Pigmentation Disorders

Frictional asymptomatic darkening of the extensor surfaces (FADES) is commonly seen in our practice but has not been well characterized in the dermatologic literature. We can find no mention of frictional dermatitis or hyperkeratosis of the elbows and knees in any of the major textbooks of dermatology.1-6 Young to middle-aged adults present with asymptomatic "dirty" brown pigmentation over the extensor surfaces of their elbows and knees, which the patients find cosmetically objectionable. The lesions are generally uniform and bilateral, with little evidence of scaling. A positive family history and a history of frictional stress to the involved areas can be elicited in some cases. Patients deny any symptoms of pain or pruritus, as well as exposure to contact allergens or a personal or family history of psoriasis vulgaris. We collected data from 9 patients diagnosed with FADES, including detailed histories, biopsy results, and treatment outcomes. The cases of 4 representative patients are discussed. 

Case Reports
Patient 1—A 47-year-old white woman presented with brownish discoloration of her knees and elbows of 5 years' duration. The left knee and both elbows showed darkening. She denied any pain, pruritus, history of trauma, family history, or contact allergen exposure. The patient reported kneeling on her left knee when working around the house. She was unable to kneel on her right knee because of pain associated with osteoarthritis. There was no history of diabetes mellitus or obesity. Results of a physical examination revealed a 3-cm area of brownish discoloration along the extensor surface of her left knee without any erythema or scaling (Figure 1). The skin over the right knee appeared normal. Similar but milder changes were noted on the extensor surfaces of her elbows bilaterally. No evidence of the velvety hyperpigmentation of acanthosis nigricans was present in flexural areas. Treatment with lactic acid 12% cream twice a day for 3 months led to slow steady improvement, which was quite satisfying to the patient, but the dark coloration was not totally eliminated.

Patient 2—A 58-year-old white man presented with "dirty" brown discoloration of his elbows bilaterally of 40 years' duration. He denied any pain or pruritus. No precipitating, exacerbating, or relieving factors were elicited. His medical history was significant for hypertension and arthritis. There was no history of diabetes mellitus or obesity. Family history was significant for the same condition in his mother and daughter. Results of a physical examination revealed a 4- to 5-cm macular area of brown discoloration along the extensor surfaces of each elbow without any erythema or scaling (Figure 2). No evidence of acanthosis nigricans was present in flexural areas. Results of a 4-mm punch biopsy on his left elbow revealed benign papillomatosis with acanthosis, hyperkeratosis, and no significant inflammation (Figure 3). Treatment was initiated with urea 40% cream twice a day for 3 to 4 months with gradual improvement of the discoloration leading to overall mild to moderate improvement.

Patient 3—A 32-year-old white woman presented with "dirty" brown discoloration of her elbows and knees of 7 years' duration without associated pain or pruritus. She noted that the area on her knees appeared darker after several days of scrubbing the floors on her knees. Family history was positive for similar lesions on her father's elbows. There was no history of diabetes mellitus. Unsuccessful treatments included over-the-counter vitamin E lotion. Results of a physical examination revealed hyperpigmentation and lichenification with very mild scaling on the extensor surfaces of her knees (Figure 4) and elbows bilaterally. The changes were more pronounced on her knees than her elbows. There was no evidence of acanthosis nigricans in flexural areas. Results of a 4-mm punch biopsy on her right knee revealed benign papillomatosis with acanthosis and hyperkeratosis without any significant atypia, intradermal melanin deposition, or inflammation. She was treated with urea 40% cream once a day and instructed to advance to twice-a-day treatment if tolerated. No improvement was noted after one month of treatment, and she refused further treatment suggestions.

Patient 4—A 68-year-old white man presented with asymptomatic brown discoloration of his elbows and knees bilaterally of 20 years' duration. He denied any known precipitating factors but stated that he worked on his elbows and knees a lot when gardening. There was no history of diabetes mellitus or obesity. Unsuccessful treatments included intermittent use of over-the-counter Udderly SMOOth® Udder Cream for 3 to 4 years without any noticeable improvement. Family history was significant for similar lesions on his son's knees. Results of a physical examination revealed mildly hyperpigmented erythematous patches bilaterally on the extensor surfaces of his knees (Figure 5) and, to a lesser degree, on his elbows without any scaling. No evidence of acanthosis nigricans was present in flexural areas. Treatment was initiated with lactic acid 12% cream twice a day. After 3 years of daily use, the brown discoloration improved by 75% to 80%.

Comment To our knowledge, this is the first report in the United States of FADES. "Dirty" brown discoloration is noted over the extensor surfaces in areas prone to frictional stress. Pain and pruritus are uniformly absent. Biopsy results of these lesions reveal mild papillomatosis with acanthosis and hyperkeratosis, with minimal underlying inflammation (Figure 3). Melanin deposition in the dermis is not identified as is commonly seen in postinflammatory hyperpigmentation (PIH). Spongiosis typical of eczema and psoriasiform hyperplasia typical of psoriasis are not present. We chose to use the word darkening in the name rather than hyperpigmentationbecause the color change in this condition is a result of papillomatosis, acanthosis, and hyperkeratosis rather than excess melanin pigment. The pathology also led us to use keratolytic agents as treatment rather than hydroquinone-based fade creams. In most cases of FADES, treatment with lactic acid 12% or urea 40% cream over 3 to 6 months is at least partially effective (Table).

