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In 1974 a new photobiologic principle i.e. light + drug, called photochemotherapy was discovered in Boston and immediately confirmed in Vienna. Psoralen + UVA (PUVA) photochemotherapy has now been applied to the treatment of more than 24 heterogeneous groups of diseases, especially psoriasis and mycosis fungoides. After 24 years of experience in thousands of patients with psoriasis and 23 other skin disorders, virtually the only risk is the development of squamous-cell carcinomas. This risk is low with two exceptions: previous history of treatment with ionizing radiation or inorganic trivalent arsenic, and patients with recalcitrant psoriasis who require continuous treatment for many years. In a recent report from a large USA clinical trial, melanoma developed in a few patients with psoriasis treated with PUVA. This prospective clinical trial did not have a control population, and therefore, the conclusion that PUVA can cause melanoma is tentative.

The goal of photochemotherapy in psoriasis is to attempt to lower the number of exposures and the total cumulative doses while still maintaining good control of the disease. PUVA has been modified by using better psoralen preparations and more effective light sources, and it also has been combined with other treatment modalities. The objectives in modifying PUVA and combining PUVA with other treatment modalities are to increase efficacy, to reduce short- and long-term adverse effects, and to reduce the cost of treatment. Modalities that have been combined with PUVA include topical corticosteroids, anthralin, calcipotriene ointment, methotrexate, UVB, retinoids, and cyclosporine.

while normal skin colour comprises a mixture of 4 biochromes, reduced and oxyhaemoglobin, carotenoids (exogenous), and melanin, it is the total amount of melanin pigment that is the principal determinant of the skin colour.

The therapeutic uses of naturally occurring psoralens in modern-day medicine (8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP), 4,5',8-trimethylpsoralen, and a few other synthetic psoralens) have evolved through five stages of development. (1) In the historical period (2000 BC to 1930 AD), the pigment-stimulating properties of naturally occurring plants containing psoralens were described anecdotally. (2) The second period (1930-1960) dealing with the chemistry of psoralens involved extraction, identification of their structure, synthesis, and the relationship between chemical structure and their photoreactivity and pigment-stimulating properties. The treatment of vitiligo with oral and topical 8-MOP became popular. (3) In the third period (1960-1974), we witnessed a new beginning and the growth of basic science studies and clinical investigations into various biological properties of psoralens including action spectrum studies, mutagenesis and carcinogenesis studies, in vitro and in vivo photoreactivity studies of various psoralens with DNA, RNA, proteins, and pharmacological and toxicological studies in vitiligo patients undergoing long-term therapy for repigmentation. (4) The fourth period (1974-1988) is recognized as the period of photochemotherapy and the development of the science of photomedicine which established the therapeutic effectiveness of psoralens in combination with newly developed UV irradiation systems that emitted high-intensity UVA radiation in the treatment of severe psoriasis, mycosis fungoides, and over 16 other skin diseases. The effectiveness of PUVA (psoralen + UVA) was confirmed by well controlled clinical trials in thousands of patients, both in the USA and in European countries. Combination therapy with oral retinoids and PUVA contributed to greater effectiveness and long-term safety of psoralen photochemotherapy. (5) In the fifth period (1989 and beyond), psoralens are now emerging as photochemoprotective agents against non-melanoma skin cancers and as immunologic modifiers in the management of certain patients with disorders of circulating T-cells using new techniques of photopheresis. In the final analysis, perhaps the application of pharmacological and therapeutic concepts and principles of using psoralens in combination with UVA has contributed to the development of a new science of photomedicine in which the interaction between basic scientists, photobiologists, and physicians has produced both basic and new clinical knowledge for the care and control of human suffering.

