in two patients with choroidal melanoma. Arch Derrnatol 118:34-36, 1982. 13. Laucius JF, Mastrangelo MJ: Cutaneous depigmentary phenomena in patients with malignant melanoma, in Clark WH, Goldman LI, Mastrangelo MJ, editors: Human malignant melanomas. New York, 1979, Grune & Stratton, Inc., pp. 209-225. 14. Kopf AW, Bart RS, Rodriguez-Sains RS, et al: Leukoderma and malignant melanomas, in Malignant melanoma. New York, 1979. Masson Publishing USA, Inc., pp. 162-165. 15. Lemer AB, Cage GW: Melanomas in horses. Yale J Biol Med 46:646-649, 1973. 16. Millikan LE, Hook RR, Manning PJ: Gross and ultrastructural studies in a new melanoma model: The Sinclair swine. Yale J Biol Med 46:631-645, 1973. 17. Lerner AB. Nord/und JJ: Should vitiligo be induced in patients after resection of primary melanoma? Arch Demaatol 113:421, 1977. 18. Fodor J. Bodrogi I: Vitiligo and malignant melanoma. Neoplasma 22:445-448, 1975. 19. Goldman L, Wilson RG, Glasgow R, et al: Perilesional leucoderma in metastatic melanoma. Acta Derm Venereol (Stockh) 47:369-372. 1967. 20. Perrot H, Ortonne JP, Schmitt D: Vitiliginous achromia with malignant melanoma. Arch Dermatol 257:247-253. 1977. 21. Epstein WL, Sagebeil R, Spitler L, et al: Halo nevi and melanoma..lAMA 225:373-377, 1973. 22. Elias EG, Didolkar MS, Goel IP, et al: A elinicopathologic study of prognostic factors in cutaneous malignant melanoma. Surg Gynecol Obstet 144:327-334, 1977. 23. Balch CM, Soong SJ. Murad TM, et al: A multifactorial analysis of melanoma. Ann Surg 193:377-388, 1981. 24. Chang P, Knapper WH: Metastatic melanoma of unknown primary. Cancer 49:1106-I I11, 1982. 25. Vcronesi U, Adamus J, Aubert C: A randomized trial of
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adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med 307:913-916, 1982. 26. Mitchell M, Nordlund JJ, Lemer AB: Comparison of cell-mediated immunity to melanoma cells in patients with vitiligo, halo nevi, and melanoma. J Invest Dermatol 75:144-147, 1980. 27. Roenigk HH, Deodhar SD, Krebs JA, et al: Microcytotoxicity and serum blocking factors in malignant melanoma and halo nevus. Arch Dermatol 111:720-725, 1975. 28. Hertz KC, Gazze LA, Kirkpatrick CH, et al: Autoimmune vitiligo. N Engl J Med 297:634-637, 1977.
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29. Nordlund JJ, Howanitz N, Bystryn JC, et al: Antipigmerit cell factors and mucocutaneous candidiasis. Arch Dermatol 117:210-212, 1981. 30. Howanitz N, Nordlund JJ, Lerner AB, et al: Antibodies to melanocytes in patients with vitiligo. Arch Dermatol 117:705-708, 1981. 31. Cooke KB, Bennett C, Staughton RCD: Melanoma specific protein: Occun'encc in the urine of patients with halo naevus and vitiligo. Br J Dermatol 98:663-668, 1978.
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Malignant melanoma and vitiligo-like leukoderma: An electron microscopic study Howard K. Koh, M.D., Arthur J. Sober, M.D., Hidemi Nakagawa, M.D., Daniel M. Albert, M.D., Martin C. Mihm, M.D., and Thomas B. Fitzpatrick, M.D. Boston, MA We report clinical and ultrastructural results in eight patients with melanoma and widespread leukoderma. Leukoderma appears to be a good prognostic sign. Although some features of this entity are suggestive of vitiligo, the patients' age, the distribution and appearance of body lesions, and ultrastructural results show a more varied clinical and ultrastructural spectrum. The high frequency of ocular pigmentary disturbances and uveitis in this patient population is noteworthy and deserves further study. We would recommend routine use of Wood's light examination in following patients with thick stage I, stage II, or stage III melanoma to facilitate detection of this phenomenon. (J AM ACAO DEaMA'roL 9:696-708, 1983.)
