ABCD syndrome

Hyperpigmentation usually can be traced to the presence and activity of melanocytes. Part I of this two-part article presents a suggested approach to patients with increased pigmentation. Part II continues the review of conditions associated with hyperpigmentation.

New, Changing, or Symptomatic Localized Lesions

A localized hyperpigmented or irregularly pigmented lesion that is new in onset, arises within a congenital nevus, or causes pain or itching could be a malignant melanoma (Figures 1 through 3). The American Cancer Society has developed useful guidelines for identifying suspicious nevi (Table 1). (1) [Evidence level C, consensus/expert guidelines]

When possible, suspicious lesions should be excised totally for pathologic evaluation. If size or location precludes complete excision, incisional biopsy (usually punch biopsy) is performed. (2)

Seborrheic keratoses are localized, benign, hyperplastic, hyperpigmented lesions that may mimic melanomas. The hyperpigmentation is associated with hyperplasia of melanocytes. (3) Experienced physicians usually can differentiate seborrheic keratoses based on their sharp borders; tan, brown, or black color; and typical appearance. These lesions have a "stuck-on" appearance, with a surface that is rough and craggy (Figure 4, left) or smooth with small keratin "pearls" (Figure 4, right). (4)

If seborrheic keratoses are symptomatic or there is a question about possible malignancy, the lesions should be removed and sent for pathologic evaluation.

Acanthosis Nigricans

Acanthosis nigricans, usually related to insulin resistance or obesity, ranges in appearance from a thickened, velvety brown streaking to a leathery, verrucous, papillomatous lesion (Table 2). The condition commonly occurs on the neck or in skin folds (e.g., in the axilla, under the breast, at the belt line, in the groin), but it may develop in other parts of the body. Patients with this condition may complain that they have a "dirty area" that cannot be cleansed (Figure 5).

Microscopically, acanthosis nigricans is characterized by an increased number of melanocytes, with papillary hypertrophy and hyperkeratosis. (5) Associated hypertrophy and hyperkeratosis cause acanthosis nigricans to be palpable rather than macular.

It is important for physicians to recognize acanthosis nigricans, because the condition can be associated with insulin resistance (as occurs in type 2 diabetes and polycystic ovary syndrome), obesity and, occasionally, malignancy. Type 2 diabetes is increasing in incidence in the United States, especially among black and hispanic children; 60 to 92 percent of these children have acanthosis nigricans. (6) According to one study (7) that compared 50 children with type 2 diabetes and 50 children with type 1 diabetes, acanthosis nigricans was present in 86 percent of the children with type 2 diabetes but in none of the children with type 1 diabetes. (7) [Evidence level B, retrospective cohort study]

If a patient rapidly develops acanthosis nigricans, especially on the palms or soles, occult malignancy is a possibility. A thorough physical examination, a review of systems, a complete blood count, fecal occult blood testing, and chest radiography should be considered if the patient does not fit the typical clinical pattern of insulin resistance. (8) [Evidence level C, consensus/expert guidelines] Adenocarcinomas are the most common malignancies found in patients with acanthosis nigricans; the tumors are most often present in the stomach (60 percent), followed by the colon, ovary, pancreas, rectum, and uterus. (9)

Treatment of acanthosis nigricans is directed at the underlying cause, rather than the appearance of the skin. If present, insulin resistance should be managed appropriately. Screening for hypercholesterolemia and coronary artery disease may be appropriate, depending on the clinical picture.

Melasma

Pregnancy or the use of hormones (e.g., oral contraceptive pills) can cause melasma, a localized facial hyperpigmentation (Figure 6). Melasma may be seen in patients who take phenytoin (Dilantin). While melasma may regress after pregnancy, it may increase with each subsequent pregnancy and become quite obvious. Because of the facial location, melasma may be quite disturbing to patients.

Frequently called the "mask of pregnancy," melasma (chloasma) differs from the ruborous glow of pregnancy. Histologically, women who have this condition develop an increased number of melanocytes, with the deposition of additional melanin and a background of solar elastosis, typically on the cheeks, forehead, and upper lip. (10) Examination using a Wood's light in a darkened room demonstrates enhanced contrast if hyperpigmentation affects the epidermal layer of skin. (11)

Patients with hyperpigmentation of the superficial epidermal layer who desire treatment may attempt a trial of bleaching agents after patch testing elsewhere on the body to confirm low levels of inflammation. Use of bleaching agents on inflamed skin could lead to postinflammatory changes and further hyperpigmentation.

