Cutis

Extramammary Paget disease (EMPD) is an uncommon neoplasm that most commonly occurs in the anogenital region but can arise in any area of the skin or mucosa.¹ On clinical examination, EMPD typically presents as a sharply demarcated, erythematous, eczematoid, weeping lesion with varying degrees of induration; it rarely presents as a palpable mass or evenly raised nodule.² Microscopically, it may be accompanied by varying degrees of epidermal hyperplasia.¹ In particular, fibroepitheliomatous hyperplasia contains lacy strands of squamous epithelium resembling fibroepithelioma of Pinkus.³ We report a case of EMPD in a 90-year-old man who presented with a verrucous nodule in the pubic area that histologically demonstrated fibroepitheliomatous hyperplasia with lacy strands of squamous epithelium.

Case Report

A 90-year-old man presented with asymptomatic, well-demarcated, erythematous plaques in the pubic area of 5 years’ duration, along with a 3.0×2.5-cm nodule on the left side of the pubic area (Figure 1). Laboratory test results including a complete blood cell count, blood chemistry, and routine urinalysis were within reference range. Punch biopsies were taken from each plaque and nodule, as marked with arrows in Figure 1. Histopathologically, the plaques were seen to contain a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei that were present at various levels of the epidermis where they formed nests and clusters but did not extend into the dermis (Figures 2A and 2B). The nodule contained lacy strands of squamous epithelium extending from the epidermis to the mid dermis as well as many glandular structures (Figures 2C and 2D). The cells in the epidermis stained positively with periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), and cytokeratin 7 (Figure 2E). We also tested for S-100 protein to rule out malignant melanoma, which was negative.

Figure 1. Well-demarcated erythematous plaques (red arrow) in the pubic area and a 3.0×2.5-cm verrucous erythematous nodule (black arrow) on the left side of the pubic area.

Based on both the clinical and histological features, a diagnosis of EMPD with fibroepitheliomatous hyperplasia was made. It was recommended that the patient undergo further evaluation and treatment; he declined due to his financial situation and was subsequently lost to follow-up.

Comment

Clinically, EMPD usually presents as a patch of macular erythema, an erythematous eruption, or erythematous papules and plaques.⁴ The palpable nodule seen in our patient is not a common presentation of EMPD. Pruritus is the most common symptom of EMPD, occurring in 70% of patients.⁵ Other symptoms include burning, irritation, pain, tenderness, bleeding, and swelling. Ten percent of EMPD cases are asymptomatic.⁵

Histologically, Paget cells primarily involve the epidermis where they usually form clusters or solid nests. In more than 90% of EMPD cases, the Paget cells contain cytoplasmic mucin that stains positively with mucicarmine and PAS. Immunohistochemical staining for cytokeratin 7, gross cystic disease fluid protein-15, S-100 protein, and CEA sometimes may be needed to differentiate from mimickers such as Bowen disease and superficial spreading melanoma.⁶ In our patient, the tumor cells stained positive for cytokeratin 7, CEA, and PAS. Malignant melanoma was ruled out with a test for S-100 protein.

Figure 2. Scanning power view demonstrated a plaque containing Pagetcells at various levels of the epidermis (A)(H&E, original magnification ×40). The lesion contained a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei (B)(H&E, original magnification ×100). The nodule contained lacy strands of squamous epithelium on scanning power view (C)(H&E, original magnification ×40). Tumor cells with numerous glandular structures were observed (D)(H&E, original magnification ×100). Paget cells stained positive with cytokeratin 7 (E)(original magnification ×40).

Extramammary Paget disease often is associated with epidermal hyperplasia, which can be classified as squamous, papillomatous, or fibroepitheliomatous.³ Microscopically, squamous hyperplasia is characterized by prominent thickening of the epidermis from diffuse plaquelike hyperplasia and is usually associated with hyperkeratosis. Papillomatous hyperplasia has an exophytic papillary or verrucous architecture and is associated with parakeratosis. Fibroepitheliomatous, or fibroepitheliomalike, hyperplasia generally consists of a discrete, broad, elevated plaque or nodule produced by hyperplasia of keratinocytes that form lacy strands of squamous epithelium.³ The biphasic pattern of proliferating epidermis and entrapped dermis simulates a so-called fibroepithelioma. Paget cells can be seen within the lacy strands of epidermal columns and in the acanthotic surface component.² The finding of fibroepitheliomatous hyperplasia in anogenital skin should prompt a search for the diagnostic Paget cells to eliminate a fibroepithelioma of Pinkus variant of basal cell carcinoma, though the latter is uncommon and rarely occurs at this site.⁷

Of the 3 types of epidermal hyperplasia, our case demonstrated the fibroepitheliomatous type. There may be some relationship between EMPD and fibroepitheliomatous hyperplasia because most reported cases of EMPD with fibroepitheliomatous hyperplasia have occurred in the anogenital region. Also, epidermal hyperplasia is more frequent in anogenital Paget disease than in axillary Paget disease.⁸

Conclusion

Our case showed the unique finding of a verrucous nodular EMPD lesion in which peculiar histological features presented as extensions of the tumor cells forming lacy strands of squamous epithelium from the epidermis to the mid dermis as well as many glandular structures.

Extramammary Paget disease (EMPD) is an uncommon neoplasm that most commonly occurs in the anogenital region but can arise in any area of the skin or mucosa.¹ On clinical examination, EMPD typically presents as a sharply demarcated, erythematous, eczematoid, weeping lesion with varying degrees of induration; it rarely presents as a palpable mass or evenly raised nodule.² Microscopically, it may be accompanied by varying degrees of epidermal hyperplasia.¹ In particular, fibroepitheliomatous hyperplasia contains lacy strands of squamous epithelium resembling fibroepithelioma of Pinkus.³ We report a case of EMPD in a 90-year-old man who presented with a verrucous nodule in the pubic area that histologically demonstrated fibroepitheliomatous hyperplasia with lacy strands of squamous epithelium.

Case Report

A 90-year-old man presented with asymptomatic, well-demarcated, erythematous plaques in the pubic area of 5 years’ duration, along with a 3.0×2.5-cm nodule on the left side of the pubic area (Figure 1). Laboratory test results including a complete blood cell count, blood chemistry, and routine urinalysis were within reference range. Punch biopsies were taken from each plaque and nodule, as marked with arrows in Figure 1. Histopathologically, the plaques were seen to contain a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei that were present at various levels of the epidermis where they formed nests and clusters but did not extend into the dermis (Figures 2A and 2B). The nodule contained lacy strands of squamous epithelium extending from the epidermis to the mid dermis as well as many glandular structures (Figures 2C and 2D). The cells in the epidermis stained positively with periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), and cytokeratin 7 (Figure 2E). We also tested for S-100 protein to rule out malignant melanoma, which was negative.

Figure 1. Well-demarcated erythematous plaques (red arrow) in the pubic area and a 3.0×2.5-cm verrucous erythematous nodule (black arrow) on the left side of the pubic area.

Based on both the clinical and histological features, a diagnosis of EMPD with fibroepitheliomatous hyperplasia was made. It was recommended that the patient undergo further evaluation and treatment; he declined due to his financial situation and was subsequently lost to follow-up.

Comment

Clinically, EMPD usually presents as a patch of macular erythema, an erythematous eruption, or erythematous papules and plaques.⁴ The palpable nodule seen in our patient is not a common presentation of EMPD. Pruritus is the most common symptom of EMPD, occurring in 70% of patients.⁵ Other symptoms include burning, irritation, pain, tenderness, bleeding, and swelling. Ten percent of EMPD cases are asymptomatic.⁵

Histologically, Paget cells primarily involve the epidermis where they usually form clusters or solid nests. In more than 90% of EMPD cases, the Paget cells contain cytoplasmic mucin that stains positively with mucicarmine and PAS. Immunohistochemical staining for cytokeratin 7, gross cystic disease fluid protein-15, S-100 protein, and CEA sometimes may be needed to differentiate from mimickers such as Bowen disease and superficial spreading melanoma.⁶ In our patient, the tumor cells stained positive for cytokeratin 7, CEA, and PAS. Malignant melanoma was ruled out with a test for S-100 protein.

Figure 2. Scanning power view demonstrated a plaque containing Pagetcells at various levels of the epidermis (A)(H&E, original magnification ×40). The lesion contained a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei (B)(H&E, original magnification ×100). The nodule contained lacy strands of squamous epithelium on scanning power view (C)(H&E, original magnification ×40). Tumor cells with numerous glandular structures were observed (D)(H&E, original magnification ×100). Paget cells stained positive with cytokeratin 7 (E)(original magnification ×40).

Extramammary Paget disease often is associated with epidermal hyperplasia, which can be classified as squamous, papillomatous, or fibroepitheliomatous.³ Microscopically, squamous hyperplasia is characterized by prominent thickening of the epidermis from diffuse plaquelike hyperplasia and is usually associated with hyperkeratosis. Papillomatous hyperplasia has an exophytic papillary or verrucous architecture and is associated with parakeratosis. Fibroepitheliomatous, or fibroepitheliomalike, hyperplasia generally consists of a discrete, broad, elevated plaque or nodule produced by hyperplasia of keratinocytes that form lacy strands of squamous epithelium.³ The biphasic pattern of proliferating epidermis and entrapped dermis simulates a so-called fibroepithelioma. Paget cells can be seen within the lacy strands of epidermal columns and in the acanthotic surface component.² The finding of fibroepitheliomatous hyperplasia in anogenital skin should prompt a search for the diagnostic Paget cells to eliminate a fibroepithelioma of Pinkus variant of basal cell carcinoma, though the latter is uncommon and rarely occurs at this site.⁷

Of the 3 types of epidermal hyperplasia, our case demonstrated the fibroepitheliomatous type. There may be some relationship between EMPD and fibroepitheliomatous hyperplasia because most reported cases of EMPD with fibroepitheliomatous hyperplasia have occurred in the anogenital region. Also, epidermal hyperplasia is more frequent in anogenital Paget disease than in axillary Paget disease.⁸

Conclusion

Our case showed the unique finding of a verrucous nodular EMPD lesion in which peculiar histological features presented as extensions of the tumor cells forming lacy strands of squamous epithelium from the epidermis to the mid dermis as well as many glandular structures.

Extramammary Paget disease (EMPD) is an uncommon neoplasm that most commonly occurs in the anogenital region but can arise in any area of the skin or mucosa.¹ On clinical examination, EMPD typically presents as a sharply demarcated, erythematous, eczematoid, weeping lesion with varying degrees of induration; it rarely presents as a palpable mass or evenly raised nodule.² Microscopically, it may be accompanied by varying degrees of epidermal hyperplasia.¹ In particular, fibroepitheliomatous hyperplasia contains lacy strands of squamous epithelium resembling fibroepithelioma of Pinkus.³ We report a case of EMPD in a 90-year-old man who presented with a verrucous nodule in the pubic area that histologically demonstrated fibroepitheliomatous hyperplasia with lacy strands of squamous epithelium.

Case Report

A 90-year-old man presented with asymptomatic, well-demarcated, erythematous plaques in the pubic area of 5 years’ duration, along with a 3.0×2.5-cm nodule on the left side of the pubic area (Figure 1). Laboratory test results including a complete blood cell count, blood chemistry, and routine urinalysis were within reference range. Punch biopsies were taken from each plaque and nodule, as marked with arrows in Figure 1. Histopathologically, the plaques were seen to contain a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei that were present at various levels of the epidermis where they formed nests and clusters but did not extend into the dermis (Figures 2A and 2B). The nodule contained lacy strands of squamous epithelium extending from the epidermis to the mid dermis as well as many glandular structures (Figures 2C and 2D). The cells in the epidermis stained positively with periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), and cytokeratin 7 (Figure 2E). We also tested for S-100 protein to rule out malignant melanoma, which was negative.

Figure 1. Well-demarcated erythematous plaques (red arrow) in the pubic area and a 3.0×2.5-cm verrucous erythematous nodule (black arrow) on the left side of the pubic area.

Based on both the clinical and histological features, a diagnosis of EMPD with fibroepitheliomatous hyperplasia was made. It was recommended that the patient undergo further evaluation and treatment; he declined due to his financial situation and was subsequently lost to follow-up.

Comment

Clinically, EMPD usually presents as a patch of macular erythema, an erythematous eruption, or erythematous papules and plaques.⁴ The palpable nodule seen in our patient is not a common presentation of EMPD. Pruritus is the most common symptom of EMPD, occurring in 70% of patients.⁵ Other symptoms include burning, irritation, pain, tenderness, bleeding, and swelling. Ten percent of EMPD cases are asymptomatic.⁵

Histologically, Paget cells primarily involve the epidermis where they usually form clusters or solid nests. In more than 90% of EMPD cases, the Paget cells contain cytoplasmic mucin that stains positively with mucicarmine and PAS. Immunohistochemical staining for cytokeratin 7, gross cystic disease fluid protein-15, S-100 protein, and CEA sometimes may be needed to differentiate from mimickers such as Bowen disease and superficial spreading melanoma.⁶ In our patient, the tumor cells stained positive for cytokeratin 7, CEA, and PAS. Malignant melanoma was ruled out with a test for S-100 protein.

Figure 2. Scanning power view demonstrated a plaque containing Pagetcells at various levels of the epidermis (A)(H&E, original magnification ×40). The lesion contained a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei (B)(H&E, original magnification ×100). The nodule contained lacy strands of squamous epithelium on scanning power view (C)(H&E, original magnification ×40). Tumor cells with numerous glandular structures were observed (D)(H&E, original magnification ×100). Paget cells stained positive with cytokeratin 7 (E)(original magnification ×40).

Extramammary Paget disease often is associated with epidermal hyperplasia, which can be classified as squamous, papillomatous, or fibroepitheliomatous.³ Microscopically, squamous hyperplasia is characterized by prominent thickening of the epidermis from diffuse plaquelike hyperplasia and is usually associated with hyperkeratosis. Papillomatous hyperplasia has an exophytic papillary or verrucous architecture and is associated with parakeratosis. Fibroepitheliomatous, or fibroepitheliomalike, hyperplasia generally consists of a discrete, broad, elevated plaque or nodule produced by hyperplasia of keratinocytes that form lacy strands of squamous epithelium.³ The biphasic pattern of proliferating epidermis and entrapped dermis simulates a so-called fibroepithelioma. Paget cells can be seen within the lacy strands of epidermal columns and in the acanthotic surface component.² The finding of fibroepitheliomatous hyperplasia in anogenital skin should prompt a search for the diagnostic Paget cells to eliminate a fibroepithelioma of Pinkus variant of basal cell carcinoma, though the latter is uncommon and rarely occurs at this site.⁷

Of the 3 types of epidermal hyperplasia, our case demonstrated the fibroepitheliomatous type. There may be some relationship between EMPD and fibroepitheliomatous hyperplasia because most reported cases of EMPD with fibroepitheliomatous hyperplasia have occurred in the anogenital region. Also, epidermal hyperplasia is more frequent in anogenital Paget disease than in axillary Paget disease.⁸

Conclusion

Our case showed the unique finding of a verrucous nodular EMPD lesion in which peculiar histological features presented as extensions of the tumor cells forming lacy strands of squamous epithelium from the epidermis to the mid dermis as well as many glandular structures.