Widespread leukoderma in patients with malignant melanoma is a striking and uncommon cliniFrom the Departments of Dermatology. Dermatopathology and Hematology-Oneology, Massachusetts General Hospital, and the Department of Pathology. Massachusetts Eye and Ear Infirmary. Supported in part by the National Cancer InstituteGrant No. R l0 CA 13651-01 CCI, the Marion Gardner Jackson Trust and National Institutes of Health Training Grant No. 5 T32 AM 07098. Accepted for publication April 19, 1983. Reprint requests to: Dr. Arthur J. Sober, Dep,'u'tmentof Dermatology, Warren 5, Massachusetts General Hospital, Boston, MA 02114.
696
cal phenomenon whose clinical significance is unclear. Over the past 20 years, scattered reports ~-'~ in the English literature (Table I) have noted this rare association and speculated on its significance. This is a report of eight patients with melanoma and widespread cutaneous depigmentation whose clinical course was studied over a long period of time. Included are the results of serial clinical observations as well as electron microscopic studies of hypopigmented and normal skin.
I
I
Vitfiigo in patients with metastatic melanoma: A good prognostic sign J a m e s J Nordlund M D , John M Klrkwood, M D , Bernadette M Forget, R N , M S N , G e r a r d M f l t o n , MD D a m e l M Albert, M D , a n d A a r o n B Lemer, M D
,
West Haven and New Haven, CT, and Sydney, Austpaha We have identified and studied twenty-seven patients with melanoma who also had Vltthgo Four patients had vttthgo before the diagnosis of melanoma, and twenty-three developed dep~gmentatton after the dmgnosJs of mahgnancy We also have revmwed pubhshed reports about twenty-four other patients with melanoma who developed Vltthgo The chmcal course of the melanoma m the fifty-one patients was remarkably similar Thirty-seven had a melanoma arlsmg at a site whmh tends to carry a poor prognosis, for example, on the trunk, under the nml, or on the mucous membranes Forty-nine patients had metastases In regional lymph nodes or at distal s~tes Thirty-three patmnts survived 5 year,;, and twenty-five survived l0 years These data suggest that the appearance of vmhgo m patients w~th metastatic melanoma portends a longer survival than expected The patients with vitdtgo are not necessarily cured and eventually may succumb to metastatic disease We were unable to detem~me whether the vltthgo caused retardation of tumor growth or whether the melanoma caused vmhgo (J AM ACAD DERMATOL 9 689-696, 1983 )
Patmnts w~th m e l a n o m a s have been observed to develop vxtdlgo or d e p l g m e n t e d spots on the skin ~-J4 M e l a n o m a and vxtdigo also have been observed together m a m m a l s , e g , Arabian horses ~ and Sinclair swine ~ The association of the two d~sorders m humans and tn other m a m m a l s suggests that the two d~seases are related not merely by chance The associat|on In some ways ~s a
From the Department of Dermatology West Haven VA Medical Center West Haven Dep',mments of Medicine and Dermatology Yale Umverslty School of Medicine New Haven and the De partment of Surgery Sydney Hospital Sydney Supported m par~ by flmds from the West Haven VA Medmal Center Natmnal Institutes of Health grant AM 25252 CA 08341 the General Chmcal Research Center RR 00125 and the Intematmnal Umon Against Cancer Accepted for pubhcatmn Feb 8 1983 Reprmt requests to Dr James J Nordlund Deparlment ol Dermatology, University of Cmcum,m College of Medicine Cmcm nat,, OH 45216
paradox because m e l a n o m a is an uncontrolled prohferatlon of m a h g n a n t m e l a n o c y t e s , vltfltgo is the result o f destrucnon o f normal p i g m e n t cells Most m v e s n g a t o r s h a v e c o n c l u d e d that the dep~gmentatlon observed in patmnts with m e l a n o m a s is indeed vltlhgo, ~-~ ,~t although not all investigators concur on th~s point tt H o w e v e r , whether or not the d e v e l o p m e n t o f v m h g o in a patient w~th a m e l a n o m a has any p r o g n o s t m s~gmficance has been e x a m i n e d in only t w o studms to ,a Tile results of one study suggested that vttdtgo had little ~mpact on the course of a p a t m n t ' s m e l a n o m a t l Others observers m suggest that vital|go is associated with visceral m e t a s t a s e s and carries a gr~m prognosis H o w e v e r , we h a v e suggested that v~tdlgo heralds prolonged survival, although not necessarily a cure, for patients w~th metastatic m e l a n o m a tv To learn more about the ~lgmficance o f the assocxatmn, we have e x a m i n e d the cllmcal course o f
689
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T a b l e I. Patients with vitiligo and melanoma Source of patients