A34-year-old male internist working at a large teaching hospital died of metastatic melanoma 3 years after a silent primary tumor was discovered by his wife. The patient’s wife, a pediatric resident, noted the lesion on his back after attending a lecture on melanoma and premelanoma. The patient had been seen annually by his primary care physician, and during these encounters the primary melanoma was present on his back but was overlooked. In addition, he had 4 of the 6 MMRISK factors: 1) inability to tan, 2) severe sunburns in youth, 3) family history of cutaneous melanoma, and 4) the presence of 6 dysplastic nevi (Table). The primary care physician was not alert to the fact that the patient had a high risk of melanoma. If the primary tumor had been identified early and excised, the patient’s probability of 5-year survival would have been >90%. Table MMRISK: a mnemonic for melanoma The “missing link” is the failure of the primary physician to discover melanoma early in a curable stage by inspecting the skin during the initial encounter. Inspection and assessment of all moles and pigmented lesions is an essential part of every physical examination. The detection of early melanoma is in the hands and eyes of the primary care physicians (generalists, gynecologists, internists). Early melanoma is missed because most physicians do not examine the skin adequately. Inspection of the skin in white patients at the time of the first visit is a necessary part of good patient care, just as is taking the blood pressure. Even if the physician cannot make the diagnosis, he or she should look for large (>1.0 cm) dark-brown lesions with the 2 cardinal signs of atypicality: irregular borders and variegation of color. The patient can then be referred to a dermatologist for dermatoscopy (epiluminescence microscopy) and/or surgical excision of the lesion for biopsy. Having each white patient complete a simple, user-friendly checklist of the MMRISK factors of cutaneous melanoma on the initial information form is enormously helpful in judging who is at high risk for acquiring melanoma and how frequently they should have a skin scan by their physician or a dermatologist. Having this at hand and seeing melanoma risk factors alerts the primary physician or nurse to inspect the total skin surface for suspicious pigmented lesions. When individuals with black skin acquire primary cutaneous melanoma, the palms, soles, mucous membranes, and nailfolds are sites of predilection. Too many people are dying of melanoma principally because most physicians are not “on the alert” for pigmented lesions in the physical examination and overlook early cutaneous melanomas, especially on the backs of men and women or on the legs of women. This failure to examine the total skin in persons at high risk for melanoma constitutes a serious deviation of the standard of care.

BACKGROUND: UV radiation induces damage to human skin. Protection of skin by an oral photoprotective agent would have substantial benefits. Objective We investigated the photoprotective effect of oral administration of an extract of the natural antioxidant Polypodium leucotomos (PL). METHODS: A total of 9 healthy participants of skin types II to III were exposed to varying doses of artificial UV radiation without and after oral administration of PL (7.5 mg/kg). At 24 hours after exposure the erythema reaction was assessed and paired biopsy specimens were obtained from PL-treated and untreated skin. RESULTS: A significant decrease in erythema was found in PL-treated skin (P

BACKGROUND: The use of psoralen-UVA (PUVA) in patients of skin phototype I to II is limited by side effects of acute phototoxicity and possible long-term carcinogenesis. OBJECTIVE: We sought to assess oral Polypodium leucotomos (PL) extract in decreasing PUVA-induced phototoxicity of human skin on a clinical and histologic level. METHODS: A total of 10 healthy patients with skin phototypes II to III were exposed to PUVA alone (using 0.6 mg/kg oral 8-methoxypsoralen) and to PUVA with 7.5 mg/kg of oral PL. RESULTS: Clinically, phototoxicity was always lower in PL-treated skin after 48 to 72 hours (P

The substance (the “what”) of the life and accomplishments of Thomas B. Fitzpatrick, familiarly known as TBF, has been extensively recorded, including laudatory and commemorative essays in the February 2004 issue of JID (volume 122, pages vii–xli). The “why” of his drive is best left to those who delve into the nature of creativity.

Dysplastic nevi are an important indicator of risk of cutaneous malignant melanoma. The study of and, particularly, international communication regarding this group of lesions have been hindered by a lack of precision in diagnosis. In an effort to broaden understanding, a panel of pathologists agreed upon a set of criteria for the diagnosis of dysplastic melanocytic nevi. Two major and four minor criteria were defined. The major criteria are (1) basilar proliferation of atypical nevomelanocytes (extending at least three rete ridges or "pegs" beyond any dermal nevo-cellular component), and (2) organization of this proliferation in a lentiginous or epithelioid-cell pattern. Minor criteria are (1) the presence of lamellar fibrosis or concentric eosinophilic fibrosis, (2) neovascularization, (3) inflammatory response, and (4) fusion of rete ridges. Diagnosis required presence of both major criteria and at least two minor criteria. One hundred fourteen histologic specimens of benign acquired nevi, dysplastic nevi, and radial-growth-phase melanomas were examined by the members of this panel; their diagnoses were compared to determine degree of concordance. The established criteria yielded 92% mean concordance overall.

