Mehregan DR

Lichenoid reactions to sulfonylurea drugs have been reported, albeit infrequently.1 To our knowledge, this is the first case of a generalized lichenoid dermatitis likely induced by the third-generation sulfonylurea hypoglycemic drug glyburide.

Lichenoid reactions to sulfonylurea hypoglycemic drugs1-4 and sulfonamides1,5-7 have been reported, albeit infrequently. A review of the indexed literature revealed prior publication of lichenoid drug reactions to the sulfonylureas chlorpropamide,1,2,8-10 tolazamide,1,2,8 and tolbutamide1,11; a single report of a reaction to glimepiride4; and no report of reactions to glipizide or glyburide. To our knowledge, this is the first case of a generalized lichenoid reaction likely induced by the third-generation sulfonylurea glyburide. 

Case Report
A 46-year-old white man presented for evaluation of a widespread skin eruption. He had diabetes for approximately 15 years that was initially treated with diet, then diet plus metformin. Seven months prior to presentation, the patient's primary care physician switched the patient's medication from metformin to glyburide. The patient denied receiving prior sulfonylurea therapy for his diabetes. Within 2 months of starting oral glyburide 2.5 mg/d, the patient noted the onset of a mildly pruritic, scaly eruption that started on the dorsa of his feet. It progressed to involve his hands, including the palms. The patient attributed the rash to his outdoor activities and thus did not seek medical care. During the next several months, the eruption progressed to involve the remainder of the upper and lower extremities and the trunk, sparing the head, neck, genitalia, nails, and mouth. The patient then sought medical advice from his primary care physician. During the next several months, various topical therapies (pimecrolimus 1% cream, mometasone 0.1% cream, and triple antibiotic ointment) were tried, with no notable improvement. During this period, there were no other changes in the patient's long-term therapeutic regimen, which included atorvastatin, pioglitazone, gabapentin, lisinopril, aspirin, and omeprazole. This regimen had been stable for several years prior to the medication change. At no time did the patient experience constitutional symptoms. The patient stated he was meticulous about using sun precautions (long sleeves, hat, covered golf cart, and sunscreen), both before his eruption began and during the time it evolved. He was married and monogamous by history. His diabetes at the time of presentation was well controlled. Prior to onset of the eruption, the patient had no personal or family history of significant dermatologic disease. There was no significant occupational chemical exposure. The results of a physical examination revealed the patient had a widespread, violaceous, polymorphic papulosquamous eruption, with lesions varying in size from several millimeters to confluent plaques and in character of the scale from none to collarette to thick and adherent (Figures 1—3). The head, neck, genitalia, nails, and mouth were not involved. Biopsy specimens were obtained, the glyburide was stopped, and a 2-week prednisone taper was initiated.

At the 2-week follow-up, the patient had complete resolution of symptoms and marked clearing of his eruption. After an additional 2 weeks with no corticosteroids, no new papules or plaques had formed. A few residual lichenoid papules remained around the ankles, and there were diffuse residual asymptomatic postinflammatory skin changes in the areas of prior involvement. The biopsy specimens showed a lichenoid tissue reaction; specifically, irregular epidermal hyperplasia, focal hydropic change at the base of the epidermis with underlying bandlike infiltrate of lymphocytes, some evidence of dyskeratotic cells in the epidermis, and very little evidence of spongiosis (Figure 4). No eosinophils were present within the inflammatory infiltrate.

Comment

Lichenoid reactions to drugs have been reported in a number of classes, including sulfonylureas1-4 and sulfonamides.1,5-7 Regarding the sulfonylurea agents, prior reports have implicated chlorpropamide,1,2,8-10 tolazamide,1,2,8 tolbutamide,1,11 and glimepiride.4 However, we found no prior reports of lichenoid reactions to glipizide or glyburide. Sulfonylurea agents are often described in the literature as a cause of drug-induced lichen planus (LP); however, in 1994, Thompson and Skaehill3 concluded there was insufficient primary literature to make a causal link. There has been a similar paucity of primary literature since then to clarify this postulated link. This report adds support for the thesis that sulfonylureas are a cause of lichenoid drug reactions and that glyburide may be included in the list of agents with that potential. In this case, there was a plausible temporal relationship between the start of glyburide therapy and the onset of a lichenoid reaction typical for a lichenoid drug eruption. Specifically, our patient exhibited a widely distributed eruption with polymorphic features.3 Also, there was a temporal relationship between the cessation of therapy and the clearing of the eruption, though corticosteroid therapy also was started because it was believed to be clinically and ethically inappropriate not to offer this option to the patient. Prior reports of sulfonylurea reactions have described intraoral reactions without cutaneous involvement,9,12 cutaneous involvement with no intraoral involvement,4,8 and involvement of both the mucous membranes and skin. With the latter, onset may be sequential and temporally disparate.2 Oral involvement in lichenoid drug reactions appears less frequently than in idiopathic LP.3 Noakes4 reported a patient who had a long-standing stable medication regimen to which glimepiride was added. A biopsy-confirmed lichenoid eruption developed 3 months later on the lower extremities. No new lesions developed after drug cessation, and the eruption cleared within several months of discontinuing the drug.4 To our knowledge, that was the only prior report of a lichenoid reaction to a third-generation sulfonylurea hypoglycemic drug. Barnett and Barnett2 reported a patient who developed oral LP 6 weeks after starting chlorpropamide, which was followed by a lichenoid cutaneous reaction about 1 year later. Similar to our patient, the face, genitalia, and nails were spared. Stopping the medication resulted in complete resolution. Subsequently, the patient was started on tolazamide; 2 months later, the patient experienced a recurrence that again resolved with cessation of medication.² This sequence supports the case for a cause-and-effect relationship. Dinsdale et al9 reported a patient who developed intraoral LP approximately 6 months after starting chlorpropamide and within 2 months after a dosage increase. By history, the lesions may have started much sooner after initiation of drug therapy. These intraoral lesions resolved within 5 days of stopping the medication. Approximately 2 months later, the patient restarted the medication. Within approximately 4 days, he experienced recurrent oral lesions. Again, the lesions resolved within a few days of discontinuing the medication.9 Once more, this sequence supports a cause-and-effect relationship between the drug and the eruption. Franz et al8 reported a patient who experienced the onset of cutaneous LP 8 months after starting chlorpropamide. The medication was discontinued, after which no new lesions formed; the eruption began to resolve within 3 weeks. Later, the patient was started on tolazamide; within 2 weeks, new lesions appeared. No oral involvement was noted with either drug.8 This pattern of events also suggests a cause-and-effect relationship between the sulfonylurea and the lichenoid eruption. Reports of lichenoid dermatitis from chemically related sulfonamide agents strengthen the case for sulfonylurea drugs as a plausible cause of lichenoid reactions. For example, Kaplan et al5 reported 3 patients who developed cutaneous LP while receiving sulfasalazine therapy. One patient developed LP after 9 months of therapy and, when the patient restarted therapy on her own, her eruption recurred within 1 week. Two other patients developed cutaneous LP—one at 3 months and one at 2 weeks into therapy.5 Alstead et al6 reported 2 patients who developed oral and cutaneous LP after sulfasalazine therapy was initiated, which cleared after the sulfasalazine was discontinued. The first patient had a 5-month interval between the start of sulfasalazine and the onset of oral and penile LP. The second patient experienced an interval of 2 years between the start of sulfasalazine and the onset of cutaneous and oral LP.6 Reports that detail lichenoid eruptions in association with a drug, then resolution of the eruption with withdrawal of the drug, suggest but do not confirm a cause-and-effect association between the drug and the eruption. When the sequence is repeated in the same patient—specifically, the patient is rechallenged with either the same or a chemically-related moiety, again followed by recurrence of the eruption, and again followed by resolution of the eruption with discontinuation of the agent (A/B/A/B experimental design)—there is a much stronger case for a cause-and-effect relationship. The tighter the temporal association, the stronger the case for a cause-and-effect relationship. For most drug reactions, the latent period between the beginning of drug therapy and the onset of eruption is days to weeks, allowing a tight temporal association.4 For lichenoid drug eruptions, the interval tends to be longer—sometimes much longer—making temporal association more difficult and the link less obvious.4