Published reports Sydney Melanoma Unit Yale New Haven Hospital Total
I
Nure- Age range bet (yr)
Male-~male ratio
24 8
24-75 48-88
13:11 5:3
19
30-70
9:10
51
24-88
Published cases. The French and English literature about patients with melanoma and vitiligo was identified with the help of Cumulated Index Medicus and a MEDLARS computerized search. Citations which omitted data on patient survival were excluded. D e f i n i t i o n o f vitiligo
27:24 (1.1:I)
twenty-seven patients in our clinics who had both a melanoma and vitiligo. In addition, we have reviewed published reports about twenty-four other patients with both diseases. The results of studies on these fifty-one patients confirm that vitiligo is associated with a relatively good prognosis for patients with metastatic melanoma. METHODS Patients Yale N e w Haven Hospital ( Y N t t l i ) . All patients cared for in the melanoma and/or oncology clinic at Yale New Haven Hospital from 1971 to the present have been examined frequently with a Wood's lamp for evidence of vitiligo. Between the years 1971 and 1981, 386 patients were entered in the melanoma registry at YNIM-I. At the time of this study, 200 of these 386 patients with melanoma were cared for in the melanoma/oncology clinic at YNHH. The remainder had either died or returned to the care of their private physicians. Sydney M e l a n o m a Unit. Two-hundred ninety-six Caucasian patients followed and cared for in the melanoma unit in Sydney Hospital, Sydney, Australia, were examined with a Wood's lamp for evidence of vitiligo. Patients were chosen randomly from 1,500 patients followed by physicians at that hospital. In addition, I00 randomly chosen Caucasian control patients without melanoma who were hospitalized at the Sydney Hospital and forty-five volunteer men, incarcerated at a local prison, were also examined with a Wood's lamp for the presence of vitiligo or halo nevi. Control patients were similar in age to those patients with melanomas. The mean and median ages of the 296 patients with melanoma were 49 and 50 years, respectively. For the control, the mean and median ages were 46 and 49 years (p > 0.05). However, more of the control subjects were male (66%) than the melanoma patients (51%). The patients and controls were all Caucasians and of English, Welsh, or Celtic ancestry.
Patients with vitiligo have acquired spreading depigmentation and exhibit large segments of depigmented skin. Only those patients with clear-cut vitiligo were included in this study. Pronounced early graying of hair and halo nevi may represent subsets of vitiligo. At times, they occur alone and at other times they are accompanied by loss of pigment in the skin. Patients with only gray hair, halo nevi, or halo metastases were not included in the analyses of survival unless they also had vitiligo. Many patients with melanomas have a sun-induced, nonspecific poikiloderma.X'a This type of depigmentation is differentiated from vitiligo by its nonprogressive course and by the mottled hyperpigmentation and depigmentation limited exclusively to the sun-exposed skin. Patients with only actinic poikiloderma were also excluded from this study. RESULTS YNHH. Nineteen patients with vitiligo and melanoma were identified between the years 1971 and 1981. Not all of the 386 patients with melanoma, registered at YNHH, were examined. Some patients were followed by other physicians after the initial diagnosis of a melanoma was made, although their names are permanently entered on the registry. They have not been seen since the initial diagnosis. Thus, at YNHH a 5% prevalence of vitiligo in patients with melanoma (19 of 386) is a minimal estimate. Sydney M e l a n o m a U n i t . Two hundred ninetysix patients with melanoma were examined by us. These patients were in all stages of disease progression, stages I-III. Eight (2.7%) were found to have vitiligo. Many others had actinic poikiloderma. Four (2.8%) of the 145 control subjects without melanoma had vitiligo. Published reports, Twenty-four patients who had both melanoma and vitiligo were identified in the English and French medical literature. 1-7,9.t' A number of other reports indicated that many other patients had the two diseases, s,lt.13.1q,~s-'2~ However, the reports did not provide sufficient information so that we could determine the course
Volume 9 Number 5 November, 1983
Vitiligo in metastatic melanoma
691
Table II. Site of primary tumor
I +r.~
Extremities
Historical Sydney Yale Total
4 5 5 14
I .+adn k
6 1 5 12
I cra'len",'.o I
Other
6 0 2 8
3 0 0 3
0 1 4 5
]
No primary 5 1 3 9
Table III. Level of primary and stage at diagnosis
Clark
Historical Sydney Yale Total
