Photo Challenge

The Diagnosis: Actinic Comedonal Plaque  

Histopathologic examination showed multiple small, keratin-filled cystic spaces in the superficial dermis lined by stratified squamous epithelium that keratinized with a granular layer with surrounding solar elastosis (Figure 1). These findings were consistent with an actinic comedonal plaque (ACP), a rare variant of Favre-Racouchot syndrome (FRS). Due to other cases of invasive squamous cell carcinomas developing within these lesions¹ and the patient's history of basal cell carcinoma in the area, it was important to rule out malignancy and further confirm the diagnosis. Thus, an additional biopsy was obtained, which revealed no sign of cellular atypia. The patient was bothered by the appearance and texture of the lesion, so he elected to pursue treatment. Because of the lesion's moderate size and location, surgical excision was not recommended. He was treated with cryosurgery followed by tretinoin gel 0.025% for 3 months (Figure 2). At 1-year follow-up, there was no recurrence and an acceptable cosmetic outcome.  

Actinic comedonal plaques are characterized by cysts, comedones, and papules that form well-defined yellow plaques on the skin after chronic sun exposure.² First described in 1980 by Eastern and Martin,³ these lesions are most often found on the neck, thorax, nasal dorsum, helix, and forearms; they often are mistaken for basal cell carcinomas, chondrodermatitis nodularis chronica helicis, and amyloidosis.^2,4 

Similar to the cases described by Eastern and Martin,³ our patient presented with a solitary 2.8×1.6-cm yellowish and bumpy plaque that was growing on chronically sun-exposed skin of the medial right cheek. The patient's history of smoking and basal cell carcinoma removal led to the following differential diagnoses: recurrent malignancy, tumors of dermal appendages, and xanthelasmalike deposition within a scar, among others.  

Histologic examination demonstrated keratin-filled cystic spaces in the superficial dermis, along with hyperkeratosis and solar elastosis. These findings were consistent with the original histologic descriptions of ACP that were cited as a rare ectopic form of FRS.⁵ Leeuwis-Fedorovich et al¹ described multifocal squamous cell carcinomas arising in a FRS lesion in 2 cases. Additional biopsy was performed in our patient to rule out this possibility. 

Aside from its role in dermatologic malignancy, exposure to UV light can lead to dilation of the sebaceous gland infundibulum and formation of comedones in various locations.² Histologically, lesions of ACP feature dilated, keratin-filled follicles within a matrix of amorphous damaged collagen in the middle and lower dermis, along with elastosis and basophilic degeneration with fragmentation of collagen bundles in the upper dermis coated with flattened epidermis.^2,3  

Several clinical diagnoses were considered in the differential for our patient. In contrast to our patient's solitary lesion, classic FRS--nodular elastosis with cysts and comedones--is characterized by a diffuse yellowish hue of large open black comedones that are symmetrically distributed on the temporal and periorbital areas.⁶  

Xanthoma has several clinical presentations. Plane xanthomas typically develop in skin folds, especially in palmar creases, while xanthelasma typically consists of yellow soft plaques on the eyelids and periorbital skin. Histologically, xanthomas contain lipid-laden macrophages, which were absent in our patient.⁷ 

Cutaneous amyloidosis can be characterized as macular, papular, and nodular. Nodular, the rarest subtype, commonly manifests on the face.⁸ However, its characteristic histologic features include atrophic epidermal changes with an amorphous, eosinophilic-appearing dermis due to amyloid deposition. These findings were absent in our case.  

Recurrent neoplasm would be in the differential diagnosis of any solitary nodule arising within a previously treated site of malignancy, which was excluded by histologic examination of our patient.⁷ 

Topical tretinoin has been demonstrated as effective treatment of both FRS and ACP.^2,9 Other effective treatment modalities include cryotherapy and photoprotection.⁹ For our patient, a combination of cryosurgery and topical tretinoin resulted in depression of the plaque and a good cosmetic outcome. 
 
Acknowledgments
We thank the patient for granting permission to publish this article. We also are indebted to Morgan L. Wilson, MD (Springfield, Illinois), for his expert dermatopathologic evaluation in this case. He has received no compensation for his contribution.  
 

The Diagnosis: Actinic Comedonal Plaque  

Histopathologic examination showed multiple small, keratin-filled cystic spaces in the superficial dermis lined by stratified squamous epithelium that keratinized with a granular layer with surrounding solar elastosis (Figure 1). These findings were consistent with an actinic comedonal plaque (ACP), a rare variant of Favre-Racouchot syndrome (FRS). Due to other cases of invasive squamous cell carcinomas developing within these lesions¹ and the patient's history of basal cell carcinoma in the area, it was important to rule out malignancy and further confirm the diagnosis. Thus, an additional biopsy was obtained, which revealed no sign of cellular atypia. The patient was bothered by the appearance and texture of the lesion, so he elected to pursue treatment. Because of the lesion's moderate size and location, surgical excision was not recommended. He was treated with cryosurgery followed by tretinoin gel 0.025% for 3 months (Figure 2). At 1-year follow-up, there was no recurrence and an acceptable cosmetic outcome.  

Actinic comedonal plaques are characterized by cysts, comedones, and papules that form well-defined yellow plaques on the skin after chronic sun exposure.² First described in 1980 by Eastern and Martin,³ these lesions are most often found on the neck, thorax, nasal dorsum, helix, and forearms; they often are mistaken for basal cell carcinomas, chondrodermatitis nodularis chronica helicis, and amyloidosis.^2,4 

Similar to the cases described by Eastern and Martin,³ our patient presented with a solitary 2.8×1.6-cm yellowish and bumpy plaque that was growing on chronically sun-exposed skin of the medial right cheek. The patient's history of smoking and basal cell carcinoma removal led to the following differential diagnoses: recurrent malignancy, tumors of dermal appendages, and xanthelasmalike deposition within a scar, among others.  

Histologic examination demonstrated keratin-filled cystic spaces in the superficial dermis, along with hyperkeratosis and solar elastosis. These findings were consistent with the original histologic descriptions of ACP that were cited as a rare ectopic form of FRS.⁵ Leeuwis-Fedorovich et al¹ described multifocal squamous cell carcinomas arising in a FRS lesion in 2 cases. Additional biopsy was performed in our patient to rule out this possibility. 

Aside from its role in dermatologic malignancy, exposure to UV light can lead to dilation of the sebaceous gland infundibulum and formation of comedones in various locations.² Histologically, lesions of ACP feature dilated, keratin-filled follicles within a matrix of amorphous damaged collagen in the middle and lower dermis, along with elastosis and basophilic degeneration with fragmentation of collagen bundles in the upper dermis coated with flattened epidermis.^2,3  

Several clinical diagnoses were considered in the differential for our patient. In contrast to our patient's solitary lesion, classic FRS--nodular elastosis with cysts and comedones--is characterized by a diffuse yellowish hue of large open black comedones that are symmetrically distributed on the temporal and periorbital areas.⁶  

Xanthoma has several clinical presentations. Plane xanthomas typically develop in skin folds, especially in palmar creases, while xanthelasma typically consists of yellow soft plaques on the eyelids and periorbital skin. Histologically, xanthomas contain lipid-laden macrophages, which were absent in our patient.⁷ 

Cutaneous amyloidosis can be characterized as macular, papular, and nodular. Nodular, the rarest subtype, commonly manifests on the face.⁸ However, its characteristic histologic features include atrophic epidermal changes with an amorphous, eosinophilic-appearing dermis due to amyloid deposition. These findings were absent in our case.  

Recurrent neoplasm would be in the differential diagnosis of any solitary nodule arising within a previously treated site of malignancy, which was excluded by histologic examination of our patient.⁷ 

Topical tretinoin has been demonstrated as effective treatment of both FRS and ACP.^2,9 Other effective treatment modalities include cryotherapy and photoprotection.⁹ For our patient, a combination of cryosurgery and topical tretinoin resulted in depression of the plaque and a good cosmetic outcome. 
 
Acknowledgments
We thank the patient for granting permission to publish this article. We also are indebted to Morgan L. Wilson, MD (Springfield, Illinois), for his expert dermatopathologic evaluation in this case. He has received no compensation for his contribution.  
 

The Diagnosis: Actinic Comedonal Plaque  

Histopathologic examination showed multiple small, keratin-filled cystic spaces in the superficial dermis lined by stratified squamous epithelium that keratinized with a granular layer with surrounding solar elastosis (Figure 1). These findings were consistent with an actinic comedonal plaque (ACP), a rare variant of Favre-Racouchot syndrome (FRS). Due to other cases of invasive squamous cell carcinomas developing within these lesions¹ and the patient's history of basal cell carcinoma in the area, it was important to rule out malignancy and further confirm the diagnosis. Thus, an additional biopsy was obtained, which revealed no sign of cellular atypia. The patient was bothered by the appearance and texture of the lesion, so he elected to pursue treatment. Because of the lesion's moderate size and location, surgical excision was not recommended. He was treated with cryosurgery followed by tretinoin gel 0.025% for 3 months (Figure 2). At 1-year follow-up, there was no recurrence and an acceptable cosmetic outcome.  

Actinic comedonal plaques are characterized by cysts, comedones, and papules that form well-defined yellow plaques on the skin after chronic sun exposure.² First described in 1980 by Eastern and Martin,³ these lesions are most often found on the neck, thorax, nasal dorsum, helix, and forearms; they often are mistaken for basal cell carcinomas, chondrodermatitis nodularis chronica helicis, and amyloidosis.^2,4 

Similar to the cases described by Eastern and Martin,³ our patient presented with a solitary 2.8×1.6-cm yellowish and bumpy plaque that was growing on chronically sun-exposed skin of the medial right cheek. The patient's history of smoking and basal cell carcinoma removal led to the following differential diagnoses: recurrent malignancy, tumors of dermal appendages, and xanthelasmalike deposition within a scar, among others.  

Histologic examination demonstrated keratin-filled cystic spaces in the superficial dermis, along with hyperkeratosis and solar elastosis. These findings were consistent with the original histologic descriptions of ACP that were cited as a rare ectopic form of FRS.⁵ Leeuwis-Fedorovich et al¹ described multifocal squamous cell carcinomas arising in a FRS lesion in 2 cases. Additional biopsy was performed in our patient to rule out this possibility. 

Aside from its role in dermatologic malignancy, exposure to UV light can lead to dilation of the sebaceous gland infundibulum and formation of comedones in various locations.² Histologically, lesions of ACP feature dilated, keratin-filled follicles within a matrix of amorphous damaged collagen in the middle and lower dermis, along with elastosis and basophilic degeneration with fragmentation of collagen bundles in the upper dermis coated with flattened epidermis.^2,3  

Several clinical diagnoses were considered in the differential for our patient. In contrast to our patient's solitary lesion, classic FRS--nodular elastosis with cysts and comedones--is characterized by a diffuse yellowish hue of large open black comedones that are symmetrically distributed on the temporal and periorbital areas.⁶  

Xanthoma has several clinical presentations. Plane xanthomas typically develop in skin folds, especially in palmar creases, while xanthelasma typically consists of yellow soft plaques on the eyelids and periorbital skin. Histologically, xanthomas contain lipid-laden macrophages, which were absent in our patient.⁷ 

Cutaneous amyloidosis can be characterized as macular, papular, and nodular. Nodular, the rarest subtype, commonly manifests on the face.⁸ However, its characteristic histologic features include atrophic epidermal changes with an amorphous, eosinophilic-appearing dermis due to amyloid deposition. These findings were absent in our case.  