Unfortunately, drug-induced and idiopathic LP are clinically and histologically indistinguishable.³ Drug-induced lichenoid reactions from sulfonylureas are too infrequent to be verified epidemiologically. Therefore, the best evidence about them is likely to come from case reports. The strongest case evidence is likely to come from reports of temporal relationships and instances where patients are reexposed to the same or a chemically-related drug. Under usual circumstances where alternatives exist, intentional rechallenge is ethically questionable.

Acknowledgment—The authors gratefully acknowledge the accommodating and expert assistance of the library staff at St. Vincent Mercy Medical Center, Toledo, Ohio.

Lichenoid reactions to sulfonylurea drugs have been reported, albeit infrequently.1 To our knowledge, this is the first case of a generalized lichenoid dermatitis likely induced by the third-generation sulfonylurea hypoglycemic drug glyburide.

Lichenoid reactions to sulfonylurea hypoglycemic drugs1-4 and sulfonamides1,5-7 have been reported, albeit infrequently. A review of the indexed literature revealed prior publication of lichenoid drug reactions to the sulfonylureas chlorpropamide,1,2,8-10 tolazamide,1,2,8 and tolbutamide1,11; a single report of a reaction to glimepiride4; and no report of reactions to glipizide or glyburide. To our knowledge, this is the first case of a generalized lichenoid reaction likely induced by the third-generation sulfonylurea glyburide. 

Case Report
A 46-year-old white man presented for evaluation of a widespread skin eruption. He had diabetes for approximately 15 years that was initially treated with diet, then diet plus metformin. Seven months prior to presentation, the patient's primary care physician switched the patient's medication from metformin to glyburide. The patient denied receiving prior sulfonylurea therapy for his diabetes. Within 2 months of starting oral glyburide 2.5 mg/d, the patient noted the onset of a mildly pruritic, scaly eruption that started on the dorsa of his feet. It progressed to involve his hands, including the palms. The patient attributed the rash to his outdoor activities and thus did not seek medical care. During the next several months, the eruption progressed to involve the remainder of the upper and lower extremities and the trunk, sparing the head, neck, genitalia, nails, and mouth. The patient then sought medical advice from his primary care physician. During the next several months, various topical therapies (pimecrolimus 1% cream, mometasone 0.1% cream, and triple antibiotic ointment) were tried, with no notable improvement. During this period, there were no other changes in the patient's long-term therapeutic regimen, which included atorvastatin, pioglitazone, gabapentin, lisinopril, aspirin, and omeprazole. This regimen had been stable for several years prior to the medication change. At no time did the patient experience constitutional symptoms. The patient stated he was meticulous about using sun precautions (long sleeves, hat, covered golf cart, and sunscreen), both before his eruption began and during the time it evolved. He was married and monogamous by history. His diabetes at the time of presentation was well controlled. Prior to onset of the eruption, the patient had no personal or family history of significant dermatologic disease. There was no significant occupational chemical exposure. The results of a physical examination revealed the patient had a widespread, violaceous, polymorphic papulosquamous eruption, with lesions varying in size from several millimeters to confluent plaques and in character of the scale from none to collarette to thick and adherent (Figures 1—3). The head, neck, genitalia, nails, and mouth were not involved. Biopsy specimens were obtained, the glyburide was stopped, and a 2-week prednisone taper was initiated.

At the 2-week follow-up, the patient had complete resolution of symptoms and marked clearing of his eruption. After an additional 2 weeks with no corticosteroids, no new papules or plaques had formed. A few residual lichenoid papules remained around the ankles, and there were diffuse residual asymptomatic postinflammatory skin changes in the areas of prior involvement. The biopsy specimens showed a lichenoid tissue reaction; specifically, irregular epidermal hyperplasia, focal hydropic change at the base of the epidermis with underlying bandlike infiltrate of lymphocytes, some evidence of dyskeratotic cells in the epidermis, and very little evidence of spongiosis (Figure 4). No eosinophils were present within the inflammatory infiltrate.