Two discoveries in the last two decades markedly improved the use of ultraviolet radiation for the treatment of disease or disorders of the skin, including psoriasis: (a) the introduction of high-intensity UVA sources (Sylvania) which are used in a therapeutic regimen in which topically administered UVA interacts in the skin with orally administered photoactive drugs; this interaction functions as a potent anti-inflammatory modality for the treatment of psoriasis and several other inflammatory disorders of the skin; (b) new protocols using newly developed high-intensity total-body UVB irradiators, but substituting emollients for crude tar, with therapeutic results equal to the Goeckerman treatment.

IN DEVELOPING new therapies for vitiligo, it is conducive to try to understand the pathogenesis of vitiligo. A stubborn fact regarding vitiligo is that there are no melanocytes in fully evolved vitiligo macules. So the pathogenesis of vitiligo centers around a mechanism for the destruction of melanocytes. The most favored is an autoimmune hypothesis; this is based on the association of vitiligo with other autoimmune disorders, especially Hashimoto thyroiditis, pernicious anemia, and adrenal insufficiency, and the occurrence of autoantibodies in these patients. Also, the use of oral and topical corticosteroids can induce pigmentation in vitiligo macules. Because there are no melanocytes in fully developed vitiligo macules, the autoimmune mechanism would appear to involve progressive destruction of melanocytes by autoantibody-dependent cellular cytotoxicity 1 or by cytotoxic T lymphocytes. 2 In contrast to epidermal melanocytes, melanocytes in the outer root sheath of the hair follicle appear to be immunologically "privileged" and, in

Sun and Skin: An Individual Risk by Karl Holubar and Cathrin Schmidt, 48 pp, Vienna, Austria, Verlag der Ostereichischem Arztekammer, 1994 Pigmentation and Pigmentary Disorders edited by Norman Levine, 553 pp, with illus, Boca Raton, Fla, CRC Press Inc, 1993 Melanin: Its Role in Human Photoprotection by Lisa Ziese, Miles R. Chedekel, and Thomas B. Fitzpatrick, 320 pp, Overland Park, Kan, Valdenmar Publishing Co, 1995. Some books are to be tasted, Others to be swallowed, and Some few to be chewed and digested. Francis Bacon Since 1946, when I first started working on melanin in a US Army chemical laboratory in Maryland with Professor Aaron Lerner of Yale University, New Haven, Conn, my singular preoccupation has been melanin: the basic biology of melanin, the regulation of melanin pigmentation, the identification and treatment of melanin pigmentary diseases, and physical anthropology, ie, races of man in relation to skin color. For years, I wanted to have at hand (for my own use) a book on all aspects of melanin. While on sabbatical at Oxford University, Oxford, England, in 1959, I started to write one; this ambitious task was waylaid when the late Professor M. Seiji and I isolated and began to characterize the metabolic unit of melanin pigmentation, the melanosome. In fact, the scope of our knowledge

Background and Design: A lack of consensus as to the clinical and histologic characteristics of dysplastic nevi has resulted in the recommendation to abandon the term dysplastic nevus for the more descriptive atypical nevus or atypical mole . The significance of the presence of one or more such lesions, histologic features notwithstanding, has not been carefully examined. The risk of melanoma was assessed in individuals with atypical nevi monitored regularly in our Pigmented Lesion Clinic. Any patient enrolled in this sub-specialty clinic between 1980 and 1985 without the diagnosis of melanoma who had at least one sufficiently atypical-appearing nevus and who was followed up for a minimum of 5 years was entered in the study. Results: A total of 155 such individuals were identified. The mean(±SEM) age of the patients at first evaluation was 26± 1 years. The group was followed for 7± 1 years. The male-female ratio was 1:1. A

