Dermatopathology

To the Editor:

A 56-year-old man was referred to our Grand Rounds by another dermatologist in our health system for evaluation of a red scaly rash on the trunk that had been present for more than a year. More recently, over the course of approximately 9 months he experienced recurrent painful penile ulcers that lasted for approximately 4 weeks and then self-resolved. He had a medical history of central retinal vein occlusion, primary hyperparathyroidism, and nonspecific colitis. A family history was notable for lung cancer in the patient’s father and myelodysplastic syndrome and breast cancer in his mother; however, there was no family history of a similar rash. A bacterial culture of the penile ulcer was negative. Testing for antibodies against HIV and herpes simplex virus (HSV) types 1 and 2 was negative. Results of a serum VDRL test were nonreactive, which ruled out syphilis. The patient was treated by the referring dermatologist with azithromycin for possible chancroid without relief.

The patient was being followed by the referring dermatologist who initially was concerned for Degos disease based on clinical examination findings, prompting biopsy of a lesion on the back, which revealed vacuolar interface dermatitis, a sparse superficial perivascular lymphocytic infiltrate, and increased mucin—all highly suspicious for connective tissue disease (Figure 1). An antinuclear antibody test was positive, with a titer of 1:640. The patient was started on prednisone and referred to rheumatology; however, further evaluation by rheumatology for an autoimmune process—including anticardiolipin antibodies—was unremarkable. A few months prior to the current presentation, he also had mildly elevated liver function test results. A colonoscopy was performed, and a biopsy revealed nonspecific colitis. A biopsy of the penile ulcer also was nonspecific, showing only ulceration and acute and chronic inflammation. No epidermal interface change was seen. Results from a Grocott-Gomori methenamine-silver stain, Treponema pallidum immunostain, and HSV polymerase chain reaction were negative for fungal organisms, spirochetes, and HSV, respectively. The differential diagnosis included trauma, aphthous ulceration, and Behçet disease. Behçet disease was suspected by the referring dermatologist, and the patient was treated with colchicine, prednisone, pimecrolimus cream, and topical lidocaine; however, the lesions persisted, and he was subsequently referred to our Grand Rounds for further evaluation.

CT113004033_e_Fig1_AB.jpg

At the current presentation, physical examination revealed several small papules with white atrophic centers and erythematous rims on the trunk and extremities (Figure 2A). An ulceration was noted on the penile shaft (Figure 2B). Further evaluation for Behçet disease, including testing for pathergy and HLA-B51, was negative. Degos disease was strongly suspected clinically, and a repeat biopsy was performed of a lesion on the abdomen, which revealed central epidermal necrosis, atrophy, and parakeratosis with an underlying wedge-shaped dermal infarct surrounded by multiple small occluded dermal vessels, perivascular inflammation, and dermal edema (Figure 3). Direct immunofluorescence was performed using antibodies against IgG, IgA, IgM, fibrinogen, albumin, and C3, which was negative. These findings from direct immunofluorescence and histopathology as well as the clinical presentation were considered compatible with Degos disease. The patient was started on aspirin and pentoxifylline. Pentoxifylline 400 mg twice daily appeared to lessen some of the pain. Pain management specialists started the patient on gabapentin.

CT113004033_e_Fig2_AB.jpg

Approximately 4 months after the Grand Rounds evaluation, during which time he continued treatment with pentoxifylline, he was admitted to the hospital for intractable nausea and vomiting. His condition acutely declined due to bowel perforation, and he was started on eculizumab 1200 mg every 14 days. Because of an increased risk for meningococcal meningitis while on this medication, he also was given erythromycin 500 mg twice daily prophylactically. He was being followed by hematology for the vasculopathy, and they were planning to monitor for any disease changes with computed tomography of the chest, abdomen, and pelvis every 3 months, as well as echocardiogram every 6 months for any development of pericardial or pleural fibrosis. Approximately 1 month later, the patient was admitted to the hospital again but died after 1 week from gastrointestinal complications (approximately 22 months after the onset of the rash).