Comment

Lichenoid reactions to drugs have been reported in a number of classes, including sulfonylureas1-4 and sulfonamides.1,5-7 Regarding the sulfonylurea agents, prior reports have implicated chlorpropamide,1,2,8-10 tolazamide,1,2,8 tolbutamide,1,11 and glimepiride.4 However, we found no prior reports of lichenoid reactions to glipizide or glyburide. Sulfonylurea agents are often described in the literature as a cause of drug-induced lichen planus (LP); however, in 1994, Thompson and Skaehill3 concluded there was insufficient primary literature to make a causal link. There has been a similar paucity of primary literature since then to clarify this postulated link. This report adds support for the thesis that sulfonylureas are a cause of lichenoid drug reactions and that glyburide may be included in the list of agents with that potential. In this case, there was a plausible temporal relationship between the start of glyburide therapy and the onset of a lichenoid reaction typical for a lichenoid drug eruption. Specifically, our patient exhibited a widely distributed eruption with polymorphic features.3 Also, there was a temporal relationship between the cessation of therapy and the clearing of the eruption, though corticosteroid therapy also was started because it was believed to be clinically and ethically inappropriate not to offer this option to the patient. Prior reports of sulfonylurea reactions have described intraoral reactions without cutaneous involvement,9,12 cutaneous involvement with no intraoral involvement,4,8 and involvement of both the mucous membranes and skin. With the latter, onset may be sequential and temporally disparate.2 Oral involvement in lichenoid drug reactions appears less frequently than in idiopathic LP.3 Noakes4 reported a patient who had a long-standing stable medication regimen to which glimepiride was added. A biopsy-confirmed lichenoid eruption developed 3 months later on the lower extremities. No new lesions developed after drug cessation, and the eruption cleared within several months of discontinuing the drug.4 To our knowledge, that was the only prior report of a lichenoid reaction to a third-generation sulfonylurea hypoglycemic drug. Barnett and Barnett2 reported a patient who developed oral LP 6 weeks after starting chlorpropamide, which was followed by a lichenoid cutaneous reaction about 1 year later. Similar to our patient, the face, genitalia, and nails were spared. Stopping the medication resulted in complete resolution. Subsequently, the patient was started on tolazamide; 2 months later, the patient experienced a recurrence that again resolved with cessation of medication.² This sequence supports the case for a cause-and-effect relationship. Dinsdale et al9 reported a patient who developed intraoral LP approximately 6 months after starting chlorpropamide and within 2 months after a dosage increase. By history, the lesions may have started much sooner after initiation of drug therapy. These intraoral lesions resolved within 5 days of stopping the medication. Approximately 2 months later, the patient restarted the medication. Within approximately 4 days, he experienced recurrent oral lesions. Again, the lesions resolved within a few days of discontinuing the medication.9 Once more, this sequence supports a cause-and-effect relationship between the drug and the eruption. Franz et al8 reported a patient who experienced the onset of cutaneous LP 8 months after starting chlorpropamide. The medication was discontinued, after which no new lesions formed; the eruption began to resolve within 3 weeks. Later, the patient was started on tolazamide; within 2 weeks, new lesions appeared. No oral involvement was noted with either drug.8 This pattern of events also suggests a cause-and-effect relationship between the sulfonylurea and the lichenoid eruption. Reports of lichenoid dermatitis from chemically related sulfonamide agents strengthen the case for sulfonylurea drugs as a plausible cause of lichenoid reactions. For example, Kaplan et al5 reported 3 patients who developed cutaneous LP while receiving sulfasalazine therapy. One patient developed LP after 9 months of therapy and, when the patient restarted therapy on her own, her eruption recurred within 1 week. Two other patients developed cutaneous LP—one at 3 months and one at 2 weeks into therapy.5 Alstead et al6 reported 2 patients who developed oral and cutaneous LP after sulfasalazine therapy was initiated, which cleared after the sulfasalazine was discontinued. The first patient had a 5-month interval between the start of sulfasalazine and the onset of oral and penile LP. The second patient experienced an interval of 2 years between the start of sulfasalazine and the onset of cutaneous and oral LP.6 Reports that detail lichenoid eruptions in association with a drug, then resolution of the eruption with withdrawal of the drug, suggest but do not confirm a cause-and-effect association between the drug and the eruption. When the sequence is repeated in the same patient—specifically, the patient is rechallenged with either the same or a chemically-related moiety, again followed by recurrence of the eruption, and again followed by resolution of the eruption with discontinuation of the agent (A/B/A/B experimental design)—there is a much stronger case for a cause-and-effect relationship. The tighter the temporal association, the stronger the case for a cause-and-effect relationship. For most drug reactions, the latent period between the beginning of drug therapy and the onset of eruption is days to weeks, allowing a tight temporal association.4 For lichenoid drug eruptions, the interval tends to be longer—sometimes much longer—making temporal association more difficult and the link less obvious.4

Unfortunately, drug-induced and idiopathic LP are clinically and histologically indistinguishable.³ Drug-induced lichenoid reactions from sulfonylureas are too infrequent to be verified epidemiologically. Therefore, the best evidence about them is likely to come from case reports. The strongest case evidence is likely to come from reports of temporal relationships and instances where patients are reexposed to the same or a chemically-related drug. Under usual circumstances where alternatives exist, intentional rechallenge is ethically questionable.

Acknowledgment—The authors gratefully acknowledge the accommodating and expert assistance of the library staff at St. Vincent Mercy Medical Center, Toledo, Ohio.

Lichenoid reactions to sulfonylurea drugs have been reported, albeit infrequently.1 To our knowledge, this is the first case of a generalized lichenoid dermatitis likely induced by the third-generation sulfonylurea hypoglycemic drug glyburide.

Lichenoid reactions to sulfonylurea hypoglycemic drugs1-4 and sulfonamides1,5-7 have been reported, albeit infrequently. A review of the indexed literature revealed prior publication of lichenoid drug reactions to the sulfonylureas chlorpropamide,1,2,8-10 tolazamide,1,2,8 and tolbutamide1,11; a single report of a reaction to glimepiride4; and no report of reactions to glipizide or glyburide. To our knowledge, this is the first case of a generalized lichenoid reaction likely induced by the third-generation sulfonylurea glyburide. 

Case Report
A 46-year-old white man presented for evaluation of a widespread skin eruption. He had diabetes for approximately 15 years that was initially treated with diet, then diet plus metformin. Seven months prior to presentation, the patient's primary care physician switched the patient's medication from metformin to glyburide. The patient denied receiving prior sulfonylurea therapy for his diabetes. Within 2 months of starting oral glyburide 2.5 mg/d, the patient noted the onset of a mildly pruritic, scaly eruption that started on the dorsa of his feet. It progressed to involve his hands, including the palms. The patient attributed the rash to his outdoor activities and thus did not seek medical care. During the next several months, the eruption progressed to involve the remainder of the upper and lower extremities and the trunk, sparing the head, neck, genitalia, nails, and mouth. The patient then sought medical advice from his primary care physician. During the next several months, various topical therapies (pimecrolimus 1% cream, mometasone 0.1% cream, and triple antibiotic ointment) were tried, with no notable improvement. During this period, there were no other changes in the patient's long-term therapeutic regimen, which included atorvastatin, pioglitazone, gabapentin, lisinopril, aspirin, and omeprazole. This regimen had been stable for several years prior to the medication change. At no time did the patient experience constitutional symptoms. The patient stated he was meticulous about using sun precautions (long sleeves, hat, covered golf cart, and sunscreen), both before his eruption began and during the time it evolved. He was married and monogamous by history. His diabetes at the time of presentation was well controlled. Prior to onset of the eruption, the patient had no personal or family history of significant dermatologic disease. There was no significant occupational chemical exposure. The results of a physical examination revealed the patient had a widespread, violaceous, polymorphic papulosquamous eruption, with lesions varying in size from several millimeters to confluent plaques and in character of the scale from none to collarette to thick and adherent (Figures 1—3). The head, neck, genitalia, nails, and mouth were not involved. Biopsy specimens were obtained, the glyburide was stopped, and a 2-week prednisone taper was initiated.