Tretinoin 0.1 percent (Retin-A) cream and hydroquinone (Eldoquin Forte), a bleaching agent available in 2 to 4 percent creams and gels, have been the mainstays of topical treatment. Combining tretinoin and hydroquinone (applied at different times during the day) can potentiate the effect.

A new medication that contains tretinoin, hydroquinone, and fluocinolone acetonide (Tri-Luma) has been effective in the treatment of melasma. In a company-sponsored, double-blind, randomized controlled trial of the triple-combination agent, 77 percent of patients showed complete or nearly complete clearing of melasma, compared with 47 percent for hydroquinone and tretinoin, 42 percent for fluocinolone acetonide and hydroquinone, and 27 percent for tretinoin and fluocinolone acetonide. (12) [Evidence level B, lower quality randomized controlled trial] The triple-combination agent should be applied daily, 30 minutes before bedtime. Azelaic acid (20 percent), kojic acid formulations, and alpha-hydroxy acids also have been useful in the treatment of melasma. (13)

Side effects of all topical treatments include allergic and contact dermatitis, depigmentation of surrounding normal skin, and postinflammatory hyperpigmentation. Tretinoin alone or combined with hydroquinone and fluocinolone acetonide should not be used during pregnancy.

If no increase in contrast is seen with use of the Wood's light, the deeper dermal tissues usually are involved, and bleaching agents will not help. (11) Laser therapy may be used for superficial epidermal or deeper dermal melasma, but strict avoidance of sun exposure is important to prevent recurrence. (14) [Evidence level C, expert opinion]

Diabetic Dermopathy

Diabetic dermopathy (pigmented pretibial papules) develops in up to 70 percent of patients with diabetes. (15) This condition usually affects the skin of the anterior tibial area, where it starts as a papular pink or brown eruption and progresses to a macular, sometimes confluent, brown dermatitis, with the coloration caused by hemosiderin deposition (Figure 7). The exact cause of the lesions is unknown.

The lesions of diabetic dermopathy may resolve spontaneously, even as new lesions arise. Treatment should focus on the patient's diabetes. No treatment for the asymptomatic cutaneous lesions is effective or recommended. (16)

Tinea Versicolor

While tinea versicolor is not truly a hyperpigmentation disorder, it is included in this review because affected skin on the trunk may appear darker than normal. Tinea versicolor rarely occurs until after adolescence, when production of sebum increases, especially in the skin of the anterior trunk and back. The increased sebum production allows the proliferation of Pityrosporum ovale or Pityrosporum orbiculare (Malassezia furfur), (17) which can cause a brown, pink, or reddish discoloration of the skin.

Technically a papulosquamous eruption, tinea versicolor presents as numerous macules or slightly raised papules with subtle scale. Patients may have a coalescence of lesions or a single patch with an irregular border. The lesions of tinea versicolor may be several centimeters in diameter, or they may cover most of the trunk.

Over time, the Pityrosporum species can block the conversion of tyrosine to melanin, (18) leading to hypopigmented patches instead of increased coloration. The scale on the surface of the affected skin (Figure 8) and the "spaghetti and meatball" appearance of fungal forms on a potassium hydroxide preparation help to clarify the diagnosis.

Tinea versicolor may be treated with topical selenium sulfide shampoo in a daily or weekly treatment regimen. Once a day for one week, the selenium sulfide shampoo is allowed to dry on the affected skin for 10 minutes before the patient showers. Alternatively, once a week for four weeks, the selenium sulfide shampoo is left on the skin for 12 to 24 hours, after which time the patient showers.

Topical antifungal agents (e.g., allylamines, azoles, undecenoic acid) also are effective therapies for tinea versicolor. (19) [Evidence level A, Cochrane review] Because of the amount of topical medication required and the length of treatment (several weeks), orally administered agents have been studied and found to be effective. (20) [Evidence level A, Cochrane review] A 2 percent ketoconazole shampoo, left in place for five minutes, has been shown to have a cure rate of 69 percent after one application. (21)

Postinflammatory Hyperpigmentation

Trauma (physical or chemical injury), skin irritation, and dermatoses can lead to postinflammatory hyperpigmentation or hypopigmentation in persons of any age. Investigators in one study (22) theorized that some persons have an inherited tendency for weak melanocytes that respond to inflammation by decreasing melanin production, or for strong melanocytes that respond by increasing melanin production. While more effect is evident when lighter-skinned persons respond with hyperpigmentation (Figure 9) or darker-skinned persons respond with hypopigmentation, persons of all races can respond to inflammation with hyperpigmentation or hypopigmentation.