,,I
,,,
1
NA* 1 4
Clinical stage
Breslow (ram)
I ,v NA 1 2
[ v NA 2 2
0.75-1.49 NA 0 1
I
1.5-4.0 [ >4.0 NA 3 1
NA 3 3
11111111 10 3 8 21
14 5 10 29
0 0 1 1
*NA:Not available. of disease for the patients. These cases are not included in this study. Demographic characteristics There were nineteen patients from YNHH, eight patients from Sydney Hospital, and twenty-four patients identified in the published reports, a total of fifty-one patients with both vitiligo and melanoma. These fifty-one patients had an age range from 28 to 88 years. Fifty-three percent were male; 47% were female (ratio 1.1:1). The ages, sex, and sites of primary tumors were similar for the three groups of patients (Table I). General characteristics of m e l a n o m a s Fourteen (27%) of the fifty-one melanomas arose on an extremity, a site which carries a better prognosis. Thirty-seven (73%) tumors arose at unfavorable sites (Table II). Eight patients had acral ]entiginous tumors, some of which were massive. :~'6 Seventeen (33%) of the fifty-one melanomas arose on the head and neck or trunk. The remainder developed in the eye or on mucosal surfaces. Nine (17%) of the patients had no known primary tumor, i.e., the diagnosis was made by a biopsy of enlarged lymph nodes. The Clark and Breslow levels were unknown for five of the twenty-nine melanomas (Table III) from the Yale and Australian patients and for all of the patients reported in the literature. A few of the
tumors reported in the literature were massive, 3"6 Statistical analysis of the available data for the thickness of the tumors in the Australian and Yale patients indicated a positive correlation between thickness of the tumors and development of vitiligo (p < 0.04). Twenty-one (41%) of the fiftyone patients were clinical stage I at the time of diagnosis, and thirty patients (59%) were clinical stage II or HI. Forty-nine of the fifty-one patients had metastases at the time of diagnosis or developed local, regional, or distant metastases later (Table IV). Three patients had pulmonary lesions which regressed during the course of the disease. One patient (Patient 5, Table V) had brain metastasis at the time of diagnosis, received radiation to the brain, and the tumor disappeared simultaneously with the onset of vitiligo. Onset of vitiligo The onset of vitiligo in all patients recorded in published reports occurred after the diagnosis of melanoma was made. One patient o f the eight from the Sydney Melanoma Unit and four of nineteen from Yale New Haven Hospital had vitiligo prior to developing melanomas (Table V); i.e., at Yale New Haven Hospital, 4/386, or 1.0% of the patients with a melanoma had preexisting vitiligo. The prevalence of vitiligo in patients with melanoma was 5%. The prevalence of vitiligo in 296 Australian pa-
692
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Nordlund et al
Table IV. Course of disease 9o x~.
8C -1
Historical Australia Yale Total
;'(l
6a
z uJ o
4o
uJ o.
Jo
Ih
=4
,~ do ~ "a'* g ~6s c~ ~,I, MONTHSFROUmAGN0SlS
%
Fig. I. Life table analysis of survival for fifty-one pa-
tients with vitiligo and melanoma. The twenty-seven Yale and Australian (Y + A) patients and twenty-four historical (H) were analyzed separately and together (fifty-one patients--Y + A + H ) . Seventy percent of the fifty-one patients survived 60 months. Survival for these fifty-one patients was substantially better than that for large groups of patients with melanoma in stages I and II published by others (CL, reference 13; E, reference 22; B, reference 23; CH, reference 24; V, reference 25). Even at 120 months, half the patients at risk were still alive. tients with melanoma was 2.7% (8/'296 patients); in the 145 control subjects, the prevalence was 2.8%. Each patient was carefully examined for white spots with fluorescent lights. Hypopigmented halos around nevocellular nevi were observed by Wood's lamp examination in thirty patients (10%) with melanoma and in fifteen control subjects (10%). A few of these hypopigmented rings were visible around nevi when the patients were re-examined under fluorescent lamps. No biopsies were obtained from these lesions. Most patients (46/51) developed vitiligo after a diagnosis of melanoma was confirmed histologically, Of the forty-six patients, fourteen developed vitiligo after the diagnosis of melanoma but before metastases were noted. Thirty-two patients developed metastases first and vitiligo later. Survival
No. and % dead*
No. and % alive*
23 8 18 49
11 (46) 1 (12) 12 (63) 24 47
13 (54) 7 (88) 7 (37) 27 53
* Numbers in parentheses indicate percent dead or alive as recorded in published report or at time study was completed.