A review of world literature reveals several cases that may be similar to FADES. In 1954, Ber7 reported "dirty" brown patches of hyperkeratosis of the elbows and knees, which he named "the sign of dirty knees and elbows," as an early clinical sign of mild hypothyroidism in adults and children. No mention is made of frictional stress in these patients.7 None of the patients we describe with FADES has a history of hypothyroidism. There have been several reports of dermatoses secondary to occupational frictional stress. Wahlberg⁸ described cases of asymptomatic hyperkeratosis on the dorsal hands and feet of Swedish carpet installers thought to be secondary to friction. Menne and Hjorth9 described cases of red, scaly, vesicular, and pustular dermatoses on the palms and fingertips of workers handling pressure-sensitive carbonless paper in Denmark. The condition typically cured in a few weeks by avoidance of frictional trauma. Menne10 also described a similar dermatitis on the palms of post office workers caused by prolonged rubbing against a rough plastic table. Physicians in Jordan,11 Mexico,12 Iraq,13 Japan,14-16 and Italy17 also described cases of skin darkening that they termed friction melanosis,11,12,14,16,17 friction dermal melanosis (lifa disease),13 and nylon clothes friction dermatoses.15 These patients presented with asymptomatic brownish patches over bony prominences that were associated with long-term rubbing with scrub pads (sedge pads,12 lifas13), clothing,12 nylon towels,14-16 and horsehair gloves.17 Most of these cases, however, occurred predominantly in young thin women and involved the skin overlying the clavicle, vertebra, lateral neck, and upper back. This differs from FADES, which appears to be equally prevalent among men and women, affects young to middle-aged adults of average body weight, and presents with discoloration of the extensor surfaces of the elbows and knees. Most significantly, results of histopathologic examinations in frictional melanosis demonstrate increased melanin deposition within the epidermis and dermal macrophages. Our patients with FADES failed to show evidence of an increase in dermal melanin pigment. This histologic difference might relate to the fact that friction more easily produces PIH in patients with darker skin types in Jordan, Mexico, Iraq, Japan, and Italy. Iwasaki et al18 described a case of biphasic amyloidosis arising from friction melanosis in a Japanese woman with a history of long-term use of nylon towels. The brown asymptomatic hyperpigmentation on the woman's back, characteristic of friction melanosis, became gradually more itchy and associated with several small papules. The results of biopsy specimens taken from both the papular and macular pigmented lesions on her back revealed dermal amyloid deposits. It appears that amyloid deposits are produced by the same frictional stress that causes friction melanosis.18,19 Our patients with FADES showed no evidence of amyloidosis. Acanthosis nigricans involving the elbows, knees, and knuckle pads in patients with diabetes mellitus and obesity rarely has been described.20,21 None of our FADES patients had a history of diabetes mellitus, obesity, or hyperpigmentation involving the neck or axilla, which are commonly involved in acanthosis nigricans. FADES can be distinguished easily from conditions that produce brown discoloration, including lichen simplex chronicus, macular amyloidosis, terra firma-forme dermatosis, PIH, psoriasis, acanthosis nigricans and pseudoacanthosis nigricans, reticular and confluent papillomatosis of Gougerot and Carteaud, and X-linked ichthyosis.22 Patients with lichen simplex chronicus23 and macular amyloidosis24 can be distinguished from patients with FADES because they have severe pruritus, xerosis, history of atopy, and specific distinguishing histopathologic changes. Terra firma-forme dermatosis is not caused by friction but is related to a buildup of dirt and scale in areas that are not scrubbed.25-27 This condition is not found on the extensor surfaces, and the patches rub off with alcohol. PIH is caused by melanin deposition within melanophages in the papillary dermis rather than by the epidermal changes of FADES.28 Psoriasis occurs on extensor surfaces but has thick, white, micaceous scaling and psoriasiform hyperplasia of the epidermis. Acanthosis nigricans and pseudoacanthosis nigricans involve flexural areas rather than the extensor surfaces.29 Reticular and confluent papillomatosis of Gougerot and Carteaud involves the central upper back or chest rather than the extensor surfaces.30 X-linked ichthyosis can be distinguished from FADES because it shows considerable scaling, involves the flexural surfaces of the extremities, occurs in young adulthood, and is restricted to men. We believe FADES is a common condition that easily can be recognized and differentiated from other conditions with skin darkening. A biopsy rarely is required. Treatment with keratolytic agents and avoidance of frictional stress are modestly effective in some cases. 

Frictional asymptomatic darkening of the extensor surfaces (FADES) is commonly seen in our practice but has not been well characterized in the dermatologic literature. We can find no mention of frictional dermatitis or hyperkeratosis of the elbows and knees in any of the major textbooks of dermatology.1-6 Young to middle-aged adults present with asymptomatic "dirty" brown pigmentation over the extensor surfaces of their elbows and knees, which the patients find cosmetically objectionable. The lesions are generally uniform and bilateral, with little evidence of scaling. A positive family history and a history of frictional stress to the involved areas can be elicited in some cases. Patients deny any symptoms of pain or pruritus, as well as exposure to contact allergens or a personal or family history of psoriasis vulgaris. We collected data from 9 patients diagnosed with FADES, including detailed histories, biopsy results, and treatment outcomes. The cases of 4 representative patients are discussed. 

Case Reports
Patient 1—A 47-year-old white woman presented with brownish discoloration of her knees and elbows of 5 years' duration. The left knee and both elbows showed darkening. She denied any pain, pruritus, history of trauma, family history, or contact allergen exposure. The patient reported kneeling on her left knee when working around the house. She was unable to kneel on her right knee because of pain associated with osteoarthritis. There was no history of diabetes mellitus or obesity. Results of a physical examination revealed a 3-cm area of brownish discoloration along the extensor surface of her left knee without any erythema or scaling (Figure 1). The skin over the right knee appeared normal. Similar but milder changes were noted on the extensor surfaces of her elbows bilaterally. No evidence of the velvety hyperpigmentation of acanthosis nigricans was present in flexural areas. Treatment with lactic acid 12% cream twice a day for 3 months led to slow steady improvement, which was quite satisfying to the patient, but the dark coloration was not totally eliminated.