Recurrent neoplasm would be in the differential diagnosis of any solitary nodule arising within a previously treated site of malignancy, which was excluded by histologic examination of our patient.⁷ 

Topical tretinoin has been demonstrated as effective treatment of both FRS and ACP.^2,9 Other effective treatment modalities include cryotherapy and photoprotection.⁹ For our patient, a combination of cryosurgery and topical tretinoin resulted in depression of the plaque and a good cosmetic outcome. 
 
Acknowledgments
We thank the patient for granting permission to publish this article. We also are indebted to Morgan L. Wilson, MD (Springfield, Illinois), for his expert dermatopathologic evaluation in this case. He has received no compensation for his contribution.  
 

The Diagnosis: Mosaic Tuberous Sclerosis 

A punch biopsy of the facial lesion was stained with hematoxylin and eosin, which demonstrated spindled and stellate fibroblasts with dilated blood vessels (Figure), consistent with an angiofibroma. Given the clinical presentation and histologic findings, there was concern for a diagnosis of tuberous sclerosis (TSC). The patient was referred for genetic workup but tested negative for mutations of the TSC genes in the blood. Because the patient had only unilateral facial lesions, a possible cortical tuber, no other symptoms, and tested negative for TSC gene mutations, mosaic TSC was considered a likely diagnosis. Her facial lesions were treated with pulsed dye vascular laser therapy. 

Tuberous sclerosis is an autosomal-dominant neurocutaneous disorder caused by inactivation of the genes TSC1 (encoding hamartin) and TSC2 (encoding tuberin). Mutation results in overactivation of the downstream mTOR (mammalian target of rapamycin) pathway, resulting in abnormal cellular proliferation and hamartomas. These benign tumors can be found in nearly every organ, most often in the central nervous system and skin, and they provide for a highly variable presentation of the disease.¹ 

Tuberous sclerosis affects 1 in 6000 to 10,000 live births and has a prevalence of 1 in 20,000 individuals. Of these individuals, 75% carry sporadic mutations, and 75% to 90% eventually test positive for a TSC gene mutation.² Genetic mosaicism has been reported in 28% of cases affected by large deletions¹ and as few as 1% of cases involving small mutations.³ 

The dermatologic manifestation of mosaic TSC most often includes unilateral angiofibromas, whereas in nonmosaic cases, angiofibromas cover both cheeks, the forehead, and the eyelids. The other skin lesions of TSC--shagreen patches, forehead plaques, hypomelanotic macules, and ungual fibromas--are seen less frequently.^4-6 Additionally, neurologic disease in mosaic patients is notably milder, with 57% of mosaic patients found to have epilepsy compared to 91% of nonmosaic patients.⁷ Our patient had both unilateral facial angiofibromas and a cortical lesion suspicious for a tuber, prompting a suspected diagnosis of mosaic TSC. 

The methods of diagnosis outlined by the International Tuberous Sclerosis Complex Consensus Group pose a challenge in diagnosing mosaic TSC. The clinical criteria require 2 major (eg, multiple angiofibromas, angiomyolipomas, a shagreen patch) and 1 minor feature (eg, dental enamel pit, renal cyst).² However, case reports detailing unilateral facial angiofibromas have described patients with isolated dermatologic findings.^5,6 Further, it has been demonstrated that genetic studies in mosaic TSC can be unreliable depending on the tissue sampled.⁸ Thus, for patients who have mosaic TSC, establishing a definitive diagnosis is not always possible and may rely solely on the clinical picture. 

Considering the differential diagnosis, benign cephalic histiocytosis usually would present with small red-brown macules and papules symmetrically located on the head and neck. The lesions occur at a younger age, usually in the first year or two of life. Fibrofolliculomas present as multiple whitish, slightly larger papules found on the central face. They are a marker for Birt-Hogg-Dubé syndrome, which also is associated with spontaneous pneumothorax.  

Agminated means clustering or grouping of lesions. Agminated melanocytic nevi and agminated Spitz nevi are clusters of nevi. These lesions can vary in size and color. They may be elevated or flat. Melanocytic nevi usually are tan-brown or black. Spitz nevi may be pink or pigmented brown or black. To definitively differentiate between these 2 diagnoses and this patient's diagnosis of angiofibroma, a biopsy is needed.

The Diagnosis: Mosaic Tuberous Sclerosis 

A punch biopsy of the facial lesion was stained with hematoxylin and eosin, which demonstrated spindled and stellate fibroblasts with dilated blood vessels (Figure), consistent with an angiofibroma. Given the clinical presentation and histologic findings, there was concern for a diagnosis of tuberous sclerosis (TSC). The patient was referred for genetic workup but tested negative for mutations of the TSC genes in the blood. Because the patient had only unilateral facial lesions, a possible cortical tuber, no other symptoms, and tested negative for TSC gene mutations, mosaic TSC was considered a likely diagnosis. Her facial lesions were treated with pulsed dye vascular laser therapy. 

Tuberous sclerosis is an autosomal-dominant neurocutaneous disorder caused by inactivation of the genes TSC1 (encoding hamartin) and TSC2 (encoding tuberin). Mutation results in overactivation of the downstream mTOR (mammalian target of rapamycin) pathway, resulting in abnormal cellular proliferation and hamartomas. These benign tumors can be found in nearly every organ, most often in the central nervous system and skin, and they provide for a highly variable presentation of the disease.¹ 

Tuberous sclerosis affects 1 in 6000 to 10,000 live births and has a prevalence of 1 in 20,000 individuals. Of these individuals, 75% carry sporadic mutations, and 75% to 90% eventually test positive for a TSC gene mutation.² Genetic mosaicism has been reported in 28% of cases affected by large deletions¹ and as few as 1% of cases involving small mutations.³ 

The dermatologic manifestation of mosaic TSC most often includes unilateral angiofibromas, whereas in nonmosaic cases, angiofibromas cover both cheeks, the forehead, and the eyelids. The other skin lesions of TSC--shagreen patches, forehead plaques, hypomelanotic macules, and ungual fibromas--are seen less frequently.^4-6 Additionally, neurologic disease in mosaic patients is notably milder, with 57% of mosaic patients found to have epilepsy compared to 91% of nonmosaic patients.⁷ Our patient had both unilateral facial angiofibromas and a cortical lesion suspicious for a tuber, prompting a suspected diagnosis of mosaic TSC. 

The methods of diagnosis outlined by the International Tuberous Sclerosis Complex Consensus Group pose a challenge in diagnosing mosaic TSC. The clinical criteria require 2 major (eg, multiple angiofibromas, angiomyolipomas, a shagreen patch) and 1 minor feature (eg, dental enamel pit, renal cyst).² However, case reports detailing unilateral facial angiofibromas have described patients with isolated dermatologic findings.^5,6 Further, it has been demonstrated that genetic studies in mosaic TSC can be unreliable depending on the tissue sampled.⁸ Thus, for patients who have mosaic TSC, establishing a definitive diagnosis is not always possible and may rely solely on the clinical picture. 

Considering the differential diagnosis, benign cephalic histiocytosis usually would present with small red-brown macules and papules symmetrically located on the head and neck. The lesions occur at a younger age, usually in the first year or two of life. Fibrofolliculomas present as multiple whitish, slightly larger papules found on the central face. They are a marker for Birt-Hogg-Dubé syndrome, which also is associated with spontaneous pneumothorax.  

Agminated means clustering or grouping of lesions. Agminated melanocytic nevi and agminated Spitz nevi are clusters of nevi. These lesions can vary in size and color. They may be elevated or flat. Melanocytic nevi usually are tan-brown or black. Spitz nevi may be pink or pigmented brown or black. To definitively differentiate between these 2 diagnoses and this patient's diagnosis of angiofibroma, a biopsy is needed.

The Diagnosis: Mosaic Tuberous Sclerosis 

A punch biopsy of the facial lesion was stained with hematoxylin and eosin, which demonstrated spindled and stellate fibroblasts with dilated blood vessels (Figure), consistent with an angiofibroma. Given the clinical presentation and histologic findings, there was concern for a diagnosis of tuberous sclerosis (TSC). The patient was referred for genetic workup but tested negative for mutations of the TSC genes in the blood. Because the patient had only unilateral facial lesions, a possible cortical tuber, no other symptoms, and tested negative for TSC gene mutations, mosaic TSC was considered a likely diagnosis. Her facial lesions were treated with pulsed dye vascular laser therapy. 

Tuberous sclerosis is an autosomal-dominant neurocutaneous disorder caused by inactivation of the genes TSC1 (encoding hamartin) and TSC2 (encoding tuberin). Mutation results in overactivation of the downstream mTOR (mammalian target of rapamycin) pathway, resulting in abnormal cellular proliferation and hamartomas. These benign tumors can be found in nearly every organ, most often in the central nervous system and skin, and they provide for a highly variable presentation of the disease.¹ 

Tuberous sclerosis affects 1 in 6000 to 10,000 live births and has a prevalence of 1 in 20,000 individuals. Of these individuals, 75% carry sporadic mutations, and 75% to 90% eventually test positive for a TSC gene mutation.² Genetic mosaicism has been reported in 28% of cases affected by large deletions¹ and as few as 1% of cases involving small mutations.³ 

The dermatologic manifestation of mosaic TSC most often includes unilateral angiofibromas, whereas in nonmosaic cases, angiofibromas cover both cheeks, the forehead, and the eyelids. The other skin lesions of TSC--shagreen patches, forehead plaques, hypomelanotic macules, and ungual fibromas--are seen less frequently.^4-6 Additionally, neurologic disease in mosaic patients is notably milder, with 57% of mosaic patients found to have epilepsy compared to 91% of nonmosaic patients.⁷ Our patient had both unilateral facial angiofibromas and a cortical lesion suspicious for a tuber, prompting a suspected diagnosis of mosaic TSC. 

The methods of diagnosis outlined by the International Tuberous Sclerosis Complex Consensus Group pose a challenge in diagnosing mosaic TSC. The clinical criteria require 2 major (eg, multiple angiofibromas, angiomyolipomas, a shagreen patch) and 1 minor feature (eg, dental enamel pit, renal cyst).² However, case reports detailing unilateral facial angiofibromas have described patients with isolated dermatologic findings.^5,6 Further, it has been demonstrated that genetic studies in mosaic TSC can be unreliable depending on the tissue sampled.⁸ Thus, for patients who have mosaic TSC, establishing a definitive diagnosis is not always possible and may rely solely on the clinical picture. 

Considering the differential diagnosis, benign cephalic histiocytosis usually would present with small red-brown macules and papules symmetrically located on the head and neck. The lesions occur at a younger age, usually in the first year or two of life. Fibrofolliculomas present as multiple whitish, slightly larger papules found on the central face. They are a marker for Birt-Hogg-Dubé syndrome, which also is associated with spontaneous pneumothorax.  

Agminated means clustering or grouping of lesions. Agminated melanocytic nevi and agminated Spitz nevi are clusters of nevi. These lesions can vary in size and color. They may be elevated or flat. Melanocytic nevi usually are tan-brown or black. Spitz nevi may be pink or pigmented brown or black. To definitively differentiate between these 2 diagnoses and this patient's diagnosis of angiofibroma, a biopsy is needed.

The Diagnosis: Congenital Self-healing Reticulohistiocytosis 

Biopsy of a representative lesion from this patient was consistent with congenital self-healing reticulohistiocytosis, as shown in the Figure. Characteristic Langerhans cells were present in the dermis that stained CD1a positive, S-100 positive, and CD68 negative to confirm the diagnosis.