CT113004033_e_Fig3_AB.jpg

Degos disease (atrophic papulosis) is a rare small vessel vasculopathy of unknown etiology, but complement-mediated endothelial injury plays a role.^1,2 It typically occurs in the fourth decade of life, with a slight female predominance.^3,4 The skin lesions are characteristic and described as 5- to 10-mm papules with atrophic white centers and erythematous telangiectatic rims, most commonly on the upper body and typically sparing the head, palms, and soles.¹ Penile ulceration is an uncommon cutaneous feature, with only a few cases reported in the literature.^5,6 Approximately one-third of patients will have only skin lesions, but two-thirds will develop systemic involvement 1 to 2 years after onset, with the gastrointestinal tract and central nervous system most commonly involved. For those with systemic involvement, the 5-year survival rate is approximately 55%, and the most common causes of death are bowel perforation, peritonitis, and stroke.^3,4 Because some patients appear to never develop systemic complications, Theodoridis et al⁴ proposed that the disease be classified as either malignant atrophic papulosis or benign atrophic papulosis to indicate the malignant systemic form and the benign cutaneous form, respectively.

The histopathology of Degos disease changes as the lesions evolve.⁷ Early lesions show a superficial and deep perivascular and periadnexal lymphocytic infiltrate, possible interface dermatitis, and dermal mucin resembling lupus. The more fully developed lesions show a greater degree of inflammation and interface change as well as lymphocytic vasculitis. This stage also may have epidermal atrophy and early papillary dermal sclerosis resembling lichen sclerosus. The late-stage lesions, clinically observed as papules with atrophic white centers and surrounding erythema, show the classic pathology of wedge-shaped dermal sclerosis and central epidermal atrophy with surrounding hyperkeratosis. Interface dermatitis and dermal mucin can be seen in all stages, though mucin is diminished in the later stage.

Effective treatment options are limited; however, antithrombotics or compounds that facilitate blood perfusion, such as aspirin or pentoxifylline, initially can be used.¹ Eculizumab, a humanized monoclonal antibody that prevents the cleavage of C5, has been used for salvage therapy,⁸ as in our case. Treprostinil, a prostacyclin analog that causes arterial vasodilation and inhibition of platelet aggregation, has been reported to improve bowel and cutaneous lesions, functional status, and neurologic symptoms.⁹

Our case highlights important features of Degos disease. First, it is important for both the clinician and the pathologist to recognize that the histopathology of Degos disease changes as the lesions evolve. In our case, although the lesions were characteristic of Degos disease clinically, the initial biopsy was suspicious for connective tissue disease, which led to an autoimmune evaluation that ultimately was unremarkable. Recognizing that early lesions of Degos disease can resemble connective tissue disease histologically could have prevented this delay in diagnosis. However, Degos disease has been reported in association with autoimmune diseases.¹⁰ Second, although penile ulceration is uncommon, it can be a prominent cutaneous manifestation of the disease. Finally, eculizumab and treprostinil are therapeutic options that have shown some efficacy in improving symptoms and cutaneous lesions.^8,9

To the Editor:

A 56-year-old man was referred to our Grand Rounds by another dermatologist in our health system for evaluation of a red scaly rash on the trunk that had been present for more than a year. More recently, over the course of approximately 9 months he experienced recurrent painful penile ulcers that lasted for approximately 4 weeks and then self-resolved. He had a medical history of central retinal vein occlusion, primary hyperparathyroidism, and nonspecific colitis. A family history was notable for lung cancer in the patient’s father and myelodysplastic syndrome and breast cancer in his mother; however, there was no family history of a similar rash. A bacterial culture of the penile ulcer was negative. Testing for antibodies against HIV and herpes simplex virus (HSV) types 1 and 2 was negative. Results of a serum VDRL test were nonreactive, which ruled out syphilis. The patient was treated by the referring dermatologist with azithromycin for possible chancroid without relief.