Patient 2—A 58-year-old white man presented with "dirty" brown discoloration of his elbows bilaterally of 40 years' duration. He denied any pain or pruritus. No precipitating, exacerbating, or relieving factors were elicited. His medical history was significant for hypertension and arthritis. There was no history of diabetes mellitus or obesity. Family history was significant for the same condition in his mother and daughter. Results of a physical examination revealed a 4- to 5-cm macular area of brown discoloration along the extensor surfaces of each elbow without any erythema or scaling (Figure 2). No evidence of acanthosis nigricans was present in flexural areas. Results of a 4-mm punch biopsy on his left elbow revealed benign papillomatosis with acanthosis, hyperkeratosis, and no significant inflammation (Figure 3). Treatment was initiated with urea 40% cream twice a day for 3 to 4 months with gradual improvement of the discoloration leading to overall mild to moderate improvement.

Patient 3—A 32-year-old white woman presented with "dirty" brown discoloration of her elbows and knees of 7 years' duration without associated pain or pruritus. She noted that the area on her knees appeared darker after several days of scrubbing the floors on her knees. Family history was positive for similar lesions on her father's elbows. There was no history of diabetes mellitus. Unsuccessful treatments included over-the-counter vitamin E lotion. Results of a physical examination revealed hyperpigmentation and lichenification with very mild scaling on the extensor surfaces of her knees (Figure 4) and elbows bilaterally. The changes were more pronounced on her knees than her elbows. There was no evidence of acanthosis nigricans in flexural areas. Results of a 4-mm punch biopsy on her right knee revealed benign papillomatosis with acanthosis and hyperkeratosis without any significant atypia, intradermal melanin deposition, or inflammation. She was treated with urea 40% cream once a day and instructed to advance to twice-a-day treatment if tolerated. No improvement was noted after one month of treatment, and she refused further treatment suggestions.

Patient 4—A 68-year-old white man presented with asymptomatic brown discoloration of his elbows and knees bilaterally of 20 years' duration. He denied any known precipitating factors but stated that he worked on his elbows and knees a lot when gardening. There was no history of diabetes mellitus or obesity. Unsuccessful treatments included intermittent use of over-the-counter Udderly SMOOth® Udder Cream for 3 to 4 years without any noticeable improvement. Family history was significant for similar lesions on his son's knees. Results of a physical examination revealed mildly hyperpigmented erythematous patches bilaterally on the extensor surfaces of his knees (Figure 5) and, to a lesser degree, on his elbows without any scaling. No evidence of acanthosis nigricans was present in flexural areas. Treatment was initiated with lactic acid 12% cream twice a day. After 3 years of daily use, the brown discoloration improved by 75% to 80%.

Comment To our knowledge, this is the first report in the United States of FADES. "Dirty" brown discoloration is noted over the extensor surfaces in areas prone to frictional stress. Pain and pruritus are uniformly absent. Biopsy results of these lesions reveal mild papillomatosis with acanthosis and hyperkeratosis, with minimal underlying inflammation (Figure 3). Melanin deposition in the dermis is not identified as is commonly seen in postinflammatory hyperpigmentation (PIH). Spongiosis typical of eczema and psoriasiform hyperplasia typical of psoriasis are not present. We chose to use the word darkening in the name rather than hyperpigmentationbecause the color change in this condition is a result of papillomatosis, acanthosis, and hyperkeratosis rather than excess melanin pigment. The pathology also led us to use keratolytic agents as treatment rather than hydroquinone-based fade creams. In most cases of FADES, treatment with lactic acid 12% or urea 40% cream over 3 to 6 months is at least partially effective (Table).