Congenital self-healing reticulohistiocytosis, or Hashimoto-Pritzker syndrome, is a rare benign form of Langerhans cell histiocytosis. It is twice as common in males than females and typically noted at birth or early during the neonatal period. Lesions may present as pink, firm, asymptomatic papulonodular lesions that often ulcerate with possible residual hypopigmentation or hyperpigmentation.¹ The differential diagnosis includes congenital infectious and hematologic diseases typically associated with blueberry muffin baby. Thus, varicella, cytomegalovirus, syphilis, toxoplasmosis, rubella, neuroblastoma, leukemia cutis, and extramedullary hematopoiesis, among others, may be considered. Juvenile xanthogranuloma or urticaria pigmentosa also enter the differential diagnosis given the yellow-brown appearance. As a clonal proliferation of Langerhans cells, pathology reveals lesions that stain positive for CD1a and S-100.²  

Although typically absent, evaluation for systemic involvement is warranted, which may be an early presentation of multisystem Langerhans cell histiocytosis. Continued monitoring is recommended given the risk of relapse and associated mortality. Our patient continues to do well. He will continue to be followed by our team and hematology/oncology during early childhood.  

The treatment of congenital self-healing reticulohistiocytosis may include conservative monitoring, topical steroids, topical nitrogen mustard, tacrolimus, or psoralen plus UVA.³ Surgical excision may be considered for large lesions.  

The Diagnosis: Congenital Self-healing Reticulohistiocytosis 

Biopsy of a representative lesion from this patient was consistent with congenital self-healing reticulohistiocytosis, as shown in the Figure. Characteristic Langerhans cells were present in the dermis that stained CD1a positive, S-100 positive, and CD68 negative to confirm the diagnosis.

Congenital self-healing reticulohistiocytosis, or Hashimoto-Pritzker syndrome, is a rare benign form of Langerhans cell histiocytosis. It is twice as common in males than females and typically noted at birth or early during the neonatal period. Lesions may present as pink, firm, asymptomatic papulonodular lesions that often ulcerate with possible residual hypopigmentation or hyperpigmentation.¹ The differential diagnosis includes congenital infectious and hematologic diseases typically associated with blueberry muffin baby. Thus, varicella, cytomegalovirus, syphilis, toxoplasmosis, rubella, neuroblastoma, leukemia cutis, and extramedullary hematopoiesis, among others, may be considered. Juvenile xanthogranuloma or urticaria pigmentosa also enter the differential diagnosis given the yellow-brown appearance. As a clonal proliferation of Langerhans cells, pathology reveals lesions that stain positive for CD1a and S-100.²  

Although typically absent, evaluation for systemic involvement is warranted, which may be an early presentation of multisystem Langerhans cell histiocytosis. Continued monitoring is recommended given the risk of relapse and associated mortality. Our patient continues to do well. He will continue to be followed by our team and hematology/oncology during early childhood.  

The treatment of congenital self-healing reticulohistiocytosis may include conservative monitoring, topical steroids, topical nitrogen mustard, tacrolimus, or psoralen plus UVA.³ Surgical excision may be considered for large lesions.  

The Diagnosis: Congenital Self-healing Reticulohistiocytosis 

Biopsy of a representative lesion from this patient was consistent with congenital self-healing reticulohistiocytosis, as shown in the Figure. Characteristic Langerhans cells were present in the dermis that stained CD1a positive, S-100 positive, and CD68 negative to confirm the diagnosis.

Congenital self-healing reticulohistiocytosis, or Hashimoto-Pritzker syndrome, is a rare benign form of Langerhans cell histiocytosis. It is twice as common in males than females and typically noted at birth or early during the neonatal period. Lesions may present as pink, firm, asymptomatic papulonodular lesions that often ulcerate with possible residual hypopigmentation or hyperpigmentation.¹ The differential diagnosis includes congenital infectious and hematologic diseases typically associated with blueberry muffin baby. Thus, varicella, cytomegalovirus, syphilis, toxoplasmosis, rubella, neuroblastoma, leukemia cutis, and extramedullary hematopoiesis, among others, may be considered. Juvenile xanthogranuloma or urticaria pigmentosa also enter the differential diagnosis given the yellow-brown appearance. As a clonal proliferation of Langerhans cells, pathology reveals lesions that stain positive for CD1a and S-100.²  

Although typically absent, evaluation for systemic involvement is warranted, which may be an early presentation of multisystem Langerhans cell histiocytosis. Continued monitoring is recommended given the risk of relapse and associated mortality. Our patient continues to do well. He will continue to be followed by our team and hematology/oncology during early childhood.  

The treatment of congenital self-healing reticulohistiocytosis may include conservative monitoring, topical steroids, topical nitrogen mustard, tacrolimus, or psoralen plus UVA.³ Surgical excision may be considered for large lesions.  

The Diagnosis: Herpes Simplex Virus 

A skin biopsy was sent for tissue culture and was negative for mycobacterial, bacterial, and fungal growth. Histopathologic examination showed ballooning degeneration of keratinocytes with herpetic cytopathic effect consistent with herpetic ulceration (Figure). A swab of the lesion on the buttock was sent for human herpesvirus (HHV) and varicella-zoster virus nucleic acid testing, which was positive for HHV-2. She was started on oral valacyclovir 1000 mg twice daily for 10 days and then was continued on chronic suppression with 500 mg once daily. The patient's ulcerations healed slowly over the following few weeks.  

Human herpesvirus 2 is the most common cause of genital ulcer disease and may present as chronic and recurrent ulcers in immunocompromised patients.¹ It usually is spread by sexual contact. Primary infection typically occurs in the cells of the dermis and epidermis. Two weeks after the primary infection, extragenital lesions can occur in the lumbosacral area on the buttocks, fingers, groin, or thighs, as seen in our patient,² which is a direct result of viral shedding and spread. Reactivation of HHV from the ganglia can occur with or without symptoms. Common locations for viral shedding in women are the cervix, vulva, and perianal areas.³ Patients should be counseled to avoid sexual contact during recurrences. 

Cancer patients have a particularly increased risk for developing HHV-2 due to their limited cell-mediated immunity and exposure to immunosuppressive drugs.⁴ Moreover, approximately 5% of immunocompromised patients develop resistance to antiviral therapy.⁵ Although this phenomenon was not observed in our patient, identification of novel strategies to treat these new groups of patients will be essential.  

The differential diagnosis includes perianal candidiasis, which is classified by erythematous plaques with satellite vesicles and pustules. Contact dermatitis is common in the buttock area and usually secondary to ingredients in cleansing wipes and topical treatments. It is defined by a well-demarcated, symmetric rash, which is more eczematous in nature. Cutaneous T-cell lymphoma was high in our differential given the patient's history of the disease. There are many variants, and tumor-stage disease may result in ulceration of the skin. Cutaneous T-cell lymphoma is differentiated by histology with immunophenotyping in conjunction with the clinical picture. Epstein-Barr virus (EBV) may cause genital ulcerations, which can be diagnosed with a positive EBV serology and detection of EBV by a polymerase chain reaction swab of the ulceration. 

The Diagnosis: Herpes Simplex Virus 

A skin biopsy was sent for tissue culture and was negative for mycobacterial, bacterial, and fungal growth. Histopathologic examination showed ballooning degeneration of keratinocytes with herpetic cytopathic effect consistent with herpetic ulceration (Figure). A swab of the lesion on the buttock was sent for human herpesvirus (HHV) and varicella-zoster virus nucleic acid testing, which was positive for HHV-2. She was started on oral valacyclovir 1000 mg twice daily for 10 days and then was continued on chronic suppression with 500 mg once daily. The patient's ulcerations healed slowly over the following few weeks.  

Human herpesvirus 2 is the most common cause of genital ulcer disease and may present as chronic and recurrent ulcers in immunocompromised patients.¹ It usually is spread by sexual contact. Primary infection typically occurs in the cells of the dermis and epidermis. Two weeks after the primary infection, extragenital lesions can occur in the lumbosacral area on the buttocks, fingers, groin, or thighs, as seen in our patient,² which is a direct result of viral shedding and spread. Reactivation of HHV from the ganglia can occur with or without symptoms. Common locations for viral shedding in women are the cervix, vulva, and perianal areas.³ Patients should be counseled to avoid sexual contact during recurrences. 

Cancer patients have a particularly increased risk for developing HHV-2 due to their limited cell-mediated immunity and exposure to immunosuppressive drugs.⁴ Moreover, approximately 5% of immunocompromised patients develop resistance to antiviral therapy.⁵ Although this phenomenon was not observed in our patient, identification of novel strategies to treat these new groups of patients will be essential.  

The differential diagnosis includes perianal candidiasis, which is classified by erythematous plaques with satellite vesicles and pustules. Contact dermatitis is common in the buttock area and usually secondary to ingredients in cleansing wipes and topical treatments. It is defined by a well-demarcated, symmetric rash, which is more eczematous in nature. Cutaneous T-cell lymphoma was high in our differential given the patient's history of the disease. There are many variants, and tumor-stage disease may result in ulceration of the skin. Cutaneous T-cell lymphoma is differentiated by histology with immunophenotyping in conjunction with the clinical picture. Epstein-Barr virus (EBV) may cause genital ulcerations, which can be diagnosed with a positive EBV serology and detection of EBV by a polymerase chain reaction swab of the ulceration. 

The Diagnosis: Herpes Simplex Virus 

A skin biopsy was sent for tissue culture and was negative for mycobacterial, bacterial, and fungal growth. Histopathologic examination showed ballooning degeneration of keratinocytes with herpetic cytopathic effect consistent with herpetic ulceration (Figure). A swab of the lesion on the buttock was sent for human herpesvirus (HHV) and varicella-zoster virus nucleic acid testing, which was positive for HHV-2. She was started on oral valacyclovir 1000 mg twice daily for 10 days and then was continued on chronic suppression with 500 mg once daily. The patient's ulcerations healed slowly over the following few weeks.  

Human herpesvirus 2 is the most common cause of genital ulcer disease and may present as chronic and recurrent ulcers in immunocompromised patients.¹ It usually is spread by sexual contact. Primary infection typically occurs in the cells of the dermis and epidermis. Two weeks after the primary infection, extragenital lesions can occur in the lumbosacral area on the buttocks, fingers, groin, or thighs, as seen in our patient,² which is a direct result of viral shedding and spread. Reactivation of HHV from the ganglia can occur with or without symptoms. Common locations for viral shedding in women are the cervix, vulva, and perianal areas.³ Patients should be counseled to avoid sexual contact during recurrences. 

Cancer patients have a particularly increased risk for developing HHV-2 due to their limited cell-mediated immunity and exposure to immunosuppressive drugs.⁴ Moreover, approximately 5% of immunocompromised patients develop resistance to antiviral therapy.⁵ Although this phenomenon was not observed in our patient, identification of novel strategies to treat these new groups of patients will be essential.  

The differential diagnosis includes perianal candidiasis, which is classified by erythematous plaques with satellite vesicles and pustules. Contact dermatitis is common in the buttock area and usually secondary to ingredients in cleansing wipes and topical treatments. It is defined by a well-demarcated, symmetric rash, which is more eczematous in nature. Cutaneous T-cell lymphoma was high in our differential given the patient's history of the disease. There are many variants, and tumor-stage disease may result in ulceration of the skin. Cutaneous T-cell lymphoma is differentiated by histology with immunophenotyping in conjunction with the clinical picture. Epstein-Barr virus (EBV) may cause genital ulcerations, which can be diagnosed with a positive EBV serology and detection of EBV by a polymerase chain reaction swab of the ulceration. 

