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THE DIAGNOSIS: Pembrolizumab-Induced Eruptive Squamous Proliferation

Histopathology showed a broad squamous proliferation with acanthosis of the epidermis. Large glassy keratinocytes were seen with scattered necrotic keratinocytes (Figure), and a dense lichenoid band of inflammation was present subjacent to the proliferation. Notably, no hypergranulosis, remarkable keratinocyte atypia, or increased mitotic figures were seen. Based on the patient’s medical history and biopsy results, a diagnosis of pembrolizumab-induced eruptive squamous proliferation was made. The diagnosis was supported by a growing body of evidence of this type of reaction in patients taking programmed death 1 (PD-1) inhibitors.^1,2 Conservative treatment with clobetasol ointment 0.05% was initiated with complete resolution of the lesions at the 2-month follow-up appointment. Other common treatments include topical steroids, injected corticosteroids, or cryosurgery to locally control the inflammation and atypical proliferation of cells.³

Pembrolizumab is a humanized IgG4 monoclonal antibody targeting the PD-1 receptor that has been utilized for its antitumor activity against various cancers, including unresectable and metastatic melanoma, head and neck cancers, and non–small cell lung cancer (NSCLC).^1,4,5 While this drug has extended the lives of many patients with cancer, there are adverse reactions associated with PD-1 inhibitors (eg, pembrolizumab, nivolumab). Skin toxicity to PD-1 inhibitors is the one of most common immune-mediated reactions worldwide, occurring in approximately 30% of patients.^6,7 Reactions can occur while a patient is taking the inciting drug and can continue up to 2 months after treatment discontinuation.⁸ Skin reactions associated with PD-1 inhibitors vary from lichenoid reactions and vitiligolike patches to psoriasis or eczema flares and are organized into 4 categories: inflammatory, immunobullous, alteration of keratinocytes, and alteration of melanocytes.⁹ Our patient demonstrated alteration of keratinocytes, which is characterized by overlapping features of hypertrophic lichen planus and early keratoacanthoma.

The differential diagnoses for pembrolizumab-induced eruptive squamous proliferation include squamous cell carcinoma (SCC), psoriasis, hypertrophic lichen planus, and cutaneous metastasis of NSCLC. Hypertrophic lupus erythematosus also is a well-documented reaction to use of immune-checkpoint inhibitors.¹⁰ Direct immunofluorescence could have helped differentiate hypertrophic lupus erythematosus from an eruptive squamous proliferation in our patient; however, due to her response to treatment, no additional workup was done.

Squamous cell carcinoma, which is the most common type of skin cancer in Black patients in the United States,¹¹ has been shown to manifest after a PD-1 inhibitor is taken.¹² Although it typically has a more chronic persistent course, the clinical appearance of SCC can be similar to the findings seen in our patient. Histologically, SCC may demonstrate necrosis, but the atypical proliferations will invade the dermis—a feature not seen in our patient’s histopathology.¹³

Lichen planus (LP) is an eruptive immune reaction of violaceous polygonal papules and plaques commonly seen on the ankles¹⁴ that has been shown to be an adverse effect of pembrolizumab.¹⁵ There are several subtypes of LP including hypertrophic versions, which can appear clinically similar to the findings seen in our patient. On dermoscopy, the classic finding of white lines, known as Wickham striae, is seen in all subtypes and can help diagnose this pathologic process. Under the microscope, LP can manifest with hyperkeratosis without parakeratosis, irregular thickening of the stratum granulosum, sawtooth rete ridges, and destruction of the basal layer.¹⁴

Psoriasis also has been shown to be exacerbated by anti–PD-1 therapy, although the majority of patients diagnosed with PD-1–induced psoriasis have a personal or family history of the disease.⁶ Clinically, psoriasis can have a hyperpigmented or violaceous appearance in patients with skin of color.¹⁶ The histopathology of psoriasis typically reveals confluent parakeratosis, neutrophils in the stratum corneum, regular acanthosis, thinning of the suprapapillary plates, and vessels in the dermal papillae.¹⁷

Although cutaneous metastasis of NSCLC may appear clinically similar to the current case, it is one of the rarer organ sites of metastasis for lung cancer.¹⁸ In our patient, biopsy quickly ruled out this diagnosis. If it had been a site of metastasis, histopathology would have shown a dermal-based proliferation of dysplastic cells without epidermal connection.¹⁹

It is important for dermatologists to recognize eruptive squamous proliferations associated with pembrolizumab, as they often respond to conservative treatment and typically do not require dose reduction or discontinuation of the inciting drug.

THE DIAGNOSIS: Pembrolizumab-Induced Eruptive Squamous Proliferation

Histopathology showed a broad squamous proliferation with acanthosis of the epidermis. Large glassy keratinocytes were seen with scattered necrotic keratinocytes (Figure), and a dense lichenoid band of inflammation was present subjacent to the proliferation. Notably, no hypergranulosis, remarkable keratinocyte atypia, or increased mitotic figures were seen. Based on the patient’s medical history and biopsy results, a diagnosis of pembrolizumab-induced eruptive squamous proliferation was made. The diagnosis was supported by a growing body of evidence of this type of reaction in patients taking programmed death 1 (PD-1) inhibitors.^1,2 Conservative treatment with clobetasol ointment 0.05% was initiated with complete resolution of the lesions at the 2-month follow-up appointment. Other common treatments include topical steroids, injected corticosteroids, or cryosurgery to locally control the inflammation and atypical proliferation of cells.³

Pembrolizumab is a humanized IgG4 monoclonal antibody targeting the PD-1 receptor that has been utilized for its antitumor activity against various cancers, including unresectable and metastatic melanoma, head and neck cancers, and non–small cell lung cancer (NSCLC).^1,4,5 While this drug has extended the lives of many patients with cancer, there are adverse reactions associated with PD-1 inhibitors (eg, pembrolizumab, nivolumab). Skin toxicity to PD-1 inhibitors is the one of most common immune-mediated reactions worldwide, occurring in approximately 30% of patients.^6,7 Reactions can occur while a patient is taking the inciting drug and can continue up to 2 months after treatment discontinuation.⁸ Skin reactions associated with PD-1 inhibitors vary from lichenoid reactions and vitiligolike patches to psoriasis or eczema flares and are organized into 4 categories: inflammatory, immunobullous, alteration of keratinocytes, and alteration of melanocytes.⁹ Our patient demonstrated alteration of keratinocytes, which is characterized by overlapping features of hypertrophic lichen planus and early keratoacanthoma.

The differential diagnoses for pembrolizumab-induced eruptive squamous proliferation include squamous cell carcinoma (SCC), psoriasis, hypertrophic lichen planus, and cutaneous metastasis of NSCLC. Hypertrophic lupus erythematosus also is a well-documented reaction to use of immune-checkpoint inhibitors.¹⁰ Direct immunofluorescence could have helped differentiate hypertrophic lupus erythematosus from an eruptive squamous proliferation in our patient; however, due to her response to treatment, no additional workup was done.

Squamous cell carcinoma, which is the most common type of skin cancer in Black patients in the United States,¹¹ has been shown to manifest after a PD-1 inhibitor is taken.¹² Although it typically has a more chronic persistent course, the clinical appearance of SCC can be similar to the findings seen in our patient. Histologically, SCC may demonstrate necrosis, but the atypical proliferations will invade the dermis—a feature not seen in our patient’s histopathology.¹³

Lichen planus (LP) is an eruptive immune reaction of violaceous polygonal papules and plaques commonly seen on the ankles¹⁴ that has been shown to be an adverse effect of pembrolizumab.¹⁵ There are several subtypes of LP including hypertrophic versions, which can appear clinically similar to the findings seen in our patient. On dermoscopy, the classic finding of white lines, known as Wickham striae, is seen in all subtypes and can help diagnose this pathologic process. Under the microscope, LP can manifest with hyperkeratosis without parakeratosis, irregular thickening of the stratum granulosum, sawtooth rete ridges, and destruction of the basal layer.¹⁴

Psoriasis also has been shown to be exacerbated by anti–PD-1 therapy, although the majority of patients diagnosed with PD-1–induced psoriasis have a personal or family history of the disease.⁶ Clinically, psoriasis can have a hyperpigmented or violaceous appearance in patients with skin of color.¹⁶ The histopathology of psoriasis typically reveals confluent parakeratosis, neutrophils in the stratum corneum, regular acanthosis, thinning of the suprapapillary plates, and vessels in the dermal papillae.¹⁷

Although cutaneous metastasis of NSCLC may appear clinically similar to the current case, it is one of the rarer organ sites of metastasis for lung cancer.¹⁸ In our patient, biopsy quickly ruled out this diagnosis. If it had been a site of metastasis, histopathology would have shown a dermal-based proliferation of dysplastic cells without epidermal connection.¹⁹

It is important for dermatologists to recognize eruptive squamous proliferations associated with pembrolizumab, as they often respond to conservative treatment and typically do not require dose reduction or discontinuation of the inciting drug.

THE DIAGNOSIS: Pembrolizumab-Induced Eruptive Squamous Proliferation

Histopathology showed a broad squamous proliferation with acanthosis of the epidermis. Large glassy keratinocytes were seen with scattered necrotic keratinocytes (Figure), and a dense lichenoid band of inflammation was present subjacent to the proliferation. Notably, no hypergranulosis, remarkable keratinocyte atypia, or increased mitotic figures were seen. Based on the patient’s medical history and biopsy results, a diagnosis of pembrolizumab-induced eruptive squamous proliferation was made. The diagnosis was supported by a growing body of evidence of this type of reaction in patients taking programmed death 1 (PD-1) inhibitors.^1,2 Conservative treatment with clobetasol ointment 0.05% was initiated with complete resolution of the lesions at the 2-month follow-up appointment. Other common treatments include topical steroids, injected corticosteroids, or cryosurgery to locally control the inflammation and atypical proliferation of cells.³

Pembrolizumab is a humanized IgG4 monoclonal antibody targeting the PD-1 receptor that has been utilized for its antitumor activity against various cancers, including unresectable and metastatic melanoma, head and neck cancers, and non–small cell lung cancer (NSCLC).^1,4,5 While this drug has extended the lives of many patients with cancer, there are adverse reactions associated with PD-1 inhibitors (eg, pembrolizumab, nivolumab). Skin toxicity to PD-1 inhibitors is the one of most common immune-mediated reactions worldwide, occurring in approximately 30% of patients.^6,7 Reactions can occur while a patient is taking the inciting drug and can continue up to 2 months after treatment discontinuation.⁸ Skin reactions associated with PD-1 inhibitors vary from lichenoid reactions and vitiligolike patches to psoriasis or eczema flares and are organized into 4 categories: inflammatory, immunobullous, alteration of keratinocytes, and alteration of melanocytes.⁹ Our patient demonstrated alteration of keratinocytes, which is characterized by overlapping features of hypertrophic lichen planus and early keratoacanthoma.

