James J. Nordlund

Vitiligo in patients with metastatic melanoma: A good prognostic sign

We have identified and studied twenty-seven patients with melanoma who also had vitiligo. Four patients had vitiligo before the diagnosis of melanoma, and twenty-three developed depigmentation after the diagnosis of malignancy. We also have reviewed published reports about twenty-four other patients with melanoma who developed vitiligo. The clinical course of the melanoma in the fifty-one patients was remarkably similar. Thirty-seven had a melanoma arising at a site which tends to carry a poor prognosis, for example, on the trunk, under the nail, or on the mucous membranes. Forty-nine patients had metastases in regional lymph nodes or at distal sites. Thirty-three patients survived 5 years, and twenty-five survived 10 years. These data suggest that the appearance of vitiligo in patients with metastatic melanoma portends a longer survival than expected. The patients with vitiligo are not necessarily cured and eventually may succumb to metastatic disease. We were unable to determine whether the vitiligo caused retardation of tumor growth or whether the melanoma caused vitiligo.

What are melanocytes really doing all day long...

Abstract:  Everyone knows and seems to agree that melanocytes are there to generate melanin – an intriguing, but underestimated multipurpose molecule that is capable of doing far more than providing pigment and UV protection to skin ( 1 ). What about the cell that generates melanin, then? Is this dendritic, neural crest‐derived cell still serving useful (or even important) functions when no‐one looks at the pigmentation of our skin and its appendages and when there is essentially no UV exposure? In other words, what do epidermal and hair follicle melanocytes do in their spare time – at night, under your bedcover? How much of the full portfolio of physiological melanocyte functions in mammalian skin has really been elucidated already? Does the presence or absence of melanoctyes matter for normal epidermal and/or hair follicle functions (beyond pigmentation and UV protection), and for skin immune responses? Do melanocytes even deserve as much credit for UV protection as conventional wisdom attributes to them? In which interactions do these promiscuous cells engage with their immediate epithelial environment and who is controlling whom? What lessons might be distilled from looking at lower vertebrate melanophores and at extracutaneous melanocytes in the endeavour to reveal the ‘secret identity’ of melanocytes? The current Controversies feature explores these far too infrequently posed, biologically and clinically important questions. Complementing a companion viewpoint essay on malignant melanocytes ( 2 ), this critical re‐examination of melanocyte biology provides a cornucopia of old, but under‐appreciated concepts and novel ideas on the slowly emerging complexity of physiological melanocyte functions, and delineates important, thought‐provoking questions that remain to be definitively answered by future research.

The effect of vitiligo on sexual relationships

To study the effect of vitiligo on interference with sexual relationships, we surveyed 158 patients by questionnaire. Although a majority of patients reported a negative impact on sexual relationships, most patients felt embarrassment when showing their body or meeting strangers. The majority of patients who reported a negative impact on sexual relationships attributed the problems to their embarrassment. Those who were particularly affected were those with low self-esteem, men, those to whom appearance is important, and single persons. Dermatologists should be especially alert to the effects of disfigurement and should attempt to assist patients with this problem.

Psychological reaction to chronic skin disorders: a study of patients with vitiligo.

Diseases that cause physical handicaps can seriously interfere with the life of a patient. Some disorders such as vitiligo cosmetically disfigure patients without producing any physical disabilities. The effects of such diseases as vitiligo on the life of a patient have not been widely investigated. The investigation reported here utilized a questionnaire survey to focus on emotional disturbances caused by vitiligo and on the factors that differentiated patients who cope well from those who cope poorly with this stress. The results indicate that the cosmetic disfigurement of a seemingly inconsequential skin disease also can seriously disrupt the lives of a large number of patients. Those who cope well with their disfigurement have higher self-esteem than a matched control group without the disorder. Those who cope poorly have significantly lower self-esteem, which suggests that response to disfiguring diseases is affected by basic ego strength. Younger patients and those individuals in the lower socioeconomic groups show especially poor adjustment. A number of suggestions for better patient care are offered.

Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method

BACKGROUND The Melasma Area and Severity Index (MASI), the most commonly used outcome measure for melasma, has not been validated. OBJECTIVE We sought to determine the reliability and validity of the MASI. METHODS After standardized training, 6 raters independently rated 21 patients with mild to severe melasma once daily over a period of 2 days to determine intrarater and interrater reliability. Validation was performed by comparing the MASI with the melasma severity scale. The darkness component of the MASI was validated by comparing it with the difference between mexameter scores for affected versus adjacent normal-appearing skin. The area component of the MASI was validated by comparing it with the area of each section of the face determined by computer-based measurement software. RESULTS The MASI score showed good reliability within and between raters and was found to be valid when compared with the melasma severity scale, mexameter scores, and area measurements. Homogeneity assessment by raters showed the least agreement and can be removed from the MASI score without any loss of reliability. LIMITATIONS Patients were limited to Hispanic, African, and Asian backgrounds. CONCLUSION The MASI is a reliable measure of melasma severity. Area of involvement and darkness are sufficient for accurate measurement of the severity of melasma and homogeneity can be eliminated.

The effects of ultraviolet light and certain drugs on Ia-bearing Langerhans cells in murine epidermis☆

Abstract Langerhans cells and indeterminate cells are immune macrophages of the epidermis and have Ia markers on their surface. Because of their position in the epidermis, they are subject to many environmental toxins like ultraviolet light. Also medications like cortisone applied topically to the skin could have important effects on these cells. We have used an anti-Ia serum and an indirect immunofluorescent technique to study Langerhans cells in epidermal sheets. We found that shortwave ultraviolet light (250–320 nm) and ultraviolet B (280–320nm) increased the density of Ia-bearing cells (Langerhans cells) in the skin. Psoralens and ultraviolet A (PUVA) (320–400 nm) depleted the skin of Ia-bearing cells, an effect which takes 2 weeks to produce but which persists for several weeks after stopping treatment. Triamcinolone acetonide administered topically or intraperitoneally also depletes the skin of Ia-bearing cells. These agents, light and steroids, either destroy the Ia-bearing cells or remove the Ia markers from the cellular surface.

Vitiligo: a manifestation of apoptosis?

Vitiligo is a common cutaneous disorder that has significant biological and social consequences for those affected. It is characterized by a loss of melanocytes from the epidermis, which results in the absence of melanin, i.e. depigmentation. There are numerous hypotheses about the etiology of vitiligo, but no data to definitively prove one theory over another. It is likely that there are numerous causes for the loss of these melanocytes. One way to approach the identification of the etiology is to determine the mechanism by which the melanocytes are destroyed. The two known mechanisms for the destruction of cells are necrosis and apoptosis. One purpose of this paper is to review the extant data that might suggest which of the two mechanisms is operative against melanocytes in patients with vitiligo. The histological data, and some laboratory data, support apoptosis, rather than necrosis, as the mechanism for removal of melanocytes. Apoptosis can be induced by a variety of factors, including immune cytokines, some environmental chemicals (for example substituted hydroquinones such as monobenzone) or other molecular mechanisms. Current therapies, such as corticosteroids and ultraviolet light, do affect apoptosis in a variety of ways. Confirmation of apoptosis as a mechanism, and identification of how apoptosis is initiated to produce vitiligo, can serve as a basis for devising medications that might stop the progression of the disorder. The problem of vitiligo would be essentially solved if there was a medication that is well tolerated in children, adults and pregnant women, and that would halt the progression of the depigmentation. The study of apoptosis, mechanisms of its induction, and the ways to block apoptosis, is one possible way to find both the causes of depigmentation and medications to prevent its progression.

Independence of dysplastic nevi from total nevi in determining risk for nonfamilial melanoma