The Diagnosis: Inflammatory Urothelial Carcinoma 

Microscopic examination revealed metastatic carcinoma with extensive dermal lymphatic invasion (Figure). Immunohistochemical stains were positive for p63 and GATA3, markers for urothelial carcinomas, and negative for S-100 and Melan-A, markers for melanoma. Thus, the biopsy was compatible with a diagnosis of urothelial carcinoma. Gram and Grocott-Gomori methenamine-silver stains were negative for bacterial or fungal organisms. An additional 4-mm punch biopsy was performed of the left thigh at the distal-most aspect of the eruption to determine the extent of cutaneous metastasis. Pathology again showed metastatic urothelial carcinoma with extensive dermal lymphatic involvement and overlying epidermal spongiosis.

The patient had a history of bladder cancer diagnosed 1.5 years prior to presentation. It was a high-grade (World Health Organization) urothelial carcinoma that penetrated the bladder muscular wall, focally infiltrating into pericystic fat with multifocal seeding of pericystic lymphatics. It was unresponsive to bacillus Calmette-Guérin therapy. He underwent a cystoprostatectomy and bilateral staging lymph node dissection with clear surgical margins without adjuvant chemotherapy or radiation. He also reported a history of 2 prior cutaneous melanomas that were excised without sentinel lymph node biopsy. 

Four months prior to presentation, he developed a mildly pruritic cutaneous eruption on the abdomen that was treated with topical miconazole for presumed tinea cruris without improvement. He also was previously diagnosed with candidiasis of his urostomy and was taking oral fluconazole. The patient was admitted for the abdominal pain and distension, and computed tomography of the abdomen and pelvis revealed peritoneal carcinomatosis resulting in mechanical small bowel obstruction as well as enlarged pelvic and retroperitoneal lymph nodes. Confirmation of metastatic disease via skin biopsy avoided an invasive peritoneal biopsy. He was treated with triamcinolone acetonide ointment 0.1% with moderate relief of pruritus, and a palliative percutaneous endoscopic gastrostomy tube was placed for bowel decompression. The patient's hospital course was complicated by Proteus mirabilis bacteremia requiring cefepime. He was transitioned to home hospice and died 1 month after presentation. 

Inflammatory carcinoma, also called carcinoma erysipeloides, is a type of cutaneous metastasis most commonly seen in breast adenocarcinoma. Reported cases secondary to urothelial carcinoma are rare and most often involve the abdomen, groin, and lower extremities.^1-5 Clinically, inflammatory carcinoma presents as erythematous indurated patches or plaques with well-defined borders, often with edema, warmth, and tenderness. Its morphologic appearance is due to the obstruction of lymphatic vessels by tumor cells and the release of inflammatory cytokines. Its presentation can mimic other dermatoses such as cellulitis, erysipelas, fungal infection, radiation dermatitis, Majocchi granuloma, or contact dermatitis.⁶ Cutaneous metastases may be the first clinical manifestations of metastatic disease, and they may occur due to hematogenous and lymphatic spread, direct contiguous tissue invasion, or iatrogenic implantation following surgical excision of the primary tumor. Histologically, nuclear markers GATA3 and p63 stain positively in urothelial carcinomas and are negative in prostatic adenocarcinomas.^7,8 Other markers may be used such as cytokeratins 7 and 20, which are cytoplasmic epithelial markers that both stain positive in urothelial neoplasms.⁹  

Inflammatory carcinoma may be treated with radiation or systemic chemotherapy depending on the extent of systemic involvement in the patient; however, its presence portends a poor prognosis. Less than 1% of genitourinary malignancies have cutaneous involvement, and median disease-specific survival is less than 6 months from presentation of the cutaneous metastasis.¹⁰ Clinicians faced with a recalcitrant inflammatory cutaneous eruption should maintain a high index of suspicion for cutaneous metastases, particularly in patients with a history of cancer. Early dermatology referral may help establish the diagnosis and guide disease-targeted therapy or goals of care discussions. 

The Diagnosis: Inflammatory Urothelial Carcinoma 

Microscopic examination revealed metastatic carcinoma with extensive dermal lymphatic invasion (Figure). Immunohistochemical stains were positive for p63 and GATA3, markers for urothelial carcinomas, and negative for S-100 and Melan-A, markers for melanoma. Thus, the biopsy was compatible with a diagnosis of urothelial carcinoma. Gram and Grocott-Gomori methenamine-silver stains were negative for bacterial or fungal organisms. An additional 4-mm punch biopsy was performed of the left thigh at the distal-most aspect of the eruption to determine the extent of cutaneous metastasis. Pathology again showed metastatic urothelial carcinoma with extensive dermal lymphatic involvement and overlying epidermal spongiosis.

The patient had a history of bladder cancer diagnosed 1.5 years prior to presentation. It was a high-grade (World Health Organization) urothelial carcinoma that penetrated the bladder muscular wall, focally infiltrating into pericystic fat with multifocal seeding of pericystic lymphatics. It was unresponsive to bacillus Calmette-Guérin therapy. He underwent a cystoprostatectomy and bilateral staging lymph node dissection with clear surgical margins without adjuvant chemotherapy or radiation. He also reported a history of 2 prior cutaneous melanomas that were excised without sentinel lymph node biopsy. 

Four months prior to presentation, he developed a mildly pruritic cutaneous eruption on the abdomen that was treated with topical miconazole for presumed tinea cruris without improvement. He also was previously diagnosed with candidiasis of his urostomy and was taking oral fluconazole. The patient was admitted for the abdominal pain and distension, and computed tomography of the abdomen and pelvis revealed peritoneal carcinomatosis resulting in mechanical small bowel obstruction as well as enlarged pelvic and retroperitoneal lymph nodes. Confirmation of metastatic disease via skin biopsy avoided an invasive peritoneal biopsy. He was treated with triamcinolone acetonide ointment 0.1% with moderate relief of pruritus, and a palliative percutaneous endoscopic gastrostomy tube was placed for bowel decompression. The patient's hospital course was complicated by Proteus mirabilis bacteremia requiring cefepime. He was transitioned to home hospice and died 1 month after presentation. 

Inflammatory carcinoma, also called carcinoma erysipeloides, is a type of cutaneous metastasis most commonly seen in breast adenocarcinoma. Reported cases secondary to urothelial carcinoma are rare and most often involve the abdomen, groin, and lower extremities.^1-5 Clinically, inflammatory carcinoma presents as erythematous indurated patches or plaques with well-defined borders, often with edema, warmth, and tenderness. Its morphologic appearance is due to the obstruction of lymphatic vessels by tumor cells and the release of inflammatory cytokines. Its presentation can mimic other dermatoses such as cellulitis, erysipelas, fungal infection, radiation dermatitis, Majocchi granuloma, or contact dermatitis.⁶ Cutaneous metastases may be the first clinical manifestations of metastatic disease, and they may occur due to hematogenous and lymphatic spread, direct contiguous tissue invasion, or iatrogenic implantation following surgical excision of the primary tumor. Histologically, nuclear markers GATA3 and p63 stain positively in urothelial carcinomas and are negative in prostatic adenocarcinomas.^7,8 Other markers may be used such as cytokeratins 7 and 20, which are cytoplasmic epithelial markers that both stain positive in urothelial neoplasms.⁹  

Inflammatory carcinoma may be treated with radiation or systemic chemotherapy depending on the extent of systemic involvement in the patient; however, its presence portends a poor prognosis. Less than 1% of genitourinary malignancies have cutaneous involvement, and median disease-specific survival is less than 6 months from presentation of the cutaneous metastasis.¹⁰ Clinicians faced with a recalcitrant inflammatory cutaneous eruption should maintain a high index of suspicion for cutaneous metastases, particularly in patients with a history of cancer. Early dermatology referral may help establish the diagnosis and guide disease-targeted therapy or goals of care discussions. 

The Diagnosis: Inflammatory Urothelial Carcinoma 

Microscopic examination revealed metastatic carcinoma with extensive dermal lymphatic invasion (Figure). Immunohistochemical stains were positive for p63 and GATA3, markers for urothelial carcinomas, and negative for S-100 and Melan-A, markers for melanoma. Thus, the biopsy was compatible with a diagnosis of urothelial carcinoma. Gram and Grocott-Gomori methenamine-silver stains were negative for bacterial or fungal organisms. An additional 4-mm punch biopsy was performed of the left thigh at the distal-most aspect of the eruption to determine the extent of cutaneous metastasis. Pathology again showed metastatic urothelial carcinoma with extensive dermal lymphatic involvement and overlying epidermal spongiosis.

The patient had a history of bladder cancer diagnosed 1.5 years prior to presentation. It was a high-grade (World Health Organization) urothelial carcinoma that penetrated the bladder muscular wall, focally infiltrating into pericystic fat with multifocal seeding of pericystic lymphatics. It was unresponsive to bacillus Calmette-Guérin therapy. He underwent a cystoprostatectomy and bilateral staging lymph node dissection with clear surgical margins without adjuvant chemotherapy or radiation. He also reported a history of 2 prior cutaneous melanomas that were excised without sentinel lymph node biopsy. 

Four months prior to presentation, he developed a mildly pruritic cutaneous eruption on the abdomen that was treated with topical miconazole for presumed tinea cruris without improvement. He also was previously diagnosed with candidiasis of his urostomy and was taking oral fluconazole. The patient was admitted for the abdominal pain and distension, and computed tomography of the abdomen and pelvis revealed peritoneal carcinomatosis resulting in mechanical small bowel obstruction as well as enlarged pelvic and retroperitoneal lymph nodes. Confirmation of metastatic disease via skin biopsy avoided an invasive peritoneal biopsy. He was treated with triamcinolone acetonide ointment 0.1% with moderate relief of pruritus, and a palliative percutaneous endoscopic gastrostomy tube was placed for bowel decompression. The patient's hospital course was complicated by Proteus mirabilis bacteremia requiring cefepime. He was transitioned to home hospice and died 1 month after presentation. 

Inflammatory carcinoma, also called carcinoma erysipeloides, is a type of cutaneous metastasis most commonly seen in breast adenocarcinoma. Reported cases secondary to urothelial carcinoma are rare and most often involve the abdomen, groin, and lower extremities.^1-5 Clinically, inflammatory carcinoma presents as erythematous indurated patches or plaques with well-defined borders, often with edema, warmth, and tenderness. Its morphologic appearance is due to the obstruction of lymphatic vessels by tumor cells and the release of inflammatory cytokines. Its presentation can mimic other dermatoses such as cellulitis, erysipelas, fungal infection, radiation dermatitis, Majocchi granuloma, or contact dermatitis.⁶ Cutaneous metastases may be the first clinical manifestations of metastatic disease, and they may occur due to hematogenous and lymphatic spread, direct contiguous tissue invasion, or iatrogenic implantation following surgical excision of the primary tumor. Histologically, nuclear markers GATA3 and p63 stain positively in urothelial carcinomas and are negative in prostatic adenocarcinomas.^7,8 Other markers may be used such as cytokeratins 7 and 20, which are cytoplasmic epithelial markers that both stain positive in urothelial neoplasms.⁹  

Inflammatory carcinoma may be treated with radiation or systemic chemotherapy depending on the extent of systemic involvement in the patient; however, its presence portends a poor prognosis. Less than 1% of genitourinary malignancies have cutaneous involvement, and median disease-specific survival is less than 6 months from presentation of the cutaneous metastasis.¹⁰ Clinicians faced with a recalcitrant inflammatory cutaneous eruption should maintain a high index of suspicion for cutaneous metastases, particularly in patients with a history of cancer. Early dermatology referral may help establish the diagnosis and guide disease-targeted therapy or goals of care discussions. 