A review of world literature reveals several cases that may be similar to FADES. In 1954, Ber7 reported "dirty" brown patches of hyperkeratosis of the elbows and knees, which he named "the sign of dirty knees and elbows," as an early clinical sign of mild hypothyroidism in adults and children. No mention is made of frictional stress in these patients.7 None of the patients we describe with FADES has a history of hypothyroidism. There have been several reports of dermatoses secondary to occupational frictional stress. Wahlberg⁸ described cases of asymptomatic hyperkeratosis on the dorsal hands and feet of Swedish carpet installers thought to be secondary to friction. Menne and Hjorth9 described cases of red, scaly, vesicular, and pustular dermatoses on the palms and fingertips of workers handling pressure-sensitive carbonless paper in Denmark. The condition typically cured in a few weeks by avoidance of frictional trauma. Menne10 also described a similar dermatitis on the palms of post office workers caused by prolonged rubbing against a rough plastic table. Physicians in Jordan,11 Mexico,12 Iraq,13 Japan,14-16 and Italy17 also described cases of skin darkening that they termed friction melanosis,11,12,14,16,17 friction dermal melanosis (lifa disease),13 and nylon clothes friction dermatoses.15 These patients presented with asymptomatic brownish patches over bony prominences that were associated with long-term rubbing with scrub pads (sedge pads,12 lifas13), clothing,12 nylon towels,14-16 and horsehair gloves.17 Most of these cases, however, occurred predominantly in young thin women and involved the skin overlying the clavicle, vertebra, lateral neck, and upper back. This differs from FADES, which appears to be equally prevalent among men and women, affects young to middle-aged adults of average body weight, and presents with discoloration of the extensor surfaces of the elbows and knees. Most significantly, results of histopathologic examinations in frictional melanosis demonstrate increased melanin deposition within the epidermis and dermal macrophages. Our patients with FADES failed to show evidence of an increase in dermal melanin pigment. This histologic difference might relate to the fact that friction more easily produces PIH in patients with darker skin types in Jordan, Mexico, Iraq, Japan, and Italy. Iwasaki et al18 described a case of biphasic amyloidosis arising from friction melanosis in a Japanese woman with a history of long-term use of nylon towels. The brown asymptomatic hyperpigmentation on the woman's back, characteristic of friction melanosis, became gradually more itchy and associated with several small papules. The results of biopsy specimens taken from both the papular and macular pigmented lesions on her back revealed dermal amyloid deposits. It appears that amyloid deposits are produced by the same frictional stress that causes friction melanosis.18,19 Our patients with FADES showed no evidence of amyloidosis. Acanthosis nigricans involving the elbows, knees, and knuckle pads in patients with diabetes mellitus and obesity rarely has been described.20,21 None of our FADES patients had a history of diabetes mellitus, obesity, or hyperpigmentation involving the neck or axilla, which are commonly involved in acanthosis nigricans. FADES can be distinguished easily from conditions that produce brown discoloration, including lichen simplex chronicus, macular amyloidosis, terra firma-forme dermatosis, PIH, psoriasis, acanthosis nigricans and pseudoacanthosis nigricans, reticular and confluent papillomatosis of Gougerot and Carteaud, and X-linked ichthyosis.22 Patients with lichen simplex chronicus23 and macular amyloidosis24 can be distinguished from patients with FADES because they have severe pruritus, xerosis, history of atopy, and specific distinguishing histopathologic changes. Terra firma-forme dermatosis is not caused by friction but is related to a buildup of dirt and scale in areas that are not scrubbed.25-27 This condition is not found on the extensor surfaces, and the patches rub off with alcohol. PIH is caused by melanin deposition within melanophages in the papillary dermis rather than by the epidermal changes of FADES.28 Psoriasis occurs on extensor surfaces but has thick, white, micaceous scaling and psoriasiform hyperplasia of the epidermis. Acanthosis nigricans and pseudoacanthosis nigricans involve flexural areas rather than the extensor surfaces.29 Reticular and confluent papillomatosis of Gougerot and Carteaud involves the central upper back or chest rather than the extensor surfaces.30 X-linked ichthyosis can be distinguished from FADES because it shows considerable scaling, involves the flexural surfaces of the extremities, occurs in young adulthood, and is restricted to men. We believe FADES is a common condition that easily can be recognized and differentiated from other conditions with skin darkening. A biopsy rarely is required. Treatment with keratolytic agents and avoidance of frictional stress are modestly effective in some cases. 

Frictional asymptomatic darkening of the extensor surfaces (FADES) is commonly seen in our practice but has not been well characterized in the dermatologic literature. We can find no mention of frictional dermatitis or hyperkeratosis of the elbows and knees in any of the major textbooks of dermatology.1-6 Young to middle-aged adults present with asymptomatic "dirty" brown pigmentation over the extensor surfaces of their elbows and knees, which the patients find cosmetically objectionable. The lesions are generally uniform and bilateral, with little evidence of scaling. A positive family history and a history of frictional stress to the involved areas can be elicited in some cases. Patients deny any symptoms of pain or pruritus, as well as exposure to contact allergens or a personal or family history of psoriasis vulgaris. We collected data from 9 patients diagnosed with FADES, including detailed histories, biopsy results, and treatment outcomes. The cases of 4 representative patients are discussed. 

Case Reports
Patient 1—A 47-year-old white woman presented with brownish discoloration of her knees and elbows of 5 years' duration. The left knee and both elbows showed darkening. She denied any pain, pruritus, history of trauma, family history, or contact allergen exposure. The patient reported kneeling on her left knee when working around the house. She was unable to kneel on her right knee because of pain associated with osteoarthritis. There was no history of diabetes mellitus or obesity. Results of a physical examination revealed a 3-cm area of brownish discoloration along the extensor surface of her left knee without any erythema or scaling (Figure 1). The skin over the right knee appeared normal. Similar but milder changes were noted on the extensor surfaces of her elbows bilaterally. No evidence of the velvety hyperpigmentation of acanthosis nigricans was present in flexural areas. Treatment with lactic acid 12% cream twice a day for 3 months led to slow steady improvement, which was quite satisfying to the patient, but the dark coloration was not totally eliminated.

Patient 2—A 58-year-old white man presented with "dirty" brown discoloration of his elbows bilaterally of 40 years' duration. He denied any pain or pruritus. No precipitating, exacerbating, or relieving factors were elicited. His medical history was significant for hypertension and arthritis. There was no history of diabetes mellitus or obesity. Family history was significant for the same condition in his mother and daughter. Results of a physical examination revealed a 4- to 5-cm macular area of brown discoloration along the extensor surfaces of each elbow without any erythema or scaling (Figure 2). No evidence of acanthosis nigricans was present in flexural areas. Results of a 4-mm punch biopsy on his left elbow revealed benign papillomatosis with acanthosis, hyperkeratosis, and no significant inflammation (Figure 3). Treatment was initiated with urea 40% cream twice a day for 3 to 4 months with gradual improvement of the discoloration leading to overall mild to moderate improvement.