IllV 9 CL 110
mB
o
Metastases
and mortality
Vitiligo and metastases did not invariably presage an imminent death (Tables I V a n d V) (Fig. 1). Fourteen (52%) of the twenty-seven patients cared
for by us at YNHH or examined by us at Sydney Melanoma Unit were still alive at the time of this writing. The duration of survival for these fourteen living patients was 5 to 241 months. The patients who succumbed to the disease survived for 36 to 234 months after diagnosis. Thirteen of the twenty-four patients in published reports were alive and well at the time of publication. The duration of survival of the patients reported as alive in these reports was 36 to more than 144 months; the patients dying from their disease survived 24 to 108 months after diagnosis. Fourteen of fifty-one (27%) patients died within 12 months o f the onset of vitiligo regardless of whether vitiligo developed before or after metastases were identified. Although all but two patients had metastatic disease either in regional lymph nodes or in distal sites, a life table analysis (Fig. 1) revealed that 67% survived 5 years and 50% of the total sample survived 10 years. All deaths were attributed to metastatic disease. DISCUSSION We have identified twenty-seven of our own patients and twenty-four patients recorded in the literature who had both vitiligo and melanoma. Many other observers have reported patients with halo metastases or halo nevi. m.v~.21,'-'2 We have excluded these subjects with only perilesional depigmentation from our study. Patients reported here had large areas of skin which were totally depigmented. We have studied depigmented skin specimens from three patients by light and electron microscopy and have confirmed almost complete loss of epidermal pigment cells. Others have observed a partial loss of epidermal melanocytes.~' 11 That vitiligo and melanoma are frequently as-
Volume 9 Number 5 November, 1983
Vitiligo in metastatic melanoma
693
Table V. Clinical characteristics of YNHH patients t Clark/Breslow Stage at Dx
Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 I5 16 17 18 19
55 42 57 46 60 65 30 56 42 50 70 51 61 32 33 64 60 70 42
F M F M M F F M M F M F F F F M M F M
IV / Unknown Ill / 10 NP NP IV / IlI/ Unknown HI/2.6 NP Unknown Unknown V/12 III / 1.04 Unknown NP V/12 NP II /
1 1 1 2 3 2 1 Unknown 1 2 2 2 2 1 1 2 2 2 1
Primary site
Leg Leg Toe None None Trunk Arm Neck Head Head Trunk Thigh Foot Trunk Trunk Head Arm None Back
Months from dlagnosist o : ~ Metastasis I
6 2 24 0 0 0 120 192 60 0 0 0 0 11 92 0 0 0 None
Vitiligo
33 36 36 48"t" 11 4 140 216 Chitdhood[ 0 Childhoodt 34 32 22 70 12 12 20* 0
Temporal sequence of I ~ a t h [ melanoma, Rx and Vit
81 46 51 26 147 232 67 90 38 36 18 29 15
M-S-S-Im-Ch-Vit M-S-Ra-Ch-Vit-Ch M-S-Im-Ch- Vit Vit-M-S-Ch M-Ra-S- Vit-Ch M-S-Im-Vit M-S-Ra-Ch-Im-Vit M-S-S- Vit-Ch Vit-M-S-Ra-Ch M-Vit-S-Im Vit-M-S-Ch M-S-Ch-Im-Ra-Vit M-S-Ch-Vit M-S-Ch-hn-Vit M-S-Vit M-Ra-S- Vit-Ch M-S-Ch-Vit Vit-M-S-Ra-Ch M-S-Vit
Ch: Chemotherapy; lm: immunotherapy, either injections of BCG or MER; M: melanoma; NP: no primary tumor found; Ra: radiation; S: surgery; Rx: therapy; Vit: vitiligo. *Age at diagnosis. tVitiligo antedated development of melanoma.