The differential diagnoses for pembrolizumab-induced eruptive squamous proliferation include squamous cell carcinoma (SCC), psoriasis, hypertrophic lichen planus, and cutaneous metastasis of NSCLC. Hypertrophic lupus erythematosus also is a well-documented reaction to use of immune-checkpoint inhibitors.¹⁰ Direct immunofluorescence could have helped differentiate hypertrophic lupus erythematosus from an eruptive squamous proliferation in our patient; however, due to her response to treatment, no additional workup was done.

Squamous cell carcinoma, which is the most common type of skin cancer in Black patients in the United States,¹¹ has been shown to manifest after a PD-1 inhibitor is taken.¹² Although it typically has a more chronic persistent course, the clinical appearance of SCC can be similar to the findings seen in our patient. Histologically, SCC may demonstrate necrosis, but the atypical proliferations will invade the dermis—a feature not seen in our patient’s histopathology.¹³

Lichen planus (LP) is an eruptive immune reaction of violaceous polygonal papules and plaques commonly seen on the ankles¹⁴ that has been shown to be an adverse effect of pembrolizumab.¹⁵ There are several subtypes of LP including hypertrophic versions, which can appear clinically similar to the findings seen in our patient. On dermoscopy, the classic finding of white lines, known as Wickham striae, is seen in all subtypes and can help diagnose this pathologic process. Under the microscope, LP can manifest with hyperkeratosis without parakeratosis, irregular thickening of the stratum granulosum, sawtooth rete ridges, and destruction of the basal layer.¹⁴

Psoriasis also has been shown to be exacerbated by anti–PD-1 therapy, although the majority of patients diagnosed with PD-1–induced psoriasis have a personal or family history of the disease.⁶ Clinically, psoriasis can have a hyperpigmented or violaceous appearance in patients with skin of color.¹⁶ The histopathology of psoriasis typically reveals confluent parakeratosis, neutrophils in the stratum corneum, regular acanthosis, thinning of the suprapapillary plates, and vessels in the dermal papillae.¹⁷

Although cutaneous metastasis of NSCLC may appear clinically similar to the current case, it is one of the rarer organ sites of metastasis for lung cancer.¹⁸ In our patient, biopsy quickly ruled out this diagnosis. If it had been a site of metastasis, histopathology would have shown a dermal-based proliferation of dysplastic cells without epidermal connection.¹⁹

It is important for dermatologists to recognize eruptive squamous proliferations associated with pembrolizumab, as they often respond to conservative treatment and typically do not require dose reduction or discontinuation of the inciting drug.

THE DIAGNOSIS: Borderline-Borderline Leprosy With Type 1 Lepra Reaction

Punch biopsies from plaques on the right elbow and right shin revealed diffuse granulomatous dermatitis (Figure 1) with a narrow Grenz zone in the superficial dermis. The upper dermis contained a dense bandlike infiltrate of histiocytes with abundant foamy-gray cytoplasm and a moderate admixture of lymphocytes. The mid and deep dermis contained a nodular, perivascular, periadnexal, and perineural infiltrate of histiocytes and a dense admixture of lymphocytes. Periodic acid-Schiff and Gram stains were negative for microorganisms. Fite stain was positive for numerous organisms in histiocytes and small dermal nerves (Figure 2). These findings and the clinical examination confirmed a diagnosis of borderline-borderline leprosy with type 1 lepra reaction. The patient was started on dapsone 100 mg, rifampin 600 mg, and clofazimine 100 mg once daily and experienced clinical improvement within 6 months.

The World Health Organization reported more than 200,000 new leprosy cases globally in 2019, with most occurring in India, Brazil, and Indonesia.¹ About 150 to 250 new cases are detected in the United States annually.¹ The Ridley-Jopling classification of leprosy divides the condition into 5 categories: tuberculoid, borderline tuberculoid, borderline-borderline (BB), borderline lepromatous, and lepromatous. At one end of the spectrum, tuberculoid leprosy—a predominant Th1 immune response mediated by CD4 lymphocytes, interleukin (IL) 2, and interferon gamma²—is characterized by sharply demarcated erythematous and hypopigmented plaques with raised borders and an annular appearance.^2,3 Lesions typically have atrophic and hypopigmented centers that often appear in an asymmetric distribution on the arms and legs.^2,3 Histologic features include dermal tuberculoid granulomas with epithelioid cells—some located directly beneath the epidermis and others around deep vessels and nerves³—multinucleated Langerhans giant cells, thickened peripheral nerves with intraneural lymphocytic infiltrates, and granulomas with central necrosis. Fite-Faraco staining exhibits few bacteria.²

Lepromatous leprosy occurs in individuals with impaired T-cell immunity, leading to multiple red-brown nodular infiltrates in the skin and mucous membranes.^2,3 Lesions typically are symmetric and favor the face and auricle of the ear.^2,3 Histologically, there are bluish-gray foamy macrophages that form diffuse or nodular infiltrates with few lymphocytes,² with a Grenz zone between the epidermis and dermis. Nerves may show lamination of the perineurium resembling an onion skin.^2,3 Immunohistochemistry shows predominant CD8-positive infiltrates with a Th2 response and positive IL-4 and IL-10. Fite-Faraco stain shows numerous mycobacteria arranged in clusters and in histiocytes.²

Tuberculoid leprosy is treated with dapsone 100 mg and rifampin 600 mg once daily for 6 months,⁴ and lepromatous leprosy is treated with dapsone 100 mg, rifampin 600 mg, and clofazimine 50 mg once daily for 12 months.⁴ The prognosis for both is good with treatment; erythema and induration of skin lesions may improve within a few months, but residual nerve damage is common, especially in those with advanced disease prior to treatment.² For direct contacts, a single dose of rifampin may be given.⁴

Borderline-borderline leprosy manifests with numerous asymmetric annular plaques, as seen in our patient (Figure 3). Histology findings can be variable and often overlap with other forms of leprosy. There can be epithelioid granulomas and only a few acid-fast bacilli (AFB) or diffuse histiocytic aggregates with foamy histiocytes containing large numbers of AFB.³ Nerve involvement is variable but can be severe in the setting of type 1 lepra reaction, which was present in our patient. Type 1 lepra reaction—a type IV cell-mediated allergic hypersensitivity reaction to Mycobacterium leprae antigens—manifests clinically with hyperesthesia, erythema, edema, and subsequent scaling.² It occurs in up to 30% of patients with borderline leprosy, usually within 12 months of treatment initiation.² Our patient had considerable edema and erythema of the hands and feet (Figure 4) along with extensive polyneuropathy prior to starting therapy.

Lucio phenomenon is a rare leprosy reaction found in patients with untreated lepromatous leprosy characterized by erythematous to violaceous macules that lead to ulceronecrotic lesions.⁵ Histologically, there are many AFB in the vascular endothelium, leukocytoclastic vasculitis, and ischemic epidermal necrosis.⁵ Our patient did not have ulcerative or necrotic lesions.

The classic skin lesions of psoriasis vulgaris can be described as well-demarcated pink plaques with white or silvery scales that usually are distributed symmetrically and often are found on extensor surfaces.⁶ Rapidly progressive lesions can be annular with normal skin in the center, mimicking the lesions seen in tuberculoid leprosy. Clinically, both psoriasis and tuberculoid forms of leprosy are sharply demarcated; however, psoriatic lesions often have micaceous overlying scale that is not present in leprosy. Characteristic histologic findings of psoriasis are hyperkeratosis, parakeratosis, and acanthosis of the epidermis with dilated blood vessels and a lymphocytic infiltrate, predominantly into the dermis.⁷ Psoriatic arthritis has a variable clinical course but tends to emerge 5 to 12 years after initial skin manifestation.⁸ Classic clinical symptoms include swelling, tenderness, stiffness, and pain in joints and surrounding tissues.⁸ Other than edema, our patient did not exhibit signs of psoriatic arthritis.

Sarcoidosis is a systemic autoimmune disease characterized by noncaseating epithelioid granulomas affecting various organs, with cutaneous manifestations present in approximately 30% of all cases. Cutaneous manifestations can be variable, including maculopapular lesions, plaques, and nodules.⁹ Differentiating between cutaneous sarcoidosis and tuberculoid leprosy can be challenging, as both are granulomatous processes; however, histology of sarcoidosis demonstrates noncaseating granulomas in the dermis and/or subcutaneous tissues without AFB9 compared to granulomas with necrotic centers in tuberculoid leprosy.

Cutaneous tuberculosis has variable morphologies. One subtype, lupus vulgaris, can manifest with violaceous, scaly, eroded plaques that could be confused for leprosy. Lupus vulgaris usually results from hematogenous or lymphatic seeding in individuals with high or moderate immunity to M tuberculosis.¹⁰

Histologically, the dermis has tuberculoid granulomas containing multinucleated giant cells,¹⁰ which can mimic those seen in BB leprosy. Tuberculin skin test results often are positive¹⁰; while this test was not performed in our patient, chest radiography was unremarkable, making this diagnosis less likely.

Mycobacterium leprae infections should be considered in a patient with a worsening rash and progressive polyneuropathy. Clinical diagnosis can be challenging due to similarities with other diseases; however, histopathologic findings can help differentiate M leprae from other conditions. This infection is treatable, and early detection can minimize long-term patient morbidity.

THE DIAGNOSIS: Borderline-Borderline Leprosy With Type 1 Lepra Reaction

Punch biopsies from plaques on the right elbow and right shin revealed diffuse granulomatous dermatitis (Figure 1) with a narrow Grenz zone in the superficial dermis. The upper dermis contained a dense bandlike infiltrate of histiocytes with abundant foamy-gray cytoplasm and a moderate admixture of lymphocytes. The mid and deep dermis contained a nodular, perivascular, periadnexal, and perineural infiltrate of histiocytes and a dense admixture of lymphocytes. Periodic acid-Schiff and Gram stains were negative for microorganisms. Fite stain was positive for numerous organisms in histiocytes and small dermal nerves (Figure 2). These findings and the clinical examination confirmed a diagnosis of borderline-borderline leprosy with type 1 lepra reaction. The patient was started on dapsone 100 mg, rifampin 600 mg, and clofazimine 100 mg once daily and experienced clinical improvement within 6 months.