REPORT OF A CASE A 42-year-old white man with human immunodeficiency virus (HIV) infection of 4 years' duration was admitted to Massachusetts General Hospital, Boston, for debilitating exacerbation of psoriasis. The skin condition, present for 3 years, had been reasonably controlled with UV-B phototherapy. For several weeks before admission, the patient had difficulty getting to the light therapy unit on a regular basis because of ambulatory problems. Progressively enlarging ''warts'' on his toes were becoming too painful for the patient to walk very far. Oxycodone with acetaminophen, morphine sulfate, and amitriptyline prescribed for his alcoholic neuropathy, manifested as leg pain, were being used for control of his toe pain. Except for HIV-associated hematologic changes, he had no other significant medical problems. In addition to the pain control medications, he was receiving zidovudine and ranitidine. He had no prior therapy for lesions on his toes. Findings from his physical examination revealed

• Background and Design.— Epiluminescence microscopy (ELM) is a clinical technique that permits in vivo visual inspection of pigmented anatomic structures of the epidermis, dermoepidermal junction, and papillary dermis. A protocol is proposed for systematic visual inspection of pigmented lesions. Seventy pigmented lesions were imaged with a digital ELM camera system. Images were visually inspected for eight "global" ELM features, 23 "local" ELM features, and 18 network features. An atlas of the most clinically significant ELM features is presented with pilot estimates of their sensitivity and specificity for detecting melanoma. Results.— Preliminary data suggest that ELM features that may be most specific for melanoma include multicomponent pattern, nodular pattern, pseudopods, radial streaming, blue-gray areas, whitish veil (milky way), and sharp network margins. Epiluminescence microscopic features that may be most sensitive for melanoma include pigment dots, peripheral erythema, peripheral dark network patches, marked mean network irregularity, network line thickness variability, radial streaming, blue-gray areas, and whitish veil (milky way). Epiluminescence microscopic features that may be most sensitive for severe melanocyte atypia include pigment dots, peripheral erythema, hypopigmented network patches, peripheral dark network patches, marked mean network irregularity, and focal absence of network. In addition, features that may have a very high specificity for benign lesions include saccular pattern (suggests hemangioma), globular pattern (suggests a compound or dermal nevus), and multiple comedolike openings (suggests seborrheic keratosis). Conclusions.— Features most sensitive for severe atypia and melanoma could form the basis for a screening test for considering biopsy. Features most specific for melanoma then could be applied to further triage management of pigmented lesions that meet initial screening criteria. In addition, features with very high specificity for benign lesions may help develop ELM criteria to avoid unnecessary surgery. ( Arch Dermatol. 1993;129:157-174)

A considerable amount of evidence exists in support of the role of ultraviolet radiation as a major etiologic factor in human skin cancer, both melanoma and carcinoma types. On the basis of epidemiologic studies a phenotype has been described which helps to identify the persons who are more susceptible to skin cancer. In an attempt to further define this population, patients with cutaneous carcinoma and a normal control group were exposed to artificial ultraviolet light (UVL) and the erythema and tanning responses of each group were measured over a 21-day period. UVL-induced erythema was prolonged in a significantly higher percentage of patients with skin cancer than in control patients, lasting two to three weeks after single exposures to 6 and 8 times the patient's minimal erythema dose. The presence of prolonged erythema correlated with this history of previous skin cancer but did not correlate with other established risk factors for cutaneous carcinoma, i.e., fair skin, light hair and light eyes, easy sunburning and poor tanning, and Celtic ancestry. Prolonged erythema following UVL radiation may therefore represent an additional risk factor and help to identify the skin cancer-susceptible population.

Histochemical (dopa reaction) and electron microscopic studies were carried out to elucidate the nature of the chemical depigmentation produced by hydroquinone (HQ). Depigmentation was induced by topical application or subcutaneous injection of HQ in black guinea pigs. The present study showed that HQ preferentially affected the nonfollicular and follicular melanocyte system. It caused decreased formation of melanosomes, a marked alteration in the internal structure of melanosomes, an increased degradation of melanosomes , and , finally, a destruction of the membranous organelles in the melanocytes. These findings indicate that HQ affects not only the formation, melanization, and degradation of melanosomes, but that it affects also the membraneous structures of melanocytes and eventually causes necrosis of whole melanocytes.