sociated is emphasized by the occurrence of the two diseases in other mammalians, e.g., Sinclair swine 1~ and a variety of horses, i.e., Arabian, Lippinzaner, and Percheron breeds. "~ However, the onset and course of depigmentation in patients with melanoma differ from classical vitiligo not associated with melanoma. In the latter, depigmentation most often begins on the hands, face, and feet and spreads centripetally to the trunk, in patients with melanoma, depigmentation begins more commonly on the trunk and spreads centrifugally to involve the neck, face, and extremities. The patterns of spread may differ because the mechanism of pigment cell destruction is different in the two groups of patients. On the other hand, the mechanism of pigment cell destruction may be the same but the route of exposure to the inciting agent, e.g., an antigen or a melanocytotoxin such as tyrosine-dopa by-product, may differ. Regardless of the mechanism, the destruction of pigment cells suggests that this depigmentation is true vitiligo. The important question to be answered is,
"What is the biologic significance of this association?" The main conclusion of this study is that patients with melanomas and vitiligo usually have metastases at least to regional lymph nodes but are capable of surviving with the tumor for longer periods of time than expected. We attempted to find an appropriate control population for the fifty-one patients with vitiligo and melanoma. We can identify many other patients with melanomas who do not have vitiligo but who have similar clinical findings, i.e,, the same age, sex, site of tumor, stage of tumor, and thickness of the primary tumor. Control patients with melanomas without vitiligo sometimes survived a few months; others survived for long periods o f time. Ideal controls are not yet available. Most of the patients with vitiligo had melanomas arising at sites which carry a poor prognosis, e.g., the tmnk, head, neck, eyes, or mucous membranes. Most (59%) had stage II disease at the time of diagnosis. Metastases occurred in forty-nine of fifty-one patients. In other reports, ~:1'''~,~:~-'~ less than 50% of patients with
694
N o r d h m d et al
thick stage I or stage I[ melanomas survived 5 years. Sixty-five percent of our patients survived 5 years and 50% survived 10 years (Fig. 1). We have observed many other patients who have survived for many years with metastasis who did not develop vitiligo. Thus, not all patients who survive for prolonged periods of time develop vitiligo, but its presence seems to be a good prognostic sign. One investigator j'3 studied a group of patients with halo metastasis, vitiligo, or nonspecific depigmentation, He concluded that depigmentation had no significance or effect on the patients' survival. However, the author studied only four patients with vitiligo and many others with actinic poikiloderma. Thus, the results and conclusions of his study cannot be compared to ours in which only those patients with obvious and widespread vitiligo were included. O r t o n n e l~ reported four patients with generalized depigmentation associated with melanoma. All four died from metastasis within 12 months after the onset of depigmentation. Two patients at the time of diagnosis were in Stage If; one was in stage III. One patient with stage II disease refused surgical therapy and died about 2 years after the onset of disease. The patient with stage III disease died shortly after diagnosis, but the duration of survival from the onset of tumor was unknown. The other two patients both survived 4 years. These observations are consistent with those reported here. We found that fourteen of the fifty-one patients died within 12 months after the onset of vitiligo. The survival of our patients is comparable to that of patients reported by Ortonne. However, the data from this larger group of fifty-one patients indicate that patients with a melanoma who get vitiligo will survive longer than generally expected. Destruction and proliferation of pigment cells would not be expected to occur together. We have asked whether one disorder causes the other. It is not clear from the findings of this or any other study that vitiligo has an influence on the course of melanoma or that melanoma causes vitiligo. It is tempting to speculate that the immune response against melanoma destroys normal epidermal pigment cells. Lymphocytes, cytotoxic to al-