Nocardiosis is a rare human infection that has been reported worldwide but occurs more frequently in patients who reside in tropical areas. Although there is no predilection for age or ethnicity, nocardiosis is slightly more common in males than in females.^1,2 The genus Nocardia belongs to the order Actinomycetales and includes more than 50 species of gram-positive, aerobic, filamentous, branching, partially acid-fast bacteria found ubiquitously in soil.³ The bacteria may be present in animals (eg, cattle, dogs),⁴ but transmission to humans is unusual. Clinical diagnosis of nocardiosis often is difficult because of its nonspecific manifestations and delays in its recognition, especially in western countries where the infection is consistently rare and probably underestimated.^5-8 Cutaneous involvement generally manifests as 1 of 4 conditions: mycetoma, lymphocutaneous (sporotrichoid) infection, superficial skin infection, or systemic disease with cutaneous involvement.⁹ Systemic disseminated disease usually occurs in individuals with cellular immune deficiency, such as patients with human immunodeficiency virus; organ transplant recipients; or patients with a history of long-term use of corticosteroids, configuring an opportunistic infection.^10-19 Incidence in these high-risk patients is 140- to 340-fold higher than in the general population.²⁰Nocardia infections usually are acquired via dust inhalation, especially in dry environments. Focal pneumonitis is the first typical manifestation in immunosuppressed patients, followed by skin dissemination and central nervous system involvement.¹

We report the case of a 65-year-old man who developed disseminated nocardiosis while undergoing long-term treatment with systemic corticosteroids for rheumatoid arthritis.

Case Report

A 65-year-old man presented to the dermatology department for evaluation of multiple papules and nodules with a puruloid discharge on the right leg. The first lesions had appeared on the right ankle approximately 1 month prior to presentation and were treated with systemic antibiotics by the patient’s general practitioner without remarkable benefits. The lesions progressed further on the right leg showing a sporotrichoid disposition.

On physical examination major involvement was evident on the right knee with papules, subcutaneous nodules, and sinuses (Figure 1). Isolated lesions also were present on the right thigh. A few days later some lesions were present on the left elbow and arm. Involvement of the popliteal and inguinal lymph nodes was noted, with painful enlarged nodules covered by erythematous skin that were mobile on deep planes. The lesions had a sudden onset while the patient was in good health, causing progressive functional impotency of the leg without general malaise or fever. The patient’s history was remarkable for chronic rheumatoid arthritis of 20 years’ duration that was treated with hydroxychloroquine (400 mg daily) and methylprednisolone (16 mg daily).

Figure 1. Multiple papules, nodules, and sinuses discharging puruloid material over the right knee showing a sporotrichoid disposition.

The patient was retired but reported daily tilling and manual labor on his farmland. He denied trauma or insect bites to the leg prior to the onset of lesions. Laboratory examination documented slight neutrophil leukocytosis (white blood cell count, 12.8×10³/μL [reference range, 4.5–11.0×10³/μL]; neutrophil count, 10.7×10³/μL [reference range, 1.8–7.8×10³/μL]; 85% neutrophils at formula count [reference range, 56%]), augmented C-reactive protein levels (15.8 mg/L [reference range, 0.08–3.1 mg/L]), a blood sedimentation rate of 74 mm/h (reference range, 0–20 mm/h), and elevated liver enzymes (aspartate aminotransferase, 52 U/L [reference range, 10–30 U/L]; alanine aminotransferase, 89 U/L [reference range, 10–40 U/L]; γ-glutamyltransferase, 68 U/L [reference range, 2–30 U/L]). Rheumatoid factor was 49.7 U/mL (reference range, 0–14.0 U/mL). Skin biopsy of a sample lesion suggested a chronic granulomatous suppuration. Tissue cultures and subsequent polymerase chain reaction assay identified Nocardia asteroides. A chest radiograph revealed multiple opaque nodules disseminated in both lungs, and a computed tomography (CT) scan confirmed multiple pulmonary lesions without involvement of the mediastinal lymph nodes (Figure 2). Computed tomography scans of the brain before and after contrast media perfusion showed the presence of an enhanced 8-mm mass among the right parietal and occipital lobes surrounded by an edematous halo (Figure 3). Neurologic examination was normal. During the radiologic assessment, the patient remembered having been hospitalized 1 year prior in a pulmonology unit at an outside institution for treatment of what was considered to be a multifocal nonspecific lung infection. A 1-month course of levofloxacin (500 mg daily) was administered at that time without any further follow-up. Review of the prior chest radiograph and CT scan confirmed the presence of the same radiologic findings as the current assessment, though of milder entity.

Figure 2. Computed tomography of the chest demonstrated multiple bilateral lung nodules (arrows) of various sizes, principally on the right side, without involvement of the mediastinal lymph nodes.

Figure 3. Computed tomography of the brain showed an enhanced 8-mm mass (arrow) among the right parietal and occipital lobes surrounded by an edematous halo.

The patient was transferred from the dermatology department to the infectious diseases unit. Fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy confirmed pulmonary nocardiosis. Treatment with a combination of endovenous carbapenem and fluoroquinolone antibiotics for 1 month led to complete resolution of both the cutaneous lesions and the single brain abscess. Improvement of pulmonary involvement was noted on radiology, but another course of endovenous treatment with antibiotics was required, followed by oral amoxicillin–clavulanic acid (2 g daily) for 3 months. The patient underwent maintenance antibiotic therapy for 1 year without relapse and is considered to be cured.

Comment

Cutaneous nocardiosis occurs either as part of a disseminated infection or as a primary skin inoculation, usually following trauma or exposure from working outdoors.^2,9,21,22 Nocardial mycetoma, also known as actinomycetoma, is a chronic condition that mainly affects the lower extremities but also can affect the hands and forearms; it is frequently reported in tropical regions,²³ but disseminated forms are rare and undervalued, especially in European countries. A certain rise in incidence has been reported in Europe as a consequence of immune suppression, and pulmonary disease is the most common presentation in these patients.^1,2,6-12 One-third of patients have disseminated disease with high morbidity and a high mortality rate.²⁰ Major case collections in Italy have been studied by a collaborative hospital network of 11 cities,^10,11 confirming difficulty of diagnosis and underestimation, prevalence of N asteroides as a pathogen, resistance to several antimicrobials, and a high relapse index. Diagnosis remains challenging, as clinical suspicion is not frequently supported by histology and/or microbiology because of difficulty in bacteria isolation. Molecular methods are not routinely available in Italy, and only stringent efforts and cooperation from different university departments has allowed final identification of nocardiosis.

The sporotrichoid pattern of the lesions on the right leg was unique; it is considered the rarest presentation of cutaneous nocardiosis.²⁴ Our first suspicion was sporotrichosis, an infection that is especially common in farmers in Italy,^25,26 but the microbiologist’s evaluation of the bacterial pure cultures growing on skin specimens was negative for deep fungal infections. Further identification and confirmation by polymerase chain reaction assay of N asteroides required several weeks. Meanwhile, the chest radiograph followed by CT scans of the lungs and brain led to the diagnosis of a disseminated infection. Documentation of lung involvement 1 year prior to the development of the cutaneous lesions excluded primary cutaneous nocardiosis with secondary dissemination as reported in other immunocompromised patients, including those undergoing long-term treatment with corticosteroids.^15-19 Continuous follow-up and physician awareness of possible unusual infections is mandatory in patients undergoing immunosuppressive therapy. Our patient had a 20-year history of rheumatoid arthritis but was otherwise healthy with no signs of lung distress, fever, or general malaise. His only concern was leg impairment following acute development of painful lesions discharging pus over 1 month.

Conclusion

This case report highlights the role of the dermatologist as the first-line physician involved in the diagnosis of rare and potentially severe infections. Cooperation with the microbiologist, pathologist, and other internal medicine specialists is crucial; however, sometimes it is just the clinical suspicion and the perseverance of the dermatologist that ultimately leads to the correct diagnosis, which often is otherwise unspecific, undervalued, and misdiagnosed as more common diseases.

Nocardiosis is a rare human infection that has been reported worldwide but occurs more frequently in patients who reside in tropical areas. Although there is no predilection for age or ethnicity, nocardiosis is slightly more common in males than in females.^1,2 The genus Nocardia belongs to the order Actinomycetales and includes more than 50 species of gram-positive, aerobic, filamentous, branching, partially acid-fast bacteria found ubiquitously in soil.³ The bacteria may be present in animals (eg, cattle, dogs),⁴ but transmission to humans is unusual. Clinical diagnosis of nocardiosis often is difficult because of its nonspecific manifestations and delays in its recognition, especially in western countries where the infection is consistently rare and probably underestimated.^5-8 Cutaneous involvement generally manifests as 1 of 4 conditions: mycetoma, lymphocutaneous (sporotrichoid) infection, superficial skin infection, or systemic disease with cutaneous involvement.⁹ Systemic disseminated disease usually occurs in individuals with cellular immune deficiency, such as patients with human immunodeficiency virus; organ transplant recipients; or patients with a history of long-term use of corticosteroids, configuring an opportunistic infection.^10-19 Incidence in these high-risk patients is 140- to 340-fold higher than in the general population.²⁰Nocardia infections usually are acquired via dust inhalation, especially in dry environments. Focal pneumonitis is the first typical manifestation in immunosuppressed patients, followed by skin dissemination and central nervous system involvement.¹

We report the case of a 65-year-old man who developed disseminated nocardiosis while undergoing long-term treatment with systemic corticosteroids for rheumatoid arthritis.

Case Report

A 65-year-old man presented to the dermatology department for evaluation of multiple papules and nodules with a puruloid discharge on the right leg. The first lesions had appeared on the right ankle approximately 1 month prior to presentation and were treated with systemic antibiotics by the patient’s general practitioner without remarkable benefits. The lesions progressed further on the right leg showing a sporotrichoid disposition.

On physical examination major involvement was evident on the right knee with papules, subcutaneous nodules, and sinuses (Figure 1). Isolated lesions also were present on the right thigh. A few days later some lesions were present on the left elbow and arm. Involvement of the popliteal and inguinal lymph nodes was noted, with painful enlarged nodules covered by erythematous skin that were mobile on deep planes. The lesions had a sudden onset while the patient was in good health, causing progressive functional impotency of the leg without general malaise or fever. The patient’s history was remarkable for chronic rheumatoid arthritis of 20 years’ duration that was treated with hydroxychloroquine (400 mg daily) and methylprednisolone (16 mg daily).

Figure 1. Multiple papules, nodules, and sinuses discharging puruloid material over the right knee showing a sporotrichoid disposition.

The patient was retired but reported daily tilling and manual labor on his farmland. He denied trauma or insect bites to the leg prior to the onset of lesions. Laboratory examination documented slight neutrophil leukocytosis (white blood cell count, 12.8×10³/μL [reference range, 4.5–11.0×10³/μL]; neutrophil count, 10.7×10³/μL [reference range, 1.8–7.8×10³/μL]; 85% neutrophils at formula count [reference range, 56%]), augmented C-reactive protein levels (15.8 mg/L [reference range, 0.08–3.1 mg/L]), a blood sedimentation rate of 74 mm/h (reference range, 0–20 mm/h), and elevated liver enzymes (aspartate aminotransferase, 52 U/L [reference range, 10–30 U/L]; alanine aminotransferase, 89 U/L [reference range, 10–40 U/L]; γ-glutamyltransferase, 68 U/L [reference range, 2–30 U/L]). Rheumatoid factor was 49.7 U/mL (reference range, 0–14.0 U/mL). Skin biopsy of a sample lesion suggested a chronic granulomatous suppuration. Tissue cultures and subsequent polymerase chain reaction assay identified Nocardia asteroides. A chest radiograph revealed multiple opaque nodules disseminated in both lungs, and a computed tomography (CT) scan confirmed multiple pulmonary lesions without involvement of the mediastinal lymph nodes (Figure 2). Computed tomography scans of the brain before and after contrast media perfusion showed the presence of an enhanced 8-mm mass among the right parietal and occipital lobes surrounded by an edematous halo (Figure 3). Neurologic examination was normal. During the radiologic assessment, the patient remembered having been hospitalized 1 year prior in a pulmonology unit at an outside institution for treatment of what was considered to be a multifocal nonspecific lung infection. A 1-month course of levofloxacin (500 mg daily) was administered at that time without any further follow-up. Review of the prior chest radiograph and CT scan confirmed the presence of the same radiologic findings as the current assessment, though of milder entity.

Figure 2. Computed tomography of the chest demonstrated multiple bilateral lung nodules (arrows) of various sizes, principally on the right side, without involvement of the mediastinal lymph nodes.

Figure 3. Computed tomography of the brain showed an enhanced 8-mm mass (arrow) among the right parietal and occipital lobes surrounded by an edematous halo.

The patient was transferred from the dermatology department to the infectious diseases unit. Fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy confirmed pulmonary nocardiosis. Treatment with a combination of endovenous carbapenem and fluoroquinolone antibiotics for 1 month led to complete resolution of both the cutaneous lesions and the single brain abscess. Improvement of pulmonary involvement was noted on radiology, but another course of endovenous treatment with antibiotics was required, followed by oral amoxicillin–clavulanic acid (2 g daily) for 3 months. The patient underwent maintenance antibiotic therapy for 1 year without relapse and is considered to be cured.

Comment

Cutaneous nocardiosis occurs either as part of a disseminated infection or as a primary skin inoculation, usually following trauma or exposure from working outdoors.^2,9,21,22 Nocardial mycetoma, also known as actinomycetoma, is a chronic condition that mainly affects the lower extremities but also can affect the hands and forearms; it is frequently reported in tropical regions,²³ but disseminated forms are rare and undervalued, especially in European countries. A certain rise in incidence has been reported in Europe as a consequence of immune suppression, and pulmonary disease is the most common presentation in these patients.^1,2,6-12 One-third of patients have disseminated disease with high morbidity and a high mortality rate.²⁰ Major case collections in Italy have been studied by a collaborative hospital network of 11 cities,^10,11 confirming difficulty of diagnosis and underestimation, prevalence of N asteroides as a pathogen, resistance to several antimicrobials, and a high relapse index. Diagnosis remains challenging, as clinical suspicion is not frequently supported by histology and/or microbiology because of difficulty in bacteria isolation. Molecular methods are not routinely available in Italy, and only stringent efforts and cooperation from different university departments has allowed final identification of nocardiosis.

The sporotrichoid pattern of the lesions on the right leg was unique; it is considered the rarest presentation of cutaneous nocardiosis.²⁴ Our first suspicion was sporotrichosis, an infection that is especially common in farmers in Italy,^25,26 but the microbiologist’s evaluation of the bacterial pure cultures growing on skin specimens was negative for deep fungal infections. Further identification and confirmation by polymerase chain reaction assay of N asteroides required several weeks. Meanwhile, the chest radiograph followed by CT scans of the lungs and brain led to the diagnosis of a disseminated infection. Documentation of lung involvement 1 year prior to the development of the cutaneous lesions excluded primary cutaneous nocardiosis with secondary dissemination as reported in other immunocompromised patients, including those undergoing long-term treatment with corticosteroids.^15-19 Continuous follow-up and physician awareness of possible unusual infections is mandatory in patients undergoing immunosuppressive therapy. Our patient had a 20-year history of rheumatoid arthritis but was otherwise healthy with no signs of lung distress, fever, or general malaise. His only concern was leg impairment following acute development of painful lesions discharging pus over 1 month.