Fifteen variables were studied for their usefulness in predicting recurrent disease in 254 patients with clinical stage I melanoma of the trunk. Thickness of the primary tumor correctly predicted outcome with an accuracy of 90 percent or greater in 176 patients with melanoma primaries with a thickness of less than 1.70 mm or 5.5 mm or greater. No other variables significantly increased predictive accuracy over these ranges of thickness. A Cox proportional hazards analysis of the remaining 78 patients with primary tumors 1.70 to 5.49 mm thick demonstrated that the following four variables functioned as independent risk factors for recurrent disease: (1) thickness of the primary tumor (p = 0.0005), (2) mitoses/mm 2 >6 (p = 0.006), (3) a nearly absent or minimal lymphocyte response at the base of the tumor (p = 0.009), and (4) location on the upper trunk (p = 0.03). Trunk lesions located near the midline did not have a worse prognosis than more lateral melanomas of similar thickness.

Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses greater than 6/min 2 (p = 0.0007), 2) location other than the forearm of leg) p = 0.009, 3) ulceration width greater than 3 mm (p = 0.04), 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4 degrees of freedom (p less than 10 (-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses greater than 6/mm 2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration greater than 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses less than or equal to 6/mm 2 and a location on the leg or forearm, or 2) mitoses less than or equal to 6/mm 2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration greater then 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.

A new structural subunit, i.e., vesiculoglobular body, of the melanosome was found in fine structure studies of melanosomes in various tissues using conventional transmission (50–80 kV), high-voltage transmission (800 kV), and scanning (25 kV) electron microscopes. The high-voltage electron microscope was used for 5 μm-thick sections to study the entire inner and outer structures of the melanosome. The scanning electron microscope was used to observe the three-dimensional structure of leached melanosomes that were treated with the bleaching agents, thioglycolic acid, and phenol, and a prolonged boiling at 130°C for 24 hours. The vesiculoglobular body, 400 A in diameter, appears to be the structural element that is incorporated in the organization and melanization of the inner matrices of the melanosome. These bodies were found to be (a) present in all stages of melanosomal development, (b) increased in number during developmental stages, (c) attached to the surface of the lamellae of the inner matrices, (d) covered by osmiophilic fine grains of melanin moieties after melanization of the melanosome, (e) not melanized within themselves during an entire course of melanosomal development, (f) unchanged in size even though the melanosome changed in size, (g) not degraded, once they have been incorporated into the inner matrices, by phenol and thioglycolic acid and prolonged boiling at 130°C for 24 hours, and (h) uninvolved in the lysosomal degradation of melanosomes in the keratinocytes.

In order to assess a relationship between small congenital nevocellular nevi and cutaneous melanoma, histologic features commonly associated with congenital nevi were sought in 234 melanomas. The detection of one or more histologic features of congenital nevi in 8.1% (19/234) of melanoma specimens was directly related to the number of slides and tissue sections with melanoma available for review, the predominance of superficial spreading melanoma (SSM) and the historic relationship to a preexisting pigmented nevus at the tumor site, The histologic association was inversely related to melanoma thickness and tumor location on the lower extremities. The observed frequency of histologic association was estimated to be approximately 4,000 to 13,000 times greater than expected on the basis of surface area by chance alone. These findings suggest that small congenital nevi may be precursors for at least some cases of cutaneous melanoma. The strength of histologic association is highly dependent on the specificity of methods used for detecting congenital nevi in melanoma specimens.

The rising incidence of this once uniformly lethal disease presents a special challenge to the primary physician--how to distinguish early, surgically curable melanoma from benign pigmented lesions. Simple visual criteria can identify more than 90% of the primary melanomas among suspected lesions. And treatment at the superficially invasive stage carries a 95% five-year survival rate.

A multivariate analysis was performed on 20 clinical and histologic variables from 327 Stage I prospectively studied melanoma patients who underwent elective regional lymph node dissection (ERLD). Primary tumor thickness, microscopic satellites, and the elapsed interval between diagnosis and ERLD, were selected as the combination of variables that were most highly associated with clinically occult regional lymph node metastases (P = 10(-15), model chi-square). Microscopic satellites were defined as tumor nests, greater than 0.05 mm in diameter, in the reticular dermis, panniculus, or vessels beneath the principal invasive tumor mass but separated from it by normal tissue on the section in which the Breslow measurement was taken. The probability of finding nodal metastases for melanomas less than 0.75 mm thick was 0% (0/41 patients); for those 0.76-1.50 mm, 4% (4/108); 1.51-3.0 mm, 14% (14/102); and greater than 3.0 mm, 39.5% (30/76). Primary melanomas greater than 1.50 mm thick with microscopic satellites were more often associated with nodal metastases than those of similar thickness without satellites (30/57 (53%) versus 14/121 (12%), P = 0.01). Some satellites probably represent intraspecimen metastases, while others do not. Any predictive model for occult regional lymph node metastases based on data from ERLD done less than 50 days after diagnosis may underestimate the prevalence of metastases.

