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VITILIGO—WHAT IS IT?' HERMANN PINKUS, M.D.

'When I first became interested in vitiligo incourse with and without therapy, and reading connection with psoralen therapy, the answer towhatever could be found in the literature, the the question: what is vitiligo? seemed to be verypicture has become more diversified and even simple. Every textbook gives a clear-cut defini-more puzzling. tion. CLINICAL MORPhOLOGy DEFINITION Concerning the clinical picture and course, it To quote Ormsby-Montgomery (1): "Vitiligois certainly true that most lesions show a com- is an acquired cutaneous achromia characterizedplete absence of pigment and a tendency to by variously sized and shaped single or multipleprogress. However, some patients report that patches of milk white color, usually presentingevery summer, on exposure to sunshine, there is hyperpigmented borders and a tendency tosome repigmentation from the borders, and small enlarge peripherally." The authors add to this:pigmented, freckle-like spots may appear in the "Absence of pigment. .. isthe only symptom incenter of white areas, only to disappear again during the winter. The difference is a real one and vitiligo". .. . "Theskin. .. presentsno textural changes and is normal in every way except ais not due to enhanced color contrast between sensitiveness to solar irradiation". .. "thecausetanned and vitiliginous skin in the summer. Re- of vitiligo is unknown". .. "thetreatment of thepigmentation of some degree occurs in 50% of disorder is unsatisfactory". patients according to Lerner (2). Other books offer similar definitions, all of Other patients exhibit what Siemens (3) re- them almost completely negative, except for thatcently has called "vitiligo gradata", a graded, one positive fact: acquired loss of pigment withstep-wise diminution of pigment. This feature is especially noticeable in colored skin, but may be a general progressive tendency. The attribute "acquired" differentiates vitiligoobserved in whites. Between the normal and the from partial albinism which is congenital. Thetotally depigmented skin, there are zones of attribute "progressive" also sets it apart fromvarying width exhibiting an intermediate hue. albinism in which the white areas do not enlarge,The borders always are sharp, not shading grad- and from leukodermas following injury, such asually. The German term "Stufen-Vitiligo" superficial burns, or inflammatory dermatoses,(vitiligo by steps) expresses this phenomenon. such as syphilis or psoriasis. These secondaryWhile Siemens describes this as a secondary leukodermas generally are transient and decreasedevelopment due to partial repigmentation, I rather than increase with time. have seen it also in progressing lesions as a step- Now, several years later, after observingwise depigmentation. numerous cases of vitiligo closely, following their Another peculiar experience is that patients under treatment with methoxsalen may show *Fromthe Departmeot of Dermatology, Waynerepigmentation of the majority of areas, while State University College of Medicine, aod Receiv- ing Hospital, Detroit, Michigan. others may progress. New areas even may appear. Supported in part by Research and Develop- The hyperpigmented border, mentioned by ment Division, Office of the Surgeon General, Department of the Army, under Research Con-niany authors, has been explained as an optical tract No.: DA-49-007-MD-584. illusion by others. We will see later that there is Presented at the Brook Lodge Invitationalhistologic evidence that hyperpigmentation is Symposium on the Psoralens, sponsored by Theindeed present. It is often quite prominent when Upjohn Company, Kalamazoo, Michigan, March 27—28, 1958. repigmentation occurs under therapy. 