The patient was being followed by the referring dermatologist who initially was concerned for Degos disease based on clinical examination findings, prompting biopsy of a lesion on the back, which revealed vacuolar interface dermatitis, a sparse superficial perivascular lymphocytic infiltrate, and increased mucin—all highly suspicious for connective tissue disease (Figure 1). An antinuclear antibody test was positive, with a titer of 1:640. The patient was started on prednisone and referred to rheumatology; however, further evaluation by rheumatology for an autoimmune process—including anticardiolipin antibodies—was unremarkable. A few months prior to the current presentation, he also had mildly elevated liver function test results. A colonoscopy was performed, and a biopsy revealed nonspecific colitis. A biopsy of the penile ulcer also was nonspecific, showing only ulceration and acute and chronic inflammation. No epidermal interface change was seen. Results from a Grocott-Gomori methenamine-silver stain, Treponema pallidum immunostain, and HSV polymerase chain reaction were negative for fungal organisms, spirochetes, and HSV, respectively. The differential diagnosis included trauma, aphthous ulceration, and Behçet disease. Behçet disease was suspected by the referring dermatologist, and the patient was treated with colchicine, prednisone, pimecrolimus cream, and topical lidocaine; however, the lesions persisted, and he was subsequently referred to our Grand Rounds for further evaluation.

CT113004033_e_Fig1_AB.jpg

At the current presentation, physical examination revealed several small papules with white atrophic centers and erythematous rims on the trunk and extremities (Figure 2A). An ulceration was noted on the penile shaft (Figure 2B). Further evaluation for Behçet disease, including testing for pathergy and HLA-B51, was negative. Degos disease was strongly suspected clinically, and a repeat biopsy was performed of a lesion on the abdomen, which revealed central epidermal necrosis, atrophy, and parakeratosis with an underlying wedge-shaped dermal infarct surrounded by multiple small occluded dermal vessels, perivascular inflammation, and dermal edema (Figure 3). Direct immunofluorescence was performed using antibodies against IgG, IgA, IgM, fibrinogen, albumin, and C3, which was negative. These findings from direct immunofluorescence and histopathology as well as the clinical presentation were considered compatible with Degos disease. The patient was started on aspirin and pentoxifylline. Pentoxifylline 400 mg twice daily appeared to lessen some of the pain. Pain management specialists started the patient on gabapentin.

CT113004033_e_Fig2_AB.jpg

Approximately 4 months after the Grand Rounds evaluation, during which time he continued treatment with pentoxifylline, he was admitted to the hospital for intractable nausea and vomiting. His condition acutely declined due to bowel perforation, and he was started on eculizumab 1200 mg every 14 days. Because of an increased risk for meningococcal meningitis while on this medication, he also was given erythromycin 500 mg twice daily prophylactically. He was being followed by hematology for the vasculopathy, and they were planning to monitor for any disease changes with computed tomography of the chest, abdomen, and pelvis every 3 months, as well as echocardiogram every 6 months for any development of pericardial or pleural fibrosis. Approximately 1 month later, the patient was admitted to the hospital again but died after 1 week from gastrointestinal complications (approximately 22 months after the onset of the rash).

CT113004033_e_Fig3_AB.jpg

Degos disease (atrophic papulosis) is a rare small vessel vasculopathy of unknown etiology, but complement-mediated endothelial injury plays a role.^1,2 It typically occurs in the fourth decade of life, with a slight female predominance.^3,4 The skin lesions are characteristic and described as 5- to 10-mm papules with atrophic white centers and erythematous telangiectatic rims, most commonly on the upper body and typically sparing the head, palms, and soles.¹ Penile ulceration is an uncommon cutaneous feature, with only a few cases reported in the literature.^5,6 Approximately one-third of patients will have only skin lesions, but two-thirds will develop systemic involvement 1 to 2 years after onset, with the gastrointestinal tract and central nervous system most commonly involved. For those with systemic involvement, the 5-year survival rate is approximately 55%, and the most common causes of death are bowel perforation, peritonitis, and stroke.^3,4 Because some patients appear to never develop systemic complications, Theodoridis et al⁴ proposed that the disease be classified as either malignant atrophic papulosis or benign atrophic papulosis to indicate the malignant systemic form and the benign cutaneous form, respectively.