SUMMARY PUVA therapy successfully cleared various dermatoses mainly confined to the palms and soles in 18 of 20 patients treated. The conditions treated were: plaque-type psoriasis, pustular psoriasis, endogenous eczema and persistent palmoplantar pustulosis. Seventeen patients were treated in a controlled study of PUVA therapy versus no treatment at all and in 16 of these patients the disease was cleared in the PUVA-treated areas while the untreated areas remained unchanged or deteriorated. Twelve of the 18 patients were maintained in a clear state by continued maintenance PUVA treatment over 6–31 months while 3 patients had a spontaneous remission and are free of disease off all treatment.

A 2.1-year prospective study of 1373 patients given oral 8-methoxypsoralen photochemotherapy for psoriasis revealed 30 patients with a total of 48 basal-cell and squamous-cell carcinomas. The observed incidence of cutaneous carcinoma was 2.63 (95 per cent confidence limits = 1.91 to 3.90) times that expected for an age, sex and geographically matched population. Relative risk to patients with history of ionizing radiation was 3.68 (99 per cent confidence limits, 2.42 to 8.69). Patients with a previous cutaneous carcinoma had a relative risk of 10.22 (99 per cent confidence limits, 4.78 to 37.08). A higher than expected proportion of squamous-cell carcinomas and an excess of squamous-cell carcinomas in areas not exposed to sun were seen. New patients with known histories of ionizing-radiation exposure or of skin tumors should be given 8-methyoxypsoralen photochemotherapy only if they understand the risks and have disabling psoriasis untreatable by other means. (N Engl J Med 300:809–813, 1979)

Thirty patients with psoriasis were treated with a 3-week course of methotrexate followed by a combination of PUVA therapy and methotrexate. When lesions cleared to less than 1% UVA-exposed body involvement, the methotrexate was stopped and PUVA therapy alone was used as maintenance therapy. This protocol achieved clearance of disease in twenty-eight of the thirty patients in a mean of 5.7 (+/- 1.0) weeks, with 9.3 (+/- 3.0) exposures to PUVA therapy and a final UVA radiation dose at clearance of 6.2 (+/- 2.5) J/cm2. The mean total dose of methotrexate was 93.0 mg (range, 67.5-127.5 mg). The only significant adverse effect seen was prolonged phototoxicity in eight patients. By reducing the total cumulative exposure dose of PUVA therapy, this treatment may reduce long-term side effects.

Dysplastic melanocytic nevi (DMN) are distinguished histologically by a hyperplasia of variably atypical intraepidermal melanocytes in a lentiginous epidermal pattern. In order to further characterize the intraepidermal melanocytes of DMN, 4 representative specimens each of DMN, acquired nevocellular nevi (NCN), solar lentigines (SL), and superficial spreading melanoma (SSM) were selected on the basis of predetermined criteria, confirmed in a blind histologic assessment, and compared in a quantitative morphologic study using 6 micron-thick hematoxylin and eosin stained sections of L-dihydroxyphenylalanine (dopa) preincubated vertical tissue slices of lesion and adjacent normal skin. The average melanocyte frequency, expressed as the percent of dopa-reactive perikarya among 600 consecutive basal unit cells, was significantly greater in DMN (60 +/- 23%) than in NCN (18 +/- 3%), SL (25 +/- 7%), and adjacent skin (14 +/- 3%), but similar to that in SSM (71 +/- 11%). The average mean diameter of 200 consecutive epidermal basal unit melanocytes was significantly larger in DMN (11 +/- 2 microns) than in NCN (7 +/- 0.4 microns), SL (6 +/- 0.1 microns), and adjacent skin (6 +/- 0.4 microns), but significantly smaller than in SSM (16 +/- 3 microns). The observed similarities of intraepidermal melanocytes in selected DMN and SSM, as well as distinct differences from melanocytes in selected NCN and SL, support the hypothesis that some varieties of DMN may represent potential precursors of cutaneous melanoma.