Conclusion

This case report highlights the role of the dermatologist as the first-line physician involved in the diagnosis of rare and potentially severe infections. Cooperation with the microbiologist, pathologist, and other internal medicine specialists is crucial; however, sometimes it is just the clinical suspicion and the perseverance of the dermatologist that ultimately leads to the correct diagnosis, which often is otherwise unspecific, undervalued, and misdiagnosed as more common diseases.

Nocardiosis is a rare human infection that has been reported worldwide but occurs more frequently in patients who reside in tropical areas. Although there is no predilection for age or ethnicity, nocardiosis is slightly more common in males than in females.^1,2 The genus Nocardia belongs to the order Actinomycetales and includes more than 50 species of gram-positive, aerobic, filamentous, branching, partially acid-fast bacteria found ubiquitously in soil.³ The bacteria may be present in animals (eg, cattle, dogs),⁴ but transmission to humans is unusual. Clinical diagnosis of nocardiosis often is difficult because of its nonspecific manifestations and delays in its recognition, especially in western countries where the infection is consistently rare and probably underestimated.^5-8 Cutaneous involvement generally manifests as 1 of 4 conditions: mycetoma, lymphocutaneous (sporotrichoid) infection, superficial skin infection, or systemic disease with cutaneous involvement.⁹ Systemic disseminated disease usually occurs in individuals with cellular immune deficiency, such as patients with human immunodeficiency virus; organ transplant recipients; or patients with a history of long-term use of corticosteroids, configuring an opportunistic infection.^10-19 Incidence in these high-risk patients is 140- to 340-fold higher than in the general population.²⁰Nocardia infections usually are acquired via dust inhalation, especially in dry environments. Focal pneumonitis is the first typical manifestation in immunosuppressed patients, followed by skin dissemination and central nervous system involvement.¹

We report the case of a 65-year-old man who developed disseminated nocardiosis while undergoing long-term treatment with systemic corticosteroids for rheumatoid arthritis.

Case Report

A 65-year-old man presented to the dermatology department for evaluation of multiple papules and nodules with a puruloid discharge on the right leg. The first lesions had appeared on the right ankle approximately 1 month prior to presentation and were treated with systemic antibiotics by the patient’s general practitioner without remarkable benefits. The lesions progressed further on the right leg showing a sporotrichoid disposition.

On physical examination major involvement was evident on the right knee with papules, subcutaneous nodules, and sinuses (Figure 1). Isolated lesions also were present on the right thigh. A few days later some lesions were present on the left elbow and arm. Involvement of the popliteal and inguinal lymph nodes was noted, with painful enlarged nodules covered by erythematous skin that were mobile on deep planes. The lesions had a sudden onset while the patient was in good health, causing progressive functional impotency of the leg without general malaise or fever. The patient’s history was remarkable for chronic rheumatoid arthritis of 20 years’ duration that was treated with hydroxychloroquine (400 mg daily) and methylprednisolone (16 mg daily).

Figure 1. Multiple papules, nodules, and sinuses discharging puruloid material over the right knee showing a sporotrichoid disposition.

The patient was retired but reported daily tilling and manual labor on his farmland. He denied trauma or insect bites to the leg prior to the onset of lesions. Laboratory examination documented slight neutrophil leukocytosis (white blood cell count, 12.8×10³/μL [reference range, 4.5–11.0×10³/μL]; neutrophil count, 10.7×10³/μL [reference range, 1.8–7.8×10³/μL]; 85% neutrophils at formula count [reference range, 56%]), augmented C-reactive protein levels (15.8 mg/L [reference range, 0.08–3.1 mg/L]), a blood sedimentation rate of 74 mm/h (reference range, 0–20 mm/h), and elevated liver enzymes (aspartate aminotransferase, 52 U/L [reference range, 10–30 U/L]; alanine aminotransferase, 89 U/L [reference range, 10–40 U/L]; γ-glutamyltransferase, 68 U/L [reference range, 2–30 U/L]). Rheumatoid factor was 49.7 U/mL (reference range, 0–14.0 U/mL). Skin biopsy of a sample lesion suggested a chronic granulomatous suppuration. Tissue cultures and subsequent polymerase chain reaction assay identified Nocardia asteroides. A chest radiograph revealed multiple opaque nodules disseminated in both lungs, and a computed tomography (CT) scan confirmed multiple pulmonary lesions without involvement of the mediastinal lymph nodes (Figure 2). Computed tomography scans of the brain before and after contrast media perfusion showed the presence of an enhanced 8-mm mass among the right parietal and occipital lobes surrounded by an edematous halo (Figure 3). Neurologic examination was normal. During the radiologic assessment, the patient remembered having been hospitalized 1 year prior in a pulmonology unit at an outside institution for treatment of what was considered to be a multifocal nonspecific lung infection. A 1-month course of levofloxacin (500 mg daily) was administered at that time without any further follow-up. Review of the prior chest radiograph and CT scan confirmed the presence of the same radiologic findings as the current assessment, though of milder entity.

Figure 2. Computed tomography of the chest demonstrated multiple bilateral lung nodules (arrows) of various sizes, principally on the right side, without involvement of the mediastinal lymph nodes.

Figure 3. Computed tomography of the brain showed an enhanced 8-mm mass (arrow) among the right parietal and occipital lobes surrounded by an edematous halo.

The patient was transferred from the dermatology department to the infectious diseases unit. Fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy confirmed pulmonary nocardiosis. Treatment with a combination of endovenous carbapenem and fluoroquinolone antibiotics for 1 month led to complete resolution of both the cutaneous lesions and the single brain abscess. Improvement of pulmonary involvement was noted on radiology, but another course of endovenous treatment with antibiotics was required, followed by oral amoxicillin–clavulanic acid (2 g daily) for 3 months. The patient underwent maintenance antibiotic therapy for 1 year without relapse and is considered to be cured.

Comment

Cutaneous nocardiosis occurs either as part of a disseminated infection or as a primary skin inoculation, usually following trauma or exposure from working outdoors.^2,9,21,22 Nocardial mycetoma, also known as actinomycetoma, is a chronic condition that mainly affects the lower extremities but also can affect the hands and forearms; it is frequently reported in tropical regions,²³ but disseminated forms are rare and undervalued, especially in European countries. A certain rise in incidence has been reported in Europe as a consequence of immune suppression, and pulmonary disease is the most common presentation in these patients.^1,2,6-12 One-third of patients have disseminated disease with high morbidity and a high mortality rate.²⁰ Major case collections in Italy have been studied by a collaborative hospital network of 11 cities,^10,11 confirming difficulty of diagnosis and underestimation, prevalence of N asteroides as a pathogen, resistance to several antimicrobials, and a high relapse index. Diagnosis remains challenging, as clinical suspicion is not frequently supported by histology and/or microbiology because of difficulty in bacteria isolation. Molecular methods are not routinely available in Italy, and only stringent efforts and cooperation from different university departments has allowed final identification of nocardiosis.

The sporotrichoid pattern of the lesions on the right leg was unique; it is considered the rarest presentation of cutaneous nocardiosis.²⁴ Our first suspicion was sporotrichosis, an infection that is especially common in farmers in Italy,^25,26 but the microbiologist’s evaluation of the bacterial pure cultures growing on skin specimens was negative for deep fungal infections. Further identification and confirmation by polymerase chain reaction assay of N asteroides required several weeks. Meanwhile, the chest radiograph followed by CT scans of the lungs and brain led to the diagnosis of a disseminated infection. Documentation of lung involvement 1 year prior to the development of the cutaneous lesions excluded primary cutaneous nocardiosis with secondary dissemination as reported in other immunocompromised patients, including those undergoing long-term treatment with corticosteroids.^15-19 Continuous follow-up and physician awareness of possible unusual infections is mandatory in patients undergoing immunosuppressive therapy. Our patient had a 20-year history of rheumatoid arthritis but was otherwise healthy with no signs of lung distress, fever, or general malaise. His only concern was leg impairment following acute development of painful lesions discharging pus over 1 month.

Conclusion

This case report highlights the role of the dermatologist as the first-line physician involved in the diagnosis of rare and potentially severe infections. Cooperation with the microbiologist, pathologist, and other internal medicine specialists is crucial; however, sometimes it is just the clinical suspicion and the perseverance of the dermatologist that ultimately leads to the correct diagnosis, which often is otherwise unspecific, undervalued, and misdiagnosed as more common diseases.

To the Editor:
Onychomycosis is a fungal infection of the nail plate by dermatophytes, yeasts, and nondermatophyte molds. It is a common problem with a prevalence of 10% to 12% in the United States.^1,2 The clinical presentation of onychomycosis is shown in the Figure. Although some patients may have mild asymptomatic cases of onychomycosis and do not inquire about treatment, many will have more advanced cases, presenting with pain and discomfort, secondary infection, unattractive appearance, or problems performing everyday functions. The goal of onychomycosis treatment is to eliminate the fungus, if possible, which usually restores the nail to its normal state when it fully grows out. Patients should be counseled that it is a long process that may take 6 months or more for fingernails and 12 to 18 months for toenails. These estimates are based on a growth rate of 2 to 3 mm per month for fingernails and 1 to 2 mm per month for toenails.³ Nails grow fastest during the teenaged years and slow down with advancing age.⁴ It should be noted that advanced cases of onychomycosis affecting the nail matrix may cause permanent scarring; therefore, the nail unit may still appear dystrophic after the causative organism is eliminated. The US Food and Drug Administration (FDA) defines a complete cure as negative potassium hydroxide preparation and negative fungal culture plus a completely normal appearance of the nail.

Treatment of onychomycosis poses a number of challenges. First, hyperkeratosis and the fungal mass may limit the delivery of topical and systemic drugs to the source of the infection. In addition, high rates of relapse and reinfection after treatment may be due to residual hyphae or spores.⁵ Furthermore, the extended length of treatment limits patient adherence and many patients are unwilling to forego wearing nail cosmetics during the course of some of the treatments.

The clinical presentation of onychomycosis. The great toenail has yellow discoloration of the nail plate, ridging, and subungual hyperkeratosis.

There are 4 approved classes of antifungal drugs for the treatment of onychomycosis: allylamines, azoles, morpholines, and hydroxypyridinones.⁶ The allylamines (eg, terbinafine) inhibit squalene epoxidase.⁷ Oral terbinafine (250 mg daily) taken for 6 weeks for fingernails and 12 weeks for toenails is considered the current systemic treatment preference in onychomycosis therapy⁸ with complete cure rates in 12-week studies of approximately 38%⁹ and 49%.¹⁰

The second class of drugs is the azoles, which inhibit lanosterol 14a-demethylase, a step in the ergosterol biosynthesis pathway.⁶ Two members of this class that are widely used in treating onychomycosis are oral itraconazole¹¹ and off-label oral fluconazole.¹² The approved dose for oral itraconazole is 200 mg daily for 3 months (or an alternative pulse regimen) with a reported complete cure rate of 14%.¹¹ Although fluconazole is not FDA approved for the treatment of onychomycosis in the United States, it is used extensively in other countries and to some extent off label in the United States. In a study of 362 patients with onychomycosis treated with oral fluconazole, complete cure rates were 48% in patients who received 450 mg weekly, 46% in those who received 300 mg weekly, and 37% in those who received 150 mg weekly for up to 9 months.¹² It should be noted that several oral triazole antifungals, namely albaconazole,¹³ posaconazole,¹⁴ and ravuconazole,¹⁵ have undergone phase 1 and 2 studies for the treatment of onychomycosis and have shown some efficacy.

Another class of antifungals are the morpholines including topical amorolfine, which is approved for use in Europe but not in North America.¹⁶ Amorolfine inhibits D14 reductase and D7-D8 isomerase, thus depleting ergosterol.¹⁷ In one randomized controlled study, the combination of amorolfine nail lacquer and oral terbinafine compared to oral terbinafine alone resulted in a higher clinical cure rate with the combination (59.2% vs 46%); complete cure rate was not reported.¹⁶

Finally, the hydroxypyridinone class includes topical ciclopirox, which has a poorly understood mechanism of action but may involve iron chelation or oxidative damage.^18,19 Ciclopirox nail lacquer 8% was approved by the FDA in 1999 and has reported complete cure rates of 5.5% to 8.5% with monthly nail debridement.²⁰

Based on the poor efficacy of many of the currently available treatments and time-consuming treatment courses, it is clear that there is a need for alternative and novel therapies. There has been a greater emphasis on topical agents due to their more favorable side-effect profile and lower risk for drug-drug interactions. Although there are many agents for the treatment of onychomycosis currently in development, many are in vitro studies or phase 1 and 2 studies. However, we will focus on drugs that are further along in phase 3 studies and those that were recently FDA approved.

Efinaconazole is a member of the azole class of drugs and has completed 2 phase 3 clinical trials (study 1, N=870; study 2, N=785).²¹ Patients in these 2 studies were randomized to receive either efinaconazole nail solution 10% or vehicle for 48 weeks followed by a 4-week washout period. Complete cure rates in the 2 studies were 17.8% and 15.2% in the treated group and 3.3% and 5.5% in the control group. The mycological cure rates were 55.2% and 53.4% in the treated group and 16.8% and 16.9% in the control group. The side-effect profile was minimal, with the most common adverse events being application-site dermatitis and vesiculation, which were not significantly higher in the treated group versus the control group.²¹ Efinaconazole received FDA approval for the treatment of toenail onychomycosis in June 2014.

There are some notable differences between ciclopirox and efinaconazole that may improve patient compliance with the latter. First, treatment with ciclopirox includes monthly nail debridement, which is not required with efinaconazole. Secondly, although ciclopirox lacquer must be removed weekly, efinaconazole is a solution, so no removal is necessary.

Terbinafine nail solution (TNS) is a member of the allylamine class and has completed phase 3 clinical trials.²² Three studies—2 vehicle controlled and 1 active comparator—were performed. The first compared TNS and vehicle, both applied daily for 24 weeks; the second study repeated the same for 48 weeks; and the third study compared TNS to amorolfine nail lacquer 5% daily for 48 weeks. The best results for complete cure were achieved with TNS for 48 weeks in the vehicle-controlled study with a rate of 2.2% versus 0%. The authors also concluded TNS was not more effective than amorolfine, as complete cure rates were 1.2% for TNS and 0.96% for amorolfine. The most common side effects were headache, nasopharyngitis, and influenza.²²

Tavaborole is a member of the new benzoxaborole class, which inhibits protein synthesis by forming an adduct with the aminoacyl–transfer RNA synthetase.²³ The topical solution was engineered to have improved penetration through the nail plate. In vitro studies showed better penetration than both ciclopirox and amorolfine.²⁴ Two identical phase 3 randomized, double-blind, vehicle-controlled studies were completed involving 1197 patients who were treated with tavaborole topical solution 5% daily compared to vehicle for 48 weeks followed by a 4-week washout period with promising results.²⁵ The incidence of treatment-related side effects was comparable to the vehicle. The most common adverse events were exfoliation, erythema, and dermatitis, all occurring at the application site.²⁵ Tavaborole was approved by the FDA for the treatment of toenail onychomycosis in July 2014.