In the determination of risk for melanoma, relatively little is known about the possible independence of two important predictors, total nevi and clinically dysplastic nevi. From a study conducted in Sydney, Australia [see J. J. Nordlund et al., Cancer Res. 45, 1855-1861 (1985)], 246 cases of melanoma (excluding 7% of targeted patients with a history of melanoma in a first-degree relative) were compared with 134 nonmelanoma controls. Participants had been examined by a dermatologist and an oncologist. Logistic regression analysis was used and included an age-sex interaction term in computing all estimates of relative risk in this report. Relative risk for melanoma in those with 16+ total nevi was significantly elevated at 1.8 but declined to a statistically nonsignificant level of 1.2 (95% confidence limit (CL): 0.7, 2.0) after adjustment for dysplastic nevi. In contrast, relative risk for melanoma in those with any dysplastic nevi was 7.6 (95% CL: 3.6, 16.0) but was maintained at a similarly elevated and statistically significant level of 7.7 (95% CL: 3.5, 17.1) after adjustment for total nevi. These patterns were even more evident in the younger half of the study population. The analyses suggest that much of the association between TN and nonfamilial melanoma is explained by the presence of dysplastic nevi and, conversely, they imply that dysplastic nevi represent a clinically distinct, qualitative disorder rather than simply a quantitative disorder wherein dysplastic nevi stem merely from an increase in total nevi. The dysplastic nevus syndrome accounts for 32% of all nonfamilial melanomas.

Ocular Abnormalities Occurring with Vitiligo

One hundred twelve patients with vitiligo were examined for ocular abnormalities. Discrete areas of depigmentation with associated pigment hyperplasia clinically appearing to involve the choroid and retinal pigment epithelium were observed in 44 patients, and active uveitis was seen in nine patients. The changes observed suggest that the spectrum of diseases that includes Haradas disease and the Vogt-Koyanagi syndrome may be broader than previously appreciated. Patients with these syndromes may represent the most severe examples of vitiligo and uveal inflammation. The occurrence of symptoms of night blindness in 12 patients and a family history of retinitis pigmentosa in two of these may signify a possible malfunction of the retinal pigment epithelium. Further evidence for a pigment epithelium disorder is suggested by the high incidence of an unusually prominent choroidal pattern in these patients.

The epidemiology and genetics of vitiligo

Commonly it is stated that about 1% of the world’s population has vitiligo vulgaris and that this prevalence is constant for all ethnic groups in all countries; however, the extant data do not confirm these assumptions. Several large studies have been done in Denmark and in India that suggest the prevalence is much lower than frequently purported. In 1973, an investigator reported the results of an extensive survey of both urban and rural populations in or around the city of Surat, India.1 He and his colleagues examined 1887 rural inhabitants and 7178 residents of the city. These ascertainment groups represent about 60% of the population of the area. He observed that vitiligo vulgaris affected 0.49% (1 per 212 individuals) in the rural areas. The prevalence was higher in the urban areas. He found that 1.78% or 1 per 56 individuals within the city of Surat had vitiligo. Men and women were equally affected, although members of certain castes or tribes had higher or lower prevalence rates than the population at large. Some castes had no affected members, others as many as 3.6%. Kinships tended to express a vitiligo trait, so that often two or three members of the primary kinship (parents, siblings and children) were affected; however the familial patterns did not conform to any obvious Mendelian trait. ’ Another investigator studied 15,865 individuals in Calcutta, India drawn from the general population.2 He found the general prevalence of vitiligo in Calcutta to be 5 per 1000 population, or 0.2%. From those with vitiligo in this group, he ascertained additional pedigree data on the familial patterns of vitiligo. He found additional 270 individuals with vitiligo in the families of the probands in the original study group. Both sexes were equally affected. There was a 4-5 fold increased prevalence of vitiligo within close biological relatives of probands with vitiligo, compared to the population at large.2 In Denmark an investigator surveyed 47,033 Danish individuals for vitiligo vulgaris. He ascertained his subjects by examining medical records, autopsy and hospital charts, and newspaper advertisements. He found that 0.38%, or 1 per 263 individuals, had vitiligo. Both sexes were equally affected. Before the age of 10 years only 0.09% of the population was affected; but the prevalence was maximum by age 60 vears, at which time 0.9% of individuals were affected.‘? From these studies, it seems reasonable to conclude that the general prevalence of vitiligo vulgaris throughout the world is about 1 per 200 individuals, and that both sexes are affected equally; however it should be noted that there are locations in the world, such as isolated villages in India, where the prevalence can be much higher, as high as 8%.-2 The most obvious explanation for this uneven distribution of vitiligo is inheritance of the disease; however there are workers who are exposed to chemicals that cause them to develop occupational depigmentation that resembles vitiligo.5 It is possible, especially in underdeveloped countries such as India that are burdened by a caste system, that the higher than expected prevalence is related to environmental factors or, more likely, to a combination of genetic and environmental factors.