At the 2-week follow-up, the patient had complete resolution of symptoms and marked clearing of his eruption. After an additional 2 weeks with no corticosteroids, no new papules or plaques had formed. A few residual lichenoid papules remained around the ankles, and there were diffuse residual asymptomatic postinflammatory skin changes in the areas of prior involvement. The biopsy specimens showed a lichenoid tissue reaction; specifically, irregular epidermal hyperplasia, focal hydropic change at the base of the epidermis with underlying bandlike infiltrate of lymphocytes, some evidence of dyskeratotic cells in the epidermis, and very little evidence of spongiosis (Figure 4). No eosinophils were present within the inflammatory infiltrate.

Comment

Lichenoid reactions to drugs have been reported in a number of classes, including sulfonylureas1-4 and sulfonamides.1,5-7 Regarding the sulfonylurea agents, prior reports have implicated chlorpropamide,1,2,8-10 tolazamide,1,2,8 tolbutamide,1,11 and glimepiride.4 However, we found no prior reports of lichenoid reactions to glipizide or glyburide. Sulfonylurea agents are often described in the literature as a cause of drug-induced lichen planus (LP); however, in 1994, Thompson and Skaehill3 concluded there was insufficient primary literature to make a causal link. There has been a similar paucity of primary literature since then to clarify this postulated link. This report adds support for the thesis that sulfonylureas are a cause of lichenoid drug reactions and that glyburide may be included in the list of agents with that potential. In this case, there was a plausible temporal relationship between the start of glyburide therapy and the onset of a lichenoid reaction typical for a lichenoid drug eruption. Specifically, our patient exhibited a widely distributed eruption with polymorphic features.3 Also, there was a temporal relationship between the cessation of therapy and the clearing of the eruption, though corticosteroid therapy also was started because it was believed to be clinically and ethically inappropriate not to offer this option to the patient. Prior reports of sulfonylurea reactions have described intraoral reactions without cutaneous involvement,9,12 cutaneous involvement with no intraoral involvement,4,8 and involvement of both the mucous membranes and skin. With the latter, onset may be sequential and temporally disparate.2 Oral involvement in lichenoid drug reactions appears less frequently than in idiopathic LP.3 Noakes4 reported a patient who had a long-standing stable medication regimen to which glimepiride was added. A biopsy-confirmed lichenoid eruption developed 3 months later on the lower extremities. No new lesions developed after drug cessation, and the eruption cleared within several months of discontinuing the drug.4 To our knowledge, that was the only prior report of a lichenoid reaction to a third-generation sulfonylurea hypoglycemic drug. Barnett and Barnett2 reported a patient who developed oral LP 6 weeks after starting chlorpropamide, which was followed by a lichenoid cutaneous reaction about 1 year later. Similar to our patient, the face, genitalia, and nails were spared. Stopping the medication resulted in complete resolution. Subsequently, the patient was started on tolazamide; 2 months later, the patient experienced a recurrence that again resolved with cessation of medication.² This sequence supports the case for a cause-and-effect relationship. Dinsdale et al9 reported a patient who developed intraoral LP approximately 6 months after starting chlorpropamide and within 2 months after a dosage increase. By history, the lesions may have started much sooner after initiation of drug therapy. These intraoral lesions resolved within 5 days of stopping the medication. Approximately 2 months later, the patient restarted the medication. Within approximately 4 days, he experienced recurrent oral lesions. Again, the lesions resolved within a few days of discontinuing the medication.9 Once more, this sequence supports a cause-and-effect relationship between the drug and the eruption. Franz et al8 reported a patient who experienced the onset of cutaneous LP 8 months after starting chlorpropamide. The medication was discontinued, after which no new lesions formed; the eruption began to resolve within 3 weeks. Later, the patient was started on tolazamide; within 2 weeks, new lesions appeared. No oral involvement was noted with either drug.8 This pattern of events also suggests a cause-and-effect relationship between the sulfonylurea and the lichenoid eruption. Reports of lichenoid dermatitis from chemically related sulfonamide agents strengthen the case for sulfonylurea drugs as a plausible cause of lichenoid reactions. For example, Kaplan et al5 reported 3 patients who developed cutaneous LP while receiving sulfasalazine therapy. One patient developed LP after 9 months of therapy and, when the patient restarted therapy on her own, her eruption recurred within 1 week. Two other patients developed cutaneous LP—one at 3 months and one at 2 weeks into therapy.5 Alstead et al6 reported 2 patients who developed oral and cutaneous LP after sulfasalazine therapy was initiated, which cleared after the sulfasalazine was discontinued. The first patient had a 5-month interval between the start of sulfasalazine and the onset of oral and penile LP. The second patient experienced an interval of 2 years between the start of sulfasalazine and the onset of cutaneous and oral LP.6 Reports that detail lichenoid eruptions in association with a drug, then resolution of the eruption with withdrawal of the drug, suggest but do not confirm a cause-and-effect association between the drug and the eruption. When the sequence is repeated in the same patient—specifically, the patient is rechallenged with either the same or a chemically-related moiety, again followed by recurrence of the eruption, and again followed by resolution of the eruption with discontinuation of the agent (A/B/A/B experimental design)—there is a much stronger case for a cause-and-effect relationship. The tighter the temporal association, the stronger the case for a cause-and-effect relationship. For most drug reactions, the latent period between the beginning of drug therapy and the onset of eruption is days to weeks, allowing a tight temporal association.4 For lichenoid drug eruptions, the interval tends to be longer—sometimes much longer—making temporal association more difficult and the link less obvious.4

Unfortunately, drug-induced and idiopathic LP are clinically and histologically indistinguishable.³ Drug-induced lichenoid reactions from sulfonylureas are too infrequent to be verified epidemiologically. Therefore, the best evidence about them is likely to come from case reports. The strongest case evidence is likely to come from reports of temporal relationships and instances where patients are reexposed to the same or a chemically-related drug. Under usual circumstances where alternatives exist, intentional rechallenge is ethically questionable.

Acknowledgment—The authors gratefully acknowledge the accommodating and expert assistance of the library staff at St. Vincent Mercy Medical Center, Toledo, Ohio.

Granuloma faciale (GF) is an uncommon inflammatory condition characterized by reddish brown papules and plaques that usually involve the facial area. Extrafacial lesions are rare. Histologically, the lesions are marked by leukocytoclastic vasculitis and extensive fibrin deposition. There are a variety of treatment options available for GF.