The World Health Organization reported more than 200,000 new leprosy cases globally in 2019, with most occurring in India, Brazil, and Indonesia.¹ About 150 to 250 new cases are detected in the United States annually.¹ The Ridley-Jopling classification of leprosy divides the condition into 5 categories: tuberculoid, borderline tuberculoid, borderline-borderline (BB), borderline lepromatous, and lepromatous. At one end of the spectrum, tuberculoid leprosy—a predominant Th1 immune response mediated by CD4 lymphocytes, interleukin (IL) 2, and interferon gamma²—is characterized by sharply demarcated erythematous and hypopigmented plaques with raised borders and an annular appearance.^2,3 Lesions typically have atrophic and hypopigmented centers that often appear in an asymmetric distribution on the arms and legs.^2,3 Histologic features include dermal tuberculoid granulomas with epithelioid cells—some located directly beneath the epidermis and others around deep vessels and nerves³—multinucleated Langerhans giant cells, thickened peripheral nerves with intraneural lymphocytic infiltrates, and granulomas with central necrosis. Fite-Faraco staining exhibits few bacteria.²

Lepromatous leprosy occurs in individuals with impaired T-cell immunity, leading to multiple red-brown nodular infiltrates in the skin and mucous membranes.^2,3 Lesions typically are symmetric and favor the face and auricle of the ear.^2,3 Histologically, there are bluish-gray foamy macrophages that form diffuse or nodular infiltrates with few lymphocytes,² with a Grenz zone between the epidermis and dermis. Nerves may show lamination of the perineurium resembling an onion skin.^2,3 Immunohistochemistry shows predominant CD8-positive infiltrates with a Th2 response and positive IL-4 and IL-10. Fite-Faraco stain shows numerous mycobacteria arranged in clusters and in histiocytes.²

Tuberculoid leprosy is treated with dapsone 100 mg and rifampin 600 mg once daily for 6 months,⁴ and lepromatous leprosy is treated with dapsone 100 mg, rifampin 600 mg, and clofazimine 50 mg once daily for 12 months.⁴ The prognosis for both is good with treatment; erythema and induration of skin lesions may improve within a few months, but residual nerve damage is common, especially in those with advanced disease prior to treatment.² For direct contacts, a single dose of rifampin may be given.⁴

Borderline-borderline leprosy manifests with numerous asymmetric annular plaques, as seen in our patient (Figure 3). Histology findings can be variable and often overlap with other forms of leprosy. There can be epithelioid granulomas and only a few acid-fast bacilli (AFB) or diffuse histiocytic aggregates with foamy histiocytes containing large numbers of AFB.³ Nerve involvement is variable but can be severe in the setting of type 1 lepra reaction, which was present in our patient. Type 1 lepra reaction—a type IV cell-mediated allergic hypersensitivity reaction to Mycobacterium leprae antigens—manifests clinically with hyperesthesia, erythema, edema, and subsequent scaling.² It occurs in up to 30% of patients with borderline leprosy, usually within 12 months of treatment initiation.² Our patient had considerable edema and erythema of the hands and feet (Figure 4) along with extensive polyneuropathy prior to starting therapy.

Lucio phenomenon is a rare leprosy reaction found in patients with untreated lepromatous leprosy characterized by erythematous to violaceous macules that lead to ulceronecrotic lesions.⁵ Histologically, there are many AFB in the vascular endothelium, leukocytoclastic vasculitis, and ischemic epidermal necrosis.⁵ Our patient did not have ulcerative or necrotic lesions.

The classic skin lesions of psoriasis vulgaris can be described as well-demarcated pink plaques with white or silvery scales that usually are distributed symmetrically and often are found on extensor surfaces.⁶ Rapidly progressive lesions can be annular with normal skin in the center, mimicking the lesions seen in tuberculoid leprosy. Clinically, both psoriasis and tuberculoid forms of leprosy are sharply demarcated; however, psoriatic lesions often have micaceous overlying scale that is not present in leprosy. Characteristic histologic findings of psoriasis are hyperkeratosis, parakeratosis, and acanthosis of the epidermis with dilated blood vessels and a lymphocytic infiltrate, predominantly into the dermis.⁷ Psoriatic arthritis has a variable clinical course but tends to emerge 5 to 12 years after initial skin manifestation.⁸ Classic clinical symptoms include swelling, tenderness, stiffness, and pain in joints and surrounding tissues.⁸ Other than edema, our patient did not exhibit signs of psoriatic arthritis.

Sarcoidosis is a systemic autoimmune disease characterized by noncaseating epithelioid granulomas affecting various organs, with cutaneous manifestations present in approximately 30% of all cases. Cutaneous manifestations can be variable, including maculopapular lesions, plaques, and nodules.⁹ Differentiating between cutaneous sarcoidosis and tuberculoid leprosy can be challenging, as both are granulomatous processes; however, histology of sarcoidosis demonstrates noncaseating granulomas in the dermis and/or subcutaneous tissues without AFB9 compared to granulomas with necrotic centers in tuberculoid leprosy.

Cutaneous tuberculosis has variable morphologies. One subtype, lupus vulgaris, can manifest with violaceous, scaly, eroded plaques that could be confused for leprosy. Lupus vulgaris usually results from hematogenous or lymphatic seeding in individuals with high or moderate immunity to M tuberculosis.¹⁰

Histologically, the dermis has tuberculoid granulomas containing multinucleated giant cells,¹⁰ which can mimic those seen in BB leprosy. Tuberculin skin test results often are positive¹⁰; while this test was not performed in our patient, chest radiography was unremarkable, making this diagnosis less likely.

Mycobacterium leprae infections should be considered in a patient with a worsening rash and progressive polyneuropathy. Clinical diagnosis can be challenging due to similarities with other diseases; however, histopathologic findings can help differentiate M leprae from other conditions. This infection is treatable, and early detection can minimize long-term patient morbidity.

THE DIAGNOSIS: Borderline-Borderline Leprosy With Type 1 Lepra Reaction

Punch biopsies from plaques on the right elbow and right shin revealed diffuse granulomatous dermatitis (Figure 1) with a narrow Grenz zone in the superficial dermis. The upper dermis contained a dense bandlike infiltrate of histiocytes with abundant foamy-gray cytoplasm and a moderate admixture of lymphocytes. The mid and deep dermis contained a nodular, perivascular, periadnexal, and perineural infiltrate of histiocytes and a dense admixture of lymphocytes. Periodic acid-Schiff and Gram stains were negative for microorganisms. Fite stain was positive for numerous organisms in histiocytes and small dermal nerves (Figure 2). These findings and the clinical examination confirmed a diagnosis of borderline-borderline leprosy with type 1 lepra reaction. The patient was started on dapsone 100 mg, rifampin 600 mg, and clofazimine 100 mg once daily and experienced clinical improvement within 6 months.

The World Health Organization reported more than 200,000 new leprosy cases globally in 2019, with most occurring in India, Brazil, and Indonesia.¹ About 150 to 250 new cases are detected in the United States annually.¹ The Ridley-Jopling classification of leprosy divides the condition into 5 categories: tuberculoid, borderline tuberculoid, borderline-borderline (BB), borderline lepromatous, and lepromatous. At one end of the spectrum, tuberculoid leprosy—a predominant Th1 immune response mediated by CD4 lymphocytes, interleukin (IL) 2, and interferon gamma²—is characterized by sharply demarcated erythematous and hypopigmented plaques with raised borders and an annular appearance.^2,3 Lesions typically have atrophic and hypopigmented centers that often appear in an asymmetric distribution on the arms and legs.^2,3 Histologic features include dermal tuberculoid granulomas with epithelioid cells—some located directly beneath the epidermis and others around deep vessels and nerves³—multinucleated Langerhans giant cells, thickened peripheral nerves with intraneural lymphocytic infiltrates, and granulomas with central necrosis. Fite-Faraco staining exhibits few bacteria.²

Lepromatous leprosy occurs in individuals with impaired T-cell immunity, leading to multiple red-brown nodular infiltrates in the skin and mucous membranes.^2,3 Lesions typically are symmetric and favor the face and auricle of the ear.^2,3 Histologically, there are bluish-gray foamy macrophages that form diffuse or nodular infiltrates with few lymphocytes,² with a Grenz zone between the epidermis and dermis. Nerves may show lamination of the perineurium resembling an onion skin.^2,3 Immunohistochemistry shows predominant CD8-positive infiltrates with a Th2 response and positive IL-4 and IL-10. Fite-Faraco stain shows numerous mycobacteria arranged in clusters and in histiocytes.²

Tuberculoid leprosy is treated with dapsone 100 mg and rifampin 600 mg once daily for 6 months,⁴ and lepromatous leprosy is treated with dapsone 100 mg, rifampin 600 mg, and clofazimine 50 mg once daily for 12 months.⁴ The prognosis for both is good with treatment; erythema and induration of skin lesions may improve within a few months, but residual nerve damage is common, especially in those with advanced disease prior to treatment.² For direct contacts, a single dose of rifampin may be given.⁴

Borderline-borderline leprosy manifests with numerous asymmetric annular plaques, as seen in our patient (Figure 3). Histology findings can be variable and often overlap with other forms of leprosy. There can be epithelioid granulomas and only a few acid-fast bacilli (AFB) or diffuse histiocytic aggregates with foamy histiocytes containing large numbers of AFB.³ Nerve involvement is variable but can be severe in the setting of type 1 lepra reaction, which was present in our patient. Type 1 lepra reaction—a type IV cell-mediated allergic hypersensitivity reaction to Mycobacterium leprae antigens—manifests clinically with hyperesthesia, erythema, edema, and subsequent scaling.² It occurs in up to 30% of patients with borderline leprosy, usually within 12 months of treatment initiation.² Our patient had considerable edema and erythema of the hands and feet (Figure 4) along with extensive polyneuropathy prior to starting therapy.

Lucio phenomenon is a rare leprosy reaction found in patients with untreated lepromatous leprosy characterized by erythematous to violaceous macules that lead to ulceronecrotic lesions.⁵ Histologically, there are many AFB in the vascular endothelium, leukocytoclastic vasculitis, and ischemic epidermal necrosis.⁵ Our patient did not have ulcerative or necrotic lesions.

The classic skin lesions of psoriasis vulgaris can be described as well-demarcated pink plaques with white or silvery scales that usually are distributed symmetrically and often are found on extensor surfaces.⁶ Rapidly progressive lesions can be annular with normal skin in the center, mimicking the lesions seen in tuberculoid leprosy. Clinically, both psoriasis and tuberculoid forms of leprosy are sharply demarcated; however, psoriatic lesions often have micaceous overlying scale that is not present in leprosy. Characteristic histologic findings of psoriasis are hyperkeratosis, parakeratosis, and acanthosis of the epidermis with dilated blood vessels and a lymphocytic infiltrate, predominantly into the dermis.⁷ Psoriatic arthritis has a variable clinical course but tends to emerge 5 to 12 years after initial skin manifestation.⁸ Classic clinical symptoms include swelling, tenderness, stiffness, and pain in joints and surrounding tissues.⁸ Other than edema, our patient did not exhibit signs of psoriatic arthritis.