Luliconazole is a member of the azole class and a phase 2b/3 clinical trial with a 10% solution involving 334 patients was completed in June 2013.²⁶ Results from this trial are expected in early 2015.

Lasers are a developing area for onychomycosis therapy and the appeal stems from their ability to selectively deliver energy to the target tissue, thus avoiding systemic side effects. Since 2010, the FDA has approved numerous laser devices for the temporary cosmetic improvement of onychomycosis, all of which are Nd:YAG 1064-nm lasers.^27,28 It was previously thought that the mechanism of action for the fungicidal effect was achieved with heat,²⁹ but newer in vitro studies have shown that the amount of time and level of heat required to kill Trichophyton rubrum would not be tolerable to patients.³⁰ Although the mechanism of action is poorly understood, some clinical trials have shown success using the Nd:YAG 1064-nm laser for treatment of onychomycosis. However, in a study of 8 patients treated with the Nd:YAG 1064-nm laser for 5 treatment sessions, none had a mycological or clinical cure and there was only mild clinical improvement. In addition, most patients had pain and burning during the treatments requiring many short breaks.³⁰ Although not yet FDA approved for the treatment of onychomycosis, other types of lasers are currently being studied, including CO₂, near-infrared diode, and femtosecond-infrared laser systems.³

Plasma therapy is a developing area for the treatment of onychomycosis. Plasma was shown to be fungicidal to T rubrum in an in vitro model (MOE Medical Devices, written communication, July 2012), and a clinical trial to evaluate the safety, tolerability, and efficacy of plasma in human subjects is ongoing (registered on March 22, 2013, at www.clinicaltrials.gov with the identifier NCT01819051).

Onychomycosis is a common problem that increases in prevalence with advancing age. Oral terbinafine is considered the first-line treatment at this point in time.³¹ Two new topical agents, efinaconazole and tavaborole, were recently FDA approved and may be used for the treatment of toenail onychomycosis without the need for nail debridement. The Nd:YAG laser has shown some promise in earlier clinical studies but was ineffective in a more recent study.

To the Editor:
Onychomycosis is a fungal infection of the nail plate by dermatophytes, yeasts, and nondermatophyte molds. It is a common problem with a prevalence of 10% to 12% in the United States.^1,2 The clinical presentation of onychomycosis is shown in the Figure. Although some patients may have mild asymptomatic cases of onychomycosis and do not inquire about treatment, many will have more advanced cases, presenting with pain and discomfort, secondary infection, unattractive appearance, or problems performing everyday functions. The goal of onychomycosis treatment is to eliminate the fungus, if possible, which usually restores the nail to its normal state when it fully grows out. Patients should be counseled that it is a long process that may take 6 months or more for fingernails and 12 to 18 months for toenails. These estimates are based on a growth rate of 2 to 3 mm per month for fingernails and 1 to 2 mm per month for toenails.³ Nails grow fastest during the teenaged years and slow down with advancing age.⁴ It should be noted that advanced cases of onychomycosis affecting the nail matrix may cause permanent scarring; therefore, the nail unit may still appear dystrophic after the causative organism is eliminated. The US Food and Drug Administration (FDA) defines a complete cure as negative potassium hydroxide preparation and negative fungal culture plus a completely normal appearance of the nail.

Treatment of onychomycosis poses a number of challenges. First, hyperkeratosis and the fungal mass may limit the delivery of topical and systemic drugs to the source of the infection. In addition, high rates of relapse and reinfection after treatment may be due to residual hyphae or spores.⁵ Furthermore, the extended length of treatment limits patient adherence and many patients are unwilling to forego wearing nail cosmetics during the course of some of the treatments.

The clinical presentation of onychomycosis. The great toenail has yellow discoloration of the nail plate, ridging, and subungual hyperkeratosis.

There are 4 approved classes of antifungal drugs for the treatment of onychomycosis: allylamines, azoles, morpholines, and hydroxypyridinones.⁶ The allylamines (eg, terbinafine) inhibit squalene epoxidase.⁷ Oral terbinafine (250 mg daily) taken for 6 weeks for fingernails and 12 weeks for toenails is considered the current systemic treatment preference in onychomycosis therapy⁸ with complete cure rates in 12-week studies of approximately 38%⁹ and 49%.¹⁰

The second class of drugs is the azoles, which inhibit lanosterol 14a-demethylase, a step in the ergosterol biosynthesis pathway.⁶ Two members of this class that are widely used in treating onychomycosis are oral itraconazole¹¹ and off-label oral fluconazole.¹² The approved dose for oral itraconazole is 200 mg daily for 3 months (or an alternative pulse regimen) with a reported complete cure rate of 14%.¹¹ Although fluconazole is not FDA approved for the treatment of onychomycosis in the United States, it is used extensively in other countries and to some extent off label in the United States. In a study of 362 patients with onychomycosis treated with oral fluconazole, complete cure rates were 48% in patients who received 450 mg weekly, 46% in those who received 300 mg weekly, and 37% in those who received 150 mg weekly for up to 9 months.¹² It should be noted that several oral triazole antifungals, namely albaconazole,¹³ posaconazole,¹⁴ and ravuconazole,¹⁵ have undergone phase 1 and 2 studies for the treatment of onychomycosis and have shown some efficacy.

Another class of antifungals are the morpholines including topical amorolfine, which is approved for use in Europe but not in North America.¹⁶ Amorolfine inhibits D14 reductase and D7-D8 isomerase, thus depleting ergosterol.¹⁷ In one randomized controlled study, the combination of amorolfine nail lacquer and oral terbinafine compared to oral terbinafine alone resulted in a higher clinical cure rate with the combination (59.2% vs 46%); complete cure rate was not reported.¹⁶

Finally, the hydroxypyridinone class includes topical ciclopirox, which has a poorly understood mechanism of action but may involve iron chelation or oxidative damage.^18,19 Ciclopirox nail lacquer 8% was approved by the FDA in 1999 and has reported complete cure rates of 5.5% to 8.5% with monthly nail debridement.²⁰

Based on the poor efficacy of many of the currently available treatments and time-consuming treatment courses, it is clear that there is a need for alternative and novel therapies. There has been a greater emphasis on topical agents due to their more favorable side-effect profile and lower risk for drug-drug interactions. Although there are many agents for the treatment of onychomycosis currently in development, many are in vitro studies or phase 1 and 2 studies. However, we will focus on drugs that are further along in phase 3 studies and those that were recently FDA approved.

Efinaconazole is a member of the azole class of drugs and has completed 2 phase 3 clinical trials (study 1, N=870; study 2, N=785).²¹ Patients in these 2 studies were randomized to receive either efinaconazole nail solution 10% or vehicle for 48 weeks followed by a 4-week washout period. Complete cure rates in the 2 studies were 17.8% and 15.2% in the treated group and 3.3% and 5.5% in the control group. The mycological cure rates were 55.2% and 53.4% in the treated group and 16.8% and 16.9% in the control group. The side-effect profile was minimal, with the most common adverse events being application-site dermatitis and vesiculation, which were not significantly higher in the treated group versus the control group.²¹ Efinaconazole received FDA approval for the treatment of toenail onychomycosis in June 2014.

There are some notable differences between ciclopirox and efinaconazole that may improve patient compliance with the latter. First, treatment with ciclopirox includes monthly nail debridement, which is not required with efinaconazole. Secondly, although ciclopirox lacquer must be removed weekly, efinaconazole is a solution, so no removal is necessary.

Terbinafine nail solution (TNS) is a member of the allylamine class and has completed phase 3 clinical trials.²² Three studies—2 vehicle controlled and 1 active comparator—were performed. The first compared TNS and vehicle, both applied daily for 24 weeks; the second study repeated the same for 48 weeks; and the third study compared TNS to amorolfine nail lacquer 5% daily for 48 weeks. The best results for complete cure were achieved with TNS for 48 weeks in the vehicle-controlled study with a rate of 2.2% versus 0%. The authors also concluded TNS was not more effective than amorolfine, as complete cure rates were 1.2% for TNS and 0.96% for amorolfine. The most common side effects were headache, nasopharyngitis, and influenza.²²

Tavaborole is a member of the new benzoxaborole class, which inhibits protein synthesis by forming an adduct with the aminoacyl–transfer RNA synthetase.²³ The topical solution was engineered to have improved penetration through the nail plate. In vitro studies showed better penetration than both ciclopirox and amorolfine.²⁴ Two identical phase 3 randomized, double-blind, vehicle-controlled studies were completed involving 1197 patients who were treated with tavaborole topical solution 5% daily compared to vehicle for 48 weeks followed by a 4-week washout period with promising results.²⁵ The incidence of treatment-related side effects was comparable to the vehicle. The most common adverse events were exfoliation, erythema, and dermatitis, all occurring at the application site.²⁵ Tavaborole was approved by the FDA for the treatment of toenail onychomycosis in July 2014.

Luliconazole is a member of the azole class and a phase 2b/3 clinical trial with a 10% solution involving 334 patients was completed in June 2013.²⁶ Results from this trial are expected in early 2015.

Lasers are a developing area for onychomycosis therapy and the appeal stems from their ability to selectively deliver energy to the target tissue, thus avoiding systemic side effects. Since 2010, the FDA has approved numerous laser devices for the temporary cosmetic improvement of onychomycosis, all of which are Nd:YAG 1064-nm lasers.^27,28 It was previously thought that the mechanism of action for the fungicidal effect was achieved with heat,²⁹ but newer in vitro studies have shown that the amount of time and level of heat required to kill Trichophyton rubrum would not be tolerable to patients.³⁰ Although the mechanism of action is poorly understood, some clinical trials have shown success using the Nd:YAG 1064-nm laser for treatment of onychomycosis. However, in a study of 8 patients treated with the Nd:YAG 1064-nm laser for 5 treatment sessions, none had a mycological or clinical cure and there was only mild clinical improvement. In addition, most patients had pain and burning during the treatments requiring many short breaks.³⁰ Although not yet FDA approved for the treatment of onychomycosis, other types of lasers are currently being studied, including CO₂, near-infrared diode, and femtosecond-infrared laser systems.³

Plasma therapy is a developing area for the treatment of onychomycosis. Plasma was shown to be fungicidal to T rubrum in an in vitro model (MOE Medical Devices, written communication, July 2012), and a clinical trial to evaluate the safety, tolerability, and efficacy of plasma in human subjects is ongoing (registered on March 22, 2013, at www.clinicaltrials.gov with the identifier NCT01819051).

Onychomycosis is a common problem that increases in prevalence with advancing age. Oral terbinafine is considered the first-line treatment at this point in time.³¹ Two new topical agents, efinaconazole and tavaborole, were recently FDA approved and may be used for the treatment of toenail onychomycosis without the need for nail debridement. The Nd:YAG laser has shown some promise in earlier clinical studies but was ineffective in a more recent study.

To the Editor:
Onychomycosis is a fungal infection of the nail plate by dermatophytes, yeasts, and nondermatophyte molds. It is a common problem with a prevalence of 10% to 12% in the United States.^1,2 The clinical presentation of onychomycosis is shown in the Figure. Although some patients may have mild asymptomatic cases of onychomycosis and do not inquire about treatment, many will have more advanced cases, presenting with pain and discomfort, secondary infection, unattractive appearance, or problems performing everyday functions. The goal of onychomycosis treatment is to eliminate the fungus, if possible, which usually restores the nail to its normal state when it fully grows out. Patients should be counseled that it is a long process that may take 6 months or more for fingernails and 12 to 18 months for toenails. These estimates are based on a growth rate of 2 to 3 mm per month for fingernails and 1 to 2 mm per month for toenails.³ Nails grow fastest during the teenaged years and slow down with advancing age.⁴ It should be noted that advanced cases of onychomycosis affecting the nail matrix may cause permanent scarring; therefore, the nail unit may still appear dystrophic after the causative organism is eliminated. The US Food and Drug Administration (FDA) defines a complete cure as negative potassium hydroxide preparation and negative fungal culture plus a completely normal appearance of the nail.

Treatment of onychomycosis poses a number of challenges. First, hyperkeratosis and the fungal mass may limit the delivery of topical and systemic drugs to the source of the infection. In addition, high rates of relapse and reinfection after treatment may be due to residual hyphae or spores.⁵ Furthermore, the extended length of treatment limits patient adherence and many patients are unwilling to forego wearing nail cosmetics during the course of some of the treatments.

The clinical presentation of onychomycosis. The great toenail has yellow discoloration of the nail plate, ridging, and subungual hyperkeratosis.

There are 4 approved classes of antifungal drugs for the treatment of onychomycosis: allylamines, azoles, morpholines, and hydroxypyridinones.⁶ The allylamines (eg, terbinafine) inhibit squalene epoxidase.⁷ Oral terbinafine (250 mg daily) taken for 6 weeks for fingernails and 12 weeks for toenails is considered the current systemic treatment preference in onychomycosis therapy⁸ with complete cure rates in 12-week studies of approximately 38%⁹ and 49%.¹⁰

The second class of drugs is the azoles, which inhibit lanosterol 14a-demethylase, a step in the ergosterol biosynthesis pathway.⁶ Two members of this class that are widely used in treating onychomycosis are oral itraconazole¹¹ and off-label oral fluconazole.¹² The approved dose for oral itraconazole is 200 mg daily for 3 months (or an alternative pulse regimen) with a reported complete cure rate of 14%.¹¹ Although fluconazole is not FDA approved for the treatment of onychomycosis in the United States, it is used extensively in other countries and to some extent off label in the United States. In a study of 362 patients with onychomycosis treated with oral fluconazole, complete cure rates were 48% in patients who received 450 mg weekly, 46% in those who received 300 mg weekly, and 37% in those who received 150 mg weekly for up to 9 months.¹² It should be noted that several oral triazole antifungals, namely albaconazole,¹³ posaconazole,¹⁴ and ravuconazole,¹⁵ have undergone phase 1 and 2 studies for the treatment of onychomycosis and have shown some efficacy.

Another class of antifungals are the morpholines including topical amorolfine, which is approved for use in Europe but not in North America.¹⁶ Amorolfine inhibits D14 reductase and D7-D8 isomerase, thus depleting ergosterol.¹⁷ In one randomized controlled study, the combination of amorolfine nail lacquer and oral terbinafine compared to oral terbinafine alone resulted in a higher clinical cure rate with the combination (59.2% vs 46%); complete cure rate was not reported.¹⁶

Finally, the hydroxypyridinone class includes topical ciclopirox, which has a poorly understood mechanism of action but may involve iron chelation or oxidative damage.^18,19 Ciclopirox nail lacquer 8% was approved by the FDA in 1999 and has reported complete cure rates of 5.5% to 8.5% with monthly nail debridement.²⁰

Based on the poor efficacy of many of the currently available treatments and time-consuming treatment courses, it is clear that there is a need for alternative and novel therapies. There has been a greater emphasis on topical agents due to their more favorable side-effect profile and lower risk for drug-drug interactions. Although there are many agents for the treatment of onychomycosis currently in development, many are in vitro studies or phase 1 and 2 studies. However, we will focus on drugs that are further along in phase 3 studies and those that were recently FDA approved.