Granuloma faciale (GF) is an uncommon disease of unknown etiology presenting with asymptomatic cutaneous papules, nodules, and plaques of the face. However, there has been some confusion and evolution of the term granuloma faciale. In 1937, the term eosinophilic granuloma of the skin was used to describe ulcerated lesions of the mouth and anus that were associated with tuberculosis.1,2 Cobane et al3 used the term facial granuloma with eosinophilia. Confusion continued until Lever and Leeper4 subdivided eosinophilic granuloma of the skin into 3 groups. The first group consisted of cases with cutaneous lesions associated with and histologically identical to eosinophilic granuloma of the bone (Langerhans cell histiocytosis). The second group included cases with cutaneous lesions consisting of torpid, asymptomatic purplish patches on the face. The last group was cases with a preponderance of eosinophils in a granulomatous infiltrate that were associated with a variety of diseases.1,4 A case described by Wigley5 in 1945 as Sarcoid of Boeck may, in fact, be the first reported case of GF.6 It was Pinkus,7 however, who in 1952 finally suggested the term granuloma faciale.

GF is characterized by papules, nodules, and plaques that are usually solitary, though multiple or disseminated lesions can be seen.8 The lesions usually are soft, elevated, well-circumscribed nodules ranging in size from millimeters to centimeters.3 The lesions can be shades of red, brown, or purple and may darken with sun exposure. Lesions usually have a smooth surface with follicular accentuation but may have telangiectasias. Ulceration or crusting rarely occurs. These lesions usually develop very slowly and remain unchanged, though occasionally they will involute.6 Tenderness, burning, and pruritus also have been reported.9,10

Although extracutaneous involvement is rare, there are reports of oral mucosa/upper airway involvement. GF can occur in patients of any age, sex, or race but is usually found in middle-aged Caucasian men.1,6,11-13 

Materials and Methods

The clinical presentation and treatment of 38 patients with GF was reviewed. Patient information was obtained from a database covering the past 10 years of patient activity at a large dermatopathology laboratory in Michigan. GF was diagnosed by clinical and histologic criteria including an infiltrate composed of lymphocytes, neutrophils, histiocytes, and eosinophils in the superficial and deep dermis and fibrin deposition within dermal blood vessels confirming the presence of vascular damage. The patients were reviewed according to demographics, location, treatment, and prognosis. Follow-up was obtained through a questionnaire sent to each referring physician. To our knowledge, this review represents the largest series of patients with GF ever described. 

Results

The clinical features of the patients are summarized in the Table. Their ages ranged from 28 to 85 years, with a mean age of 51.9 years for men and 55.4 years for women. The study consisted of 24 men and 14 women, which is in concordance with an early study showing a predominance of GF in men.1 One man and one woman (patients 1 and 7) had multiple lesions. Interestingly, five men (patients 19, 22, 25, 29, and 38) had extrafacial lesions; there are very few reported cases of extrafacial GF.

Comment

GF is characterized by solitary nodules and plaques.1 Most lesions are asymptomatic red, brown, or purple nodules that are soft, elevated, well-circumscribed, and slow to develop (Figure 1).

Lesions usually are seen on the face but may occur elsewhere.14 Particularly, lesions may appear on light-exposed areas, and some lesions are photoexacerbated.10 Sites of predilection are the sides (30%) and tip (7%) of the nose, preauricular area (22%), cheeks (22%), forehead (15%), and helix of the ear (4%).10,15 In a clinical and histopathologic review, Pedace and Perry1 described 21 cases of GF seen at the Mayo Clinic from 1945 to 1965. They noted a predominance of the lesions on the face (nose, forehead, malar, preauricular and postauricular areas, and chin) and less frequently on the forearms and elsewhere.

A review of the literature reveals 14 reported cases of extrafacial involvement.14-18 The clinical aspects of facial and extrafacial lesions are similar.8 Extrafacial lesions usually are found on the trunk and proximal extremities.19 Extrafacial lesions have been reported as isolated findings and in conjunction with facial lesions.17,18 The infrequent reports of extrafacial lesions may reflect either the inconspicuous nature of extrafacial lesions or a failure to examine patients specifically for the lesions.8

Extrafacial GF may be difficult to differentiate from erythema elevatum diutinum (EED). In fact, some authors believe EED and GF represent different parts of the spectrum of the same disease.20 Both are rare chronic forms of cutaneous small vessel vasculitis and may share some pathogenic mechanisms, but there are several clinical and histologic differences. EED is characterized by multiple lesions localized on the extensor surfaces of extremities in an acral, bilateral, and symmetrical distribution. Bulla formation and hemorrhagic crusting may be seen. The trunk is usually spared, and facial lesions are rare. Histopathologic features of EED include a dense superficial and deep polymorphous dermal infiltrate where neutrophils are prominent and eosinophils are scanty or absent. A grenz zone of normal collagen beneath the epidermis rarely exists and the epidermis is not always spared. EED may be associated with systemic conditions, primarily gammopathies. EED shows an excellent response to dapsone.15,21,22

There is a relatively large clinical differential diagnosis for GF including lupus erythematosus, polymorphous light eruption, fixed drug eruption, benign and malignant lymphoid proliferations, sarcoidosis, granuloma annulare, foreign body reaction, tinea faciei, insect bite reaction, juvenile xanthogranuloma, mastocytoma, Spitz nevus, EED, mycosis fungoides, basal cell carcinoma, histiocytosis X, and rosacea.1,6,23-26

There is one case report of Trichophyton rubrum causing histologic changes similar to GF.26 There also has been a case of GF mimicking rhinophyma.27

Histologic findings of GF show a normal epidermis that may be thinned and flattened by underlying infiltrate (Figure 2). There is a narrow grenz zone between the epidermis and the dermal inflammatory infiltrate consisting of lymphocytes, eosinophils, and neutrophils with leukocytoclasis (Figure 3). The infiltrate usually is distributed diffusely in the upper two thirds of the dermis. Fibrin deposition around blood vessels is evidence of vasculitis (Figure 4). In the later fibrotic stage, perivascular fibrin deposition predominates, and the number of inflammatory cells is greatly reduced.6

Microscopically, the primary differential diagnosis is EED, insect bite reaction, cutaneous lymphoma, or leukocytoclastic vasculitis. The exact pathogenesis is unclear, but some consider it a variant of leukocytoclastic vasculitis. Immunoglobulins, fibrin, and complement can be found at the dermal-epidermal junction and around blood vessels on direct immunofluorescence.28-30

GF usually lacks systemic symptoms or laboratory findings other than rare peripheral eosinophilia.31 Immunohistochemical analysis revealed the majority of lymphocytes to be helper T-cell lymphocytes. The cells stained strongly with antibodies against IL-2 receptor and with antibodies to lymphocyte functional antigen-1 α. Overlying keratinocytes did not stain with intracellular adhesion molecule-1 or HLA-DR, which may account for the presence of the grenz zone in GF. These findings suggest that a γ–interferon-mediated process may play some role in the pathogenesis of this disorder.32