The Diagnosis: Irritant Contact Dermatitis and Hyperpigmentation Due to Juglone  

Clinical suspicion, resemblance to similar cases, and questioning the patient about his behavior prior to the onset of symptoms led to the diagnosis of irritant contact dermatitis and hyperpigmentation due to juglone in this case. Walnuts belong to the botanical family of Juglandaceae and are the seed of the trees of the genus Juglans, which encompass 24 different species. The nuts from all species included in this genus are edible.¹ The most well-known species of walnut is the common walnut (Juglans regia), which is native to the Balkans region in southeast Europe, southwest and central Asia extending to the Himalayas, and southwest China.¹  

Walnut fruits are rich in phenolic compounds. Thirteen phenolic compounds have been identified in walnut husks including chlorogenic acid, caffeic acid, ferulic acid, sinapic acid, gallic acid, ellagic acid, protocatechuic acid, syringic acid, vanillic acid, catechin, epicatechin, myricetin, and juglone.² Juglone, also called 5-hydroxy-1,4-napthoquinone, is a yellow naphthoquinone pigment that occurs naturally in the leaves, roots, husks, and bark of plants in the Juglandaceae family, particularly the black walnut (Juglans nigra).^3,4 

Juglans regia, also known as English or Persian walnut, contains potent chemical constituents and has been used to treat diverse ailments such as diarrhea, hyperglycemia, cancer, infectious diseases, anorexia, asthma, helminthiasis, arthritis, sinusitis, stomachache, and skin disorders (eg, eczema; acne; alopecia; scalp itching, peeling, and dandruff), and as an adjunctive emollient and itch-relieving treatment.^5,6 

The juice of walnut shells from the J regia tree have been used for centuries to color the skin and hair.⁷ Irritation and skin hyperpigmentation have been associated with topical walnut use.⁵ As a naphthoquinone, juglone also is reported to exert some toxic effects on normal tissues including acute irritant contact dermatitis.⁴ As the active ingredient from the green husk of walnuts, it has been considered a strong sensitizer in guinea pigs,¹ but contact sensitivity in humans rarely has been reported.⁷  

Juglone is known to react with the keratin proteins present in the skin to form sclerojuglonic compounds, which have UV protection properties and a red-brown color.⁸ The resulting reaction gives rise to chromophore groups with a strong pigmenting action that absorbs visible colors (especially violet) and reflects yellow and red, resulting in the coloration ranging from red to deep brown.⁷ The mechanism of skin pigmentation does not involve the melanocytes. Hyperchromia involving the hands--particularly the palms, fingers, and nails--lasts 1 to 4 weeks depending on the intensity of the pigmentation. Housewives and agricultural workers are the at-risk population.⁷ Acute irritant contact dermatitis and hyperpigmentation due to juglone mainly has been observed during the early autumn in agricultural workers and housewives who remove the green husk of walnuts.⁹  

Addison disease can present with pigmentary changes in the skin and mucous membranes; it also is accompanied by fatigue, anorexia, weakness, and weight loss, none of which were noted in our patient. A fixed drug eruption tends to have an annular or oval form and is related to the intake of medication (mostly antibiotics) up to 2 weeks prior to the onset of the dermatosis. Our patient did not have any chronic disease or take any medication prior to the dermatosis and lacked the classic clinical morphology of this entity. Hemochromatosis affects not only the skin but also the liver, myocardial fibers, and other internal organs. Our patient did not have any clinical manifestations of liver or heart failure or diabetes mellitus.  

Our patient was treated with drainage of the blisters. Due to the extent of the dermatosis, prednisone 25 mg/d also was initiated. The patient was instructed to avoid direct contact with the husk of walnuts. At 1-month follow-up, the hyperpigmentation had resolved with no relapse (Figure). 

The Diagnosis: Irritant Contact Dermatitis and Hyperpigmentation Due to Juglone  

Clinical suspicion, resemblance to similar cases, and questioning the patient about his behavior prior to the onset of symptoms led to the diagnosis of irritant contact dermatitis and hyperpigmentation due to juglone in this case. Walnuts belong to the botanical family of Juglandaceae and are the seed of the trees of the genus Juglans, which encompass 24 different species. The nuts from all species included in this genus are edible.¹ The most well-known species of walnut is the common walnut (Juglans regia), which is native to the Balkans region in southeast Europe, southwest and central Asia extending to the Himalayas, and southwest China.¹  

Walnut fruits are rich in phenolic compounds. Thirteen phenolic compounds have been identified in walnut husks including chlorogenic acid, caffeic acid, ferulic acid, sinapic acid, gallic acid, ellagic acid, protocatechuic acid, syringic acid, vanillic acid, catechin, epicatechin, myricetin, and juglone.² Juglone, also called 5-hydroxy-1,4-napthoquinone, is a yellow naphthoquinone pigment that occurs naturally in the leaves, roots, husks, and bark of plants in the Juglandaceae family, particularly the black walnut (Juglans nigra).^3,4 

Juglans regia, also known as English or Persian walnut, contains potent chemical constituents and has been used to treat diverse ailments such as diarrhea, hyperglycemia, cancer, infectious diseases, anorexia, asthma, helminthiasis, arthritis, sinusitis, stomachache, and skin disorders (eg, eczema; acne; alopecia; scalp itching, peeling, and dandruff), and as an adjunctive emollient and itch-relieving treatment.^5,6 

The juice of walnut shells from the J regia tree have been used for centuries to color the skin and hair.⁷ Irritation and skin hyperpigmentation have been associated with topical walnut use.⁵ As a naphthoquinone, juglone also is reported to exert some toxic effects on normal tissues including acute irritant contact dermatitis.⁴ As the active ingredient from the green husk of walnuts, it has been considered a strong sensitizer in guinea pigs,¹ but contact sensitivity in humans rarely has been reported.⁷  

Juglone is known to react with the keratin proteins present in the skin to form sclerojuglonic compounds, which have UV protection properties and a red-brown color.⁸ The resulting reaction gives rise to chromophore groups with a strong pigmenting action that absorbs visible colors (especially violet) and reflects yellow and red, resulting in the coloration ranging from red to deep brown.⁷ The mechanism of skin pigmentation does not involve the melanocytes. Hyperchromia involving the hands--particularly the palms, fingers, and nails--lasts 1 to 4 weeks depending on the intensity of the pigmentation. Housewives and agricultural workers are the at-risk population.⁷ Acute irritant contact dermatitis and hyperpigmentation due to juglone mainly has been observed during the early autumn in agricultural workers and housewives who remove the green husk of walnuts.⁹  

Addison disease can present with pigmentary changes in the skin and mucous membranes; it also is accompanied by fatigue, anorexia, weakness, and weight loss, none of which were noted in our patient. A fixed drug eruption tends to have an annular or oval form and is related to the intake of medication (mostly antibiotics) up to 2 weeks prior to the onset of the dermatosis. Our patient did not have any chronic disease or take any medication prior to the dermatosis and lacked the classic clinical morphology of this entity. Hemochromatosis affects not only the skin but also the liver, myocardial fibers, and other internal organs. Our patient did not have any clinical manifestations of liver or heart failure or diabetes mellitus.  

Our patient was treated with drainage of the blisters. Due to the extent of the dermatosis, prednisone 25 mg/d also was initiated. The patient was instructed to avoid direct contact with the husk of walnuts. At 1-month follow-up, the hyperpigmentation had resolved with no relapse (Figure). 

The Diagnosis: Irritant Contact Dermatitis and Hyperpigmentation Due to Juglone  

Clinical suspicion, resemblance to similar cases, and questioning the patient about his behavior prior to the onset of symptoms led to the diagnosis of irritant contact dermatitis and hyperpigmentation due to juglone in this case. Walnuts belong to the botanical family of Juglandaceae and are the seed of the trees of the genus Juglans, which encompass 24 different species. The nuts from all species included in this genus are edible.¹ The most well-known species of walnut is the common walnut (Juglans regia), which is native to the Balkans region in southeast Europe, southwest and central Asia extending to the Himalayas, and southwest China.¹  

Walnut fruits are rich in phenolic compounds. Thirteen phenolic compounds have been identified in walnut husks including chlorogenic acid, caffeic acid, ferulic acid, sinapic acid, gallic acid, ellagic acid, protocatechuic acid, syringic acid, vanillic acid, catechin, epicatechin, myricetin, and juglone.² Juglone, also called 5-hydroxy-1,4-napthoquinone, is a yellow naphthoquinone pigment that occurs naturally in the leaves, roots, husks, and bark of plants in the Juglandaceae family, particularly the black walnut (Juglans nigra).^3,4 

Juglans regia, also known as English or Persian walnut, contains potent chemical constituents and has been used to treat diverse ailments such as diarrhea, hyperglycemia, cancer, infectious diseases, anorexia, asthma, helminthiasis, arthritis, sinusitis, stomachache, and skin disorders (eg, eczema; acne; alopecia; scalp itching, peeling, and dandruff), and as an adjunctive emollient and itch-relieving treatment.^5,6 

The juice of walnut shells from the J regia tree have been used for centuries to color the skin and hair.⁷ Irritation and skin hyperpigmentation have been associated with topical walnut use.⁵ As a naphthoquinone, juglone also is reported to exert some toxic effects on normal tissues including acute irritant contact dermatitis.⁴ As the active ingredient from the green husk of walnuts, it has been considered a strong sensitizer in guinea pigs,¹ but contact sensitivity in humans rarely has been reported.⁷  

Juglone is known to react with the keratin proteins present in the skin to form sclerojuglonic compounds, which have UV protection properties and a red-brown color.⁸ The resulting reaction gives rise to chromophore groups with a strong pigmenting action that absorbs visible colors (especially violet) and reflects yellow and red, resulting in the coloration ranging from red to deep brown.⁷ The mechanism of skin pigmentation does not involve the melanocytes. Hyperchromia involving the hands--particularly the palms, fingers, and nails--lasts 1 to 4 weeks depending on the intensity of the pigmentation. Housewives and agricultural workers are the at-risk population.⁷ Acute irritant contact dermatitis and hyperpigmentation due to juglone mainly has been observed during the early autumn in agricultural workers and housewives who remove the green husk of walnuts.⁹  

Addison disease can present with pigmentary changes in the skin and mucous membranes; it also is accompanied by fatigue, anorexia, weakness, and weight loss, none of which were noted in our patient. A fixed drug eruption tends to have an annular or oval form and is related to the intake of medication (mostly antibiotics) up to 2 weeks prior to the onset of the dermatosis. Our patient did not have any chronic disease or take any medication prior to the dermatosis and lacked the classic clinical morphology of this entity. Hemochromatosis affects not only the skin but also the liver, myocardial fibers, and other internal organs. Our patient did not have any clinical manifestations of liver or heart failure or diabetes mellitus.  

Our patient was treated with drainage of the blisters. Due to the extent of the dermatosis, prednisone 25 mg/d also was initiated. The patient was instructed to avoid direct contact with the husk of walnuts. At 1-month follow-up, the hyperpigmentation had resolved with no relapse (Figure). 

The Diagnosis: Cutaneous Tuberculosis 

The patient's medical history was notable for bone tuberculosis (TB) treated in childhood. Skin biopsy revealed neutrophilic infiltrates with necrosis without granulomas. A real-time polymerase chain reaction test detected Mycobacterium tuberculosis complex in the skin fragment, which was confirmed by culture of the biopsy specimen using a liquid growth medium that grew M tuberculosis. Tuberculotic foci were not present on the lungs, gastrointestinal tract, kidneys, and bones by radiologic, microbiologic, and ultrasonographic investigations. The patient was started on 4 antituberculotic drugs--isoniazid 300 mg, rifampicin 600 mg, ethambutol 1200 mg, pyrazinamide 1500 mg--once daily for 2 months followed by isoniazid 300 mg and rifampicin 600 mg once daily for another 4 months with resolution of the skin lesions. 