281 282 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Another point worth mentioning is the behav-sweat response to pilocarpin has been reported ior of hair color. In some vitiliginous patches, theby several authors, but has been denied by others hairs retain their natural color, even in large(7). Among recent authors, Halter (8) found areas of long standing. In other cases, the hairsheat sweating absent in vitiliginous skin although become white sooner or later. In this connection,response to pilocarpin was not disturbed. Lerncr it has been a general experience that the freckle-(9) reports that under resting conditions, more like pigment spots, which appear within vitiligi-sweat occurs in areas of vitiligo than on adjacent nous areas spontaneously or under therapy,normal skin and that the electrical resistance is almost always are perifollicular and seem todecreased in the vitiliginous areas (2). Lerner occur only where the hairs have preserved their(9) also quotes reports that blood vessels are color. It is quite rare for new centers of pigmentconstricted in patches of vitiligo and that viti- to appear on the non-hairy surfaces. Prognosis forliginous skin does not become yellow during repigmentation is better if the color of the hair isjaundice or on ingestion of atabrine. Hypesthesia preserved because each hair may then serve as ahas been claimed occasionally to occur in cases center from which pigmentation spreads. On thein which leprosy could be ruled out. Habermann other hand, the epidermis of relatively smallwonders whether such cases may not have been areas may become repigmented from the bordersincipient tabes dorsalis in which according to even though the hairs remain white. In rare cases,him, vitiligo is found not infrequently. white hairs may turn dark again under treat- ment. ASSOCIATION WITH SYSTEMIC DI5EASE The pigmentary systems of epidermis and hairs This brings up the much discussed question of thus seem to be under independent control.systemic diseases associated with and perhaps Similarly lijima and Kanazawa (4) observedcausative of vitiligo. Habermann listed the fol- that a blue nevus did not depigment and retained lowing: a positive dopa reaction when the epidennis above it become vitiliginous. Another peculiar observa-T7itiligo and Systemic Disease tion is the "halo nevus" or lcucoderma acquisitum centrifugum (Sutton (5)). Here a brown mole A. Diseases of the Nervous System becomes surrounded by a depigmented halo that a. psychic disturbances and neuroses has all the earmarks of vitiligo and may be asso- b. disorders of sensory or motor nerves ciated with other vitiliginous patches in the same c. disorders of the vegetative nervous patient. It happens not infrequently that even- system tually the central nevus also becomes depig- B. Endocrine Disorders mented. It may even disappear completely, a. thyroid (hyper- or hypo-) being destroyed or absorbed by inflammatory b. adrenals infiltrate. c. ovaries d. others (parathyroid, thymus, pit- ASSOCIATED LOCAL CHANGES uitary) The statement that absence of melanin is the C. Infectious Diseases only symptom in vitiligo has been challenged a. syphilis repeatedly. Even Ormsby-Montgomery write b. tuberculosis that histologic evidence of mild inflammation is c. others (typhoid, scarlet fever, etc.) found in the border of the lesions. Cases have D. Other Systemic Diseases been reported in which there was a narrow in- a. pernicious anemia flamed edge around the enlarging areas of b. alcoholism vitiligo (Habermanu (6)). c. liver, kidney, gastro-intestinal Habermann (6) writing in Jadassohn's Hand- Most of these reports arc based on few or even buch in 1933 quotes a variety of contradictoryindividual cases in which the association certainly observations that the vitiliginous skin is eithercould have been coincidental. Among the few more or less susceptible to irritants such ascorrelations that seem to be more valid, is that croton oil or mustard, and shows hyperreactivitywith thyroid dysfunction, especially with thyro- or hyporcactivity when tested with old tuber-toxicosis in which figures as high as ten per cent culin, diphtheria toxin and other allergens. have been reported (Habermann). Allison and Diminution of spontaneous sweating and ofCurtis (10) found an association of pernicious VITILIGO—WHAT IS IT? 283 anemia and vitiligo in 22 eases out of 801,670the border of the vitiliginous area. Here, one also hospital admissions. Chance would have ac-finds melanin-carrying macrophages in the cutis, counted for only one case of this combination.and often there is more or less inflammatory in- Lerner (2) found a tendency to hypochlorhydriafiltrate around blood vessels of the upper corium. in a study of 25 patients. Excretion of norad-These changes probably are responsible for the renaline and melanocyte stimulating hormoneclinical impression of a hyperpigmented