Sarcoidosis is a systemic autoimmune disease characterized by noncaseating epithelioid granulomas affecting various organs, with cutaneous manifestations present in approximately 30% of all cases. Cutaneous manifestations can be variable, including maculopapular lesions, plaques, and nodules.⁹ Differentiating between cutaneous sarcoidosis and tuberculoid leprosy can be challenging, as both are granulomatous processes; however, histology of sarcoidosis demonstrates noncaseating granulomas in the dermis and/or subcutaneous tissues without AFB9 compared to granulomas with necrotic centers in tuberculoid leprosy.

Cutaneous tuberculosis has variable morphologies. One subtype, lupus vulgaris, can manifest with violaceous, scaly, eroded plaques that could be confused for leprosy. Lupus vulgaris usually results from hematogenous or lymphatic seeding in individuals with high or moderate immunity to M tuberculosis.¹⁰

Histologically, the dermis has tuberculoid granulomas containing multinucleated giant cells,¹⁰ which can mimic those seen in BB leprosy. Tuberculin skin test results often are positive¹⁰; while this test was not performed in our patient, chest radiography was unremarkable, making this diagnosis less likely.

Mycobacterium leprae infections should be considered in a patient with a worsening rash and progressive polyneuropathy. Clinical diagnosis can be challenging due to similarities with other diseases; however, histopathologic findings can help differentiate M leprae from other conditions. This infection is treatable, and early detection can minimize long-term patient morbidity.

THE DIAGNOSIS: Lichen Sclerosus

Given the clinical appearance of white atrophic plaques with characteristic wrinkling of the skin, a diagnosis of lichen sclerosus was strongly suspected. At the initial office visit, the patient was prescribed clobetasol 0.05% ointment twice daily for 6 weeks. Histopathology revealed hyperkeratosis, follicular plugging, papillary dermal pallor, and adjacent lymphocytic inflammation, confirming the clinical diagnosis of lichen sclerosus (Figure). The patient then was lost to follow-up.

Lichen sclerosus is a chronic benign dermatologic condition of unknown etiology that is characterized by epidermal atrophy and inflammation and is common in postmenopausal women. It features pale, ivory-colored lesions with partially atrophic skin and a wrinkled cigarette paper appearance.¹ The differential for lichen sclerosus is broad, and definitive diagnosis is made via biopsy to rule out potential malignancy and other inflammatory skin diseases.¹ Lichen sclerosus is an immune-mediated disorder driven by type 1 T helper cells and regulated by miR-155. There has been an association with extracellular matrix protein 1, a glycoprotein that is found in the dermal-epidermal basement membrane zone, which provides structural integrity to the skin. Autoantibodies against extracellular matrix protein 1 and other antigens in the basement membrane generally are found in anogenital lichen sclerosus; however, their precise roles in the pathogenesis of lichen sclerosus remains unclear.¹

The differential diagnoses for lichen sclerosus include psoriasis, tinea corporis, lichen simplex chronicus, and atopic dermatitis. Psoriasis typically manifests as pink plaques with silver scales on the elbows, knees, and scalp in adult patients.² Our patient’s white plaques may have suggested psoriasis, but the partially atrophic skin with a wrinkled cigarette paper appearance was not compatible with that diagnosis.

Tinea corporis, a superficial fungal infection of the skin, manifests as circular or ovoid lesions with raised erythematous scaly borders, often with central clearing resembling a ring, that can occur anywhere on the body other than the feet, groin, face, scalp, or beard area.³ The fact that our patient previously had tried topical antifungal medications with no relief and that the skin lesions were atrophic rather than ring shaped made the diagnosis of tinea corporis unlikely.

Lichen simplex chronicus is a chronic condition caused by friction or scratching that is characterized by dry, patchy, scaly, and thickened areas of the skin. Typically affecting the head, arms, neck, scalp, and genital region, lichen simplex chronicus manifests with violaceous or hyperpigmented lesions.⁴ The nonpruritic atrophic plaques on the inner thighs and the presence of white patches on the vaginal area were not indicative of lichen simplex chronicus in our patient.

Atopic dermatitis manifests as pruritic erythematous scaly papules and plaques with secondary excoriation and possible lichenification. In adults, atopic dermatitis commonly appears on flexural surfaces.² Atopic dermatitis does not manifest with atrophy and skin wrinkling as seen in our patient.

In the management of lichen sclerosus, the standard treatment is potent topical corticosteroids. Alternatively, topical calcineurin inhibitors can be employed; however, due to the unknown nature of the condition’s underlying cause, targeted treatment is challenging. Our case underscores how lichen sclerosus can be misdiagnosed, highlighting the need for more frequent reporting in the literature to enhance early recognition and reduce delays in patient treatment.

THE DIAGNOSIS: Lichen Sclerosus

Given the clinical appearance of white atrophic plaques with characteristic wrinkling of the skin, a diagnosis of lichen sclerosus was strongly suspected. At the initial office visit, the patient was prescribed clobetasol 0.05% ointment twice daily for 6 weeks. Histopathology revealed hyperkeratosis, follicular plugging, papillary dermal pallor, and adjacent lymphocytic inflammation, confirming the clinical diagnosis of lichen sclerosus (Figure). The patient then was lost to follow-up.

Lichen sclerosus is a chronic benign dermatologic condition of unknown etiology that is characterized by epidermal atrophy and inflammation and is common in postmenopausal women. It features pale, ivory-colored lesions with partially atrophic skin and a wrinkled cigarette paper appearance.¹ The differential for lichen sclerosus is broad, and definitive diagnosis is made via biopsy to rule out potential malignancy and other inflammatory skin diseases.¹ Lichen sclerosus is an immune-mediated disorder driven by type 1 T helper cells and regulated by miR-155. There has been an association with extracellular matrix protein 1, a glycoprotein that is found in the dermal-epidermal basement membrane zone, which provides structural integrity to the skin. Autoantibodies against extracellular matrix protein 1 and other antigens in the basement membrane generally are found in anogenital lichen sclerosus; however, their precise roles in the pathogenesis of lichen sclerosus remains unclear.¹

The differential diagnoses for lichen sclerosus include psoriasis, tinea corporis, lichen simplex chronicus, and atopic dermatitis. Psoriasis typically manifests as pink plaques with silver scales on the elbows, knees, and scalp in adult patients.² Our patient’s white plaques may have suggested psoriasis, but the partially atrophic skin with a wrinkled cigarette paper appearance was not compatible with that diagnosis.

Tinea corporis, a superficial fungal infection of the skin, manifests as circular or ovoid lesions with raised erythematous scaly borders, often with central clearing resembling a ring, that can occur anywhere on the body other than the feet, groin, face, scalp, or beard area.³ The fact that our patient previously had tried topical antifungal medications with no relief and that the skin lesions were atrophic rather than ring shaped made the diagnosis of tinea corporis unlikely.

Lichen simplex chronicus is a chronic condition caused by friction or scratching that is characterized by dry, patchy, scaly, and thickened areas of the skin. Typically affecting the head, arms, neck, scalp, and genital region, lichen simplex chronicus manifests with violaceous or hyperpigmented lesions.⁴ The nonpruritic atrophic plaques on the inner thighs and the presence of white patches on the vaginal area were not indicative of lichen simplex chronicus in our patient.

Atopic dermatitis manifests as pruritic erythematous scaly papules and plaques with secondary excoriation and possible lichenification. In adults, atopic dermatitis commonly appears on flexural surfaces.² Atopic dermatitis does not manifest with atrophy and skin wrinkling as seen in our patient.

In the management of lichen sclerosus, the standard treatment is potent topical corticosteroids. Alternatively, topical calcineurin inhibitors can be employed; however, due to the unknown nature of the condition’s underlying cause, targeted treatment is challenging. Our case underscores how lichen sclerosus can be misdiagnosed, highlighting the need for more frequent reporting in the literature to enhance early recognition and reduce delays in patient treatment.

THE DIAGNOSIS: Lichen Sclerosus

Given the clinical appearance of white atrophic plaques with characteristic wrinkling of the skin, a diagnosis of lichen sclerosus was strongly suspected. At the initial office visit, the patient was prescribed clobetasol 0.05% ointment twice daily for 6 weeks. Histopathology revealed hyperkeratosis, follicular plugging, papillary dermal pallor, and adjacent lymphocytic inflammation, confirming the clinical diagnosis of lichen sclerosus (Figure). The patient then was lost to follow-up.

Lichen sclerosus is a chronic benign dermatologic condition of unknown etiology that is characterized by epidermal atrophy and inflammation and is common in postmenopausal women. It features pale, ivory-colored lesions with partially atrophic skin and a wrinkled cigarette paper appearance.¹ The differential for lichen sclerosus is broad, and definitive diagnosis is made via biopsy to rule out potential malignancy and other inflammatory skin diseases.¹ Lichen sclerosus is an immune-mediated disorder driven by type 1 T helper cells and regulated by miR-155. There has been an association with extracellular matrix protein 1, a glycoprotein that is found in the dermal-epidermal basement membrane zone, which provides structural integrity to the skin. Autoantibodies against extracellular matrix protein 1 and other antigens in the basement membrane generally are found in anogenital lichen sclerosus; however, their precise roles in the pathogenesis of lichen sclerosus remains unclear.¹

The differential diagnoses for lichen sclerosus include psoriasis, tinea corporis, lichen simplex chronicus, and atopic dermatitis. Psoriasis typically manifests as pink plaques with silver scales on the elbows, knees, and scalp in adult patients.² Our patient’s white plaques may have suggested psoriasis, but the partially atrophic skin with a wrinkled cigarette paper appearance was not compatible with that diagnosis.

Tinea corporis, a superficial fungal infection of the skin, manifests as circular or ovoid lesions with raised erythematous scaly borders, often with central clearing resembling a ring, that can occur anywhere on the body other than the feet, groin, face, scalp, or beard area.³ The fact that our patient previously had tried topical antifungal medications with no relief and that the skin lesions were atrophic rather than ring shaped made the diagnosis of tinea corporis unlikely.