Between 1976 and 1980, 136 patients were evaluated for primary treatment of cutaneous melanoma. Forty-nine lesions were invasive to Clark's Level II (38 patients) or III (II patients) with a thickness of 0.3 to 1.2 mm. Conservative re-excision was advised as definitive therapy for these patients. The margin of resection was defined as the maximum excision that would allow primary closure of the wound. Pathology reports of the re-excised specimens revealed the narrowest margins to be 0.7 to 4 cm. Unexpected residual tumor was present in 2 specimens and melanocytic hyperplasia in 12 specimens. After a follow-up period of 2.5 to 7.0 years, there have been no local recurrences. One patient developed regional lymph node metastases 16 months and, then central nervous system (CNS) metastases 25 months after primary treatment. A second patient died with pulmonary metastases 4.5 years after initial therapy. Melanomas that are not deeply invasive do not require wide excision and skin grafting for local control. Occasionally these thin lesions do produce systemic metastases, emphasizing the need for long-term follow-up of even “low-risk” patients. Cancer53:1256–1259, 1984. Cancer 53:1256-1259, 1984.

The lesions of 163 patients with superficial spreading melanoma (SSM) were examined for the presence of white, depressed areas; and lesions with and without these areas of "regression" were compared. There was no statistically significant correlation with the histological level of invasion (Clark-Mihm), sex or age of the patient, location of the melanoma, or presence of local, intransit or regional lymph node metastases. It is apparent from examining the recurrence rate and patient survival, that white depressed areas in an SSM are not of prognostic importance. There was a striking correlation of the presence of white depressed areas with the size of the area covered by the malignant melanoma (p less than or equal to 0.001).

Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%).

A 5.7-year prospective study of 1380 patients treated for psoriasis with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA) revealed that after adjustment for exposures to ionizing radiation and topical tar preparations, the risk that cutaneous squamous-cell carcinoma would develop at least 22 months after the first exposure to PUVA was 12.8 times higher in patients exposed to a high dose than in those exposed to a low dose (95 per cent confidence interval, 5.8 to 28.5). No substantial dose-related increase was noted for basal-cell carcinoma. The dose-dependent risk of cutaneous squamous-cell carcinoma suggests that PUVA can act as an independent carcinogen. In our study, morbidity associated with these tumors has been limited, but further follow-up is needed. Meanwhile, patients treated with PUVA should be followed closely for the possible development of cutaneous squamous-cell carcinoma.

Tumor-free hyperpigmented skin from a patient with diffuse melanosis secondary to metastatic melanoma was examined by light and electron microscopy. Our findings indicate that the pathogenesis of this diffuse slate blue color is due primarily to pigment deposition within perivascular dermal macrophages. We did not find intact melanosomes or individual tumor cell metastases in clinically normal skin, as has been previously reported.

To determine the extent of clinical actinic damage that occurred in association with exposure to oral methoxsalen photochemotherapy (PUVA), dermatologists at 16 university centers assessed the wrinkling, telangiectasia, and altered skin markings on the buttocks and the dorsa of the hands among 1380 patients treated with PUVA. These changes are similar to those seen in skin that is chronically exposed to sunlight. After more than 5 years of prospective study, patients with psoriasis exposed to PUVA showed a significant dose-dependent increase in the prevalence of clinical actinic degeneration of the skin of the buttocks (p less than .05, F-test). The prevalence of moderate or severe change among those patients exposed to high doses of PUVA (more than 160 treatments) was low (11%). The degree of increased clinical actinic degeneration noted on the dorsa of the hands was also significantly related to total exposure to PUVA (p less than .05, F-test). Our findings indicate that long-term PUVA exposure is associated with an increase in clinical actinic degeneration of the skin. However, the magnitude of this increase is small and, after more than 5 years, is of limited clinical consequence to most patients.