Patient 3—A 32-year-old white woman presented with "dirty" brown discoloration of her elbows and knees of 7 years' duration without associated pain or pruritus. She noted that the area on her knees appeared darker after several days of scrubbing the floors on her knees. Family history was positive for similar lesions on her father's elbows. There was no history of diabetes mellitus. Unsuccessful treatments included over-the-counter vitamin E lotion. Results of a physical examination revealed hyperpigmentation and lichenification with very mild scaling on the extensor surfaces of her knees (Figure 4) and elbows bilaterally. The changes were more pronounced on her knees than her elbows. There was no evidence of acanthosis nigricans in flexural areas. Results of a 4-mm punch biopsy on her right knee revealed benign papillomatosis with acanthosis and hyperkeratosis without any significant atypia, intradermal melanin deposition, or inflammation. She was treated with urea 40% cream once a day and instructed to advance to twice-a-day treatment if tolerated. No improvement was noted after one month of treatment, and she refused further treatment suggestions.

Patient 4—A 68-year-old white man presented with asymptomatic brown discoloration of his elbows and knees bilaterally of 20 years' duration. He denied any known precipitating factors but stated that he worked on his elbows and knees a lot when gardening. There was no history of diabetes mellitus or obesity. Unsuccessful treatments included intermittent use of over-the-counter Udderly SMOOth® Udder Cream for 3 to 4 years without any noticeable improvement. Family history was significant for similar lesions on his son's knees. Results of a physical examination revealed mildly hyperpigmented erythematous patches bilaterally on the extensor surfaces of his knees (Figure 5) and, to a lesser degree, on his elbows without any scaling. No evidence of acanthosis nigricans was present in flexural areas. Treatment was initiated with lactic acid 12% cream twice a day. After 3 years of daily use, the brown discoloration improved by 75% to 80%.

Comment To our knowledge, this is the first report in the United States of FADES. "Dirty" brown discoloration is noted over the extensor surfaces in areas prone to frictional stress. Pain and pruritus are uniformly absent. Biopsy results of these lesions reveal mild papillomatosis with acanthosis and hyperkeratosis, with minimal underlying inflammation (Figure 3). Melanin deposition in the dermis is not identified as is commonly seen in postinflammatory hyperpigmentation (PIH). Spongiosis typical of eczema and psoriasiform hyperplasia typical of psoriasis are not present. We chose to use the word darkening in the name rather than hyperpigmentationbecause the color change in this condition is a result of papillomatosis, acanthosis, and hyperkeratosis rather than excess melanin pigment. The pathology also led us to use keratolytic agents as treatment rather than hydroquinone-based fade creams. In most cases of FADES, treatment with lactic acid 12% or urea 40% cream over 3 to 6 months is at least partially effective (Table).

A review of world literature reveals several cases that may be similar to FADES. In 1954, Ber7 reported "dirty" brown patches of hyperkeratosis of the elbows and knees, which he named "the sign of dirty knees and elbows," as an early clinical sign of mild hypothyroidism in adults and children. No mention is made of frictional stress in these patients.7 None of the patients we describe with FADES has a history of hypothyroidism. There have been several reports of dermatoses secondary to occupational frictional stress. Wahlberg⁸ described cases of asymptomatic hyperkeratosis on the dorsal hands and feet of Swedish carpet installers thought to be secondary to friction. Menne and Hjorth9 described cases of red, scaly, vesicular, and pustular dermatoses on the palms and fingertips of workers handling pressure-sensitive carbonless paper in Denmark. The condition typically cured in a few weeks by avoidance of frictional trauma. Menne10 also described a similar dermatitis on the palms of post office workers caused by prolonged rubbing against a rough plastic table. Physicians in Jordan,11 Mexico,12 Iraq,13 Japan,14-16 and Italy17 also described cases of skin darkening that they termed friction melanosis,11,12,14,16,17 friction dermal melanosis (lifa disease),13 and nylon clothes friction dermatoses.15 These patients presented with asymptomatic brownish patches over bony prominences that were associated with long-term rubbing with scrub pads (sedge pads,12 lifas13), clothing,12 nylon towels,14-16 and horsehair gloves.17 Most of these cases, however, occurred predominantly in young thin women and involved the skin overlying the clavicle, vertebra, lateral neck, and upper back. This differs from FADES, which appears to be equally prevalent among men and women, affects young to middle-aged adults of average body weight, and presents with discoloration of the extensor surfaces of the elbows and knees. Most significantly, results of histopathologic examinations in frictional melanosis demonstrate increased melanin deposition within the epidermis and dermal macrophages. Our patients with FADES failed to show evidence of an increase in dermal melanin pigment. This histologic difference might relate to the fact that friction more easily produces PIH in patients with darker skin types in Jordan, Mexico, Iraq, Japan, and Italy. Iwasaki et al18 described a case of biphasic amyloidosis arising from friction melanosis in a Japanese woman with a history of long-term use of nylon towels. The brown asymptomatic hyperpigmentation on the woman's back, characteristic of friction melanosis, became gradually more itchy and associated with several small papules. The results of biopsy specimens taken from both the papular and macular pigmented lesions on her back revealed dermal amyloid deposits. It appears that amyloid deposits are produced by the same frictional stress that causes friction melanosis.18,19 Our patients with FADES showed no evidence of amyloidosis. Acanthosis nigricans involving the elbows, knees, and knuckle pads in patients with diabetes mellitus and obesity rarely has been described.20,21 None of our FADES patients had a history of diabetes mellitus, obesity, or hyperpigmentation involving the neck or axilla, which are commonly involved in acanthosis nigricans. FADES can be distinguished easily from conditions that produce brown discoloration, including lichen simplex chronicus, macular amyloidosis, terra firma-forme dermatosis, PIH, psoriasis, acanthosis nigricans and pseudoacanthosis nigricans, reticular and confluent papillomatosis of Gougerot and Carteaud, and X-linked ichthyosis.22 Patients with lichen simplex chronicus23 and macular amyloidosis24 can be distinguished from patients with FADES because they have severe pruritus, xerosis, history of atopy, and specific distinguishing histopathologic changes. Terra firma-forme dermatosis is not caused by friction but is related to a buildup of dirt and scale in areas that are not scrubbed.25-27 This condition is not found on the extensor surfaces, and the patches rub off with alcohol. PIH is caused by melanin deposition within melanophages in the papillary dermis rather than by the epidermal changes of FADES.28 Psoriasis occurs on extensor surfaces but has thick, white, micaceous scaling and psoriasiform hyperplasia of the epidermis. Acanthosis nigricans and pseudoacanthosis nigricans involve flexural areas rather than the extensor surfaces.29 Reticular and confluent papillomatosis of Gougerot and Carteaud involves the central upper back or chest rather than the extensor surfaces.30 X-linked ichthyosis can be distinguished from FADES because it shows considerable scaling, involves the flexural surfaces of the extremities, occurs in young adulthood, and is restricted to men. We believe FADES is a common condition that easily can be recognized and differentiated from other conditions with skin darkening. A biopsy rarely is required. Treatment with keratolytic agents and avoidance of frictional stress are modestly effective in some cases. 