The histopathology of Degos disease changes as the lesions evolve.⁷ Early lesions show a superficial and deep perivascular and periadnexal lymphocytic infiltrate, possible interface dermatitis, and dermal mucin resembling lupus. The more fully developed lesions show a greater degree of inflammation and interface change as well as lymphocytic vasculitis. This stage also may have epidermal atrophy and early papillary dermal sclerosis resembling lichen sclerosus. The late-stage lesions, clinically observed as papules with atrophic white centers and surrounding erythema, show the classic pathology of wedge-shaped dermal sclerosis and central epidermal atrophy with surrounding hyperkeratosis. Interface dermatitis and dermal mucin can be seen in all stages, though mucin is diminished in the later stage.

Effective treatment options are limited; however, antithrombotics or compounds that facilitate blood perfusion, such as aspirin or pentoxifylline, initially can be used.¹ Eculizumab, a humanized monoclonal antibody that prevents the cleavage of C5, has been used for salvage therapy,⁸ as in our case. Treprostinil, a prostacyclin analog that causes arterial vasodilation and inhibition of platelet aggregation, has been reported to improve bowel and cutaneous lesions, functional status, and neurologic symptoms.⁹

Our case highlights important features of Degos disease. First, it is important for both the clinician and the pathologist to recognize that the histopathology of Degos disease changes as the lesions evolve. In our case, although the lesions were characteristic of Degos disease clinically, the initial biopsy was suspicious for connective tissue disease, which led to an autoimmune evaluation that ultimately was unremarkable. Recognizing that early lesions of Degos disease can resemble connective tissue disease histologically could have prevented this delay in diagnosis. However, Degos disease has been reported in association with autoimmune diseases.¹⁰ Second, although penile ulceration is uncommon, it can be a prominent cutaneous manifestation of the disease. Finally, eculizumab and treprostinil are therapeutic options that have shown some efficacy in improving symptoms and cutaneous lesions.^8,9

To the Editor:

A 56-year-old man was referred to our Grand Rounds by another dermatologist in our health system for evaluation of a red scaly rash on the trunk that had been present for more than a year. More recently, over the course of approximately 9 months he experienced recurrent painful penile ulcers that lasted for approximately 4 weeks and then self-resolved. He had a medical history of central retinal vein occlusion, primary hyperparathyroidism, and nonspecific colitis. A family history was notable for lung cancer in the patient’s father and myelodysplastic syndrome and breast cancer in his mother; however, there was no family history of a similar rash. A bacterial culture of the penile ulcer was negative. Testing for antibodies against HIV and herpes simplex virus (HSV) types 1 and 2 was negative. Results of a serum VDRL test were nonreactive, which ruled out syphilis. The patient was treated by the referring dermatologist with azithromycin for possible chancroid without relief.

The patient was being followed by the referring dermatologist who initially was concerned for Degos disease based on clinical examination findings, prompting biopsy of a lesion on the back, which revealed vacuolar interface dermatitis, a sparse superficial perivascular lymphocytic infiltrate, and increased mucin—all highly suspicious for connective tissue disease (Figure 1). An antinuclear antibody test was positive, with a titer of 1:640. The patient was started on prednisone and referred to rheumatology; however, further evaluation by rheumatology for an autoimmune process—including anticardiolipin antibodies—was unremarkable. A few months prior to the current presentation, he also had mildly elevated liver function test results. A colonoscopy was performed, and a biopsy revealed nonspecific colitis. A biopsy of the penile ulcer also was nonspecific, showing only ulceration and acute and chronic inflammation. No epidermal interface change was seen. Results from a Grocott-Gomori methenamine-silver stain, Treponema pallidum immunostain, and HSV polymerase chain reaction were negative for fungal organisms, spirochetes, and HSV, respectively. The differential diagnosis included trauma, aphthous ulceration, and Behçet disease. Behçet disease was suspected by the referring dermatologist, and the patient was treated with colchicine, prednisone, pimecrolimus cream, and topical lidocaine; however, the lesions persisted, and he was subsequently referred to our Grand Rounds for further evaluation.