GF is known to be resistant to therapy. Numerous physical modalities and medical therapeutics have been tried. Laser therapy, including the CO2,33 argon,34 pulsed dye, and long-pulsed tunable dye lasers,35-38 all have been attempted with varying success. A study showed that lesions treated with a CO2 laser and dermabrasion had a more even texture compared with lesions treated with electrosurgery alone. Healing times were similar between lesions treated with electrosurgery and CO2 laser; however, lesions treated with dermabrasion healed more quickly.39 Studies of patients treated with an argon laser resulted in total resolution of plaques of GF but had a remaining white collagenous scar.34

A case report by Elston37 showed complete resolution of 3 lesions of GF when treated with a pulsed dye laser after the patient failed topical corticosteroids and oral dapsone. A case report by Ammirati et al35 of a patient treated with the 585-nm pulsed dye laser showed clinical eradication of the lesion at 6-year follow-up. Another report by Welsh et al36 showed good results when GF was treated with the pulsed dye laser. Recently, the long-pulsed tunable dye laser was used successfully with no scarring.38 Other modalities that have been used include surgical excision,7,10 dermabrasion, superficial ionizing radiation,6,10 topical psoralen plus UV light,40 cryosurgery,41 intralesional corticosteroids,42 combined cryosurgery and intralesional steroid injection,43 and electrodesiccation.10,39

Medical treatment has included intralesional gold, colchicine, isoniazid, corticosteroids, potassium arsenite, testosterone, antimalarials, dapsone, and clofazimine.9,10,25,27,34,39,44-46 Most medical therapies have shown varying success. No controlled trials are available because of the rarity of the condition.

In our review, most patients were treated with topical and intralesional steroids with varying results that ranged from mild improvement to complete resolution. Because there is a lack of scarring with steroid therapy, we recommend this as a good first-line therapy. Although none of the patients were treated with pulsed dye laser therapy, review of the literature demonstrates favorable results with this treatment modality. Pulsed dye laser should be considered as an alternative therapy.

Granuloma faciale (GF) is an uncommon inflammatory condition characterized by reddish brown papules and plaques that usually involve the facial area. Extrafacial lesions are rare. Histologically, the lesions are marked by leukocytoclastic vasculitis and extensive fibrin deposition. There are a variety of treatment options available for GF.

Granuloma faciale (GF) is an uncommon disease of unknown etiology presenting with asymptomatic cutaneous papules, nodules, and plaques of the face. However, there has been some confusion and evolution of the term granuloma faciale. In 1937, the term eosinophilic granuloma of the skin was used to describe ulcerated lesions of the mouth and anus that were associated with tuberculosis.1,2 Cobane et al3 used the term facial granuloma with eosinophilia. Confusion continued until Lever and Leeper4 subdivided eosinophilic granuloma of the skin into 3 groups. The first group consisted of cases with cutaneous lesions associated with and histologically identical to eosinophilic granuloma of the bone (Langerhans cell histiocytosis). The second group included cases with cutaneous lesions consisting of torpid, asymptomatic purplish patches on the face. The last group was cases with a preponderance of eosinophils in a granulomatous infiltrate that were associated with a variety of diseases.1,4 A case described by Wigley5 in 1945 as Sarcoid of Boeck may, in fact, be the first reported case of GF.6 It was Pinkus,7 however, who in 1952 finally suggested the term granuloma faciale.

GF is characterized by papules, nodules, and plaques that are usually solitary, though multiple or disseminated lesions can be seen.8 The lesions usually are soft, elevated, well-circumscribed nodules ranging in size from millimeters to centimeters.3 The lesions can be shades of red, brown, or purple and may darken with sun exposure. Lesions usually have a smooth surface with follicular accentuation but may have telangiectasias. Ulceration or crusting rarely occurs. These lesions usually develop very slowly and remain unchanged, though occasionally they will involute.6 Tenderness, burning, and pruritus also have been reported.9,10

Although extracutaneous involvement is rare, there are reports of oral mucosa/upper airway involvement. GF can occur in patients of any age, sex, or race but is usually found in middle-aged Caucasian men.1,6,11-13 

Materials and Methods

The clinical presentation and treatment of 38 patients with GF was reviewed. Patient information was obtained from a database covering the past 10 years of patient activity at a large dermatopathology laboratory in Michigan. GF was diagnosed by clinical and histologic criteria including an infiltrate composed of lymphocytes, neutrophils, histiocytes, and eosinophils in the superficial and deep dermis and fibrin deposition within dermal blood vessels confirming the presence of vascular damage. The patients were reviewed according to demographics, location, treatment, and prognosis. Follow-up was obtained through a questionnaire sent to each referring physician. To our knowledge, this review represents the largest series of patients with GF ever described. 

Results

The clinical features of the patients are summarized in the Table. Their ages ranged from 28 to 85 years, with a mean age of 51.9 years for men and 55.4 years for women. The study consisted of 24 men and 14 women, which is in concordance with an early study showing a predominance of GF in men.1 One man and one woman (patients 1 and 7) had multiple lesions. Interestingly, five men (patients 19, 22, 25, 29, and 38) had extrafacial lesions; there are very few reported cases of extrafacial GF.

Comment

GF is characterized by solitary nodules and plaques.1 Most lesions are asymptomatic red, brown, or purple nodules that are soft, elevated, well-circumscribed, and slow to develop (Figure 1).

Lesions usually are seen on the face but may occur elsewhere.14 Particularly, lesions may appear on light-exposed areas, and some lesions are photoexacerbated.10 Sites of predilection are the sides (30%) and tip (7%) of the nose, preauricular area (22%), cheeks (22%), forehead (15%), and helix of the ear (4%).10,15 In a clinical and histopathologic review, Pedace and Perry1 described 21 cases of GF seen at the Mayo Clinic from 1945 to 1965. They noted a predominance of the lesions on the face (nose, forehead, malar, preauricular and postauricular areas, and chin) and less frequently on the forearms and elsewhere.

A review of the literature reveals 14 reported cases of extrafacial involvement.14-18 The clinical aspects of facial and extrafacial lesions are similar.8 Extrafacial lesions usually are found on the trunk and proximal extremities.19 Extrafacial lesions have been reported as isolated findings and in conjunction with facial lesions.17,18 The infrequent reports of extrafacial lesions may reflect either the inconspicuous nature of extrafacial lesions or a failure to examine patients specifically for the lesions.8

Extrafacial GF may be difficult to differentiate from erythema elevatum diutinum (EED). In fact, some authors believe EED and GF represent different parts of the spectrum of the same disease.20 Both are rare chronic forms of cutaneous small vessel vasculitis and may share some pathogenic mechanisms, but there are several clinical and histologic differences. EED is characterized by multiple lesions localized on the extensor surfaces of extremities in an acral, bilateral, and symmetrical distribution. Bulla formation and hemorrhagic crusting may be seen. The trunk is usually spared, and facial lesions are rare. Histopathologic features of EED include a dense superficial and deep polymorphous dermal infiltrate where neutrophils are prominent and eosinophils are scanty or absent. A grenz zone of normal collagen beneath the epidermis rarely exists and the epidermis is not always spared. EED may be associated with systemic conditions, primarily gammopathies. EED shows an excellent response to dapsone.15,21,22