Scars may become pigmented for a variety of reasons, including the persistence and/or recurrence of an incompletely removed melanocytic nevus. However, development of an intensely hyperpigmented scar not long after a surgical procedure, in the absence of a clear explanation, would be a distinctly uncommon event. We recently encountered such a lesion in an otherwise healthy 20-year-old patient. In this case, the histopathologic findings led to further questioning of the patient and revealed a cause that had not been previously suspected. 

Case Report

A 20-year-old woman was seen for evaluation of a lesion on the left lower abdomen. Six weeks earlier, the lesion had been shave excised by an outside physician; pathology results were not initially available. The patient reported that the lesion had quadrupled in size and darkened considerably since the time of the excision. Her grandmother had died of malignant melanoma. She reported that her only medication was birth control pills. On physical examination, there was a 13X8-mm brown-black nodule with discrete but irregular borders (Figure 1). The clinical impression was recurrent nevus in a shave excision scar. However, because of the rapid growth, dark color, and family history of melanoma, there also was concern about the possibility of an atypical nevus or malignant melanoma. Therefore, an elliptical excision was performed. A report of the initial biopsy specimen was received, with the interpretation benign compound nevus.

Results of histopathologic evaluation of the reexcision specimen showed no residual melanocytic lesion. There was a prominent pigmented, cellular scar occupying the superficial to mid dermis in the central portion of the specimen. The pigmented material consisted of refractile, golden brown granules within macrophages and extracellularly, having a resemblance to hemosiderin (Figure 2). These granules stained positively with Perls stain for iron and with Fontana-Masson stain (Figure 3). Fontana-Masson staining was negative when performed after a bleaching procedure that employed potassium permanganate solution at a concentration of 3 g/L.

The staining results suggested the possibility of minocycline-related hyperpigmentation. Subsequent questioning of the patient revealed that she had been taking minocycline 100 mg twice daily during the 2 years prior to her clinic visit. 

Comment

Pigmented scars can arise occasionally because of a number of factors. The sites of persistent and/or recurrent nevus are often pigmented. This pigment, confined to the scar, often shows irregular borders and may have a mottled appearance.1 Pigmented scars also are observed in spontaneously regressing malignant melanoma.2 In a related phenomenon called tumoral melanosis, sheets of melanophages may accompany either a regressed melanoma or epithelial neoplasm.3,4 Pigmentation of scars related to hemorrhage also could occur, eg, following postsurgical trauma or in association with clotting abnormalities, though it is difficult to find literature directly addressing this problem. Other reported associations with hyperpigmented scars include leishmaniasis,5 chickenpox,6 burns,7 Addison disease,8 and hemosiderin-related pigmentation in endometriosis arising in cesarean scars.9 Among other agents that cause cutaneous pigmentation and could potentially produce hyperpigmented scars are heavy metals (eg, gold) and drugs such as amiodarone, phenothiazines, and antimalarials.10,11 Biopsy results of oral hyperpigmentation due to long-term antimalarial therapy have shown macrophages that contain melanin and ferric iron,12 findings resembling those reported here. None of these causes was pertinent to our case.

Minocycline first became available for clinical use in 1967. An association between minocycline administration and black discoloration of thyroid gland follicles in animals was reported that same year.13,14 As early as 1972, Velasco et al15 reported a macular pigmentation of the legs in patients receiving minocycline for the treatment of venereal disease. Since that time, there have been a number of reports of minocycline-induced pigmentation of skin and mucous membranes. Journal articles and textbooks usually divide minocycline-related cutaneous pigmentation into 3 major types. The first, type I, is a blue-black pigmentation that develops in areas of inflammation and scar13,16-19; this is the type that we report here. The second, type II, is a blue-gray pigmentation that develops particularly over otherwise normal-appearing skin of the arms, legs, or face.18,20,21 The third, type III, is usually described as a diffuse or generalized "muddy brown" pigmentation,13,22-25 though in one report this type of pigmentation was actually described as dark blue-gray.24 The Table provides a summary of the clinical and histopathologic changes associated with the 3 major types of minocycline pigmentation. Pigmentation of the nails and nail beds also occurs19,26 and has coexisted with diffuse cutaneous and scleral pigmentation.25 A fourth type of pigmentation that is not specific to minocycline results from fixed drug eruption, as described by Chu et al27 and possibly also represented by the case of Tanzi and Hecker.28 Minocycline also has been associated with discoloration of teeth,23 pigmented conjunctival cysts,29 and black galactorrhea,30 as well as pigmentation of internal organs such as cardiac valves.31,32

The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25

As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26

The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.