Lichen simplex chronicus is a chronic condition caused by friction or scratching that is characterized by dry, patchy, scaly, and thickened areas of the skin. Typically affecting the head, arms, neck, scalp, and genital region, lichen simplex chronicus manifests with violaceous or hyperpigmented lesions.⁴ The nonpruritic atrophic plaques on the inner thighs and the presence of white patches on the vaginal area were not indicative of lichen simplex chronicus in our patient.

Atopic dermatitis manifests as pruritic erythematous scaly papules and plaques with secondary excoriation and possible lichenification. In adults, atopic dermatitis commonly appears on flexural surfaces.² Atopic dermatitis does not manifest with atrophy and skin wrinkling as seen in our patient.

In the management of lichen sclerosus, the standard treatment is potent topical corticosteroids. Alternatively, topical calcineurin inhibitors can be employed; however, due to the unknown nature of the condition’s underlying cause, targeted treatment is challenging. Our case underscores how lichen sclerosus can be misdiagnosed, highlighting the need for more frequent reporting in the literature to enhance early recognition and reduce delays in patient treatment.

THE DIAGNOSIS: Plaquelike Myofibroblastic Tumor

An incisional biopsy of the plaque demonstrated a hypercellular proliferation of bland spindle cells in the dermis that infiltrated the subcutis. The overlying epidermis was mildly acanthotic with both ulceration and follicular induction. There was trapping of individual adipocytes in a honeycomb pattern with foci of erythrocyte extravasation, microvesiculation, and widened fibrous septa (Figure 1). Immunohistochemistry was positive for vimentin, actin, and smooth muscle actin (SMA)(Figure 2A). Variable positivity for Factor XIIIa antibodies was noted. CD68 staining was focal positive, suggesting fibrohistiocytic lineage. Expression of CD31, CD34, S100, and anaplastic lymphoma kinase was negative, and Ki-67 was present in less than 10% of cells (Figure 2B).

We reviewed the case in conjunction with a soft-tissue pathologist (Y.L.), and based on the clinical and immunophenotypic features, a diagnosis of plaquelike myofibroblastic tumor (PLMT) was made. The patient’s parents refused further treatment, and there was no sign of disease progression at 6-month follow-up.

Plaquelike myofibroblastic tumor is an unusual pediatric dermal tumor that was first described by Clarke et al¹ in 2007. Clinical manifestation of PLMT on the right abdomen was unique in our patient, as the lesions typically present as indurated plaques on the lower back, but the central ulceration in our case resembled a report by Marqueling et al.² Ulceration and induration of PLMT developing at 8 months of age can suggest an aggressive disease course corresponding with deep infiltration and is seen mostly in children.

The histopathologic features of PLMT include an acanthotic epidermis and follicular induction, which also are characteristic of dermatofibroma (DF). The proliferation of spindle cells extended deep into the fat with foci of erythrocyte extravasation and microvesiculation of the stroma similar to nodular fasciitis and proliferative fasciitis. The presentation of infiltrating and expanding fibrous septae and trapping of individual adipocytes in a honeycomb pattern is similar to dermatofibrosarcoma protuberans (DFSP). Most cases of PLMT are positive for SMA. Factor XIIIa typically is variably positive, and in one report, 31% (4/13) of cases showed positive staining for calponin.³ Rapid growth, ulceration, and recurrence emphasize that PLMT can be locally aggressive, similar to DFSP.⁴

The main differential diagnoses include DF and its variants, dermatomyofibroma, DFSP, and proliferative fasciitis.^3,5 In the cases mentioned above, microscopic features were similar with a relatively well-circumscribed proliferation of spindle cells arranged in short fascicles through the entire reticular dermis, and the overlying epidermis was acanthotic.

Dermatofibroma commonly manifests in adults as a minor nodular lesion (commonly <1 cm), and usually is located on the legs. It has several clinical and histologic variants, including multiple clustered DF (MCDF)—a rare condition that has been reported in children and young adults and generally appears in the first and second decades of life. Of the reported cases of MCDF, immunohistochemical staining for SMA was performed in 8 cases. All these cases showed negative or minimal staining.^3-5 Smooth muscle actin staining in DFs is negative, or weak and patchy, unlike in PLMT where it is diffuse, uniform, and strong.

Dermatofibrosarcoma protuberans typically occurs in young adults and manifests as dermal and subcutaneous nodular/multinodular or plaquelike masses, with rare congenital cases. Immunohistochemical staining for CD34, which typically is firmly and diffusely positive, is the most reliable marker of DFSP.⁶ Factor XIIIA in DFSP typically is negative for focal staining, mainly at periphery or in scattered dendritic cells. The prognosis of DFSP generally is excellent, with local recurrences in up to 30% of cases and extremely low metastatic potential (essentially only in cases with fibrosarcomatous transformation).⁶ Dermatomyofibroma is another rare benign dermal myofibroblastic tumor that typically manifests with indurated hyperpigmented or erythematous plaques or nodules on the shoulders and torso.⁶ This condition occurs mainly in adolescents and young adults, unlike PLMT. The most striking features of dermatomyofibroma are the horizontal orientation of the spindle cell nuclei and the pattern of the proliferation concerning the adnexal structures, especially hair follicles. The hair follicles have a normal appearance, and the proliferation extends up to each follicle, then continues to the other side without any displacement of the follicle. Tumor cells are variably positive for SMA in dermatomyofibromas and are negative for muscle-specific actin, desmin, S100, CD34, and Factor XIIIA.⁶

Immunohistochemistry can be very useful in differentiating PLMT from other conditions. Neoplastic cells stain positively for CD34 but not for Factor XIIIa and SMA in cases of DFSP. Dermatofibroma and its variants always present with collagen trapping at the periphery of the lesions and may demonstrate foamy macrophages, hemosiderin, or plasma cells FXIIIA(+), CD34(-), and variable SMA reactivity. This positivity usually is less prominent in DF than in PLMT. Neoplastic cells in dermatomyofibroma often stain positive for calponin, but only focally for SMA. The clinical features of dermatomyofibroma include early onset, large size, multiple nodules, and plaquelike morphology. Moulonguet et al⁴ hypothesized that, although MCDF and PLMT appear to show some distinctive clinical and histologic features, they also show similarities that could suggest they form part of the myofibroblastic spectrum. Furthermore, Moradi et al⁷ also considered them as part of the same disease spectrum because of their overlapping clinical, histologic, and immunohistochemical features.

The microscopic features in our case are notable, as the lesion demonstrated overlying acanthosis and follicular induction, resembling DF. The stroma contained microvesicular changes and erythrocyte extravasation, characteristic of nodular or proliferative fasciitis. Additionally, densely packed spindle cells infiltrated deep into the subcutaneous adipose tissue, similar to DFSP.^2,3 Our findings expand on the reported histopathologic spectrum of this tumor to date.

THE DIAGNOSIS: Plaquelike Myofibroblastic Tumor

An incisional biopsy of the plaque demonstrated a hypercellular proliferation of bland spindle cells in the dermis that infiltrated the subcutis. The overlying epidermis was mildly acanthotic with both ulceration and follicular induction. There was trapping of individual adipocytes in a honeycomb pattern with foci of erythrocyte extravasation, microvesiculation, and widened fibrous septa (Figure 1). Immunohistochemistry was positive for vimentin, actin, and smooth muscle actin (SMA)(Figure 2A). Variable positivity for Factor XIIIa antibodies was noted. CD68 staining was focal positive, suggesting fibrohistiocytic lineage. Expression of CD31, CD34, S100, and anaplastic lymphoma kinase was negative, and Ki-67 was present in less than 10% of cells (Figure 2B).

We reviewed the case in conjunction with a soft-tissue pathologist (Y.L.), and based on the clinical and immunophenotypic features, a diagnosis of plaquelike myofibroblastic tumor (PLMT) was made. The patient’s parents refused further treatment, and there was no sign of disease progression at 6-month follow-up.

Plaquelike myofibroblastic tumor is an unusual pediatric dermal tumor that was first described by Clarke et al¹ in 2007. Clinical manifestation of PLMT on the right abdomen was unique in our patient, as the lesions typically present as indurated plaques on the lower back, but the central ulceration in our case resembled a report by Marqueling et al.² Ulceration and induration of PLMT developing at 8 months of age can suggest an aggressive disease course corresponding with deep infiltration and is seen mostly in children.

The histopathologic features of PLMT include an acanthotic epidermis and follicular induction, which also are characteristic of dermatofibroma (DF). The proliferation of spindle cells extended deep into the fat with foci of erythrocyte extravasation and microvesiculation of the stroma similar to nodular fasciitis and proliferative fasciitis. The presentation of infiltrating and expanding fibrous septae and trapping of individual adipocytes in a honeycomb pattern is similar to dermatofibrosarcoma protuberans (DFSP). Most cases of PLMT are positive for SMA. Factor XIIIa typically is variably positive, and in one report, 31% (4/13) of cases showed positive staining for calponin.³ Rapid growth, ulceration, and recurrence emphasize that PLMT can be locally aggressive, similar to DFSP.⁴

The main differential diagnoses include DF and its variants, dermatomyofibroma, DFSP, and proliferative fasciitis.^3,5 In the cases mentioned above, microscopic features were similar with a relatively well-circumscribed proliferation of spindle cells arranged in short fascicles through the entire reticular dermis, and the overlying epidermis was acanthotic.

Dermatofibroma commonly manifests in adults as a minor nodular lesion (commonly <1 cm), and usually is located on the legs. It has several clinical and histologic variants, including multiple clustered DF (MCDF)—a rare condition that has been reported in children and young adults and generally appears in the first and second decades of life. Of the reported cases of MCDF, immunohistochemical staining for SMA was performed in 8 cases. All these cases showed negative or minimal staining.^3-5 Smooth muscle actin staining in DFs is negative, or weak and patchy, unlike in PLMT where it is diffuse, uniform, and strong.