Efinaconazole is a member of the azole class of drugs and has completed 2 phase 3 clinical trials (study 1, N=870; study 2, N=785).²¹ Patients in these 2 studies were randomized to receive either efinaconazole nail solution 10% or vehicle for 48 weeks followed by a 4-week washout period. Complete cure rates in the 2 studies were 17.8% and 15.2% in the treated group and 3.3% and 5.5% in the control group. The mycological cure rates were 55.2% and 53.4% in the treated group and 16.8% and 16.9% in the control group. The side-effect profile was minimal, with the most common adverse events being application-site dermatitis and vesiculation, which were not significantly higher in the treated group versus the control group.²¹ Efinaconazole received FDA approval for the treatment of toenail onychomycosis in June 2014.

There are some notable differences between ciclopirox and efinaconazole that may improve patient compliance with the latter. First, treatment with ciclopirox includes monthly nail debridement, which is not required with efinaconazole. Secondly, although ciclopirox lacquer must be removed weekly, efinaconazole is a solution, so no removal is necessary.

Terbinafine nail solution (TNS) is a member of the allylamine class and has completed phase 3 clinical trials.²² Three studies—2 vehicle controlled and 1 active comparator—were performed. The first compared TNS and vehicle, both applied daily for 24 weeks; the second study repeated the same for 48 weeks; and the third study compared TNS to amorolfine nail lacquer 5% daily for 48 weeks. The best results for complete cure were achieved with TNS for 48 weeks in the vehicle-controlled study with a rate of 2.2% versus 0%. The authors also concluded TNS was not more effective than amorolfine, as complete cure rates were 1.2% for TNS and 0.96% for amorolfine. The most common side effects were headache, nasopharyngitis, and influenza.²²

Tavaborole is a member of the new benzoxaborole class, which inhibits protein synthesis by forming an adduct with the aminoacyl–transfer RNA synthetase.²³ The topical solution was engineered to have improved penetration through the nail plate. In vitro studies showed better penetration than both ciclopirox and amorolfine.²⁴ Two identical phase 3 randomized, double-blind, vehicle-controlled studies were completed involving 1197 patients who were treated with tavaborole topical solution 5% daily compared to vehicle for 48 weeks followed by a 4-week washout period with promising results.²⁵ The incidence of treatment-related side effects was comparable to the vehicle. The most common adverse events were exfoliation, erythema, and dermatitis, all occurring at the application site.²⁵ Tavaborole was approved by the FDA for the treatment of toenail onychomycosis in July 2014.

Luliconazole is a member of the azole class and a phase 2b/3 clinical trial with a 10% solution involving 334 patients was completed in June 2013.²⁶ Results from this trial are expected in early 2015.

Lasers are a developing area for onychomycosis therapy and the appeal stems from their ability to selectively deliver energy to the target tissue, thus avoiding systemic side effects. Since 2010, the FDA has approved numerous laser devices for the temporary cosmetic improvement of onychomycosis, all of which are Nd:YAG 1064-nm lasers.^27,28 It was previously thought that the mechanism of action for the fungicidal effect was achieved with heat,²⁹ but newer in vitro studies have shown that the amount of time and level of heat required to kill Trichophyton rubrum would not be tolerable to patients.³⁰ Although the mechanism of action is poorly understood, some clinical trials have shown success using the Nd:YAG 1064-nm laser for treatment of onychomycosis. However, in a study of 8 patients treated with the Nd:YAG 1064-nm laser for 5 treatment sessions, none had a mycological or clinical cure and there was only mild clinical improvement. In addition, most patients had pain and burning during the treatments requiring many short breaks.³⁰ Although not yet FDA approved for the treatment of onychomycosis, other types of lasers are currently being studied, including CO₂, near-infrared diode, and femtosecond-infrared laser systems.³

Plasma therapy is a developing area for the treatment of onychomycosis. Plasma was shown to be fungicidal to T rubrum in an in vitro model (MOE Medical Devices, written communication, July 2012), and a clinical trial to evaluate the safety, tolerability, and efficacy of plasma in human subjects is ongoing (registered on March 22, 2013, at www.clinicaltrials.gov with the identifier NCT01819051).

Onychomycosis is a common problem that increases in prevalence with advancing age. Oral terbinafine is considered the first-line treatment at this point in time.³¹ Two new topical agents, efinaconazole and tavaborole, were recently FDA approved and may be used for the treatment of toenail onychomycosis without the need for nail debridement. The Nd:YAG laser has shown some promise in earlier clinical studies but was ineffective in a more recent study.

Darier-White disease (DD), also known as keratosis follicularis, is a rare skin disease that is inherited in an autosomal-dominant fashion. It was first described by both Darier¹ and White² more than 120 years ago. The incidence is 1 to 9 per 100,000 individuals, and onset usually occurs between 8 and 15 years of age. Classic DD is characterized by malodorous, brown, keratotic, warty papules arising mainly in seborrheic areas; palmoplantar pits; and nail dystrophy with typical worsening in summer. Unilateral and segmental variants of DD rarely have been described.^3,4

Few cases of hemorrhagic DD involving acral surfaces have been reported.^5-8 Most patients develop hemorrhagic bullae at the onset of the disease together with the other characteristic features of DD. The disease also can be associated with salivary gland obstruction, renal and testicular agenesis, bone cysts, and neuropsychiatric disorders.⁹ Diagnosis is confirmed by hyperkeratosis, papillomatosis, acantholysis, dyskeratosis (corps ronds and grains), and small fissures above the basal layer in the epidermis (suprabasal clefts) noted on biopsy of papular lesions. Darier-White disease is caused by a malfunctioning sarcoplasmic/endoplasmic reticulum calcium pump, SERCA2, encoded by the ATP2A2 (ATPase, Ca⁺⁺  transporting, cardiac muscle, slow twitch 2) gene, which transports calcium ions from the cytosol into the sarcoplasmic/endoplasmic reticulum, catalyzing the hydrolysis of adenosine triphosphate coupled with the transport of the calcium. Mutations in ATP2A2 have only been identified in up to 50% of reported DD patients.¹⁰

Treatment of localized DD usually includes emollients and topical retinoids, and systemic retinoids are recommended as the first-line treatment of diffuse DD.¹¹ Many dermatologic side effects of systemic retinoids have been reported, including frequent dry lips and cheilitis.¹² Other skin manifestations include scaling of the palms and soles, excoriations and erosions, alopecia, pruritus, nail fragility, and skin atrophy or fragility. Additionally, common nondermatologic side effects include hepatotoxicity, epistaxis, ophthalmologic effects (eg, loss of eyebrows or eyelashes, redness/swelling of the eyelid, redness of the eyes, sensitivity of the eyes to light, decreased night vision) pancreatitis, bipedal edema, and skeletal alterations.^13-15 We report the case of a patient with DD who developed hemorrhagic macules and vesicles in response to the administration of oral retinoids.

Case Report

An 84-year-old woman was admitted to our hospital for treatment of hyperkeratotic papules and plaques on the face, back, groin, submammary folds, and dorsum of the hands and feet that had been present since childhood and typically worsened during the summer. She previously had refused treatment and reported a poor social life due to the cutaneous manifestations of her disease.

Biopsy of a histologic specimen taken from a palmar pit revealed hyperkeratosis, loss of cohesion between suprabasal epidermal cells (acantholysis), and dyskeratotic cells (corps ronds and grains)(Figure 1). On the basis of both clinical and histologic findings, a diagnosis of DD was made. Genetic analysis did not reveal any mutations in the ATP2A2 gene, and a reduced epidermal expression of SERCA2b was demonstrated by immunochemistry.¹⁶ Treatment with the oral retinoid acitretin (25 mg daily) for 4 months led to almost complete resolution of the lesions. After 4 months, treatment was reduced to a maintenance dose of 12.5 mg once daily.

Figure 1. Histopathologic findings of a skin biopsy specimen obtained from a palmar pit before treatment indicated hyperkeratosis, acantholysis, and the presence of corps ronds and grains (H&E, original magnification ×200).

The patient returned monthly for follow-up to undergo clinical examination and routine laboratory tests (ie, complete blood cell counts, electrolyte panel, renal and hepatic tests, serum lipid levels, cholesterol level). After beginning the maintenance dose, she returned for follow-up every 2 months.

On follow-up 3 months after beginning the maintenance dose, the patient reported the onset of red and black punctiform macules and vesicles with jagged borders located on the palmoplantar surfaces and dorsal aspect of the fingers on both hands. Lesions were either isolated or confluent. The patient did not report pain or itching, though the skin was severely xerotic, especially on the hands and feet (Figures 2A and 2B). The patient reported no local trauma associated with the lesions, and blood counts and coagulation tests were within reference range. It also was noted that the cutaneous manifestations of DD showed a striking improvement. Histologic analysis of a skin biopsy taken from a hemorrhagic lesion on the palmar surface showed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, focal dyskeratosis, and hemorrhagic vesicles in the horny layer of the epidermis (Figure 3), leading to a diagnosis of DD.

After 12 months of therapy, the patient spontaneously stopped taking acitretin, and the hemorrhagic lesions spontaneously regressed within 2 weeks (Figures 2C and 2D). Unfortunately, the cutaneous manifestations of DD (eg, papular lesions) progressively reappeared in the previously reported sites. Based on this relapse, the patient was advised to restart treatment with acitretin (25 mg daily). In the follow-up visit 1 month after restarting acitretin, physical examination revealed the reappearance of hemorrhagic lesions on the palmoplantar surfaces and the dorsal aspect of the fingers.

Figure 2. Palmoplantar hemorrhagic vesicles and macules with diffuse xerosis and scaling were present 7 months after beginning acitretin therapy (A and B). Within 2 weeks of discontinuing acitretin, the hemorrhagic lesions spontaneously regressed (C and D).

Figure 3. Histopathologic analysis of a skin biopsy specimen obtained from a hemorrhagic lesion during treatment with acitretin revealed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, and subcorneal hemorrhagic vesicles (H&E, original magnification ×45).

Comment

We report the case of an 84-year-old woman who developed hemorrhagic lesions on the palmoplantar surfaces and dorsal aspect of the feet as a side effect of oral retinoids for treatment of DD. The first reported case of acral hemorrhagic lesions associated with DD was described 50 years ago in 4 patients with manifestations located mainly on the palms, soles, and dorsal fingers. Local trauma was identified as a triggering factor in the development of the vesicles; however, data regarding the temporal relationship between keratotic papules and hemorrhagic elements and treatment were not specified.⁵ Twenty-five years later, Coulson and Misch⁶ described a case of DD in which the hemorrhagic lesions were the first sign of the disease, but correlation with therapy was not reported. A case of retinoid-induced hemorrhagic DD was reported in a female who was treated with etretinate for approximately 10 years after the diagnosis of DD with good clinical response. After 10 years of therapy, she developed hemorrhagic bullae solely on the dorsal aspect of the hands without any direct association with local trauma, along with a small number of nonhemorrhagic bullae.¹⁷

In our patient, the onset of hemorrhagic vesicles and red maculae occurred primarily on the palmoplantar surfaces. The lesions were smaller than bullae and contained hemorrhagic elements. Of note, the skin lesions appeared as early as 7 months after the patient started acitretin therapy.

The development of hemorrhagic lesions on different body sites as a consequence of oral retinoid administration also has been reported in patients with psoriasis.¹⁵ Emerging evidence indicates that retinoic acid activates vascular endothelial growth factor gene transcription,¹⁸ and vascular endothelial growth factor can modify permeability of the endothelial cells. Based on these observations, we propose that DD is characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. This defect favors the formation of empty intraepidermal lacunae. An increase in endothelial permeability due to oral retinoid administration promotes the gathering of serum and red blood cells into the lacunae, leading to the onset of hemorrhagic blisters. Moreover, continued microtrauma to the palmoplantar surfaces may account for the peculiar localization of the hemorrhagic lesions described in our patient.

Our unique report of hemorrhagic lesions (vesicles and maculae) presenting in a DD patient treated with acitretin is rare. The first histologic specimen taken from a palmar pit revealed the characteristic histopathologic findings of DD and did not support the diagnosis of the hemorrhagic variant of DD. In the second biopsy, the absence of acantholysis and the poor content of dyskeratotic cells were evident, together with superficial hemorrhagic vesicles. Additionally, the appearance and the disappearance of the cutaneous manifestations were closely correlated with the beginning and suspension of the acitretin therapy, together with an improvement of typical lesions of DD during acitretin treatment. These occurrences indicated a strict causal relationship between treatment with the retinoid and the appearance of hemorrhagic lesions.

Conclusion

We report a rare case of palmoplantar hemorrhagic lesions induced by acitretin for treatment of DD. In our patient, the lesions could have been triggered by a combination of noxious effects of the drug and alterations in keratinocyte physiology due to DD. There is a need for clinicians to be aware of the possible side effects of acitretin and to inform their patients, particularly those presenting with DD, about the possibility of developing hemorrhagic lesions. The latter should be added to the list of potential dermatologic adverse effects of acitretin.

Darier-White disease (DD), also known as keratosis follicularis, is a rare skin disease that is inherited in an autosomal-dominant fashion. It was first described by both Darier¹ and White² more than 120 years ago. The incidence is 1 to 9 per 100,000 individuals, and onset usually occurs between 8 and 15 years of age. Classic DD is characterized by malodorous, brown, keratotic, warty papules arising mainly in seborrheic areas; palmoplantar pits; and nail dystrophy with typical worsening in summer. Unilateral and segmental variants of DD rarely have been described.^3,4

Few cases of hemorrhagic DD involving acral surfaces have been reported.^5-8 Most patients develop hemorrhagic bullae at the onset of the disease together with the other characteristic features of DD. The disease also can be associated with salivary gland obstruction, renal and testicular agenesis, bone cysts, and neuropsychiatric disorders.⁹ Diagnosis is confirmed by hyperkeratosis, papillomatosis, acantholysis, dyskeratosis (corps ronds and grains), and small fissures above the basal layer in the epidermis (suprabasal clefts) noted on biopsy of papular lesions. Darier-White disease is caused by a malfunctioning sarcoplasmic/endoplasmic reticulum calcium pump, SERCA2, encoded by the ATP2A2 (ATPase, Ca⁺⁺  transporting, cardiac muscle, slow twitch 2) gene, which transports calcium ions from the cytosol into the sarcoplasmic/endoplasmic reticulum, catalyzing the hydrolysis of adenosine triphosphate coupled with the transport of the calcium. Mutations in ATP2A2 have only been identified in up to 50% of reported DD patients.¹⁰

Treatment of localized DD usually includes emollients and topical retinoids, and systemic retinoids are recommended as the first-line treatment of diffuse DD.¹¹ Many dermatologic side effects of systemic retinoids have been reported, including frequent dry lips and cheilitis.¹² Other skin manifestations include scaling of the palms and soles, excoriations and erosions, alopecia, pruritus, nail fragility, and skin atrophy or fragility. Additionally, common nondermatologic side effects include hepatotoxicity, epistaxis, ophthalmologic effects (eg, loss of eyebrows or eyelashes, redness/swelling of the eyelid, redness of the eyes, sensitivity of the eyes to light, decreased night vision) pancreatitis, bipedal edema, and skeletal alterations.^13-15 We report the case of a patient with DD who developed hemorrhagic macules and vesicles in response to the administration of oral retinoids.