The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37 

Conclusion

Minocycline therapy should be included in the differential diagnosis of hyperpigmented scars. Careful history taking and even repeated questioning may be necessary to elicit an accurate medication history. The pigmentation is most likely due to a minocycline metabolite, bound to iron; Fontana-Masson positivity may result from the action of reducing agents other than melanin. Slow resolution of the pigment can be expected following discontinuation of the drug. Nevertheless, biopsy is indicated when, as in this case, an atypical pigmented skin lesion raises concerns about malignant melanoma.

Scars may become pigmented for a variety of reasons, including the persistence and/or recurrence of an incompletely removed melanocytic nevus. However, development of an intensely hyperpigmented scar not long after a surgical procedure, in the absence of a clear explanation, would be a distinctly uncommon event. We recently encountered such a lesion in an otherwise healthy 20-year-old patient. In this case, the histopathologic findings led to further questioning of the patient and revealed a cause that had not been previously suspected. 

Case Report

A 20-year-old woman was seen for evaluation of a lesion on the left lower abdomen. Six weeks earlier, the lesion had been shave excised by an outside physician; pathology results were not initially available. The patient reported that the lesion had quadrupled in size and darkened considerably since the time of the excision. Her grandmother had died of malignant melanoma. She reported that her only medication was birth control pills. On physical examination, there was a 13X8-mm brown-black nodule with discrete but irregular borders (Figure 1). The clinical impression was recurrent nevus in a shave excision scar. However, because of the rapid growth, dark color, and family history of melanoma, there also was concern about the possibility of an atypical nevus or malignant melanoma. Therefore, an elliptical excision was performed. A report of the initial biopsy specimen was received, with the interpretation benign compound nevus.

Results of histopathologic evaluation of the reexcision specimen showed no residual melanocytic lesion. There was a prominent pigmented, cellular scar occupying the superficial to mid dermis in the central portion of the specimen. The pigmented material consisted of refractile, golden brown granules within macrophages and extracellularly, having a resemblance to hemosiderin (Figure 2). These granules stained positively with Perls stain for iron and with Fontana-Masson stain (Figure 3). Fontana-Masson staining was negative when performed after a bleaching procedure that employed potassium permanganate solution at a concentration of 3 g/L.

The staining results suggested the possibility of minocycline-related hyperpigmentation. Subsequent questioning of the patient revealed that she had been taking minocycline 100 mg twice daily during the 2 years prior to her clinic visit. 

Comment

Pigmented scars can arise occasionally because of a number of factors. The sites of persistent and/or recurrent nevus are often pigmented. This pigment, confined to the scar, often shows irregular borders and may have a mottled appearance.1 Pigmented scars also are observed in spontaneously regressing malignant melanoma.2 In a related phenomenon called tumoral melanosis, sheets of melanophages may accompany either a regressed melanoma or epithelial neoplasm.3,4 Pigmentation of scars related to hemorrhage also could occur, eg, following postsurgical trauma or in association with clotting abnormalities, though it is difficult to find literature directly addressing this problem. Other reported associations with hyperpigmented scars include leishmaniasis,5 chickenpox,6 burns,7 Addison disease,8 and hemosiderin-related pigmentation in endometriosis arising in cesarean scars.9 Among other agents that cause cutaneous pigmentation and could potentially produce hyperpigmented scars are heavy metals (eg, gold) and drugs such as amiodarone, phenothiazines, and antimalarials.10,11 Biopsy results of oral hyperpigmentation due to long-term antimalarial therapy have shown macrophages that contain melanin and ferric iron,12 findings resembling those reported here. None of these causes was pertinent to our case.

Minocycline first became available for clinical use in 1967. An association between minocycline administration and black discoloration of thyroid gland follicles in animals was reported that same year.13,14 As early as 1972, Velasco et al15 reported a macular pigmentation of the legs in patients receiving minocycline for the treatment of venereal disease. Since that time, there have been a number of reports of minocycline-induced pigmentation of skin and mucous membranes. Journal articles and textbooks usually divide minocycline-related cutaneous pigmentation into 3 major types. The first, type I, is a blue-black pigmentation that develops in areas of inflammation and scar13,16-19; this is the type that we report here. The second, type II, is a blue-gray pigmentation that develops particularly over otherwise normal-appearing skin of the arms, legs, or face.18,20,21 The third, type III, is usually described as a diffuse or generalized "muddy brown" pigmentation,13,22-25 though in one report this type of pigmentation was actually described as dark blue-gray.24 The Table provides a summary of the clinical and histopathologic changes associated with the 3 major types of minocycline pigmentation. Pigmentation of the nails and nail beds also occurs19,26 and has coexisted with diffuse cutaneous and scleral pigmentation.25 A fourth type of pigmentation that is not specific to minocycline results from fixed drug eruption, as described by Chu et al27 and possibly also represented by the case of Tanzi and Hecker.28 Minocycline also has been associated with discoloration of teeth,23 pigmented conjunctival cysts,29 and black galactorrhea,30 as well as pigmentation of internal organs such as cardiac valves.31,32

The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25

As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26

The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.