With time and resolution of the inflammation, the pigmentary changes usually tend to normalize. If cosmesis is desired, it should be performed by a physician with experience in cosmetic dermatology, because treatments such as bleaching agents can cause further postinflammatory pigmentary changes.

REFERENCES

(1.) What you should know about melanoma. Atlanta: American Cancer Society, 1999.

(2.) Goldstein BG, Goldstein AO. Diagnosis and management of malignant melanoma. Am Fam Physician 2001;63:1359-68,1374.

(3.) Jimbow K, Quevedo WC Jr, Fitzpatrick TB, Szabo G. Biology of melanocytes. In: Freedberg IM, Fitzpatrick TB, eds. Fitzpatrick's Dermatology in general medicine. 4th ed. New York: McGraw-Hill, 1993:261-89.

(4.) Benign skin tumors. In: Habif TP. Clinical dermatology: a color guide to diagnosis and therapy. 3d ed. St. Louis: Mosby, 1996:627-48.

(5.) Paron NG, Lambert PW. Cutaneous manifestations of diabetes mellitus. Prim Care 2000;27:371-83.

(6.) Dabelea D, Pettitt DJ, Jones KL, Arslanian SA. Type 2 diabetes mellitus in minority children and adolescents. An emerging problem. Endocrinol Metab Clin North Am 1999;28:709-29,viii.

(7.) Scott CR, Smith JM, Cradock MM, Pihoker C. Characteristics of youth-onset noninsulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus at diagnosis. Pediatrics 1997;100: 84-91.

(8.) Kim NY, Pandya AG. Pigmentary diseases. Med Clin North Am 1998;82:1185-207.

(9.) Rendon MI, Cruz PD Jr, Sontheimer RD, Bergstresser PR. Acanthosis nigricans: a cutaneous marker of tissue resistance to insulin. J Am Acad Dermatol 1989;21(3 pt 1):461-9.

(10.) Kang WH, Yoon KH, Lee ES, Kim J, Lee KB, Yim H, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol 2002;146:228-37.

(11.) Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol 2001;45:1-19.

(12.) Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis 2003;72:67-72.

(13.) Grimes PE. Skin and hair cosmetic issues in women of color. Dermatol Clin 2000;18:659-65.

(14.) Dover JS, Arndt KA, Dinehart SM, Fitzpatrick RE, Gonzalez E. Guidelines of care for laser surgery. American Academy of Dermatology Guidelines/ Outcomes Committee. J Am Acad Dermatol 1999; 41(3 pt 1):484-95.

(15.) Sibbald RG, Landolt SJ, Toth D. Skin and diabetes. Endocrinol Metab Clin North Am 1996;25:463-72.

(16.) Ferringer T, Miller F 3d. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002;20:483-92.

(17.) Faergemann J. Pityrosporum infections. J Am Acad Dermatol 1994;31(3 pt 2):S18-20.

(18.) Nazzaro-Porro M, Passi S. Identification of tyrosinase inhibitors in cultures of Pityrosporum. J Invest Dermatol 1978;71:205-8.

(19.) Crawford F, Hart R, Bell-Syer S, Torgerson D, Young P, Russell I. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev 2003;(2):CD001434.

(20.) Bell-Syer SE, Hart R, Crawford F, Torgerson DJ, Tyrrell W, Russell I. Oral treatments for fungal infections of the skin of the foot. Cochrane Database Syst Rev 2003;(2):CD003584.

(21.) Lange DS, Richards HM, Guarnieri J, Humeniuk JM, Savin RC, Reyes BA, et al. Ketoconazole 2% shampoo in the treatment of tinea versicolor: a multicenter, randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 1998;39:944-50.

(22.) Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and hyperpigmentation. Semin Cutan Med Surg 1997;16:36-43.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

Figures 1 and 4 through 9 from the Utah Valley Family Practice Residency Program, Provo. Figure 2 from the Skin Cancer Foundation, New York City. Figure 3 from Adam Goldstein, M.D., University of North Carolina at Chapel Hill School of Medicine.

This is part II of a two-part article on hyperpigmentation in adults. Part I, "Diagnostic Approach, Cafe au Lait Macules, Diffuse Hyperpigmentation, Sun Exposure, and Phototoxic Reactions," appears in this issue on page 1955.

This article is one in a series coordinated by Daniel L. Stulberg, M.D., director of dermatology curriculum at the Utah Valley Family Practice Residency Program, Provo, Utah.

DANIEL L. STULBERG, M.D., and NICOLE CLARK, M.D., Utah Valley Family Practice Residency Program, Provo, Utah

DANIEL TOVEY, M.D., Intermountain Health Care Health Center, Springville, Utah

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