Case Report

An 84-year-old woman was admitted to our hospital for treatment of hyperkeratotic papules and plaques on the face, back, groin, submammary folds, and dorsum of the hands and feet that had been present since childhood and typically worsened during the summer. She previously had refused treatment and reported a poor social life due to the cutaneous manifestations of her disease.

Biopsy of a histologic specimen taken from a palmar pit revealed hyperkeratosis, loss of cohesion between suprabasal epidermal cells (acantholysis), and dyskeratotic cells (corps ronds and grains)(Figure 1). On the basis of both clinical and histologic findings, a diagnosis of DD was made. Genetic analysis did not reveal any mutations in the ATP2A2 gene, and a reduced epidermal expression of SERCA2b was demonstrated by immunochemistry.¹⁶ Treatment with the oral retinoid acitretin (25 mg daily) for 4 months led to almost complete resolution of the lesions. After 4 months, treatment was reduced to a maintenance dose of 12.5 mg once daily.

Figure 1. Histopathologic findings of a skin biopsy specimen obtained from a palmar pit before treatment indicated hyperkeratosis, acantholysis, and the presence of corps ronds and grains (H&E, original magnification ×200).

The patient returned monthly for follow-up to undergo clinical examination and routine laboratory tests (ie, complete blood cell counts, electrolyte panel, renal and hepatic tests, serum lipid levels, cholesterol level). After beginning the maintenance dose, she returned for follow-up every 2 months.

On follow-up 3 months after beginning the maintenance dose, the patient reported the onset of red and black punctiform macules and vesicles with jagged borders located on the palmoplantar surfaces and dorsal aspect of the fingers on both hands. Lesions were either isolated or confluent. The patient did not report pain or itching, though the skin was severely xerotic, especially on the hands and feet (Figures 2A and 2B). The patient reported no local trauma associated with the lesions, and blood counts and coagulation tests were within reference range. It also was noted that the cutaneous manifestations of DD showed a striking improvement. Histologic analysis of a skin biopsy taken from a hemorrhagic lesion on the palmar surface showed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, focal dyskeratosis, and hemorrhagic vesicles in the horny layer of the epidermis (Figure 3), leading to a diagnosis of DD.

After 12 months of therapy, the patient spontaneously stopped taking acitretin, and the hemorrhagic lesions spontaneously regressed within 2 weeks (Figures 2C and 2D). Unfortunately, the cutaneous manifestations of DD (eg, papular lesions) progressively reappeared in the previously reported sites. Based on this relapse, the patient was advised to restart treatment with acitretin (25 mg daily). In the follow-up visit 1 month after restarting acitretin, physical examination revealed the reappearance of hemorrhagic lesions on the palmoplantar surfaces and the dorsal aspect of the fingers.

Figure 2. Palmoplantar hemorrhagic vesicles and macules with diffuse xerosis and scaling were present 7 months after beginning acitretin therapy (A and B). Within 2 weeks of discontinuing acitretin, the hemorrhagic lesions spontaneously regressed (C and D).

Figure 3. Histopathologic analysis of a skin biopsy specimen obtained from a hemorrhagic lesion during treatment with acitretin revealed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, and subcorneal hemorrhagic vesicles (H&E, original magnification ×45).

Comment

We report the case of an 84-year-old woman who developed hemorrhagic lesions on the palmoplantar surfaces and dorsal aspect of the feet as a side effect of oral retinoids for treatment of DD. The first reported case of acral hemorrhagic lesions associated with DD was described 50 years ago in 4 patients with manifestations located mainly on the palms, soles, and dorsal fingers. Local trauma was identified as a triggering factor in the development of the vesicles; however, data regarding the temporal relationship between keratotic papules and hemorrhagic elements and treatment were not specified.⁵ Twenty-five years later, Coulson and Misch⁶ described a case of DD in which the hemorrhagic lesions were the first sign of the disease, but correlation with therapy was not reported. A case of retinoid-induced hemorrhagic DD was reported in a female who was treated with etretinate for approximately 10 years after the diagnosis of DD with good clinical response. After 10 years of therapy, she developed hemorrhagic bullae solely on the dorsal aspect of the hands without any direct association with local trauma, along with a small number of nonhemorrhagic bullae.¹⁷

In our patient, the onset of hemorrhagic vesicles and red maculae occurred primarily on the palmoplantar surfaces. The lesions were smaller than bullae and contained hemorrhagic elements. Of note, the skin lesions appeared as early as 7 months after the patient started acitretin therapy.

The development of hemorrhagic lesions on different body sites as a consequence of oral retinoid administration also has been reported in patients with psoriasis.¹⁵ Emerging evidence indicates that retinoic acid activates vascular endothelial growth factor gene transcription,¹⁸ and vascular endothelial growth factor can modify permeability of the endothelial cells. Based on these observations, we propose that DD is characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. This defect favors the formation of empty intraepidermal lacunae. An increase in endothelial permeability due to oral retinoid administration promotes the gathering of serum and red blood cells into the lacunae, leading to the onset of hemorrhagic blisters. Moreover, continued microtrauma to the palmoplantar surfaces may account for the peculiar localization of the hemorrhagic lesions described in our patient.

Our unique report of hemorrhagic lesions (vesicles and maculae) presenting in a DD patient treated with acitretin is rare. The first histologic specimen taken from a palmar pit revealed the characteristic histopathologic findings of DD and did not support the diagnosis of the hemorrhagic variant of DD. In the second biopsy, the absence of acantholysis and the poor content of dyskeratotic cells were evident, together with superficial hemorrhagic vesicles. Additionally, the appearance and the disappearance of the cutaneous manifestations were closely correlated with the beginning and suspension of the acitretin therapy, together with an improvement of typical lesions of DD during acitretin treatment. These occurrences indicated a strict causal relationship between treatment with the retinoid and the appearance of hemorrhagic lesions.

Conclusion

We report a rare case of palmoplantar hemorrhagic lesions induced by acitretin for treatment of DD. In our patient, the lesions could have been triggered by a combination of noxious effects of the drug and alterations in keratinocyte physiology due to DD. There is a need for clinicians to be aware of the possible side effects of acitretin and to inform their patients, particularly those presenting with DD, about the possibility of developing hemorrhagic lesions. The latter should be added to the list of potential dermatologic adverse effects of acitretin.

Darier-White disease (DD), also known as keratosis follicularis, is a rare skin disease that is inherited in an autosomal-dominant fashion. It was first described by both Darier¹ and White² more than 120 years ago. The incidence is 1 to 9 per 100,000 individuals, and onset usually occurs between 8 and 15 years of age. Classic DD is characterized by malodorous, brown, keratotic, warty papules arising mainly in seborrheic areas; palmoplantar pits; and nail dystrophy with typical worsening in summer. Unilateral and segmental variants of DD rarely have been described.^3,4

Few cases of hemorrhagic DD involving acral surfaces have been reported.^5-8 Most patients develop hemorrhagic bullae at the onset of the disease together with the other characteristic features of DD. The disease also can be associated with salivary gland obstruction, renal and testicular agenesis, bone cysts, and neuropsychiatric disorders.⁹ Diagnosis is confirmed by hyperkeratosis, papillomatosis, acantholysis, dyskeratosis (corps ronds and grains), and small fissures above the basal layer in the epidermis (suprabasal clefts) noted on biopsy of papular lesions. Darier-White disease is caused by a malfunctioning sarcoplasmic/endoplasmic reticulum calcium pump, SERCA2, encoded by the ATP2A2 (ATPase, Ca⁺⁺  transporting, cardiac muscle, slow twitch 2) gene, which transports calcium ions from the cytosol into the sarcoplasmic/endoplasmic reticulum, catalyzing the hydrolysis of adenosine triphosphate coupled with the transport of the calcium. Mutations in ATP2A2 have only been identified in up to 50% of reported DD patients.¹⁰

Treatment of localized DD usually includes emollients and topical retinoids, and systemic retinoids are recommended as the first-line treatment of diffuse DD.¹¹ Many dermatologic side effects of systemic retinoids have been reported, including frequent dry lips and cheilitis.¹² Other skin manifestations include scaling of the palms and soles, excoriations and erosions, alopecia, pruritus, nail fragility, and skin atrophy or fragility. Additionally, common nondermatologic side effects include hepatotoxicity, epistaxis, ophthalmologic effects (eg, loss of eyebrows or eyelashes, redness/swelling of the eyelid, redness of the eyes, sensitivity of the eyes to light, decreased night vision) pancreatitis, bipedal edema, and skeletal alterations.^13-15 We report the case of a patient with DD who developed hemorrhagic macules and vesicles in response to the administration of oral retinoids.

Case Report

An 84-year-old woman was admitted to our hospital for treatment of hyperkeratotic papules and plaques on the face, back, groin, submammary folds, and dorsum of the hands and feet that had been present since childhood and typically worsened during the summer. She previously had refused treatment and reported a poor social life due to the cutaneous manifestations of her disease.

Biopsy of a histologic specimen taken from a palmar pit revealed hyperkeratosis, loss of cohesion between suprabasal epidermal cells (acantholysis), and dyskeratotic cells (corps ronds and grains)(Figure 1). On the basis of both clinical and histologic findings, a diagnosis of DD was made. Genetic analysis did not reveal any mutations in the ATP2A2 gene, and a reduced epidermal expression of SERCA2b was demonstrated by immunochemistry.¹⁶ Treatment with the oral retinoid acitretin (25 mg daily) for 4 months led to almost complete resolution of the lesions. After 4 months, treatment was reduced to a maintenance dose of 12.5 mg once daily.

Figure 1. Histopathologic findings of a skin biopsy specimen obtained from a palmar pit before treatment indicated hyperkeratosis, acantholysis, and the presence of corps ronds and grains (H&E, original magnification ×200).

The patient returned monthly for follow-up to undergo clinical examination and routine laboratory tests (ie, complete blood cell counts, electrolyte panel, renal and hepatic tests, serum lipid levels, cholesterol level). After beginning the maintenance dose, she returned for follow-up every 2 months.

On follow-up 3 months after beginning the maintenance dose, the patient reported the onset of red and black punctiform macules and vesicles with jagged borders located on the palmoplantar surfaces and dorsal aspect of the fingers on both hands. Lesions were either isolated or confluent. The patient did not report pain or itching, though the skin was severely xerotic, especially on the hands and feet (Figures 2A and 2B). The patient reported no local trauma associated with the lesions, and blood counts and coagulation tests were within reference range. It also was noted that the cutaneous manifestations of DD showed a striking improvement. Histologic analysis of a skin biopsy taken from a hemorrhagic lesion on the palmar surface showed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, focal dyskeratosis, and hemorrhagic vesicles in the horny layer of the epidermis (Figure 3), leading to a diagnosis of DD.

After 12 months of therapy, the patient spontaneously stopped taking acitretin, and the hemorrhagic lesions spontaneously regressed within 2 weeks (Figures 2C and 2D). Unfortunately, the cutaneous manifestations of DD (eg, papular lesions) progressively reappeared in the previously reported sites. Based on this relapse, the patient was advised to restart treatment with acitretin (25 mg daily). In the follow-up visit 1 month after restarting acitretin, physical examination revealed the reappearance of hemorrhagic lesions on the palmoplantar surfaces and the dorsal aspect of the fingers.

Figure 2. Palmoplantar hemorrhagic vesicles and macules with diffuse xerosis and scaling were present 7 months after beginning acitretin therapy (A and B). Within 2 weeks of discontinuing acitretin, the hemorrhagic lesions spontaneously regressed (C and D).

Figure 3. Histopathologic analysis of a skin biopsy specimen obtained from a hemorrhagic lesion during treatment with acitretin revealed hyperkeratosis, acanthosis, papillomatosis, hypergranulosis, and subcorneal hemorrhagic vesicles (H&E, original magnification ×45).

Comment

We report the case of an 84-year-old woman who developed hemorrhagic lesions on the palmoplantar surfaces and dorsal aspect of the feet as a side effect of oral retinoids for treatment of DD. The first reported case of acral hemorrhagic lesions associated with DD was described 50 years ago in 4 patients with manifestations located mainly on the palms, soles, and dorsal fingers. Local trauma was identified as a triggering factor in the development of the vesicles; however, data regarding the temporal relationship between keratotic papules and hemorrhagic elements and treatment were not specified.⁵ Twenty-five years later, Coulson and Misch⁶ described a case of DD in which the hemorrhagic lesions were the first sign of the disease, but correlation with therapy was not reported. A case of retinoid-induced hemorrhagic DD was reported in a female who was treated with etretinate for approximately 10 years after the diagnosis of DD with good clinical response. After 10 years of therapy, she developed hemorrhagic bullae solely on the dorsal aspect of the hands without any direct association with local trauma, along with a small number of nonhemorrhagic bullae.¹⁷

In our patient, the onset of hemorrhagic vesicles and red maculae occurred primarily on the palmoplantar surfaces. The lesions were smaller than bullae and contained hemorrhagic elements. Of note, the skin lesions appeared as early as 7 months after the patient started acitretin therapy.

The development of hemorrhagic lesions on different body sites as a consequence of oral retinoid administration also has been reported in patients with psoriasis.¹⁵ Emerging evidence indicates that retinoic acid activates vascular endothelial growth factor gene transcription,¹⁸ and vascular endothelial growth factor can modify permeability of the endothelial cells. Based on these observations, we propose that DD is characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. This defect favors the formation of empty intraepidermal lacunae. An increase in endothelial permeability due to oral retinoid administration promotes the gathering of serum and red blood cells into the lacunae, leading to the onset of hemorrhagic blisters. Moreover, continued microtrauma to the palmoplantar surfaces may account for the peculiar localization of the hemorrhagic lesions described in our patient.

Our unique report of hemorrhagic lesions (vesicles and maculae) presenting in a DD patient treated with acitretin is rare. The first histologic specimen taken from a palmar pit revealed the characteristic histopathologic findings of DD and did not support the diagnosis of the hemorrhagic variant of DD. In the second biopsy, the absence of acantholysis and the poor content of dyskeratotic cells were evident, together with superficial hemorrhagic vesicles. Additionally, the appearance and the disappearance of the cutaneous manifestations were closely correlated with the beginning and suspension of the acitretin therapy, together with an improvement of typical lesions of DD during acitretin treatment. These occurrences indicated a strict causal relationship between treatment with the retinoid and the appearance of hemorrhagic lesions.