The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37 

Conclusion

Minocycline therapy should be included in the differential diagnosis of hyperpigmented scars. Careful history taking and even repeated questioning may be necessary to elicit an accurate medication history. The pigmentation is most likely due to a minocycline metabolite, bound to iron; Fontana-Masson positivity may result from the action of reducing agents other than melanin. Slow resolution of the pigment can be expected following discontinuation of the drug. Nevertheless, biopsy is indicated when, as in this case, an atypical pigmented skin lesion raises concerns about malignant melanoma.

Scars may become pigmented for a variety of reasons, including the persistence and/or recurrence of an incompletely removed melanocytic nevus. However, development of an intensely hyperpigmented scar not long after a surgical procedure, in the absence of a clear explanation, would be a distinctly uncommon event. We recently encountered such a lesion in an otherwise healthy 20-year-old patient. In this case, the histopathologic findings led to further questioning of the patient and revealed a cause that had not been previously suspected. 

Case Report

A 20-year-old woman was seen for evaluation of a lesion on the left lower abdomen. Six weeks earlier, the lesion had been shave excised by an outside physician; pathology results were not initially available. The patient reported that the lesion had quadrupled in size and darkened considerably since the time of the excision. Her grandmother had died of malignant melanoma. She reported that her only medication was birth control pills. On physical examination, there was a 13X8-mm brown-black nodule with discrete but irregular borders (Figure 1). The clinical impression was recurrent nevus in a shave excision scar. However, because of the rapid growth, dark color, and family history of melanoma, there also was concern about the possibility of an atypical nevus or malignant melanoma. Therefore, an elliptical excision was performed. A report of the initial biopsy specimen was received, with the interpretation benign compound nevus.

Results of histopathologic evaluation of the reexcision specimen showed no residual melanocytic lesion. There was a prominent pigmented, cellular scar occupying the superficial to mid dermis in the central portion of the specimen. The pigmented material consisted of refractile, golden brown granules within macrophages and extracellularly, having a resemblance to hemosiderin (Figure 2). These granules stained positively with Perls stain for iron and with Fontana-Masson stain (Figure 3). Fontana-Masson staining was negative when performed after a bleaching procedure that employed potassium permanganate solution at a concentration of 3 g/L.

The staining results suggested the possibility of minocycline-related hyperpigmentation. Subsequent questioning of the patient revealed that she had been taking minocycline 100 mg twice daily during the 2 years prior to her clinic visit. 

Comment

Pigmented scars can arise occasionally because of a number of factors. The sites of persistent and/or recurrent nevus are often pigmented. This pigment, confined to the scar, often shows irregular borders and may have a mottled appearance.1 Pigmented scars also are observed in spontaneously regressing malignant melanoma.2 In a related phenomenon called tumoral melanosis, sheets of melanophages may accompany either a regressed melanoma or epithelial neoplasm.3,4 Pigmentation of scars related to hemorrhage also could occur, eg, following postsurgical trauma or in association with clotting abnormalities, though it is difficult to find literature directly addressing this problem. Other reported associations with hyperpigmented scars include leishmaniasis,5 chickenpox,6 burns,7 Addison disease,8 and hemosiderin-related pigmentation in endometriosis arising in cesarean scars.9 Among other agents that cause cutaneous pigmentation and could potentially produce hyperpigmented scars are heavy metals (eg, gold) and drugs such as amiodarone, phenothiazines, and antimalarials.10,11 Biopsy results of oral hyperpigmentation due to long-term antimalarial therapy have shown macrophages that contain melanin and ferric iron,12 findings resembling those reported here. None of these causes was pertinent to our case.

Minocycline first became available for clinical use in 1967. An association between minocycline administration and black discoloration of thyroid gland follicles in animals was reported that same year.13,14 As early as 1972, Velasco et al15 reported a macular pigmentation of the legs in patients receiving minocycline for the treatment of venereal disease. Since that time, there have been a number of reports of minocycline-induced pigmentation of skin and mucous membranes. Journal articles and textbooks usually divide minocycline-related cutaneous pigmentation into 3 major types. The first, type I, is a blue-black pigmentation that develops in areas of inflammation and scar13,16-19; this is the type that we report here. The second, type II, is a blue-gray pigmentation that develops particularly over otherwise normal-appearing skin of the arms, legs, or face.18,20,21 The third, type III, is usually described as a diffuse or generalized "muddy brown" pigmentation,13,22-25 though in one report this type of pigmentation was actually described as dark blue-gray.24 The Table provides a summary of the clinical and histopathologic changes associated with the 3 major types of minocycline pigmentation. Pigmentation of the nails and nail beds also occurs19,26 and has coexisted with diffuse cutaneous and scleral pigmentation.25 A fourth type of pigmentation that is not specific to minocycline results from fixed drug eruption, as described by Chu et al27 and possibly also represented by the case of Tanzi and Hecker.28 Minocycline also has been associated with discoloration of teeth,23 pigmented conjunctival cysts,29 and black galactorrhea,30 as well as pigmentation of internal organs such as cardiac valves.31,32

The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25

As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26

The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.

The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37 

Conclusion

Minocycline therapy should be included in the differential diagnosis of hyperpigmented scars. Careful history taking and even repeated questioning may be necessary to elicit an accurate medication history. The pigmentation is most likely due to a minocycline metabolite, bound to iron; Fontana-Masson positivity may result from the action of reducing agents other than melanin. Slow resolution of the pigment can be expected following discontinuation of the drug. Nevertheless, biopsy is indicated when, as in this case, an atypical pigmented skin lesion raises concerns about malignant melanoma.