Cutaneous TB is an infectious disease caused by M tuberculosis and accounts for only 1.5% of extrapulmonary TB cases.^1,2 Similar to other forms of TB, a resurgence of cutaneous TB has been noted in parts of the world where human immunodeficiency virus infection is prevalent and remains to be one of the most elusive and more difficult diseases to diagnose.³ Thought to be a predominantly occupational disease, it is being encountered more frequently in healthy individuals where the source of infection remains unidentified in most cases.⁴ The clinical types depend on the method of infection, virulence of the bacillus, immune status of the host, and presence or absence of host sensitization to M tuberculosis.² The route of infection is used to classify cutaneous mycobacteriosis.⁵ Inoculation from an exogenous source can produce TB verrucosa cutis in individuals who have previously been sensitized to M tuberculosis or tuberculous chancre in individuals without prior exposure to the bacterium.⁴ Cutaneous TB resulting from direct spread to the skin from an underlying contiguous structure in most cases spreads from lymph nodes and bone (scrofuloderma). Immunosuppressed patients with advanced TB of the lung, gastrointestinal tract, or the genitourinary tract may present with periorificial TB.⁴ Dissemination to the skin caused by hematogenous spread can occur in the form of lupus vulgaris, miliary TB, or metastatic tuberculous abscesses (gummas).^4,5 A fourth category--cutaneous TB from paradoxical expansion--also was proposed. Paradoxical expansion is defined as the transient expansion of a preexisting lesion or the appearance of new lesions during appropriate anti-TB therapy.⁵ 

Although histopathology and protein chain reaction tests are useful, the gold standard for diagnosis is still the isolation of M tuberculosis on culture.^3,6 Treatment regimens of cutaneous TB are similar to those of pulmonary TB, with a 4-agent regimen given for 2 months followed by a 2-drug regimen for the next 4 months.^1,7 The differential diagnosis of leg ulcers includes stasis ulcer, necrobiotic xanthogranuloma, pyoderma gangrenosum, and squamous cell carcinoma, among others. Cutaneous biopsy, microbiological culture, and a high degree of suspicion are fundamental for the final diagnosis. Cutaneous TB should be suspected in immunocompetent as well as in immunosuppressed patients who present with ulcerated lesions that do not respond to antibacterial treatment.

The Diagnosis: Cutaneous Tuberculosis 

The patient's medical history was notable for bone tuberculosis (TB) treated in childhood. Skin biopsy revealed neutrophilic infiltrates with necrosis without granulomas. A real-time polymerase chain reaction test detected Mycobacterium tuberculosis complex in the skin fragment, which was confirmed by culture of the biopsy specimen using a liquid growth medium that grew M tuberculosis. Tuberculotic foci were not present on the lungs, gastrointestinal tract, kidneys, and bones by radiologic, microbiologic, and ultrasonographic investigations. The patient was started on 4 antituberculotic drugs--isoniazid 300 mg, rifampicin 600 mg, ethambutol 1200 mg, pyrazinamide 1500 mg--once daily for 2 months followed by isoniazid 300 mg and rifampicin 600 mg once daily for another 4 months with resolution of the skin lesions. 

Cutaneous TB is an infectious disease caused by M tuberculosis and accounts for only 1.5% of extrapulmonary TB cases.^1,2 Similar to other forms of TB, a resurgence of cutaneous TB has been noted in parts of the world where human immunodeficiency virus infection is prevalent and remains to be one of the most elusive and more difficult diseases to diagnose.³ Thought to be a predominantly occupational disease, it is being encountered more frequently in healthy individuals where the source of infection remains unidentified in most cases.⁴ The clinical types depend on the method of infection, virulence of the bacillus, immune status of the host, and presence or absence of host sensitization to M tuberculosis.² The route of infection is used to classify cutaneous mycobacteriosis.⁵ Inoculation from an exogenous source can produce TB verrucosa cutis in individuals who have previously been sensitized to M tuberculosis or tuberculous chancre in individuals without prior exposure to the bacterium.⁴ Cutaneous TB resulting from direct spread to the skin from an underlying contiguous structure in most cases spreads from lymph nodes and bone (scrofuloderma). Immunosuppressed patients with advanced TB of the lung, gastrointestinal tract, or the genitourinary tract may present with periorificial TB.⁴ Dissemination to the skin caused by hematogenous spread can occur in the form of lupus vulgaris, miliary TB, or metastatic tuberculous abscesses (gummas).^4,5 A fourth category--cutaneous TB from paradoxical expansion--also was proposed. Paradoxical expansion is defined as the transient expansion of a preexisting lesion or the appearance of new lesions during appropriate anti-TB therapy.⁵ 

Although histopathology and protein chain reaction tests are useful, the gold standard for diagnosis is still the isolation of M tuberculosis on culture.^3,6 Treatment regimens of cutaneous TB are similar to those of pulmonary TB, with a 4-agent regimen given for 2 months followed by a 2-drug regimen for the next 4 months.^1,7 The differential diagnosis of leg ulcers includes stasis ulcer, necrobiotic xanthogranuloma, pyoderma gangrenosum, and squamous cell carcinoma, among others. Cutaneous biopsy, microbiological culture, and a high degree of suspicion are fundamental for the final diagnosis. Cutaneous TB should be suspected in immunocompetent as well as in immunosuppressed patients who present with ulcerated lesions that do not respond to antibacterial treatment.

The Diagnosis: Cutaneous Tuberculosis 

The patient's medical history was notable for bone tuberculosis (TB) treated in childhood. Skin biopsy revealed neutrophilic infiltrates with necrosis without granulomas. A real-time polymerase chain reaction test detected Mycobacterium tuberculosis complex in the skin fragment, which was confirmed by culture of the biopsy specimen using a liquid growth medium that grew M tuberculosis. Tuberculotic foci were not present on the lungs, gastrointestinal tract, kidneys, and bones by radiologic, microbiologic, and ultrasonographic investigations. The patient was started on 4 antituberculotic drugs--isoniazid 300 mg, rifampicin 600 mg, ethambutol 1200 mg, pyrazinamide 1500 mg--once daily for 2 months followed by isoniazid 300 mg and rifampicin 600 mg once daily for another 4 months with resolution of the skin lesions. 

Cutaneous TB is an infectious disease caused by M tuberculosis and accounts for only 1.5% of extrapulmonary TB cases.^1,2 Similar to other forms of TB, a resurgence of cutaneous TB has been noted in parts of the world where human immunodeficiency virus infection is prevalent and remains to be one of the most elusive and more difficult diseases to diagnose.³ Thought to be a predominantly occupational disease, it is being encountered more frequently in healthy individuals where the source of infection remains unidentified in most cases.⁴ The clinical types depend on the method of infection, virulence of the bacillus, immune status of the host, and presence or absence of host sensitization to M tuberculosis.² The route of infection is used to classify cutaneous mycobacteriosis.⁵ Inoculation from an exogenous source can produce TB verrucosa cutis in individuals who have previously been sensitized to M tuberculosis or tuberculous chancre in individuals without prior exposure to the bacterium.⁴ Cutaneous TB resulting from direct spread to the skin from an underlying contiguous structure in most cases spreads from lymph nodes and bone (scrofuloderma). Immunosuppressed patients with advanced TB of the lung, gastrointestinal tract, or the genitourinary tract may present with periorificial TB.⁴ Dissemination to the skin caused by hematogenous spread can occur in the form of lupus vulgaris, miliary TB, or metastatic tuberculous abscesses (gummas).^4,5 A fourth category--cutaneous TB from paradoxical expansion--also was proposed. Paradoxical expansion is defined as the transient expansion of a preexisting lesion or the appearance of new lesions during appropriate anti-TB therapy.⁵ 

Although histopathology and protein chain reaction tests are useful, the gold standard for diagnosis is still the isolation of M tuberculosis on culture.^3,6 Treatment regimens of cutaneous TB are similar to those of pulmonary TB, with a 4-agent regimen given for 2 months followed by a 2-drug regimen for the next 4 months.^1,7 The differential diagnosis of leg ulcers includes stasis ulcer, necrobiotic xanthogranuloma, pyoderma gangrenosum, and squamous cell carcinoma, among others. Cutaneous biopsy, microbiological culture, and a high degree of suspicion are fundamental for the final diagnosis. Cutaneous TB should be suspected in immunocompetent as well as in immunosuppressed patients who present with ulcerated lesions that do not respond to antibacterial treatment.

The Diagnosis: Fracture Blisters 

The shave biopsy pathology demonstrated a subepidermal bulla with re-epithelialization that was clinically consistent with fracture blisters (also known as fracture bullae)(Figure). Fracture blisters are a complication of bone fractures, usually occurring 24 to 48 hours after the trauma but possibly up to 3 weeks later. The skin usually is edematous with tense bullae overlying the fracture (in this case it was distal to the fracture); most blisters contain clear fluid, but older blisters tend to be more flaccid with hemorrhagic fluid.¹ The cause is thought to be the result of skin strain during fracture formation.² Edema and hypoxia from injured vessels and lymphatics contribute to the formation of bullae, which are seen as a dermoepidermal junction split on histology.¹ 

The bullae are histologically indistinguishable from edema blisters. A clinical history can help to differentiate. Edema blisters occur in the setting of an acute exacerbation of chronic edema, usually on the lower extremities in the setting of fluid overload.³ Bullous cellulitis is associated with skin erythema, warmth, and systemic symptoms. Bullous pemphigoid can be localized to the lower legs at times; however, biopsy would show a subepidermal bulla with eosinophils along the dermoepidermal junction. Linear IgA bullous dermatosis can be drug induced from vancomycin; however, pathology would show a subepidermal blister with a neutrophil predominant infiltrate. Nonsteroidal anti-inflammatory medications such as naproxen are a common culprit for bullous drug eruptions, which can be localized or generalized and include diagnoses such as fixed drug eruption, toxic epidermal necrolysis, and drug-induced pseudoporphyria. Naproxen-induced pseudoporphyria more commonly presents with blisters, erosions, and scarring with a predilection for the dorsal hands. Histology also will demonstrate subepidermal bullae. Clues to differentiate pseudoporphyria from fracture blisters include festooning of the dermal papilla and caterpillar bodies consisting of basement membrane material and colloid bodies in the basal layer of the epidermis, though they are not always present.⁴ 

Fracture blisters can be localized to the injury site or extend beyond the fracture site. They usually are found where there is minimal subcutaneous tissue, such as the tibia, ankles, and elbows. Fractures treated within 24 hours are much less likely to have bullae formation.¹ The bullae are sterile but may lead to wound healing complications, such as infections or delay in surgical management. However, there are no major adverse effects of postoperative fracture blisters.¹ Fracture blisters are self-healing, though silver sulfadiazine has been shown to minimize soft-tissue complications by promoting re-epithelialization.⁵ 
 

The Diagnosis: Fracture Blisters 

The shave biopsy pathology demonstrated a subepidermal bulla with re-epithelialization that was clinically consistent with fracture blisters (also known as fracture bullae)(Figure). Fracture blisters are a complication of bone fractures, usually occurring 24 to 48 hours after the trauma but possibly up to 3 weeks later. The skin usually is edematous with tense bullae overlying the fracture (in this case it was distal to the fracture); most blisters contain clear fluid, but older blisters tend to be more flaccid with hemorrhagic fluid.¹ The cause is thought to be the result of skin strain during fracture formation.² Edema and hypoxia from injured vessels and lymphatics contribute to the formation of bullae, which are seen as a dermoepidermal junction split on histology.¹ 