Conclusion

We report a rare case of palmoplantar hemorrhagic lesions induced by acitretin for treatment of DD. In our patient, the lesions could have been triggered by a combination of noxious effects of the drug and alterations in keratinocyte physiology due to DD. There is a need for clinicians to be aware of the possible side effects of acitretin and to inform their patients, particularly those presenting with DD, about the possibility of developing hemorrhagic lesions. The latter should be added to the list of potential dermatologic adverse effects of acitretin.

To the Editor:
A 62-year-old woman was referred to the dermatology clinic for papules on both eyelids of 6 months’ duration. She underwent surgery for a thyroid gland adenoma 3 years prior and subsequently experienced hypothyroidism. Levothyroxine sodium was administered daily (100 µg initially; 50 µg over the last 1.5 years). Papules occurred on both eyelids 6 months prior to presentation and gradually increased in number. The center of each papule was filled with a black keratinous plug. The skin lesions became raised after the patient ate fatty foods. The lesions remained entirely asymptomatic and there was no family history of a similar disorder.

Physical examinations showed no systemic abnormalities. Dermatologic examination showed clustered 3- to 4-mm flesh-colored papules on both upper eyelids; the centers of the papules were filled with 1- to 2-mm black keratinous plugs (Figure 1A). Several similar skin lesions existed on the lower eyelids, nasal root, and right side of the nasal dorsum. On laboratory examination, the results of routine blood, urine, and stool tests, as well as renal and hepatic functions, electrolytes, and blood sugar levels, were within reference range. Indicators including triglyceride of 2.50 mmol/L (reference range, 0.40–1.90 mmol/L), total cholesterol of 6.31 mmol/L (reference range, 3.00–5.70 mmol/L), serum total thyroxine (T₄) of 5.32 µg/dL (reference range, 6.09–12.23 µg/dL), total triiodothyronine (T₃) of 64 ng/dL (reference range, 87–178 ng/dL), serum free thyroxine (FT₄) of 0.41 ng/dL (reference range, 0.61–1.12 ng/dL), serum free triiodothyronine (FT₃) of 182 pg/dL (reference range, 250–390 pg/dL), and thyrotropin of 33.75 µIU/mL (reference range, 0.34–5.60 µIU/mL) were not within reference range; however, thyroperoxidase antibodies, thyrotropin receptor antibodies, thyroglobulin antibodies, thyroglobulin, and calcitonin were within reference range. Color ultrasonography indicated post–subtotal resection of the bilateral thyroid glands.

Figure 1. Clustered flesh-colored papules on both upper eyelids; the centers of the papules were filled with black keratinous plugs (A). Following treatment with levothyroxine sodium, most of the skin lesions had resolved (B).

Histopathologic analysis of the skin lesions showed that the epidermis became atrophic and thinner, and several atrophic and cyst-dilated follicular structures existed inside the dermis. Some structures opened through the epidermis; the walls were squamous epithelium and keratin filled the structures (Figure 2). The condition was diagnosed as nevus comedonicus (NC).

The patient was referred to the endocrinology department and treated with levothyroxine sodium (100 µg daily). At 5-month follow-up, the T₄, T₃, FT₄, FT₃, and thyrotropin levels were within reference range and most of the skin lesions had resolved (Figure 1B).

Nevus comedonicus is an unusual skin lesion with a predilection for the face, neck, shoulders, upper arms, and trunk. The clinical manifestations include comedonelike papules with centers that are characterized by large, black, solid keratinous plugs. When the plugs are peeled off, volcanic craterlike pits will be left. The skin lesions usually are ribbonlike and clustered on 1 side of the body. Pathologic examination often shows that the epidermis is pitted downward, and the dilated follicular ostia are plugged with keratin.^1,2 Paige and Mendelson³ divided NC into 2 types: inflammatory and noninflammatory. Approximately half of NC patients experience cysts, abscesses, fistulae, and scars.⁴

The exact etiology of NC is unclear. Some researchers believe that it is a congenital hair follicle deformity; more specifically, that it is caused by a developmental defect in the hair follicles in the embryonic stage (ie, abnormal differentiation of epithelial stem cells that differentiate into follicles). Most incidences of NC occur at birth or before growth and development. However, few studies have reported late-onset NC.⁵

Figure 2. Several atrophic and cyst-dilated follicular structures existed inside the dermis. Some of them opened through the epidermis and were filled with keratin (A and B)(both H&E, original magnifications ×4 and ×10).

The relationship between NC and thyroid disease is unique. Clinical research has shown that hypothyroidism can result in hair loss and cracks.⁶ In animal experiments, hypothyroidism model mice often experienced degenerative changes of their hair follicles and hair papillae as well as changes in the telogen phase, such as thinning of the outer and inner root sheaths.⁷ Meanwhile, decreased cell proliferation activity in the hair follicles was observed. Therefore, it is reasonable to conclude that thyroid hormones have regulatory effects on the growth and development of hair follicles.⁷

A study on human hair follicles found that thyroid hormone receptor β1 is expressed in human hair follicles.⁸ Research on in vitro–cultured human hair follicles showed that thyroid hormones T₃ and T₄ upregulated the proliferation of hair matrix cells and downregulated their apoptosis. Thyroid hormones also prolonged the duration of the hair growth phase (anagen).⁹ Furthermore, expression of thyrotropin receptor was detected in human hair follicles. Because increased serum thyrotropin levels can lead to clinical hair loss, thyrotropin may inhibit the growth of hair follicles via thyrotropin receptor.¹⁰ In our patient, NC occurred on both eyelids when the patient experienced hypothyroidism following thyroid gland adenoma surgery. Following treatment with levothyroxine sodium, the T₄, T₃, FT₄, FT₃, and thyrotropin levels were within reference range and most of the skin lesions resolved. Therefore, the occurrence of NC may be related to hypothyroidism in this patient. The low thyroid hormone levels and elevated thyrotropin level possibly induced degenerative changes and injuries to the hair matrix cells, resulting in hair follicle obstruction and accumulation of keratin, which ultimately led to NC. However, the exact relationship between NC and thyroid diseases requires elucidation in future studies.

To the Editor:
A 62-year-old woman was referred to the dermatology clinic for papules on both eyelids of 6 months’ duration. She underwent surgery for a thyroid gland adenoma 3 years prior and subsequently experienced hypothyroidism. Levothyroxine sodium was administered daily (100 µg initially; 50 µg over the last 1.5 years). Papules occurred on both eyelids 6 months prior to presentation and gradually increased in number. The center of each papule was filled with a black keratinous plug. The skin lesions became raised after the patient ate fatty foods. The lesions remained entirely asymptomatic and there was no family history of a similar disorder.

Physical examinations showed no systemic abnormalities. Dermatologic examination showed clustered 3- to 4-mm flesh-colored papules on both upper eyelids; the centers of the papules were filled with 1- to 2-mm black keratinous plugs (Figure 1A). Several similar skin lesions existed on the lower eyelids, nasal root, and right side of the nasal dorsum. On laboratory examination, the results of routine blood, urine, and stool tests, as well as renal and hepatic functions, electrolytes, and blood sugar levels, were within reference range. Indicators including triglyceride of 2.50 mmol/L (reference range, 0.40–1.90 mmol/L), total cholesterol of 6.31 mmol/L (reference range, 3.00–5.70 mmol/L), serum total thyroxine (T₄) of 5.32 µg/dL (reference range, 6.09–12.23 µg/dL), total triiodothyronine (T₃) of 64 ng/dL (reference range, 87–178 ng/dL), serum free thyroxine (FT₄) of 0.41 ng/dL (reference range, 0.61–1.12 ng/dL), serum free triiodothyronine (FT₃) of 182 pg/dL (reference range, 250–390 pg/dL), and thyrotropin of 33.75 µIU/mL (reference range, 0.34–5.60 µIU/mL) were not within reference range; however, thyroperoxidase antibodies, thyrotropin receptor antibodies, thyroglobulin antibodies, thyroglobulin, and calcitonin were within reference range. Color ultrasonography indicated post–subtotal resection of the bilateral thyroid glands.

Figure 1. Clustered flesh-colored papules on both upper eyelids; the centers of the papules were filled with black keratinous plugs (A). Following treatment with levothyroxine sodium, most of the skin lesions had resolved (B).

Histopathologic analysis of the skin lesions showed that the epidermis became atrophic and thinner, and several atrophic and cyst-dilated follicular structures existed inside the dermis. Some structures opened through the epidermis; the walls were squamous epithelium and keratin filled the structures (Figure 2). The condition was diagnosed as nevus comedonicus (NC).

The patient was referred to the endocrinology department and treated with levothyroxine sodium (100 µg daily). At 5-month follow-up, the T₄, T₃, FT₄, FT₃, and thyrotropin levels were within reference range and most of the skin lesions had resolved (Figure 1B).

Nevus comedonicus is an unusual skin lesion with a predilection for the face, neck, shoulders, upper arms, and trunk. The clinical manifestations include comedonelike papules with centers that are characterized by large, black, solid keratinous plugs. When the plugs are peeled off, volcanic craterlike pits will be left. The skin lesions usually are ribbonlike and clustered on 1 side of the body. Pathologic examination often shows that the epidermis is pitted downward, and the dilated follicular ostia are plugged with keratin.^1,2 Paige and Mendelson³ divided NC into 2 types: inflammatory and noninflammatory. Approximately half of NC patients experience cysts, abscesses, fistulae, and scars.⁴

The exact etiology of NC is unclear. Some researchers believe that it is a congenital hair follicle deformity; more specifically, that it is caused by a developmental defect in the hair follicles in the embryonic stage (ie, abnormal differentiation of epithelial stem cells that differentiate into follicles). Most incidences of NC occur at birth or before growth and development. However, few studies have reported late-onset NC.⁵

Figure 2. Several atrophic and cyst-dilated follicular structures existed inside the dermis. Some of them opened through the epidermis and were filled with keratin (A and B)(both H&E, original magnifications ×4 and ×10).

The relationship between NC and thyroid disease is unique. Clinical research has shown that hypothyroidism can result in hair loss and cracks.⁶ In animal experiments, hypothyroidism model mice often experienced degenerative changes of their hair follicles and hair papillae as well as changes in the telogen phase, such as thinning of the outer and inner root sheaths.⁷ Meanwhile, decreased cell proliferation activity in the hair follicles was observed. Therefore, it is reasonable to conclude that thyroid hormones have regulatory effects on the growth and development of hair follicles.⁷

A study on human hair follicles found that thyroid hormone receptor β1 is expressed in human hair follicles.⁸ Research on in vitro–cultured human hair follicles showed that thyroid hormones T₃ and T₄ upregulated the proliferation of hair matrix cells and downregulated their apoptosis. Thyroid hormones also prolonged the duration of the hair growth phase (anagen).⁹ Furthermore, expression of thyrotropin receptor was detected in human hair follicles. Because increased serum thyrotropin levels can lead to clinical hair loss, thyrotropin may inhibit the growth of hair follicles via thyrotropin receptor.¹⁰ In our patient, NC occurred on both eyelids when the patient experienced hypothyroidism following thyroid gland adenoma surgery. Following treatment with levothyroxine sodium, the T₄, T₃, FT₄, FT₃, and thyrotropin levels were within reference range and most of the skin lesions resolved. Therefore, the occurrence of NC may be related to hypothyroidism in this patient. The low thyroid hormone levels and elevated thyrotropin level possibly induced degenerative changes and injuries to the hair matrix cells, resulting in hair follicle obstruction and accumulation of keratin, which ultimately led to NC. However, the exact relationship between NC and thyroid diseases requires elucidation in future studies.

To the Editor:
A 62-year-old woman was referred to the dermatology clinic for papules on both eyelids of 6 months’ duration. She underwent surgery for a thyroid gland adenoma 3 years prior and subsequently experienced hypothyroidism. Levothyroxine sodium was administered daily (100 µg initially; 50 µg over the last 1.5 years). Papules occurred on both eyelids 6 months prior to presentation and gradually increased in number. The center of each papule was filled with a black keratinous plug. The skin lesions became raised after the patient ate fatty foods. The lesions remained entirely asymptomatic and there was no family history of a similar disorder.

Physical examinations showed no systemic abnormalities. Dermatologic examination showed clustered 3- to 4-mm flesh-colored papules on both upper eyelids; the centers of the papules were filled with 1- to 2-mm black keratinous plugs (Figure 1A). Several similar skin lesions existed on the lower eyelids, nasal root, and right side of the nasal dorsum. On laboratory examination, the results of routine blood, urine, and stool tests, as well as renal and hepatic functions, electrolytes, and blood sugar levels, were within reference range. Indicators including triglyceride of 2.50 mmol/L (reference range, 0.40–1.90 mmol/L), total cholesterol of 6.31 mmol/L (reference range, 3.00–5.70 mmol/L), serum total thyroxine (T₄) of 5.32 µg/dL (reference range, 6.09–12.23 µg/dL), total triiodothyronine (T₃) of 64 ng/dL (reference range, 87–178 ng/dL), serum free thyroxine (FT₄) of 0.41 ng/dL (reference range, 0.61–1.12 ng/dL), serum free triiodothyronine (FT₃) of 182 pg/dL (reference range, 250–390 pg/dL), and thyrotropin of 33.75 µIU/mL (reference range, 0.34–5.60 µIU/mL) were not within reference range; however, thyroperoxidase antibodies, thyrotropin receptor antibodies, thyroglobulin antibodies, thyroglobulin, and calcitonin were within reference range. Color ultrasonography indicated post–subtotal resection of the bilateral thyroid glands.

Figure 1. Clustered flesh-colored papules on both upper eyelids; the centers of the papules were filled with black keratinous plugs (A). Following treatment with levothyroxine sodium, most of the skin lesions had resolved (B).

Histopathologic analysis of the skin lesions showed that the epidermis became atrophic and thinner, and several atrophic and cyst-dilated follicular structures existed inside the dermis. Some structures opened through the epidermis; the walls were squamous epithelium and keratin filled the structures (Figure 2). The condition was diagnosed as nevus comedonicus (NC).

The patient was referred to the endocrinology department and treated with levothyroxine sodium (100 µg daily). At 5-month follow-up, the T₄, T₃, FT₄, FT₃, and thyrotropin levels were within reference range and most of the skin lesions had resolved (Figure 1B).

Nevus comedonicus is an unusual skin lesion with a predilection for the face, neck, shoulders, upper arms, and trunk. The clinical manifestations include comedonelike papules with centers that are characterized by large, black, solid keratinous plugs. When the plugs are peeled off, volcanic craterlike pits will be left. The skin lesions usually are ribbonlike and clustered on 1 side of the body. Pathologic examination often shows that the epidermis is pitted downward, and the dilated follicular ostia are plugged with keratin.^1,2 Paige and Mendelson³ divided NC into 2 types: inflammatory and noninflammatory. Approximately half of NC patients experience cysts, abscesses, fistulae, and scars.⁴

The exact etiology of NC is unclear. Some researchers believe that it is a congenital hair follicle deformity; more specifically, that it is caused by a developmental defect in the hair follicles in the embryonic stage (ie, abnormal differentiation of epithelial stem cells that differentiate into follicles). Most incidences of NC occur at birth or before growth and development. However, few studies have reported late-onset NC.⁵

Figure 2. Several atrophic and cyst-dilated follicular structures existed inside the dermis. Some of them opened through the epidermis and were filled with keratin (A and B)(both H&E, original magnifications ×4 and ×10).