Dermatofibrosarcoma protuberans typically occurs in young adults and manifests as dermal and subcutaneous nodular/multinodular or plaquelike masses, with rare congenital cases. Immunohistochemical staining for CD34, which typically is firmly and diffusely positive, is the most reliable marker of DFSP.⁶ Factor XIIIA in DFSP typically is negative for focal staining, mainly at periphery or in scattered dendritic cells. The prognosis of DFSP generally is excellent, with local recurrences in up to 30% of cases and extremely low metastatic potential (essentially only in cases with fibrosarcomatous transformation).⁶ Dermatomyofibroma is another rare benign dermal myofibroblastic tumor that typically manifests with indurated hyperpigmented or erythematous plaques or nodules on the shoulders and torso.⁶ This condition occurs mainly in adolescents and young adults, unlike PLMT. The most striking features of dermatomyofibroma are the horizontal orientation of the spindle cell nuclei and the pattern of the proliferation concerning the adnexal structures, especially hair follicles. The hair follicles have a normal appearance, and the proliferation extends up to each follicle, then continues to the other side without any displacement of the follicle. Tumor cells are variably positive for SMA in dermatomyofibromas and are negative for muscle-specific actin, desmin, S100, CD34, and Factor XIIIA.⁶

Immunohistochemistry can be very useful in differentiating PLMT from other conditions. Neoplastic cells stain positively for CD34 but not for Factor XIIIa and SMA in cases of DFSP. Dermatofibroma and its variants always present with collagen trapping at the periphery of the lesions and may demonstrate foamy macrophages, hemosiderin, or plasma cells FXIIIA(+), CD34(-), and variable SMA reactivity. This positivity usually is less prominent in DF than in PLMT. Neoplastic cells in dermatomyofibroma often stain positive for calponin, but only focally for SMA. The clinical features of dermatomyofibroma include early onset, large size, multiple nodules, and plaquelike morphology. Moulonguet et al⁴ hypothesized that, although MCDF and PLMT appear to show some distinctive clinical and histologic features, they also show similarities that could suggest they form part of the myofibroblastic spectrum. Furthermore, Moradi et al⁷ also considered them as part of the same disease spectrum because of their overlapping clinical, histologic, and immunohistochemical features.

The microscopic features in our case are notable, as the lesion demonstrated overlying acanthosis and follicular induction, resembling DF. The stroma contained microvesicular changes and erythrocyte extravasation, characteristic of nodular or proliferative fasciitis. Additionally, densely packed spindle cells infiltrated deep into the subcutaneous adipose tissue, similar to DFSP.^2,3 Our findings expand on the reported histopathologic spectrum of this tumor to date.

THE DIAGNOSIS: Plaquelike Myofibroblastic Tumor

An incisional biopsy of the plaque demonstrated a hypercellular proliferation of bland spindle cells in the dermis that infiltrated the subcutis. The overlying epidermis was mildly acanthotic with both ulceration and follicular induction. There was trapping of individual adipocytes in a honeycomb pattern with foci of erythrocyte extravasation, microvesiculation, and widened fibrous septa (Figure 1). Immunohistochemistry was positive for vimentin, actin, and smooth muscle actin (SMA)(Figure 2A). Variable positivity for Factor XIIIa antibodies was noted. CD68 staining was focal positive, suggesting fibrohistiocytic lineage. Expression of CD31, CD34, S100, and anaplastic lymphoma kinase was negative, and Ki-67 was present in less than 10% of cells (Figure 2B).

We reviewed the case in conjunction with a soft-tissue pathologist (Y.L.), and based on the clinical and immunophenotypic features, a diagnosis of plaquelike myofibroblastic tumor (PLMT) was made. The patient’s parents refused further treatment, and there was no sign of disease progression at 6-month follow-up.

Plaquelike myofibroblastic tumor is an unusual pediatric dermal tumor that was first described by Clarke et al¹ in 2007. Clinical manifestation of PLMT on the right abdomen was unique in our patient, as the lesions typically present as indurated plaques on the lower back, but the central ulceration in our case resembled a report by Marqueling et al.² Ulceration and induration of PLMT developing at 8 months of age can suggest an aggressive disease course corresponding with deep infiltration and is seen mostly in children.

The histopathologic features of PLMT include an acanthotic epidermis and follicular induction, which also are characteristic of dermatofibroma (DF). The proliferation of spindle cells extended deep into the fat with foci of erythrocyte extravasation and microvesiculation of the stroma similar to nodular fasciitis and proliferative fasciitis. The presentation of infiltrating and expanding fibrous septae and trapping of individual adipocytes in a honeycomb pattern is similar to dermatofibrosarcoma protuberans (DFSP). Most cases of PLMT are positive for SMA. Factor XIIIa typically is variably positive, and in one report, 31% (4/13) of cases showed positive staining for calponin.³ Rapid growth, ulceration, and recurrence emphasize that PLMT can be locally aggressive, similar to DFSP.⁴

The main differential diagnoses include DF and its variants, dermatomyofibroma, DFSP, and proliferative fasciitis.^3,5 In the cases mentioned above, microscopic features were similar with a relatively well-circumscribed proliferation of spindle cells arranged in short fascicles through the entire reticular dermis, and the overlying epidermis was acanthotic.

Dermatofibroma commonly manifests in adults as a minor nodular lesion (commonly <1 cm), and usually is located on the legs. It has several clinical and histologic variants, including multiple clustered DF (MCDF)—a rare condition that has been reported in children and young adults and generally appears in the first and second decades of life. Of the reported cases of MCDF, immunohistochemical staining for SMA was performed in 8 cases. All these cases showed negative or minimal staining.^3-5 Smooth muscle actin staining in DFs is negative, or weak and patchy, unlike in PLMT where it is diffuse, uniform, and strong.

Dermatofibrosarcoma protuberans typically occurs in young adults and manifests as dermal and subcutaneous nodular/multinodular or plaquelike masses, with rare congenital cases. Immunohistochemical staining for CD34, which typically is firmly and diffusely positive, is the most reliable marker of DFSP.⁶ Factor XIIIA in DFSP typically is negative for focal staining, mainly at periphery or in scattered dendritic cells. The prognosis of DFSP generally is excellent, with local recurrences in up to 30% of cases and extremely low metastatic potential (essentially only in cases with fibrosarcomatous transformation).⁶ Dermatomyofibroma is another rare benign dermal myofibroblastic tumor that typically manifests with indurated hyperpigmented or erythematous plaques or nodules on the shoulders and torso.⁶ This condition occurs mainly in adolescents and young adults, unlike PLMT. The most striking features of dermatomyofibroma are the horizontal orientation of the spindle cell nuclei and the pattern of the proliferation concerning the adnexal structures, especially hair follicles. The hair follicles have a normal appearance, and the proliferation extends up to each follicle, then continues to the other side without any displacement of the follicle. Tumor cells are variably positive for SMA in dermatomyofibromas and are negative for muscle-specific actin, desmin, S100, CD34, and Factor XIIIA.⁶

Immunohistochemistry can be very useful in differentiating PLMT from other conditions. Neoplastic cells stain positively for CD34 but not for Factor XIIIa and SMA in cases of DFSP. Dermatofibroma and its variants always present with collagen trapping at the periphery of the lesions and may demonstrate foamy macrophages, hemosiderin, or plasma cells FXIIIA(+), CD34(-), and variable SMA reactivity. This positivity usually is less prominent in DF than in PLMT. Neoplastic cells in dermatomyofibroma often stain positive for calponin, but only focally for SMA. The clinical features of dermatomyofibroma include early onset, large size, multiple nodules, and plaquelike morphology. Moulonguet et al⁴ hypothesized that, although MCDF and PLMT appear to show some distinctive clinical and histologic features, they also show similarities that could suggest they form part of the myofibroblastic spectrum. Furthermore, Moradi et al⁷ also considered them as part of the same disease spectrum because of their overlapping clinical, histologic, and immunohistochemical features.

The microscopic features in our case are notable, as the lesion demonstrated overlying acanthosis and follicular induction, resembling DF. The stroma contained microvesicular changes and erythrocyte extravasation, characteristic of nodular or proliferative fasciitis. Additionally, densely packed spindle cells infiltrated deep into the subcutaneous adipose tissue, similar to DFSP.^2,3 Our findings expand on the reported histopathologic spectrum of this tumor to date.

THE DIAGNOSIS: Metastatic Renal Cell Carcinoma

The shave biopsy revealed large cells with prominent nucleoli, clear cytoplasm, and thin cell borders in a nestlike arrangement (Figure 1). Immunohistochemical examination was negative for cytokeratin 5/6 and positive for PAX8 (Figure 2), which finalized the diagnosis of metastatic renal cell carcinoma (RCC). Later, our patient had a core biopsy-proven metastasis to the C6 spinous process, with concern for additional metastasis to the liver and lungs on positron emission tomography. Our patient’s treatment plan included pembrolizumab and axitinib to manage further cutaneous metastasis and radiation therapy for the C6 spinous process metastasis.

Renal cell carcinoma denotes cancer originating from the renal epithelium and is the most common kidney tumor in adults.¹ Renal cell carcinoma accounts for more than 90% of kidney malignancies in the United States and has 3 main subtypes: clear cell RCC, papillary RCC, and chromophobe RCC.² About 25% of cases metastasize, commonly to the lungs, liver, bones, lymph nodes, contralateral kidney, and adrenal glands.³

Cutaneous metastasis of RCC is rare, with an incidence of approximately 3.3%.⁴ Notably, 80% to 90% of patients with metastatic skin lesions had a prior diagnosis of RCC.² Skin metastases associated with RCC predominantly are found on the face and scalp, appearing as nodular, swiftly expanding, circular, or oval-shaped growths. The robust vascular element of these lesions can lead to confusion with regard to the proper diagnosis, as they often resemble hemangiomas, pyogenic granulomas, or Kaposi sarcomas.⁴

Many cutaneous metastases linked to RCC exhibit a histomorphologic pattern consistent with clear cell adenocarcinoma.² The malignant cells are large and possess transparent cytoplasm, round to oval nuclei, and prominent nucleoli. The cells can form glandular, acinar, or papillary arrangements; extravasated red blood cells frequently are found within the surrounding fibrovascular tissue.⁵ The presence of cytoplasmic glycogen can be revealed through periodic acid–Schiff staining. Other immunohistochemical markers commonly used to identify skin metastasis of RCC include epithelioid membrane antigen, carcinoembryonic antigen, and CD-10.¹

Various mechanisms are involved in the cutaneous metastases of RCC. The most common pathway involves infiltration of the skin directly overlying the malignant renal mass; additional potential mechanisms include the introduction of abnormal cells into the skin during surgical or diagnostic interventions and their dissemination through the lymphatic system or bloodstream.¹ Among urogenital malignancies other than RCC, skin metastases predominantly manifest in the abdominal region.² Conversely, the head and neck region are more frequently impacted in RCC. The vascular composition of these tumors plays a role in facilitating the extension of cancer cells through the bloodstream, fostering the emergence of distant metastases.⁶

The development of cutaneous metastasis in RCC is associated with a poor prognosis, as most patients die within 6 months of detection.³ Treatment options thus are limited and palliative. Although local excision is an alternative treatment for localized cutaneous metastasis, it often provides little benefit in the presence of extensive metastasis; radiotherapy also has been shown to have a limited effect on primary RCC, though its devascularization of the lesion may be effective in metastatic cases.⁵ Immune checkpoint inhibitors such as nivolumab and ipilimumab have improved progression-free survival in patients with metastatic RCC, though uncertainty remains regarding their efficacy in attenuating cutaneous metastasis.^5,6

THE DIAGNOSIS: Metastatic Renal Cell Carcinoma

The shave biopsy revealed large cells with prominent nucleoli, clear cytoplasm, and thin cell borders in a nestlike arrangement (Figure 1). Immunohistochemical examination was negative for cytokeratin 5/6 and positive for PAX8 (Figure 2), which finalized the diagnosis of metastatic renal cell carcinoma (RCC). Later, our patient had a core biopsy-proven metastasis to the C6 spinous process, with concern for additional metastasis to the liver and lungs on positron emission tomography. Our patient’s treatment plan included pembrolizumab and axitinib to manage further cutaneous metastasis and radiation therapy for the C6 spinous process metastasis.