The bullae are histologically indistinguishable from edema blisters. A clinical history can help to differentiate. Edema blisters occur in the setting of an acute exacerbation of chronic edema, usually on the lower extremities in the setting of fluid overload.³ Bullous cellulitis is associated with skin erythema, warmth, and systemic symptoms. Bullous pemphigoid can be localized to the lower legs at times; however, biopsy would show a subepidermal bulla with eosinophils along the dermoepidermal junction. Linear IgA bullous dermatosis can be drug induced from vancomycin; however, pathology would show a subepidermal blister with a neutrophil predominant infiltrate. Nonsteroidal anti-inflammatory medications such as naproxen are a common culprit for bullous drug eruptions, which can be localized or generalized and include diagnoses such as fixed drug eruption, toxic epidermal necrolysis, and drug-induced pseudoporphyria. Naproxen-induced pseudoporphyria more commonly presents with blisters, erosions, and scarring with a predilection for the dorsal hands. Histology also will demonstrate subepidermal bullae. Clues to differentiate pseudoporphyria from fracture blisters include festooning of the dermal papilla and caterpillar bodies consisting of basement membrane material and colloid bodies in the basal layer of the epidermis, though they are not always present.⁴ 

Fracture blisters can be localized to the injury site or extend beyond the fracture site. They usually are found where there is minimal subcutaneous tissue, such as the tibia, ankles, and elbows. Fractures treated within 24 hours are much less likely to have bullae formation.¹ The bullae are sterile but may lead to wound healing complications, such as infections or delay in surgical management. However, there are no major adverse effects of postoperative fracture blisters.¹ Fracture blisters are self-healing, though silver sulfadiazine has been shown to minimize soft-tissue complications by promoting re-epithelialization.⁵ 
 

The Diagnosis: Fracture Blisters 

The shave biopsy pathology demonstrated a subepidermal bulla with re-epithelialization that was clinically consistent with fracture blisters (also known as fracture bullae)(Figure). Fracture blisters are a complication of bone fractures, usually occurring 24 to 48 hours after the trauma but possibly up to 3 weeks later. The skin usually is edematous with tense bullae overlying the fracture (in this case it was distal to the fracture); most blisters contain clear fluid, but older blisters tend to be more flaccid with hemorrhagic fluid.¹ The cause is thought to be the result of skin strain during fracture formation.² Edema and hypoxia from injured vessels and lymphatics contribute to the formation of bullae, which are seen as a dermoepidermal junction split on histology.¹ 

The bullae are histologically indistinguishable from edema blisters. A clinical history can help to differentiate. Edema blisters occur in the setting of an acute exacerbation of chronic edema, usually on the lower extremities in the setting of fluid overload.³ Bullous cellulitis is associated with skin erythema, warmth, and systemic symptoms. Bullous pemphigoid can be localized to the lower legs at times; however, biopsy would show a subepidermal bulla with eosinophils along the dermoepidermal junction. Linear IgA bullous dermatosis can be drug induced from vancomycin; however, pathology would show a subepidermal blister with a neutrophil predominant infiltrate. Nonsteroidal anti-inflammatory medications such as naproxen are a common culprit for bullous drug eruptions, which can be localized or generalized and include diagnoses such as fixed drug eruption, toxic epidermal necrolysis, and drug-induced pseudoporphyria. Naproxen-induced pseudoporphyria more commonly presents with blisters, erosions, and scarring with a predilection for the dorsal hands. Histology also will demonstrate subepidermal bullae. Clues to differentiate pseudoporphyria from fracture blisters include festooning of the dermal papilla and caterpillar bodies consisting of basement membrane material and colloid bodies in the basal layer of the epidermis, though they are not always present.⁴ 

Fracture blisters can be localized to the injury site or extend beyond the fracture site. They usually are found where there is minimal subcutaneous tissue, such as the tibia, ankles, and elbows. Fractures treated within 24 hours are much less likely to have bullae formation.¹ The bullae are sterile but may lead to wound healing complications, such as infections or delay in surgical management. However, there are no major adverse effects of postoperative fracture blisters.¹ Fracture blisters are self-healing, though silver sulfadiazine has been shown to minimize soft-tissue complications by promoting re-epithelialization.⁵ 
 

The Diagnosis: Bleomycin-Induced Flagellate Hyperpigmentation 

Histopathology of the affected skin demonstrated a slight increase in collagen bundle thickness, a chronic dermal perivascular inflammation, and associated pigment incontinence with dermal melanophages compared to unaffected skin (Figure). CD34 was faintly decreased, and dermal mucin increased in affected skin. This postinflammatory pigmentary alteration with subtle dermal sclerosis had persisted unchanged for more than 5 years after cessation of bleomycin therapy. Topical hydroquinone, physical blocker photoprotection, and laser modalities such as the Q-switched alexandrite (755-nm)/Nd:YAG (1064-nm) and ablative CO₂ resurfacing lasers were attempted with minimal overall impact on cosmesis. 

Bleomycin is a chemotherapeutic antibiotic that has been commonly used to treat Hodgkin lymphoma, germ cell tumors, and recurrent malignant pleural effusions.¹ The drug is inactivated in most tissues by the enzyme bleomycin hydrolase. This enzyme is not present in skin and lung tissue; as a result, these organs are the most common sites of bleomycin toxicity.¹ There are a variety of cutaneous effects associated with bleomycin including alopecia, hyperpigmentation, acral erythema, Raynaud phenomenon, and nail dystrophy.² Flagellate hyperpigmentation is a less common cutaneous toxicity. It is an unusual eruption that appears as whiplike linear streaks on the upper chest and back, limbs, and flanks.³ This cutaneous manifestation was once thought to be specific to bleomycin use; however, it also has been described in dermatomyositis, adult-onset Still disease, and after the ingestion of uncooked or undercooked shiitake mushrooms.⁴ Flagellate hyperpigmentation also was once thought to be dose dependent; however, it has been described in even very small doses.⁵ The eruption has been described as independent of the route of drug administration, appearing with intravenous, subcutaneous, and intramuscular bleomycin.² The association of bleomycin and flagellate hyperpigmentation has been reported since 1970; however, it is less commonly seen in clinical practice with the declining use of bleomycin.¹  

The exact mechanism for the hyperpigmentation is unknown. It has been proposed that the linear lesions are related to areas of pruritus and subsequent excoriations.¹ Dermatographism may be present to a limited extent, but it is unlikely to be a chief cause of flagellate hyperpigmentation, as linear streaks have been reported in the absence of trauma. It also has been proposed that bleomycin has a direct toxic effect on the melanocytes, which stimulates increased melanin secretion.² The hyperpigmentation also may be due to pigmentary incontinence secondary to inflammation.⁵ Histopathologic findings usually are varied and nonspecific.² There may be a deep perivascular lymphocytic infiltrate, which is nonspecific but can be associated with drug-induced pathology.⁴ Bleomycin also is used to induce localized scleroderma in mouse-model research⁶ and has been reported to cause localized scleroderma at an infusion site or after an intralesional injection,^7,8 which is not typically reported in flagellate erythema, but bleomycin's sclerosing effects may have played a role in the visible and sclerosing atrophy noted in our patient. Yamamoto et al⁹ reported a similar case of dermal sclerosis induced by bleomycin.  

Flagellate hyperpigmentation typically lasts for up to 6 months.³ Patients with cutaneous manifestations from bleomycin therapy usually respond to steroid therapy and discontinuation of the drug. Bleomycin re-exposure should be avoided, as it may cause extension or widespread recurrence of flagellate hyperpigmentation.³ Postinflammatory pigment alteration may persist in patients with darker skin types and in patients with dramatic inciting inflammation.  

Atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents with 1 or more sharply demarcated depressed patches. There is some debate whether it is a distinct entity or a primary atrophic morphea.¹⁰ Linear atrophoderma of Moulin has a similar morphology with hyperpigmented depressions and "cliff-drop" borders, but these lesions follow the lines of Blaschko.¹¹ Linear morphea initially can present as a linear erythematous streak but more commonly appears as a plaque-type morphea lesion that forms a scarlike band.¹² Erythema dyschromicum perstans is an ashy dermatosis characterized by gray or blue-brown macules seen in Fitzpatrick skin types III through V and typically is chronic and progressive.¹³  

The Diagnosis: Bleomycin-Induced Flagellate Hyperpigmentation 

Histopathology of the affected skin demonstrated a slight increase in collagen bundle thickness, a chronic dermal perivascular inflammation, and associated pigment incontinence with dermal melanophages compared to unaffected skin (Figure). CD34 was faintly decreased, and dermal mucin increased in affected skin. This postinflammatory pigmentary alteration with subtle dermal sclerosis had persisted unchanged for more than 5 years after cessation of bleomycin therapy. Topical hydroquinone, physical blocker photoprotection, and laser modalities such as the Q-switched alexandrite (755-nm)/Nd:YAG (1064-nm) and ablative CO₂ resurfacing lasers were attempted with minimal overall impact on cosmesis. 

Bleomycin is a chemotherapeutic antibiotic that has been commonly used to treat Hodgkin lymphoma, germ cell tumors, and recurrent malignant pleural effusions.¹ The drug is inactivated in most tissues by the enzyme bleomycin hydrolase. This enzyme is not present in skin and lung tissue; as a result, these organs are the most common sites of bleomycin toxicity.¹ There are a variety of cutaneous effects associated with bleomycin including alopecia, hyperpigmentation, acral erythema, Raynaud phenomenon, and nail dystrophy.² Flagellate hyperpigmentation is a less common cutaneous toxicity. It is an unusual eruption that appears as whiplike linear streaks on the upper chest and back, limbs, and flanks.³ This cutaneous manifestation was once thought to be specific to bleomycin use; however, it also has been described in dermatomyositis, adult-onset Still disease, and after the ingestion of uncooked or undercooked shiitake mushrooms.⁴ Flagellate hyperpigmentation also was once thought to be dose dependent; however, it has been described in even very small doses.⁵ The eruption has been described as independent of the route of drug administration, appearing with intravenous, subcutaneous, and intramuscular bleomycin.² The association of bleomycin and flagellate hyperpigmentation has been reported since 1970; however, it is less commonly seen in clinical practice with the declining use of bleomycin.¹  

The exact mechanism for the hyperpigmentation is unknown. It has been proposed that the linear lesions are related to areas of pruritus and subsequent excoriations.¹ Dermatographism may be present to a limited extent, but it is unlikely to be a chief cause of flagellate hyperpigmentation, as linear streaks have been reported in the absence of trauma. It also has been proposed that bleomycin has a direct toxic effect on the melanocytes, which stimulates increased melanin secretion.² The hyperpigmentation also may be due to pigmentary incontinence secondary to inflammation.⁵ Histopathologic findings usually are varied and nonspecific.² There may be a deep perivascular lymphocytic infiltrate, which is nonspecific but can be associated with drug-induced pathology.⁴ Bleomycin also is used to induce localized scleroderma in mouse-model research⁶ and has been reported to cause localized scleroderma at an infusion site or after an intralesional injection,^7,8 which is not typically reported in flagellate erythema, but bleomycin's sclerosing effects may have played a role in the visible and sclerosing atrophy noted in our patient. Yamamoto et al⁹ reported a similar case of dermal sclerosis induced by bleomycin.  

Flagellate hyperpigmentation typically lasts for up to 6 months.³ Patients with cutaneous manifestations from bleomycin therapy usually respond to steroid therapy and discontinuation of the drug. Bleomycin re-exposure should be avoided, as it may cause extension or widespread recurrence of flagellate hyperpigmentation.³ Postinflammatory pigment alteration may persist in patients with darker skin types and in patients with dramatic inciting inflammation.  

Atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents with 1 or more sharply demarcated depressed patches. There is some debate whether it is a distinct entity or a primary atrophic morphea.¹⁰ Linear atrophoderma of Moulin has a similar morphology with hyperpigmented depressions and "cliff-drop" borders, but these lesions follow the lines of Blaschko.¹¹ Linear morphea initially can present as a linear erythematous streak but more commonly appears as a plaque-type morphea lesion that forms a scarlike band.¹² Erythema dyschromicum perstans is an ashy dermatosis characterized by gray or blue-brown macules seen in Fitzpatrick skin types III through V and typically is chronic and progressive.¹³  

The Diagnosis: Bleomycin-Induced Flagellate Hyperpigmentation 

Histopathology of the affected skin demonstrated a slight increase in collagen bundle thickness, a chronic dermal perivascular inflammation, and associated pigment incontinence with dermal melanophages compared to unaffected skin (Figure). CD34 was faintly decreased, and dermal mucin increased in affected skin. This postinflammatory pigmentary alteration with subtle dermal sclerosis had persisted unchanged for more than 5 years after cessation of bleomycin therapy. Topical hydroquinone, physical blocker photoprotection, and laser modalities such as the Q-switched alexandrite (755-nm)/Nd:YAG (1064-nm) and ablative CO₂ resurfacing lasers were attempted with minimal overall impact on cosmesis. 

Bleomycin is a chemotherapeutic antibiotic that has been commonly used to treat Hodgkin lymphoma, germ cell tumors, and recurrent malignant pleural effusions.¹ The drug is inactivated in most tissues by the enzyme bleomycin hydrolase. This enzyme is not present in skin and lung tissue; as a result, these organs are the most common sites of bleomycin toxicity.¹ There are a variety of cutaneous effects associated with bleomycin including alopecia, hyperpigmentation, acral erythema, Raynaud phenomenon, and nail dystrophy.² Flagellate hyperpigmentation is a less common cutaneous toxicity. It is an unusual eruption that appears as whiplike linear streaks on the upper chest and back, limbs, and flanks.³ This cutaneous manifestation was once thought to be specific to bleomycin use; however, it also has been described in dermatomyositis, adult-onset Still disease, and after the ingestion of uncooked or undercooked shiitake mushrooms.⁴ Flagellate hyperpigmentation also was once thought to be dose dependent; however, it has been described in even very small doses.⁵ The eruption has been described as independent of the route of drug administration, appearing with intravenous, subcutaneous, and intramuscular bleomycin.² The association of bleomycin and flagellate hyperpigmentation has been reported since 1970; however, it is less commonly seen in clinical practice with the declining use of bleomycin.¹  

The exact mechanism for the hyperpigmentation is unknown. It has been proposed that the linear lesions are related to areas of pruritus and subsequent excoriations.¹ Dermatographism may be present to a limited extent, but it is unlikely to be a chief cause of flagellate hyperpigmentation, as linear streaks have been reported in the absence of trauma. It also has been proposed that bleomycin has a direct toxic effect on the melanocytes, which stimulates increased melanin secretion.² The hyperpigmentation also may be due to pigmentary incontinence secondary to inflammation.⁵ Histopathologic findings usually are varied and nonspecific.² There may be a deep perivascular lymphocytic infiltrate, which is nonspecific but can be associated with drug-induced pathology.⁴ Bleomycin also is used to induce localized scleroderma in mouse-model research⁶ and has been reported to cause localized scleroderma at an infusion site or after an intralesional injection,^7,8 which is not typically reported in flagellate erythema, but bleomycin's sclerosing effects may have played a role in the visible and sclerosing atrophy noted in our patient. Yamamoto et al⁹ reported a similar case of dermal sclerosis induced by bleomycin.  

Flagellate hyperpigmentation typically lasts for up to 6 months.³ Patients with cutaneous manifestations from bleomycin therapy usually respond to steroid therapy and discontinuation of the drug. Bleomycin re-exposure should be avoided, as it may cause extension or widespread recurrence of flagellate hyperpigmentation.³ Postinflammatory pigment alteration may persist in patients with darker skin types and in patients with dramatic inciting inflammation.  

Atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents with 1 or more sharply demarcated depressed patches. There is some debate whether it is a distinct entity or a primary atrophic morphea.¹⁰ Linear atrophoderma of Moulin has a similar morphology with hyperpigmented depressions and "cliff-drop" borders, but these lesions follow the lines of Blaschko.¹¹ Linear morphea initially can present as a linear erythematous streak but more commonly appears as a plaque-type morphea lesion that forms a scarlike band.¹² Erythema dyschromicum perstans is an ashy dermatosis characterized by gray or blue-brown macules seen in Fitzpatrick skin types III through V and typically is chronic and progressive.¹³  

The Diagnosis: Irritant Contact Dermatitis  

A slang term for volatile alkyl nitrites, poppers are inhaled for recreational purposes. They produce    rapid-onset euphoria and sexual arousal, as well as relax anal and vaginal sphincters, facilitating sexual intercourse. Alkyl nitrites initially were developed to treat coronary disease and angina but were replaced by more potent drugs.¹ Because of their psychoactive effects and smooth muscle relaxation properties, they are widely used by homosexual and bisexual men.^1-3 The term poppers was originated by the sound generated when the glass vials are crushed; currently, they also may be found in other formats.¹  

Nausea, hypotension, and headache are mild common adverse effects of volatile alkyl nitrites¹; cardiac arrhythmia, oxidative hemolysis,⁴ and poppers maculopathy^5,6 with permanent eye damage also have been reported.⁷ On the skin, volatile alkyl nitrites induce irritant contact dermatitis that heals without scarring, characteristically involving the face and upper thoracic region, as they are volatile vapors.² However, the reaction can occur elsewhere. There have been reports of contact dermatitis on other locations, such as the thigh or the ankle, due to vials broken while stored in pockets or on the cuff of the socks.¹ There also is a report of irritant contact dermatitis manifesting as a penile ulcer.³ Albeit rare, allergic contact dermatitis to volatile alkyl nitrites and other nitrites also can occur.⁸  

The abuse of alkyl nitrites may increase the risk for sexually transmitted infections (STIs), as they may decrease safer sexual practices and increase the propensity to engage in risky sexual behavior. It has been suggested to screen for STIs in patients with history of volatile alkyl nitrite use. In the past, volatile alkyl nitrites were believed to be a potential vector of human immunodeficiency virus.⁹ Other popular drugs used in social context or "club drugs," such as 3,4-methylenedioxymethamphetamine, gamma hydroxybutyrate, methamphetamine, and ketamine, do not produce irritant dermatitis as an adverse cutaneous reaction.¹⁰ The differential diagnosis in our patient included herpes simplex virus and contagious impetigo¹ as well as bullous lupus erythematosus and periorificial dermatitis; however, the clinical picture, acute onset of the reaction, and the patient's medical history were critical in making the correct diagnosis.  

The patient was treated with topical hydrocortisone and fusidic acid cream twice daily for 7 days with complete response. Sexually transmitted infection screening was unremarkable. We suggest performing an STI workup on patients with history of volatile alkyl nitrite use. 

The Diagnosis: Irritant Contact Dermatitis  

A slang term for volatile alkyl nitrites, poppers are inhaled for recreational purposes. They produce    rapid-onset euphoria and sexual arousal, as well as relax anal and vaginal sphincters, facilitating sexual intercourse. Alkyl nitrites initially were developed to treat coronary disease and angina but were replaced by more potent drugs.¹ Because of their psychoactive effects and smooth muscle relaxation properties, they are widely used by homosexual and bisexual men.^1-3 The term poppers was originated by the sound generated when the glass vials are crushed; currently, they also may be found in other formats.¹  

Nausea, hypotension, and headache are mild common adverse effects of volatile alkyl nitrites¹; cardiac arrhythmia, oxidative hemolysis,⁴ and poppers maculopathy^5,6 with permanent eye damage also have been reported.⁷ On the skin, volatile alkyl nitrites induce irritant contact dermatitis that heals without scarring, characteristically involving the face and upper thoracic region, as they are volatile vapors.² However, the reaction can occur elsewhere. There have been reports of contact dermatitis on other locations, such as the thigh or the ankle, due to vials broken while stored in pockets or on the cuff of the socks.¹ There also is a report of irritant contact dermatitis manifesting as a penile ulcer.³ Albeit rare, allergic contact dermatitis to volatile alkyl nitrites and other nitrites also can occur.⁸  

The abuse of alkyl nitrites may increase the risk for sexually transmitted infections (STIs), as they may decrease safer sexual practices and increase the propensity to engage in risky sexual behavior. It has been suggested to screen for STIs in patients with history of volatile alkyl nitrite use. In the past, volatile alkyl nitrites were believed to be a potential vector of human immunodeficiency virus.⁹ Other popular drugs used in social context or "club drugs," such as 3,4-methylenedioxymethamphetamine, gamma hydroxybutyrate, methamphetamine, and ketamine, do not produce irritant dermatitis as an adverse cutaneous reaction.¹⁰ The differential diagnosis in our patient included herpes simplex virus and contagious impetigo¹ as well as bullous lupus erythematosus and periorificial dermatitis; however, the clinical picture, acute onset of the reaction, and the patient's medical history were critical in making the correct diagnosis.  

The patient was treated with topical hydrocortisone and fusidic acid cream twice daily for 7 days with complete response. Sexually transmitted infection screening was unremarkable. We suggest performing an STI workup on patients with history of volatile alkyl nitrite use. 

The Diagnosis: Irritant Contact Dermatitis  

A slang term for volatile alkyl nitrites, poppers are inhaled for recreational purposes. They produce    rapid-onset euphoria and sexual arousal, as well as relax anal and vaginal sphincters, facilitating sexual intercourse. Alkyl nitrites initially were developed to treat coronary disease and angina but were replaced by more potent drugs.¹ Because of their psychoactive effects and smooth muscle relaxation properties, they are widely used by homosexual and bisexual men.^1-3 The term poppers was originated by the sound generated when the glass vials are crushed; currently, they also may be found in other formats.¹  

Nausea, hypotension, and headache are mild common adverse effects of volatile alkyl nitrites¹; cardiac arrhythmia, oxidative hemolysis,⁴ and poppers maculopathy^5,6 with permanent eye damage also have been reported.⁷ On the skin, volatile alkyl nitrites induce irritant contact dermatitis that heals without scarring, characteristically involving the face and upper thoracic region, as they are volatile vapors.² However, the reaction can occur elsewhere. There have been reports of contact dermatitis on other locations, such as the thigh or the ankle, due to vials broken while stored in pockets or on the cuff of the socks.¹ There also is a report of irritant contact dermatitis manifesting as a penile ulcer.³ Albeit rare, allergic contact dermatitis to volatile alkyl nitrites and other nitrites also can occur.⁸  

The abuse of alkyl nitrites may increase the risk for sexually transmitted infections (STIs), as they may decrease safer sexual practices and increase the propensity to engage in risky sexual behavior. It has been suggested to screen for STIs in patients with history of volatile alkyl nitrite use. In the past, volatile alkyl nitrites were believed to be a potential vector of human immunodeficiency virus.⁹ Other popular drugs used in social context or "club drugs," such as 3,4-methylenedioxymethamphetamine, gamma hydroxybutyrate, methamphetamine, and ketamine, do not produce irritant dermatitis as an adverse cutaneous reaction.¹⁰ The differential diagnosis in our patient included herpes simplex virus and contagious impetigo¹ as well as bullous lupus erythematosus and periorificial dermatitis; however, the clinical picture, acute onset of the reaction, and the patient's medical history were critical in making the correct diagnosis.  

The patient was treated with topical hydrocortisone and fusidic acid cream twice daily for 7 days with complete response. Sexually transmitted infection screening was unremarkable. We suggest performing an STI workup on patients with history of volatile alkyl nitrite use.