Journal of the American Academyof Dermatology logeneic melanoma cells, and antimelanoma antibodies can be identified in the blood of patients with melanomas 26.27 or halo nevi 27 but not in the blood of patients with vitiligo only. 2~ Antimelanoma antibodies have been identified in the blood of patients with mucocutaneous candidiasis, some of whom have vitiligo ~,2:~ but none has melanoma? ~ The antibodies did not seem to be cytotoxic to pigment cells.28 A melanoma-specific protein has been isolated from the urine of patients with melanoma or with vitiligo, a' However, its presence does not confirm or negate a role for the immune response in vitiligo or in the destruction of tumor cells. The clinical course of several patients suggests that the vitiligo could be mediated by an immune response. One patient (Patient 5, Table V) cared for at YNHH had documented metastases to the lung, brain, and kidney soon after the diagnosis of cancer was made. He received radiation therapy to the brain. Shortly thereafter all known deposits of tumor disappeared and he developed widespread vitiligo. He survived for over 4 years. Similar observations were made of patients receiving injections of bacillus Calmette-Gudrin (BCG) for treatment of parenchymal metastases. 6 It is possible that the sudden destruction of tumor may release antigens which boost the immune response that destroys normal epidermal pigment cells. On the other hand, the destroyed tumor may also release toxic tyrosine-melanin precursors or byproducts which destroy pigment cells. All fifty-one patients had the melanoma excised. Many received additional treatments, including a variety of chemotherapeutic agents, injections of BCG, or radiation. No common factors were found in the type of treatment or in the response to treatment by patients to explain the onset of vitiligo (Table V). One other point is worth noting. Some patients were known to have vitiligo several years before the onset of melanoma. Four of 386 patients recorded in the Yale melanoma registry had vitiligo prior to the onset of melanoma. The prevalence of preexisting vitiligo in this group of patients with melanoma was 1.0%. This is the expected prevalence for vitiligo in the United States. Overall, 8/296 (2.7%) Australian patients had
Volume 9 Number 5 November, 1983
vitiligo. Four (2.8%) of 145 control subjects in Sydney Hospital and prison who did not have melanoma had vitiligo. The prevalence of vitiligo in the patient and control samples was identical. Patients with total vitiligo cannot be susceptible to developing cutaneous m e l a n o m a since the cell of origin, the epidermal p i g m e n t cell, is not present in the skin. H o w e v e r , most patients with vitiligo have only partial depigmentation. From our limited series, it would s e e m that patients with vitiligo are as susceptible to acquiring a m e l a n o m a as patients without the disease. In the Australian population, the n u m b e r of patients with melanoma who acquired vitiligo after their m e l a n o m a s (2.7%) is identical to the n u m b e r without melanoma (2.8%). This prevalence is higher than those recorded in most other countries. Equally of interest is that h y p o p i g m e n t e d halos were observed around nevi in 10% o f 296 patients with treated m e l a n o m a and in 10% of 145 control subjects. Some of the halos around nevi were visible only by careful examination with a W o o d ' s lamp and not under fluorescent illumination. Are these lesions halo nevi? A separate study must be carried out to determine the nature of halos around any kind of papule as c o m p a r e d with those around nevi. Do the pigment cells around nevi respond to sunlight differently f r o m pigment cells in other locations? How do these faint halos found in 10% of the patients and controls c o m p a r e with true halo nevi with respect to histologic and immunologic parameters? We hope that further studies will answer these questions. In conclusion, we find that the association of the two diseases does presage a good prognosis for patients with metastatic m e l a n o m a . Possibly the induction of vitiligo in patients with high-risk m e l a n o m a s will delay recurrence o f the disease. A trial testing this hypothesis is in progress. REFERENCES
I. Balabanov K, Andreev VC, Tchemozemsky 1: Malignant melanoma and vitiligo. Dermatologica 139:211219, 1968. 2. Cohen Y. Haim S, Bartal A, et al: Vitiligo associated with BCG-methanol extraction residue in malignant melanoma. Dermatologica 158:8-12, 1979. 3. Frenk E: Depigmentations vitiligineuses chez des patients atteints de melanomes malins. Dcrmatologica 139:84-91, 1969.
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4. Nirankari MS, Khanna KK, Mathur RP: Uveal malignant melanoma with leucoderma. J All-India Ophthalmol Soc 16:63-66, 1968. 5. Milton GW, McCarthy WH, Carlon A: Malignant melanoma and vitiligo. Australas J Demaatol 12:131-142, 1971. 6. Donaldson RC, Canaan SA, McLean RB, et al: Uveitis and vitiligo associated with BCG treatment for malignant melanoma. Surgery 76:771-778, 1974. 7. Gregor RT: Vitiligo and malignant melanoma: A significant association? S Afr Med J 70:1447-1449. 1976. 8. Ortonne JP, Perrot H: Giant melanin granules in vitiliginous achromia with malignant melanoma. Acta Derm Venereol (Stockh) 58:475-480, 1978. 9. Sober A J, Haynes HA: Uveitis. poliosis, hypomelanosis, and alopecia in a patient with malignant melanoma. Arch Dermatol 114:439-441, 1978. 10. Ortonne JP, Gauthier Y, Guillet G, et al: Depigmentation cutanee associee au melanome malin. Ann Dermatol Venereol 105:1043-1052, 1978. 