Renal cell carcinoma denotes cancer originating from the renal epithelium and is the most common kidney tumor in adults.¹ Renal cell carcinoma accounts for more than 90% of kidney malignancies in the United States and has 3 main subtypes: clear cell RCC, papillary RCC, and chromophobe RCC.² About 25% of cases metastasize, commonly to the lungs, liver, bones, lymph nodes, contralateral kidney, and adrenal glands.³

Cutaneous metastasis of RCC is rare, with an incidence of approximately 3.3%.⁴ Notably, 80% to 90% of patients with metastatic skin lesions had a prior diagnosis of RCC.² Skin metastases associated with RCC predominantly are found on the face and scalp, appearing as nodular, swiftly expanding, circular, or oval-shaped growths. The robust vascular element of these lesions can lead to confusion with regard to the proper diagnosis, as they often resemble hemangiomas, pyogenic granulomas, or Kaposi sarcomas.⁴

Many cutaneous metastases linked to RCC exhibit a histomorphologic pattern consistent with clear cell adenocarcinoma.² The malignant cells are large and possess transparent cytoplasm, round to oval nuclei, and prominent nucleoli. The cells can form glandular, acinar, or papillary arrangements; extravasated red blood cells frequently are found within the surrounding fibrovascular tissue.⁵ The presence of cytoplasmic glycogen can be revealed through periodic acid–Schiff staining. Other immunohistochemical markers commonly used to identify skin metastasis of RCC include epithelioid membrane antigen, carcinoembryonic antigen, and CD-10.¹

Various mechanisms are involved in the cutaneous metastases of RCC. The most common pathway involves infiltration of the skin directly overlying the malignant renal mass; additional potential mechanisms include the introduction of abnormal cells into the skin during surgical or diagnostic interventions and their dissemination through the lymphatic system or bloodstream.¹ Among urogenital malignancies other than RCC, skin metastases predominantly manifest in the abdominal region.² Conversely, the head and neck region are more frequently impacted in RCC. The vascular composition of these tumors plays a role in facilitating the extension of cancer cells through the bloodstream, fostering the emergence of distant metastases.⁶

The development of cutaneous metastasis in RCC is associated with a poor prognosis, as most patients die within 6 months of detection.³ Treatment options thus are limited and palliative. Although local excision is an alternative treatment for localized cutaneous metastasis, it often provides little benefit in the presence of extensive metastasis; radiotherapy also has been shown to have a limited effect on primary RCC, though its devascularization of the lesion may be effective in metastatic cases.⁵ Immune checkpoint inhibitors such as nivolumab and ipilimumab have improved progression-free survival in patients with metastatic RCC, though uncertainty remains regarding their efficacy in attenuating cutaneous metastasis.^5,6

THE DIAGNOSIS: Metastatic Renal Cell Carcinoma

The shave biopsy revealed large cells with prominent nucleoli, clear cytoplasm, and thin cell borders in a nestlike arrangement (Figure 1). Immunohistochemical examination was negative for cytokeratin 5/6 and positive for PAX8 (Figure 2), which finalized the diagnosis of metastatic renal cell carcinoma (RCC). Later, our patient had a core biopsy-proven metastasis to the C6 spinous process, with concern for additional metastasis to the liver and lungs on positron emission tomography. Our patient’s treatment plan included pembrolizumab and axitinib to manage further cutaneous metastasis and radiation therapy for the C6 spinous process metastasis.

Renal cell carcinoma denotes cancer originating from the renal epithelium and is the most common kidney tumor in adults.¹ Renal cell carcinoma accounts for more than 90% of kidney malignancies in the United States and has 3 main subtypes: clear cell RCC, papillary RCC, and chromophobe RCC.² About 25% of cases metastasize, commonly to the lungs, liver, bones, lymph nodes, contralateral kidney, and adrenal glands.³

Cutaneous metastasis of RCC is rare, with an incidence of approximately 3.3%.⁴ Notably, 80% to 90% of patients with metastatic skin lesions had a prior diagnosis of RCC.² Skin metastases associated with RCC predominantly are found on the face and scalp, appearing as nodular, swiftly expanding, circular, or oval-shaped growths. The robust vascular element of these lesions can lead to confusion with regard to the proper diagnosis, as they often resemble hemangiomas, pyogenic granulomas, or Kaposi sarcomas.⁴

Many cutaneous metastases linked to RCC exhibit a histomorphologic pattern consistent with clear cell adenocarcinoma.² The malignant cells are large and possess transparent cytoplasm, round to oval nuclei, and prominent nucleoli. The cells can form glandular, acinar, or papillary arrangements; extravasated red blood cells frequently are found within the surrounding fibrovascular tissue.⁵ The presence of cytoplasmic glycogen can be revealed through periodic acid–Schiff staining. Other immunohistochemical markers commonly used to identify skin metastasis of RCC include epithelioid membrane antigen, carcinoembryonic antigen, and CD-10.¹

Various mechanisms are involved in the cutaneous metastases of RCC. The most common pathway involves infiltration of the skin directly overlying the malignant renal mass; additional potential mechanisms include the introduction of abnormal cells into the skin during surgical or diagnostic interventions and their dissemination through the lymphatic system or bloodstream.¹ Among urogenital malignancies other than RCC, skin metastases predominantly manifest in the abdominal region.² Conversely, the head and neck region are more frequently impacted in RCC. The vascular composition of these tumors plays a role in facilitating the extension of cancer cells through the bloodstream, fostering the emergence of distant metastases.⁶

The development of cutaneous metastasis in RCC is associated with a poor prognosis, as most patients die within 6 months of detection.³ Treatment options thus are limited and palliative. Although local excision is an alternative treatment for localized cutaneous metastasis, it often provides little benefit in the presence of extensive metastasis; radiotherapy also has been shown to have a limited effect on primary RCC, though its devascularization of the lesion may be effective in metastatic cases.⁵ Immune checkpoint inhibitors such as nivolumab and ipilimumab have improved progression-free survival in patients with metastatic RCC, though uncertainty remains regarding their efficacy in attenuating cutaneous metastasis.^5,6

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Nail-Patella Syndrome

Nail-patella syndrome (NPS) is an autosomaldominant disorder that is present in approximately 1 in 50,000 live births worldwide.^1,2 It manifests with a spectrum of clinical findings affecting the nails, skeletal system, kidneys, and eyes.³ Most cases of NPS are caused by loss-of-function mutations in LMX1B,¹ a gene encoding the LIM homeobox transcription factor.⁴ The LMX1B gene plays a critical role in the dorsoventral patterning of developing limbs.⁵ Mutations of this gene impair the development and function of podocytes and glomerular filtration slits⁶ and have been found to affect the development of the dopaminergic and mesencephalic serotoninergic neurons.² Approximately 5% of patients with NPS have an unexplained genetic cause, suggesting an alternate mechanism for disease.¹ Loss-of-function mutations also were observed in the Wnt inhibitory factor 1 gene (WIF1) in a family with an NPS-like presentation and could represent a novel cause of the condition.¹ Regardless, NPS may be diagnosed clinically based on characteristic medical history, imaging, and physical examination findings.

Nail changes are the most consistent feature of NPS. The nails may be absent, hypoplastic, dystrophic, ridged (horizontally or vertically), or pitted or may demonstrate characteristic triangular lacunae. Nail findings often are congenital, bilateral, and symmetrical. The first digits typically are most severely affected, with progressive improvement appreciated toward the fifth fingers, as seen in our patient. The nail changes can be subtle, sometimes manifesting only as a single triangular lacuna on both thumbnails. Toenail involvement is less common and, when present, tends to be even more discreet. In contrast to the fingernails, the fifth toenails are most commonly affected.⁷

There are many skeletal manifestations of NPS. Patellae may be absent, hypoplastic, or irregularly shaped on physical examination or imaging, and changes may involve one or both knees. The Figure shows plain radiographs of the knees with bilateral patellar subluxation. Elbow dysplasia or radial head subluxation may result in physical limitations in extension, pronation, or supination of the joint.⁷ In approximately 70% of patients seen with the disorder, imaging may reveal symmetric posterior and lateral bony projections from the iliac crests, known as iliac horns; when present, these are considered pathognomonic.⁸

Open-angle glaucoma is the most common ocular finding in NPS. Other less commonly associated eye abnormalities include hyperpigmentation of the pupillary margin (Lester iris).⁶ Renal involvement occurs in 30% to 50% of patients with NPS and is the main predictor of mortality, with percentages as high as 5% to 14%.⁷ Defects occur in the glomerular basement membrane and manifest clinically with hematuria and/or proteinuria. The course of proteinuria is unpredictable. Some cases remit spontaneously, while others remain asymptomatic, progress to nephrotic syndrome, or, although rare, advance to renal failure.^7,9

Bowel symptoms, neurologic problems, vasomotor concerns, thin dental enamel, attention-deficit disorder or attention-deficit/hyperactivity disorder, and major depressive disorder all have been reported in association with NPS.^2,7

Nail psoriasis typically exhibits nail pitting and onycholysis. Other manifestations include subungual hyperkeratosis, oil drop discoloration, and splinter hemorrhages. Topical and intralesional treatments are used to manage symptoms of the disease, as it can become debilitating if left untreated, unlike the nail disease seen in NPS.¹⁰ Onychomycosis can have a similar manifestation to psoriasis with sublingual hyperkeratosis of the nail, but it usually is caused by dermatophytes or yeasts such as Candida albicans. Onycholysis and thickening of the subungual region also can be seen. Diagnosis relies on direct microscopy and fungal culture, and a thorough patient history will help distinguish fungal vs nonfungal etiology. New-generation antifungals are used to eradicate the infection.¹¹ Leukonychia manifests with white-appearing nails due to nail-plate or nail-bed abnormalities. Leukonychia can have multisystem involvement, but nails demonstrate a white discoloration rather than the other abnormalities discussed here.¹² Hypohidrotic ectodermal dysplasia is a rare hereditary congenital disease that affects ectodermal structures and manifests with a triad of symptoms: hypotrichosis, hypohidrosis, and hypodontia. The condition often manifests in childhood with characteristic features such as light-pigmented sparse and fine hair. Physical growth as well as psychomotor development are within normal limits. Neither bone nor renal involvement is typical for hypohidrotic ectodermal dysplasia.¹³

Our case highlights the typical manifestation of NPS with multisystem involvement, demonstrating the complexity of the disease. For cases in which a clinical diagnosis of NPS is uncertain, gene-targeted or comprehensive genomic testing is recommended, as well as genetic counseling. Given the broad spectrum of clinical manifestations, it is imperative that patients undergo screening for musculoskeletal, renal, and ophthalmologic involvement. Treatment is targeted at symptom management and prevention of long-term complications, reliant on clinical presentation, and specific to each patient.