CT113004033_e_Fig1_AB.jpg

At the current presentation, physical examination revealed several small papules with white atrophic centers and erythematous rims on the trunk and extremities (Figure 2A). An ulceration was noted on the penile shaft (Figure 2B). Further evaluation for Behçet disease, including testing for pathergy and HLA-B51, was negative. Degos disease was strongly suspected clinically, and a repeat biopsy was performed of a lesion on the abdomen, which revealed central epidermal necrosis, atrophy, and parakeratosis with an underlying wedge-shaped dermal infarct surrounded by multiple small occluded dermal vessels, perivascular inflammation, and dermal edema (Figure 3). Direct immunofluorescence was performed using antibodies against IgG, IgA, IgM, fibrinogen, albumin, and C3, which was negative. These findings from direct immunofluorescence and histopathology as well as the clinical presentation were considered compatible with Degos disease. The patient was started on aspirin and pentoxifylline. Pentoxifylline 400 mg twice daily appeared to lessen some of the pain. Pain management specialists started the patient on gabapentin.

CT113004033_e_Fig2_AB.jpg

Approximately 4 months after the Grand Rounds evaluation, during which time he continued treatment with pentoxifylline, he was admitted to the hospital for intractable nausea and vomiting. His condition acutely declined due to bowel perforation, and he was started on eculizumab 1200 mg every 14 days. Because of an increased risk for meningococcal meningitis while on this medication, he also was given erythromycin 500 mg twice daily prophylactically. He was being followed by hematology for the vasculopathy, and they were planning to monitor for any disease changes with computed tomography of the chest, abdomen, and pelvis every 3 months, as well as echocardiogram every 6 months for any development of pericardial or pleural fibrosis. Approximately 1 month later, the patient was admitted to the hospital again but died after 1 week from gastrointestinal complications (approximately 22 months after the onset of the rash).

CT113004033_e_Fig3_AB.jpg

Degos disease (atrophic papulosis) is a rare small vessel vasculopathy of unknown etiology, but complement-mediated endothelial injury plays a role.^1,2 It typically occurs in the fourth decade of life, with a slight female predominance.^3,4 The skin lesions are characteristic and described as 5- to 10-mm papules with atrophic white centers and erythematous telangiectatic rims, most commonly on the upper body and typically sparing the head, palms, and soles.¹ Penile ulceration is an uncommon cutaneous feature, with only a few cases reported in the literature.^5,6 Approximately one-third of patients will have only skin lesions, but two-thirds will develop systemic involvement 1 to 2 years after onset, with the gastrointestinal tract and central nervous system most commonly involved. For those with systemic involvement, the 5-year survival rate is approximately 55%, and the most common causes of death are bowel perforation, peritonitis, and stroke.^3,4 Because some patients appear to never develop systemic complications, Theodoridis et al⁴ proposed that the disease be classified as either malignant atrophic papulosis or benign atrophic papulosis to indicate the malignant systemic form and the benign cutaneous form, respectively.

The histopathology of Degos disease changes as the lesions evolve.⁷ Early lesions show a superficial and deep perivascular and periadnexal lymphocytic infiltrate, possible interface dermatitis, and dermal mucin resembling lupus. The more fully developed lesions show a greater degree of inflammation and interface change as well as lymphocytic vasculitis. This stage also may have epidermal atrophy and early papillary dermal sclerosis resembling lichen sclerosus. The late-stage lesions, clinically observed as papules with atrophic white centers and surrounding erythema, show the classic pathology of wedge-shaped dermal sclerosis and central epidermal atrophy with surrounding hyperkeratosis. Interface dermatitis and dermal mucin can be seen in all stages, though mucin is diminished in the later stage.