areola. was normal in the same group of patients. So Pathological changes of myelinated and non- were liver and thyroid function tests. Agarwalamyelinated nerve fibers have been claimed by et at. (11) found 17-ketosteroid excretion in-some old and recent investigators, but these creased. findings need confirmation. Histamin (Quiroga The relationship of vitiligo to syphilis de-ci at. (13)) and sulfhydryl groups (Lajmanovich serves a few comments. It is well known thatand Magnin (14)) have been reported present in secondary syphilis may give rise to a character-normal quantity. istic and long lasting leukoderma, which should DISCUSSION not be confused with true vitiligo. Tabes dorsalis, formerly of very widespread occurrence, was Vitiligo seems to be an achromia of the skin, implicated because it is a nervous disorder, anddue not to any marked anatomical disturbance, the influence of the nervous system on pigmenta-but purely to a functional abnormality of the tion has been discussed by many and for a longmelanocytes. If the literature offers any hint to time. Lerner (2) recently proposed the hypothesisan underlying systemic disturbance, this may be that vitiligo may result from increased activityin the neuro-endocrine field. Familial incidence is of the sympathetic nerves in the skin. It seemscommon (Lerner (2)). that the causative role of syphilis had proponents There have been several attempts to elucidate especially in France. Habermann wrote that inthe seat of the disturbance in the skin by ex- France, even in 1933, most cases of vitiligo werechange transplantation between normal and subjected to thorough antisyphilitic treatmentvitiliginous areas. Results have been somewhat (pg. 933). contradictory. Haxthausen (quoted by Tolmach (15)) found that split skin grafts changed color HJ5T0PATH0L0GJc CHANGES quickly. Comel's (16) pedicle grafts preserved In this confusion of opinions it is tempting totheir original color for several months, then turn to histopathologic examination for someassumed the character of the surrounding skin. solid ground. Unfortunately, histologic data areSpencer (17) and Spencer and Tolmach (18) not too numerous. Many of the older ones mustfound that full thickness grafts preserved their be discounted because in a disease affecting theoriginal characteristics for as long as 16 months. pigment forming mechanism of the skin, exactKato (19) confirmed this difference in the behav- knowledge of that mechanism under normal con-ior of thin and thick grafts. There is, however, in ditions is essential for correct interpretation ofthe work of Gillman et at. (20) some indication its pathology. It has not been too many yearsthat the epidermis of split skin grafts may be re- that the melanoeyte has been recognized as theplaced by hair sheath cells of the host site even sole pigment forming cell and its extra-epidermalafter the graft seemingly has taken successfully. derivation acknowledged by the great majorityThis line of experimentation thus has not been of investigators. Becker, Jr. et at. (12) havetoo helpful. If anything, the results seem to argue demonstrated the presence of junctional cells,against any immediate neural control of pig- corresponding to melanocytes, but lacking thementation. ability of forming pigment, in sections of vitiligo. There are a few clinical peculiarities which They used gold impregnation for this purpose.make one wonder what the actual mechanism of These "clear cells" or "white melanocytes" canmelanocyte inhibition is. In most cases, there is be seen at the dermo-epidermal junction in H andan all-or-nothing effect. Not only clinically, even E sections. All that is lacking is enzyme activityunder the microscope, the transition from normal when the sections are treated with dopa orto abnormal skin is abrupt. Also, if repigmenta- tyrosine, and of course there are no melanintion takes place spontaneously or under therapy, granules in melanocytes or epidermal cells. Onit does not come in the form of gradual darkening the other hand, one often sees unusually large,of the entire area, but by creeping extension of highly dendritie, and highly melanized cells atpigment from the borders or from perifollicular 284 THEJOTJHNAL OF INVESTIGATIVE DERMATOLOGY