The visible cutaneous pigmentary response to ultraviolet-A (UVA) is immediate and, following sufficient exposure, may persist, whereas ultraviolet-B (UVB)-induced pigmentation appears after a delay of several days. We compared the in vivo response of melanocytes to single and multiple exposures of narrow band UVA and UVB irradiation which produced visibly equal increases in pigmentation. Using a xenon-mercury source matched to a monochromator, human volunteers were exposed to 304 (+/- 5) and 365 (+/- 10) nm radiation. Biopsies were performed 1, 7, and 14 days after irradiation. For each biopsy, the number of melanocytes per square millimeter of epidermis was determined using L-3,4-dihydroxyphenylalanine (dopa)- and tyrosine-incubated split epidermal preparations. Vertical sections were also examined. At days 7 and 14, after both 304 and 365 nm radiation, melanocytes were more intensely dopa-positive than in unirradiated controls, and demonstrated enlarged perikarya and a greater number of enlarged dendrites. Following both 304 and 365 nm radiation the number of dopa-positive melanocytes was increased at days 7 and 14 by 44% and 58%, respectively. Tyrosine positivity, an indicator of enhanced tyrosinase activity and increased melanin formation, was absent in controls and at day 1, and became positive in all but one sample at day 7 and day 14. Therefore, one day after UVA exposure, visible pigmentation but not tyrosinase activity was increased. At day 7, the number of tyrosine-positive melanocytes approximately equaled the number of dopa-positive melanocytes. Although UVA and UVB induce different pigmentary responses, their effects on melanocyte number and function were indistinguishable.

To investigate the usefulness of melanin macroglobules (MMG) as a cellular marker for neurofibromatosis, their density was quantified in biopsies of café-au-lait spots (macules) (CALM) from 22 patients with von Recklinghausen's neurofibromatosis, 6 patients with bilateral acoustic neurofibromatosis, and 19 controls. The density of MMG was significantly higher in biopsies of the CALM of patients with von Recklinghausen's neurofibromatosis than in patients with bilateral acoustic neurofibromatosis (p less than .01) or controls (p less than .0008). The mode of acquisition of von Recklinghausen's neurofibromatosis (inherited vs new mutation) was not related to the density of MMG. On light microscopy, 14/22 (64%) patients with von Recklinghausen's neurofibromatosis had 11 or more MMG per 5 high-power fields. In contrast, none of the other two groups had more than 10 MMG per 5 high-power fields.

Fifteen variables were tested for their value in predicting recurrent disease in 46 clinical Stage I melanoma patients with metastases to regional nodes. A stepwise proportional hazards general linear model (Cox multivariate analysis) separated these melanoma patients with regional node metastases into at least two risk groups. Twenty patients in the relatively low-risk group had a five-year disease-free survival of 80% (in spite of having nodal metastases). This compares to a five-year disease-free survival of 17.5% for 26 patients in the high-risk group (P less than 0.001, Lee-Desu Statistic). Criteria for the high-risk group required that a patient have only one of the following two values: (1) The number of regional lymph nodes that contained tumor divided by the total number of nodes removed x 100% (percentage of positive nodes) greater than or equal to 20%; or (2) a primary tumor thickness of greater than 3.5 mm (regardless of node percentage). Conversely, patients in the low-risk group had neither of the above features. The high-risk group could further be stratified by the lymphocytic response at the base of the tumor. These findings have direct immediate application to the elective regional node dissection controversy and to adjuvant therapy studies containing these patients.

Melasma is a circumscribed brown macular hypermelanosis of the areas of the face and neck that are exposed to light. Clinical trials with various depigmenting formulations containing hydroquinone were conducted to determine the ideal concentration of hydroquinone, retinoic acid, and corticosteroids for the treatment of melasma. The compounds were tested with and without the concomitant use of topical sunscreen preparations. Based on the results of the trials and our earlier clinical experience, we conclude that treatment of melasma should involve the following: avoidance of sun exposure, constant use of broad-spectrum sunscreens, and topical application of a cream or lotion containing 2% hydroquinone and 0.05% to 0.1% retinoic acid (tretinoin). Patients should suspend use of oral contraceptives and other agents that promote skin pigmentation. The monobenzyl ether of hydroquinone should never be used in melasma therapy.