1I. Takahashi M, Sober AJ, Mosher DB, et al: Vitiligo-like leukoderma in patients with metastatic malignant melanoma. Pigment Cell 5:73-87, 1979. 12. Albert DM, Todes-Taylor N, Wagoner M, et al: Vitiligo or halo nevi occurring in two patients with choroidal melanoma. Arch Derrnatol 118:34-36, 1982. 13. Laucius JF, Mastrangelo MJ: Cutaneous depigmentary phenomena in patients with malignant melanoma, in Clark WH, Goldman LI, Mastrangelo MJ, editors: Human malignant melanomas. New York, 1979, Grune & Stratton, Inc., pp. 209-225. 14. Kopf AW, Bart RS, Rodriguez-Sains RS, et al: Leukoderma and malignant melanomas, in Malignant melanoma. New York, 1979. Masson Publishing USA, Inc., pp. 162-165. 15. Lemer AB, Cage GW: Melanomas in horses. Yale J Biol Med 46:646-649, 1973. 16. Millikan LE, Hook RR, Manning PJ: Gross and ultrastructural studies in a new melanoma model: The Sinclair swine. Yale J Biol Med 46:631-645, 1973. 17. Lerner AB. Nord/und JJ: Should vitiligo be induced in patients after resection of primary melanoma? Arch Demaatol 113:421, 1977. 18. Fodor J. Bodrogi I: Vitiligo and malignant melanoma. Neoplasma 22:445-448, 1975. 19. Goldman L, Wilson RG, Glasgow R, et al: Perilesional leucoderma in metastatic melanoma. Acta Derm Venereol (Stockh) 47:369-372. 1967. 20. Perrot H, Ortonne JP, Schmitt D: Vitiliginous achromia with malignant melanoma. Arch Dermatol 257:247-253. 1977. 21. Epstein WL, Sagebeil R, Spitler L, et al: Halo nevi and melanoma..lAMA 225:373-377, 1973. 22. Elias EG, Didolkar MS, Goel IP, et al: A elinicopathologic study of prognostic factors in cutaneous malignant melanoma. Surg Gynecol Obstet 144:327-334, 1977. 23. Balch CM, Soong SJ. Murad TM, et al: A multifactorial analysis of melanoma. Ann Surg 193:377-388, 1981. 24. Chang P, Knapper WH: Metastatic melanoma of unknown primary. Cancer 49:1106-I I11, 1982. 25. Vcronesi U, Adamus J, Aubert C: A randomized trial of
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adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med 307:913-916, 1982. 26. Mitchell M, Nordlund JJ, Lemer AB: Comparison of cell-mediated immunity to melanoma cells in patients with vitiligo, halo nevi, and melanoma. J Invest Dermatol 75:144-147, 1980. 27. Roenigk HH, Deodhar SD, Krebs JA, et al: Microcytotoxicity and serum blocking factors in malignant melanoma and halo nevus. Arch Dermatol 111:720-725, 1975. 28. Hertz KC, Gazze LA, Kirkpatrick CH, et al: Autoimmune vitiligo. N Engl J Med 297:634-637, 1977.
I
I
29. Nordlund JJ, Howanitz N, Bystryn JC, et al: Antipigmerit cell factors and mucocutaneous candidiasis. Arch Dermatol 117:210-212, 1981. 30. Howanitz N, Nordlund JJ, Lerner AB, et al: Antibodies to melanocytes in patients with vitiligo. Arch Dermatol 117:705-708, 1981. 31. Cooke KB, Bennett C, Staughton RCD: Melanoma specific protein: Occun'encc in the urine of patients with halo naevus and vitiligo. Br J Dermatol 98:663-668, 1978.
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I
Malignant melanoma and vitiligo-like leukoderma: An electron microscopic study Howard K. Koh, M.D., Arthur J. Sober, M.D., Hidemi Nakagawa, M.D., Daniel M. Albert, M.D., Martin C. Mihm, M.D., and Thomas B. Fitzpatrick, M.D. Boston, MA We report clinical and ultrastructural results in eight patients with melanoma and widespread leukoderma. Leukoderma appears to be a good prognostic sign. Although some features of this entity are suggestive of vitiligo, the patients' age, the distribution and appearance of body lesions, and ultrastructural results show a more varied clinical and ultrastructural spectrum. The high frequency of ocular pigmentary disturbances and uveitis in this patient population is noteworthy and deserves further study. We would recommend routine use of Wood's light examination in following patients with thick stage I, stage II, or stage III melanoma to facilitate detection of this phenomenon. (J AM ACAO DEaMA'roL 9:696-708, 1983.)
Widespread leukoderma in patients with malignant melanoma is a striking and uncommon cliniFrom the Departments of Dermatology. Dermatopathology and Hematology-Oneology, Massachusetts General Hospital, and the Department of Pathology. Massachusetts Eye and Ear Infirmary. Supported in part by the National Cancer InstituteGrant No. R l0 CA 13651-01 CCI, the Marion Gardner Jackson Trust and National Institutes of Health Training Grant No. 5 T32 AM 07098. Accepted for publication April 19, 1983. Reprint requests to: Dr. Arthur J. Sober, Dep,'u'tmentof Dermatology, Warren 5, Massachusetts General Hospital, Boston, MA 02114.
696
cal phenomenon whose clinical significance is unclear. Over the past 20 years, scattered reports ~-'~ in the English literature (Table I) have noted this rare association and speculated on its significance. This is a report of eight patients with melanoma and widespread cutaneous depigmentation whose clinical course was studied over a long period of time. Included are the results of serial clinical observations as well as electron microscopic studies of hypopigmented and normal skin.