ones is emphasized in the explanation of spon- taneous and therapeutic repigmentation, and the question is raised whether the psoralens exert their action on the normal melanocyte rather than on the diseased one. REFERENCES 1. ORMSBY, 0. 5. ANI) MONTGOMERY, H.: Diseases of the Skin. 8th edition, pg. 721. Philadel- phia, Lea & Febiger, 1954. 2. LERNER, A. B.: Vitiligo. Transactions, Pacific PSrr Dermatologic Association, 7th Annual Meet- Fio.1 ing, Mexico City, 1955. pg. 25—26. 3. SIEMENS, H. W.: Vitiligo gradata (Stufen Vitiligo). Dermatologica, 109: 228, 1954. foci. As the latter form oniy where the hair is 4. Irmt&, S. AND KANAzAwA, T.: The relation- pigmented, it seems a fair assumption that ship between blue nevus and vitiligo. Tohoku J. Exper. Med., 57: 144, 1953. melanoeytes in the hair bulb serve as a source of 5. SUTTON, R. L., JR.: Diseases of the Skin. 11th new pigment. edition, pg. 1079. St. Louis, C. V. Mosby Theoretically, two mechanisms seem plausible Co.,1956. 6. HABEEMANN, R.: Paratypische Pigment- at the cellular level. Either, there is in vitiligo anomalien, V.Vitiligo. in Handbuch der a heritable change of melanocytes in certain foci, Hautund Geschlechtskrankheiten, edited by J. Jadassohn, Vol. IV, 2. pg. 896—930. Berlin, and these abnormal achromatic melanocytes Julius Springer, 1933. multiply and push back the normal ones. In 7.ROTHMAN,S.,RUnIN,L. AND HOUSTON, M.: repigmentation the tide of battle turns and the Vitiligo. Arch. Dermat. & Syph., 48: 400, 1943. abnormal cells are crowded out. Or, the cells 8. HALTER, K.: Tiber eine MOgliehkeit der "funk- stay where they are and there is an "infectious" tionellen Differentialdiagoose" bei Dc- und spread of inhibition of pigment formation from Apigmentierungen der Haut. Derm. Wehschr., 125: 1, 1952. cell to cell. Inhibition may result from some kind 9. LEENER, A. B.: Melanin pigmentation. Am. of blockage of the enzyme or from actual loss J. Med., 19: 902, 1955. 10. ALLIsoN, J. R., JR. AND CURTIS, A. C.: Vitiligo of the enzyme forming mechanism. Repigmenta- and pernicious anemia. Arch. Dermat. & tion then would take place by a similar "in- Syph., 72: 407, 1955. fectious" spread of either the enzyme mechanism 11. AGARwALA, S. C., MUREEJI, B. AND SHARMA, A.: Urinary 17ketosteroid excretion in or an "unblocking" agent. Examples for either leukoderma. J. Endocrinol., 13: 185, 1956. cell migration or infectious spread of pigment 12. BECKER, S. W., Ja., FITZPATRICK, T. B. AND MONTGOMERY, H.: Human melanogenesis: forming ability are present in experimental work cytology and histology of pigment cells in animals. (melanodendroeytes). Arch. Dermat. & In any case, the therapeutic action of the Syph., 65: 511, 1952. 13. QIJIROGA, M. I., GUJLLOT, C. F. AND MANJOU, psoralens in vitiligo seems to require the presence F.: El contenido histaminieo de la piel en el of four cooperating factors: The drug, photo- vitiligo. Rev. Argent. Dermatosifll., 33: 17, chemical energy, the presence of achromatic 1949. 14. LAJMANOYICH, S. AND MAGNIN, P. H.: Total "diseased" melanocytes, and last but not least, sulfhydryl content in normal and vitilig- the presence of normal melanocytes in contact inous human skin. J. Invest. Dermat., 25: with the diseased ones. It seems open to argu- 79,1955. 15.TOLMACH, J. A.: discussion to Spencer (17). ment whether the drug and ultraviolet exert 16.COMEL,M.:Modificazioni della alterazione their influence on the diseased cell, or perhaps eutanee della vitiligo e della selerodermiain rather on the normal one, if not both (Fig. 1). zonedi trapianto eutaneo. Dermatologiea, 96: 366, 1948. 17. SPENCER, Skin transplantation in exten- SUMMARY 0.: sivevitiligo. Arch. Dermat. & Syph., 64: (1) Vitiligo is an acquired progressive aehro- 514, 1951. mia due to loss of function of the tyrosinase sys-18. SPENCER, 0. A. AND TOLMACII, J. A.: Ex- change grafts in vitiligo. J. Invest. Dermat, tem of the melanocytes at the epidermo-dermal 19: 1, 1952. 19. KATO, T.: Studies of vitiligo vulgaris. Jap. J. junction. Dermat. and Vener., 65: 455, 1955. (2) Clinical peculiarities and systemic asso-20.GILLMAN,T., PENN, J., BEONK5, D. AND ciations of vitiligo are reviewed. ROUX, M.: Reactions of healing wounds and (3) The importance of the presence of func- granulation tissue in man to auto-Thierseh, autodermal,and homodermal grafts. Brit. tional melanocytes in contact with the diseased J. Plastic Surg., 6: 153, 1953.