There is a relatively large clinical differential diagnosis for GF including lupus erythematosus, polymorphous light eruption, fixed drug eruption, benign and malignant lymphoid proliferations, sarcoidosis, granuloma annulare, foreign body reaction, tinea faciei, insect bite reaction, juvenile xanthogranuloma, mastocytoma, Spitz nevus, EED, mycosis fungoides, basal cell carcinoma, histiocytosis X, and rosacea.1,6,23-26

There is one case report of Trichophyton rubrum causing histologic changes similar to GF.26 There also has been a case of GF mimicking rhinophyma.27

Histologic findings of GF show a normal epidermis that may be thinned and flattened by underlying infiltrate (Figure 2). There is a narrow grenz zone between the epidermis and the dermal inflammatory infiltrate consisting of lymphocytes, eosinophils, and neutrophils with leukocytoclasis (Figure 3). The infiltrate usually is distributed diffusely in the upper two thirds of the dermis. Fibrin deposition around blood vessels is evidence of vasculitis (Figure 4). In the later fibrotic stage, perivascular fibrin deposition predominates, and the number of inflammatory cells is greatly reduced.6

Microscopically, the primary differential diagnosis is EED, insect bite reaction, cutaneous lymphoma, or leukocytoclastic vasculitis. The exact pathogenesis is unclear, but some consider it a variant of leukocytoclastic vasculitis. Immunoglobulins, fibrin, and complement can be found at the dermal-epidermal junction and around blood vessels on direct immunofluorescence.28-30

GF usually lacks systemic symptoms or laboratory findings other than rare peripheral eosinophilia.31 Immunohistochemical analysis revealed the majority of lymphocytes to be helper T-cell lymphocytes. The cells stained strongly with antibodies against IL-2 receptor and with antibodies to lymphocyte functional antigen-1 α. Overlying keratinocytes did not stain with intracellular adhesion molecule-1 or HLA-DR, which may account for the presence of the grenz zone in GF. These findings suggest that a γ–interferon-mediated process may play some role in the pathogenesis of this disorder.32

GF is known to be resistant to therapy. Numerous physical modalities and medical therapeutics have been tried. Laser therapy, including the CO2,33 argon,34 pulsed dye, and long-pulsed tunable dye lasers,35-38 all have been attempted with varying success. A study showed that lesions treated with a CO2 laser and dermabrasion had a more even texture compared with lesions treated with electrosurgery alone. Healing times were similar between lesions treated with electrosurgery and CO2 laser; however, lesions treated with dermabrasion healed more quickly.39 Studies of patients treated with an argon laser resulted in total resolution of plaques of GF but had a remaining white collagenous scar.34

A case report by Elston37 showed complete resolution of 3 lesions of GF when treated with a pulsed dye laser after the patient failed topical corticosteroids and oral dapsone. A case report by Ammirati et al35 of a patient treated with the 585-nm pulsed dye laser showed clinical eradication of the lesion at 6-year follow-up. Another report by Welsh et al36 showed good results when GF was treated with the pulsed dye laser. Recently, the long-pulsed tunable dye laser was used successfully with no scarring.38 Other modalities that have been used include surgical excision,7,10 dermabrasion, superficial ionizing radiation,6,10 topical psoralen plus UV light,40 cryosurgery,41 intralesional corticosteroids,42 combined cryosurgery and intralesional steroid injection,43 and electrodesiccation.10,39

Medical treatment has included intralesional gold, colchicine, isoniazid, corticosteroids, potassium arsenite, testosterone, antimalarials, dapsone, and clofazimine.9,10,25,27,34,39,44-46 Most medical therapies have shown varying success. No controlled trials are available because of the rarity of the condition.

In our review, most patients were treated with topical and intralesional steroids with varying results that ranged from mild improvement to complete resolution. Because there is a lack of scarring with steroid therapy, we recommend this as a good first-line therapy. Although none of the patients were treated with pulsed dye laser therapy, review of the literature demonstrates favorable results with this treatment modality. Pulsed dye laser should be considered as an alternative therapy.

Granuloma faciale (GF) is an uncommon inflammatory condition characterized by reddish brown papules and plaques that usually involve the facial area. Extrafacial lesions are rare. Histologically, the lesions are marked by leukocytoclastic vasculitis and extensive fibrin deposition. There are a variety of treatment options available for GF.

Granuloma faciale (GF) is an uncommon disease of unknown etiology presenting with asymptomatic cutaneous papules, nodules, and plaques of the face. However, there has been some confusion and evolution of the term granuloma faciale. In 1937, the term eosinophilic granuloma of the skin was used to describe ulcerated lesions of the mouth and anus that were associated with tuberculosis.1,2 Cobane et al3 used the term facial granuloma with eosinophilia. Confusion continued until Lever and Leeper4 subdivided eosinophilic granuloma of the skin into 3 groups. The first group consisted of cases with cutaneous lesions associated with and histologically identical to eosinophilic granuloma of the bone (Langerhans cell histiocytosis). The second group included cases with cutaneous lesions consisting of torpid, asymptomatic purplish patches on the face. The last group was cases with a preponderance of eosinophils in a granulomatous infiltrate that were associated with a variety of diseases.1,4 A case described by Wigley5 in 1945 as Sarcoid of Boeck may, in fact, be the first reported case of GF.6 It was Pinkus,7 however, who in 1952 finally suggested the term granuloma faciale.

GF is characterized by papules, nodules, and plaques that are usually solitary, though multiple or disseminated lesions can be seen.8 The lesions usually are soft, elevated, well-circumscribed nodules ranging in size from millimeters to centimeters.3 The lesions can be shades of red, brown, or purple and may darken with sun exposure. Lesions usually have a smooth surface with follicular accentuation but may have telangiectasias. Ulceration or crusting rarely occurs. These lesions usually develop very slowly and remain unchanged, though occasionally they will involute.6 Tenderness, burning, and pruritus also have been reported.9,10

Although extracutaneous involvement is rare, there are reports of oral mucosa/upper airway involvement. GF can occur in patients of any age, sex, or race but is usually found in middle-aged Caucasian men.1,6,11-13 

Materials and Methods

The clinical presentation and treatment of 38 patients with GF was reviewed. Patient information was obtained from a database covering the past 10 years of patient activity at a large dermatopathology laboratory in Michigan. GF was diagnosed by clinical and histologic criteria including an infiltrate composed of lymphocytes, neutrophils, histiocytes, and eosinophils in the superficial and deep dermis and fibrin deposition within dermal blood vessels confirming the presence of vascular damage. The patients were reviewed according to demographics, location, treatment, and prognosis. Follow-up was obtained through a questionnaire sent to each referring physician. To our knowledge, this review represents the largest series of patients with GF ever described. 