The relationship between NC and thyroid disease is unique. Clinical research has shown that hypothyroidism can result in hair loss and cracks.⁶ In animal experiments, hypothyroidism model mice often experienced degenerative changes of their hair follicles and hair papillae as well as changes in the telogen phase, such as thinning of the outer and inner root sheaths.⁷ Meanwhile, decreased cell proliferation activity in the hair follicles was observed. Therefore, it is reasonable to conclude that thyroid hormones have regulatory effects on the growth and development of hair follicles.⁷

A study on human hair follicles found that thyroid hormone receptor β1 is expressed in human hair follicles.⁸ Research on in vitro–cultured human hair follicles showed that thyroid hormones T₃ and T₄ upregulated the proliferation of hair matrix cells and downregulated their apoptosis. Thyroid hormones also prolonged the duration of the hair growth phase (anagen).⁹ Furthermore, expression of thyrotropin receptor was detected in human hair follicles. Because increased serum thyrotropin levels can lead to clinical hair loss, thyrotropin may inhibit the growth of hair follicles via thyrotropin receptor.¹⁰ In our patient, NC occurred on both eyelids when the patient experienced hypothyroidism following thyroid gland adenoma surgery. Following treatment with levothyroxine sodium, the T₄, T₃, FT₄, FT₃, and thyrotropin levels were within reference range and most of the skin lesions resolved. Therefore, the occurrence of NC may be related to hypothyroidism in this patient. The low thyroid hormone levels and elevated thyrotropin level possibly induced degenerative changes and injuries to the hair matrix cells, resulting in hair follicle obstruction and accumulation of keratin, which ultimately led to NC. However, the exact relationship between NC and thyroid diseases requires elucidation in future studies.

The Diagnosis: Madelung Disease (Benign Symmetric Lipomatosis)

A 56-year-old man presented for evaluation of massive subcutaneous nodules the bilateral upper arms, shoulders, chest, abdomen, and lateral aspect of the proximal thighs (Figures 1 and 2) that developed over the last 12 to 18 months and continued to enlarge. In addition, he was beginning to develop symptoms of neuropathy of the bilateral hands. The patient had a long-standing history of alcohol abuse. Biopsies performed by the patient’s primary care physician revealed benign adipose tissue. He was referred to the dermatology clinic and subsequently diagnosed with Madelung disease.

Figure 1. Extensive symmetric fat deposits on the bilateral upper arms, shoulders, chest, and abdomen.

Figure 2. Masses of adipose tissue on the lateral aspect of the proximal thighs and abdomen.

Madelung disease, also known as benign symmetric lipomatosis and Launois-Bensaude syndrome, is characterized by multiple large masses of nonencapsulated adipose tissue. These masses are symmetric and most prominent on the head, neck, trunk, and proximal extremities. Classically, a pseudoathletic appearance is described. Madelung disease most frequently affects men aged 30 to 60 years. In more than 90% of cases, it is associated with alcoholism.

In general, the masses of adipose tissue are asymptomatic. However, airway compression and dysphagia requiring surgical intervention has been reported in the otolaryngology literature.¹ In addition, neuropathy develops in 84% of cases.² Nerve biopsies from patients with Madelung disease have revealed a pattern of axonopathy that is distinct from alcohol-induced neuropathy.³ This neuropathy can involve sensory and motor nerves, with the most prominent findings being muscle weakness, tendon areflexia, interosseous muscle atrophy, vibratory sensation loss, and hypoesthesia. Furthermore, dysfunction of the autonomic nervous system can lead to segmental hyperhidrosis, gustatory sweating, and abnormal autonomic cardiovascular reflexes.² Many patients who develop neuropathy will eventually become incapacitated.

The etiology of Madelung disease is not fully understood. There are several theories on the pathogenesis of this disease, most describing metabolic disturbances induced by alcohol. Specifically, studies have revealed chronic alcohol use causes numerous deletions in mitochondrial DNA.^4,5 The mitochondrial DNA damage may explain both the resistance of the lipomatous masses to lipolysis and the nerve-related changes. Comparisons between human immunodeficiency virus/highly active antiretroviral therapy–associated lipodystrophy and Madelung disease lend credence to the metabolic disturbance theory and may help clarify the specific mechanisms involved.⁶

There have been no cases of spontaneous resolution, even in patients who stop consuming alcohol. For this reason, most patients are referred to a surgeon. Many surgeons prefer open excision for debulking large lipomatous masses, but this technique typically requires general anesthesia. For those in whom this treatment is not an appropriate option, liposuction can be considered with tumescent anesthesia.⁷ A combination of these surgical modalities also is an option.

Madelung disease is a distinctive disorder typically affecting chronic alcoholics. Recognition of this clinical entity is important, as severe neuropathy and airway compromise may ensue. Although surgical excision is an attractive option for cosmesis and airway compromise, the associated neuropathy can be extremely difficult to treat and can be quite debilitating.

The Diagnosis: Madelung Disease (Benign Symmetric Lipomatosis)

A 56-year-old man presented for evaluation of massive subcutaneous nodules the bilateral upper arms, shoulders, chest, abdomen, and lateral aspect of the proximal thighs (Figures 1 and 2) that developed over the last 12 to 18 months and continued to enlarge. In addition, he was beginning to develop symptoms of neuropathy of the bilateral hands. The patient had a long-standing history of alcohol abuse. Biopsies performed by the patient’s primary care physician revealed benign adipose tissue. He was referred to the dermatology clinic and subsequently diagnosed with Madelung disease.

Figure 1. Extensive symmetric fat deposits on the bilateral upper arms, shoulders, chest, and abdomen.

Figure 2. Masses of adipose tissue on the lateral aspect of the proximal thighs and abdomen.

Madelung disease, also known as benign symmetric lipomatosis and Launois-Bensaude syndrome, is characterized by multiple large masses of nonencapsulated adipose tissue. These masses are symmetric and most prominent on the head, neck, trunk, and proximal extremities. Classically, a pseudoathletic appearance is described. Madelung disease most frequently affects men aged 30 to 60 years. In more than 90% of cases, it is associated with alcoholism.

In general, the masses of adipose tissue are asymptomatic. However, airway compression and dysphagia requiring surgical intervention has been reported in the otolaryngology literature.¹ In addition, neuropathy develops in 84% of cases.² Nerve biopsies from patients with Madelung disease have revealed a pattern of axonopathy that is distinct from alcohol-induced neuropathy.³ This neuropathy can involve sensory and motor nerves, with the most prominent findings being muscle weakness, tendon areflexia, interosseous muscle atrophy, vibratory sensation loss, and hypoesthesia. Furthermore, dysfunction of the autonomic nervous system can lead to segmental hyperhidrosis, gustatory sweating, and abnormal autonomic cardiovascular reflexes.² Many patients who develop neuropathy will eventually become incapacitated.

The etiology of Madelung disease is not fully understood. There are several theories on the pathogenesis of this disease, most describing metabolic disturbances induced by alcohol. Specifically, studies have revealed chronic alcohol use causes numerous deletions in mitochondrial DNA.^4,5 The mitochondrial DNA damage may explain both the resistance of the lipomatous masses to lipolysis and the nerve-related changes. Comparisons between human immunodeficiency virus/highly active antiretroviral therapy–associated lipodystrophy and Madelung disease lend credence to the metabolic disturbance theory and may help clarify the specific mechanisms involved.⁶

There have been no cases of spontaneous resolution, even in patients who stop consuming alcohol. For this reason, most patients are referred to a surgeon. Many surgeons prefer open excision for debulking large lipomatous masses, but this technique typically requires general anesthesia. For those in whom this treatment is not an appropriate option, liposuction can be considered with tumescent anesthesia.⁷ A combination of these surgical modalities also is an option.

Madelung disease is a distinctive disorder typically affecting chronic alcoholics. Recognition of this clinical entity is important, as severe neuropathy and airway compromise may ensue. Although surgical excision is an attractive option for cosmesis and airway compromise, the associated neuropathy can be extremely difficult to treat and can be quite debilitating.

The Diagnosis: Madelung Disease (Benign Symmetric Lipomatosis)

A 56-year-old man presented for evaluation of massive subcutaneous nodules the bilateral upper arms, shoulders, chest, abdomen, and lateral aspect of the proximal thighs (Figures 1 and 2) that developed over the last 12 to 18 months and continued to enlarge. In addition, he was beginning to develop symptoms of neuropathy of the bilateral hands. The patient had a long-standing history of alcohol abuse. Biopsies performed by the patient’s primary care physician revealed benign adipose tissue. He was referred to the dermatology clinic and subsequently diagnosed with Madelung disease.

Figure 1. Extensive symmetric fat deposits on the bilateral upper arms, shoulders, chest, and abdomen.

Figure 2. Masses of adipose tissue on the lateral aspect of the proximal thighs and abdomen.

Madelung disease, also known as benign symmetric lipomatosis and Launois-Bensaude syndrome, is characterized by multiple large masses of nonencapsulated adipose tissue. These masses are symmetric and most prominent on the head, neck, trunk, and proximal extremities. Classically, a pseudoathletic appearance is described. Madelung disease most frequently affects men aged 30 to 60 years. In more than 90% of cases, it is associated with alcoholism.

In general, the masses of adipose tissue are asymptomatic. However, airway compression and dysphagia requiring surgical intervention has been reported in the otolaryngology literature.¹ In addition, neuropathy develops in 84% of cases.² Nerve biopsies from patients with Madelung disease have revealed a pattern of axonopathy that is distinct from alcohol-induced neuropathy.³ This neuropathy can involve sensory and motor nerves, with the most prominent findings being muscle weakness, tendon areflexia, interosseous muscle atrophy, vibratory sensation loss, and hypoesthesia. Furthermore, dysfunction of the autonomic nervous system can lead to segmental hyperhidrosis, gustatory sweating, and abnormal autonomic cardiovascular reflexes.² Many patients who develop neuropathy will eventually become incapacitated.

The etiology of Madelung disease is not fully understood. There are several theories on the pathogenesis of this disease, most describing metabolic disturbances induced by alcohol. Specifically, studies have revealed chronic alcohol use causes numerous deletions in mitochondrial DNA.^4,5 The mitochondrial DNA damage may explain both the resistance of the lipomatous masses to lipolysis and the nerve-related changes. Comparisons between human immunodeficiency virus/highly active antiretroviral therapy–associated lipodystrophy and Madelung disease lend credence to the metabolic disturbance theory and may help clarify the specific mechanisms involved.⁶

There have been no cases of spontaneous resolution, even in patients who stop consuming alcohol. For this reason, most patients are referred to a surgeon. Many surgeons prefer open excision for debulking large lipomatous masses, but this technique typically requires general anesthesia. For those in whom this treatment is not an appropriate option, liposuction can be considered with tumescent anesthesia.⁷ A combination of these surgical modalities also is an option.

Madelung disease is a distinctive disorder typically affecting chronic alcoholics. Recognition of this clinical entity is important, as severe neuropathy and airway compromise may ensue. Although surgical excision is an attractive option for cosmesis and airway compromise, the associated neuropathy can be extremely difficult to treat and can be quite debilitating.

Communicating expectations to patients at their first visit and at follow-up is an important aspect of managing your dermatology practice. Dr. Gary Goldenberg discusses patient expectations for clinical conditions such as acne or psoriasis and for cosmetic treatments. He also advises what to do if you encounter a patient with unreasonable expectations.

Communicating expectations to patients at their first visit and at follow-up is an important aspect of managing your dermatology practice. Dr. Gary Goldenberg discusses patient expectations for clinical conditions such as acne or psoriasis and for cosmetic treatments. He also advises what to do if you encounter a patient with unreasonable expectations.

Communicating expectations to patients at their first visit and at follow-up is an important aspect of managing your dermatology practice. Dr. Gary Goldenberg discusses patient expectations for clinical conditions such as acne or psoriasis and for cosmetic treatments. He also advises what to do if you encounter a patient with unreasonable expectations.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top facial scrubs. Consideration must be given to:

• Facial Fuel Energizing Scrub
  Kiehl’s
  “This product isn’t terribly expensive and is great for men with all skin types. Patients love the mild stinging the product produces—that’s how they know it’s working!”—Gary Goldenberg, MD, New York, New York
  “It is great for women and men. It has menthol and caffeine that gives a refreshing feel to the skin and great exfoliating without excessive irritation.”—Anthony M. Rossi, MD, New York, New York

• NIA24 Physical Cleansing Scrub
  Niadyne, Inc.
  “It offers a beaded but gentle approach to a facial scrub and is highly rated by our patients and customers.”—Joel Schlessinger, MD, Omaha, Nebraska

• Olay Skin Smoothing Cream Scrub
  Proctor & Gamble
  “Effective, not expensive, and does not dry the skin.”—Antonella Tosti, MD, Miami, Florida
  “This product is inexpensive and great before applying moisturizer or after wearing makeup.”—Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Mineral makeup and eyelash enhancers will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top facial scrubs. Consideration must be given to:

• Facial Fuel Energizing Scrub
  Kiehl’s
  “This product isn’t terribly expensive and is great for men with all skin types. Patients love the mild stinging the product produces—that’s how they know it’s working!”—Gary Goldenberg, MD, New York, New York
  “It is great for women and men. It has menthol and caffeine that gives a refreshing feel to the skin and great exfoliating without excessive irritation.”—Anthony M. Rossi, MD, New York, New York

• NIA24 Physical Cleansing Scrub
  Niadyne, Inc.
  “It offers a beaded but gentle approach to a facial scrub and is highly rated by our patients and customers.”—Joel Schlessinger, MD, Omaha, Nebraska

• Olay Skin Smoothing Cream Scrub
  Proctor & Gamble
  “Effective, not expensive, and does not dry the skin.”—Antonella Tosti, MD, Miami, Florida
  “This product is inexpensive and great before applying moisturizer or after wearing makeup.”—Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Mineral makeup and eyelash enhancers will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top facial scrubs. Consideration must be given to:

• Facial Fuel Energizing Scrub
  Kiehl’s
  “This product isn’t terribly expensive and is great for men with all skin types. Patients love the mild stinging the product produces—that’s how they know it’s working!”—Gary Goldenberg, MD, New York, New York
  “It is great for women and men. It has menthol and caffeine that gives a refreshing feel to the skin and great exfoliating without excessive irritation.”—Anthony M. Rossi, MD, New York, New York

• NIA24 Physical Cleansing Scrub
  Niadyne, Inc.
  “It offers a beaded but gentle approach to a facial scrub and is highly rated by our patients and customers.”—Joel Schlessinger, MD, Omaha, Nebraska

• Olay Skin Smoothing Cream Scrub
  Proctor & Gamble
  “Effective, not expensive, and does not dry the skin.”—Antonella Tosti, MD, Miami, Florida
  “This product is inexpensive and great before applying moisturizer or after wearing makeup.”—Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Mineral makeup and eyelash enhancers will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.