THE DIAGNOSIS: Nail-Patella Syndrome

Nail-patella syndrome (NPS) is an autosomaldominant disorder that is present in approximately 1 in 50,000 live births worldwide.^1,2 It manifests with a spectrum of clinical findings affecting the nails, skeletal system, kidneys, and eyes.³ Most cases of NPS are caused by loss-of-function mutations in LMX1B,¹ a gene encoding the LIM homeobox transcription factor.⁴ The LMX1B gene plays a critical role in the dorsoventral patterning of developing limbs.⁵ Mutations of this gene impair the development and function of podocytes and glomerular filtration slits⁶ and have been found to affect the development of the dopaminergic and mesencephalic serotoninergic neurons.² Approximately 5% of patients with NPS have an unexplained genetic cause, suggesting an alternate mechanism for disease.¹ Loss-of-function mutations also were observed in the Wnt inhibitory factor 1 gene (WIF1) in a family with an NPS-like presentation and could represent a novel cause of the condition.¹ Regardless, NPS may be diagnosed clinically based on characteristic medical history, imaging, and physical examination findings.

Nail changes are the most consistent feature of NPS. The nails may be absent, hypoplastic, dystrophic, ridged (horizontally or vertically), or pitted or may demonstrate characteristic triangular lacunae. Nail findings often are congenital, bilateral, and symmetrical. The first digits typically are most severely affected, with progressive improvement appreciated toward the fifth fingers, as seen in our patient. The nail changes can be subtle, sometimes manifesting only as a single triangular lacuna on both thumbnails. Toenail involvement is less common and, when present, tends to be even more discreet. In contrast to the fingernails, the fifth toenails are most commonly affected.⁷

There are many skeletal manifestations of NPS. Patellae may be absent, hypoplastic, or irregularly shaped on physical examination or imaging, and changes may involve one or both knees. The Figure shows plain radiographs of the knees with bilateral patellar subluxation. Elbow dysplasia or radial head subluxation may result in physical limitations in extension, pronation, or supination of the joint.⁷ In approximately 70% of patients seen with the disorder, imaging may reveal symmetric posterior and lateral bony projections from the iliac crests, known as iliac horns; when present, these are considered pathognomonic.⁸

Open-angle glaucoma is the most common ocular finding in NPS. Other less commonly associated eye abnormalities include hyperpigmentation of the pupillary margin (Lester iris).⁶ Renal involvement occurs in 30% to 50% of patients with NPS and is the main predictor of mortality, with percentages as high as 5% to 14%.⁷ Defects occur in the glomerular basement membrane and manifest clinically with hematuria and/or proteinuria. The course of proteinuria is unpredictable. Some cases remit spontaneously, while others remain asymptomatic, progress to nephrotic syndrome, or, although rare, advance to renal failure.^7,9

Bowel symptoms, neurologic problems, vasomotor concerns, thin dental enamel, attention-deficit disorder or attention-deficit/hyperactivity disorder, and major depressive disorder all have been reported in association with NPS.^2,7

Nail psoriasis typically exhibits nail pitting and onycholysis. Other manifestations include subungual hyperkeratosis, oil drop discoloration, and splinter hemorrhages. Topical and intralesional treatments are used to manage symptoms of the disease, as it can become debilitating if left untreated, unlike the nail disease seen in NPS.¹⁰ Onychomycosis can have a similar manifestation to psoriasis with sublingual hyperkeratosis of the nail, but it usually is caused by dermatophytes or yeasts such as Candida albicans. Onycholysis and thickening of the subungual region also can be seen. Diagnosis relies on direct microscopy and fungal culture, and a thorough patient history will help distinguish fungal vs nonfungal etiology. New-generation antifungals are used to eradicate the infection.¹¹ Leukonychia manifests with white-appearing nails due to nail-plate or nail-bed abnormalities. Leukonychia can have multisystem involvement, but nails demonstrate a white discoloration rather than the other abnormalities discussed here.¹² Hypohidrotic ectodermal dysplasia is a rare hereditary congenital disease that affects ectodermal structures and manifests with a triad of symptoms: hypotrichosis, hypohidrosis, and hypodontia. The condition often manifests in childhood with characteristic features such as light-pigmented sparse and fine hair. Physical growth as well as psychomotor development are within normal limits. Neither bone nor renal involvement is typical for hypohidrotic ectodermal dysplasia.¹³

Our case highlights the typical manifestation of NPS with multisystem involvement, demonstrating the complexity of the disease. For cases in which a clinical diagnosis of NPS is uncertain, gene-targeted or comprehensive genomic testing is recommended, as well as genetic counseling. Given the broad spectrum of clinical manifestations, it is imperative that patients undergo screening for musculoskeletal, renal, and ophthalmologic involvement. Treatment is targeted at symptom management and prevention of long-term complications, reliant on clinical presentation, and specific to each patient.

THE DIAGNOSIS: Nail-Patella Syndrome

Nail-patella syndrome (NPS) is an autosomaldominant disorder that is present in approximately 1 in 50,000 live births worldwide.^1,2 It manifests with a spectrum of clinical findings affecting the nails, skeletal system, kidneys, and eyes.³ Most cases of NPS are caused by loss-of-function mutations in LMX1B,¹ a gene encoding the LIM homeobox transcription factor.⁴ The LMX1B gene plays a critical role in the dorsoventral patterning of developing limbs.⁵ Mutations of this gene impair the development and function of podocytes and glomerular filtration slits⁶ and have been found to affect the development of the dopaminergic and mesencephalic serotoninergic neurons.² Approximately 5% of patients with NPS have an unexplained genetic cause, suggesting an alternate mechanism for disease.¹ Loss-of-function mutations also were observed in the Wnt inhibitory factor 1 gene (WIF1) in a family with an NPS-like presentation and could represent a novel cause of the condition.¹ Regardless, NPS may be diagnosed clinically based on characteristic medical history, imaging, and physical examination findings.

Nail changes are the most consistent feature of NPS. The nails may be absent, hypoplastic, dystrophic, ridged (horizontally or vertically), or pitted or may demonstrate characteristic triangular lacunae. Nail findings often are congenital, bilateral, and symmetrical. The first digits typically are most severely affected, with progressive improvement appreciated toward the fifth fingers, as seen in our patient. The nail changes can be subtle, sometimes manifesting only as a single triangular lacuna on both thumbnails. Toenail involvement is less common and, when present, tends to be even more discreet. In contrast to the fingernails, the fifth toenails are most commonly affected.⁷

There are many skeletal manifestations of NPS. Patellae may be absent, hypoplastic, or irregularly shaped on physical examination or imaging, and changes may involve one or both knees. The Figure shows plain radiographs of the knees with bilateral patellar subluxation. Elbow dysplasia or radial head subluxation may result in physical limitations in extension, pronation, or supination of the joint.⁷ In approximately 70% of patients seen with the disorder, imaging may reveal symmetric posterior and lateral bony projections from the iliac crests, known as iliac horns; when present, these are considered pathognomonic.⁸

Open-angle glaucoma is the most common ocular finding in NPS. Other less commonly associated eye abnormalities include hyperpigmentation of the pupillary margin (Lester iris).⁶ Renal involvement occurs in 30% to 50% of patients with NPS and is the main predictor of mortality, with percentages as high as 5% to 14%.⁷ Defects occur in the glomerular basement membrane and manifest clinically with hematuria and/or proteinuria. The course of proteinuria is unpredictable. Some cases remit spontaneously, while others remain asymptomatic, progress to nephrotic syndrome, or, although rare, advance to renal failure.^7,9

Bowel symptoms, neurologic problems, vasomotor concerns, thin dental enamel, attention-deficit disorder or attention-deficit/hyperactivity disorder, and major depressive disorder all have been reported in association with NPS.^2,7

Nail psoriasis typically exhibits nail pitting and onycholysis. Other manifestations include subungual hyperkeratosis, oil drop discoloration, and splinter hemorrhages. Topical and intralesional treatments are used to manage symptoms of the disease, as it can become debilitating if left untreated, unlike the nail disease seen in NPS.¹⁰ Onychomycosis can have a similar manifestation to psoriasis with sublingual hyperkeratosis of the nail, but it usually is caused by dermatophytes or yeasts such as Candida albicans. Onycholysis and thickening of the subungual region also can be seen. Diagnosis relies on direct microscopy and fungal culture, and a thorough patient history will help distinguish fungal vs nonfungal etiology. New-generation antifungals are used to eradicate the infection.¹¹ Leukonychia manifests with white-appearing nails due to nail-plate or nail-bed abnormalities. Leukonychia can have multisystem involvement, but nails demonstrate a white discoloration rather than the other abnormalities discussed here.¹² Hypohidrotic ectodermal dysplasia is a rare hereditary congenital disease that affects ectodermal structures and manifests with a triad of symptoms: hypotrichosis, hypohidrosis, and hypodontia. The condition often manifests in childhood with characteristic features such as light-pigmented sparse and fine hair. Physical growth as well as psychomotor development are within normal limits. Neither bone nor renal involvement is typical for hypohidrotic ectodermal dysplasia.¹³

Our case highlights the typical manifestation of NPS with multisystem involvement, demonstrating the complexity of the disease. For cases in which a clinical diagnosis of NPS is uncertain, gene-targeted or comprehensive genomic testing is recommended, as well as genetic counseling. Given the broad spectrum of clinical manifestations, it is imperative that patients undergo screening for musculoskeletal, renal, and ophthalmologic involvement. Treatment is targeted at symptom management and prevention of long-term complications, reliant on clinical presentation, and specific to each patient.