Results

The clinical features of the patients are summarized in the Table. Their ages ranged from 28 to 85 years, with a mean age of 51.9 years for men and 55.4 years for women. The study consisted of 24 men and 14 women, which is in concordance with an early study showing a predominance of GF in men.1 One man and one woman (patients 1 and 7) had multiple lesions. Interestingly, five men (patients 19, 22, 25, 29, and 38) had extrafacial lesions; there are very few reported cases of extrafacial GF.

Comment

GF is characterized by solitary nodules and plaques.1 Most lesions are asymptomatic red, brown, or purple nodules that are soft, elevated, well-circumscribed, and slow to develop (Figure 1).

Lesions usually are seen on the face but may occur elsewhere.14 Particularly, lesions may appear on light-exposed areas, and some lesions are photoexacerbated.10 Sites of predilection are the sides (30%) and tip (7%) of the nose, preauricular area (22%), cheeks (22%), forehead (15%), and helix of the ear (4%).10,15 In a clinical and histopathologic review, Pedace and Perry1 described 21 cases of GF seen at the Mayo Clinic from 1945 to 1965. They noted a predominance of the lesions on the face (nose, forehead, malar, preauricular and postauricular areas, and chin) and less frequently on the forearms and elsewhere.

A review of the literature reveals 14 reported cases of extrafacial involvement.14-18 The clinical aspects of facial and extrafacial lesions are similar.8 Extrafacial lesions usually are found on the trunk and proximal extremities.19 Extrafacial lesions have been reported as isolated findings and in conjunction with facial lesions.17,18 The infrequent reports of extrafacial lesions may reflect either the inconspicuous nature of extrafacial lesions or a failure to examine patients specifically for the lesions.8

Extrafacial GF may be difficult to differentiate from erythema elevatum diutinum (EED). In fact, some authors believe EED and GF represent different parts of the spectrum of the same disease.20 Both are rare chronic forms of cutaneous small vessel vasculitis and may share some pathogenic mechanisms, but there are several clinical and histologic differences. EED is characterized by multiple lesions localized on the extensor surfaces of extremities in an acral, bilateral, and symmetrical distribution. Bulla formation and hemorrhagic crusting may be seen. The trunk is usually spared, and facial lesions are rare. Histopathologic features of EED include a dense superficial and deep polymorphous dermal infiltrate where neutrophils are prominent and eosinophils are scanty or absent. A grenz zone of normal collagen beneath the epidermis rarely exists and the epidermis is not always spared. EED may be associated with systemic conditions, primarily gammopathies. EED shows an excellent response to dapsone.15,21,22

There is a relatively large clinical differential diagnosis for GF including lupus erythematosus, polymorphous light eruption, fixed drug eruption, benign and malignant lymphoid proliferations, sarcoidosis, granuloma annulare, foreign body reaction, tinea faciei, insect bite reaction, juvenile xanthogranuloma, mastocytoma, Spitz nevus, EED, mycosis fungoides, basal cell carcinoma, histiocytosis X, and rosacea.1,6,23-26

There is one case report of Trichophyton rubrum causing histologic changes similar to GF.26 There also has been a case of GF mimicking rhinophyma.27

Histologic findings of GF show a normal epidermis that may be thinned and flattened by underlying infiltrate (Figure 2). There is a narrow grenz zone between the epidermis and the dermal inflammatory infiltrate consisting of lymphocytes, eosinophils, and neutrophils with leukocytoclasis (Figure 3). The infiltrate usually is distributed diffusely in the upper two thirds of the dermis. Fibrin deposition around blood vessels is evidence of vasculitis (Figure 4). In the later fibrotic stage, perivascular fibrin deposition predominates, and the number of inflammatory cells is greatly reduced.6

Microscopically, the primary differential diagnosis is EED, insect bite reaction, cutaneous lymphoma, or leukocytoclastic vasculitis. The exact pathogenesis is unclear, but some consider it a variant of leukocytoclastic vasculitis. Immunoglobulins, fibrin, and complement can be found at the dermal-epidermal junction and around blood vessels on direct immunofluorescence.28-30

GF usually lacks systemic symptoms or laboratory findings other than rare peripheral eosinophilia.31 Immunohistochemical analysis revealed the majority of lymphocytes to be helper T-cell lymphocytes. The cells stained strongly with antibodies against IL-2 receptor and with antibodies to lymphocyte functional antigen-1 α. Overlying keratinocytes did not stain with intracellular adhesion molecule-1 or HLA-DR, which may account for the presence of the grenz zone in GF. These findings suggest that a γ–interferon-mediated process may play some role in the pathogenesis of this disorder.32

GF is known to be resistant to therapy. Numerous physical modalities and medical therapeutics have been tried. Laser therapy, including the CO2,33 argon,34 pulsed dye, and long-pulsed tunable dye lasers,35-38 all have been attempted with varying success. A study showed that lesions treated with a CO2 laser and dermabrasion had a more even texture compared with lesions treated with electrosurgery alone. Healing times were similar between lesions treated with electrosurgery and CO2 laser; however, lesions treated with dermabrasion healed more quickly.39 Studies of patients treated with an argon laser resulted in total resolution of plaques of GF but had a remaining white collagenous scar.34

A case report by Elston37 showed complete resolution of 3 lesions of GF when treated with a pulsed dye laser after the patient failed topical corticosteroids and oral dapsone. A case report by Ammirati et al35 of a patient treated with the 585-nm pulsed dye laser showed clinical eradication of the lesion at 6-year follow-up. Another report by Welsh et al36 showed good results when GF was treated with the pulsed dye laser. Recently, the long-pulsed tunable dye laser was used successfully with no scarring.38 Other modalities that have been used include surgical excision,7,10 dermabrasion, superficial ionizing radiation,6,10 topical psoralen plus UV light,40 cryosurgery,41 intralesional corticosteroids,42 combined cryosurgery and intralesional steroid injection,43 and electrodesiccation.10,39

Medical treatment has included intralesional gold, colchicine, isoniazid, corticosteroids, potassium arsenite, testosterone, antimalarials, dapsone, and clofazimine.9,10,25,27,34,39,44-46 Most medical therapies have shown varying success. No controlled trials are available because of the rarity of the condition.

In our review, most patients were treated with topical and intralesional steroids with varying results that ranged from mild improvement to complete resolution. Because there is a lack of scarring with steroid therapy, we recommend this as a good first-line therapy. Although none of the patients were treated with pulsed dye laser therapy, review of the literature demonstrates favorable results with this treatment modality. Pulsed dye laser should be considered as an alternative therapy.