Effective treatment options are limited; however, antithrombotics or compounds that facilitate blood perfusion, such as aspirin or pentoxifylline, initially can be used.¹ Eculizumab, a humanized monoclonal antibody that prevents the cleavage of C5, has been used for salvage therapy,⁸ as in our case. Treprostinil, a prostacyclin analog that causes arterial vasodilation and inhibition of platelet aggregation, has been reported to improve bowel and cutaneous lesions, functional status, and neurologic symptoms.⁹

Our case highlights important features of Degos disease. First, it is important for both the clinician and the pathologist to recognize that the histopathology of Degos disease changes as the lesions evolve. In our case, although the lesions were characteristic of Degos disease clinically, the initial biopsy was suspicious for connective tissue disease, which led to an autoimmune evaluation that ultimately was unremarkable. Recognizing that early lesions of Degos disease can resemble connective tissue disease histologically could have prevented this delay in diagnosis. However, Degos disease has been reported in association with autoimmune diseases.¹⁰ Second, although penile ulceration is uncommon, it can be a prominent cutaneous manifestation of the disease. Finally, eculizumab and treprostinil are therapeutic options that have shown some efficacy in improving symptoms and cutaneous lesions.^8,9

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

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The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

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The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

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To the Editor:

Sporotrichosis refers to a subacute to chronic fungal infection that usually involves the cutaneous and subcutaneous tissues and is caused by the introduction of Sporothrix, a dimorphic fungus, through the skin. We present a case of chronic atypical lymphocutaneous sporotrichosis.

A 46-year-old man presented to the outpatient dermatology clinic for follow-up for a rash on the right leg that spread to the thigh and became painful and pruritic. It initially developed 8 years prior to the current presentation after he sustained trauma to the leg from an electroshock weapon. One year prior to the current presentation, he had presented to the emergency department and was prescribed doxycycline 100 mg twice daily for 7 days as well as bacitracin ointment. He also was instructed to follow up with dermatology, but a lack of health insurance and other socioeconomic barriers prevented him from seeking dermatologic care. Nine months later, he again presented to the emergency department due to a motor vehicle accident. Computed tomography (CT) of the right leg revealed exophytic dermal masses, inflammatory stranding of the subcutaneous tissue, and right inguinal lymph nodes measuring up to 1.4 cm; there was no osteoarticular involvement. At that time, the patient was applying gentian violet to the skin lesions and taking hydroxyzine 50 mg 3 times daily as needed for pruritus with minimal relief. Financial support was provided for follow-up with dermatology, which occurred almost 5 months later.

At the current presentation, physical examination revealed a large annular plaque with verrucous, scaly, erythematous borders and a hypopigmented atrophic center extending from the medial aspect of the right leg to the posterior thigh. Numerous pink, scaly, crusted nodules were scattered primarily along the periphery, with some evidence of draining sinus tracts. In addition, a fibrotic pink linear plaque extended from the medial right leg to the popliteal fossa, consistent with a keloid. Violet staining along the periphery of the lesion also was appreciated secondary to the application of topical gentian violet (Figure 1).

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Based on the chronic history and morphology, a diagnosis of a chronic fungal or atypical mycobacterial infection was favored. In particular, chromoblastomycosis, cutaneous tuberculosis (eg, scrofuloderma, lupus vulgaris, tuberculosis verrucosa cutis), and atypical mycobacterial infection were highest on the differential, as these conditions often exhibit annular, nodular, verrucous, and/or atrophic lesions. The nodularity, crusting, and draining sinus tracts also raised the possibility of mycetoma. Given the extension of the lesion from the lower to upper leg, a sporotrichoid infection also was considered but was thought to be less likely based on the annular configuration.

Two 4-mm punch biopsies were taken from a peripheral nodule—one for routine histology and another for bacterial, fungal, and mycobacterial cultures. An ­interferon-gamma release assay also was ordered to evaluate for immune responses indicative of prior Mycobacterium tuberculosis infection, but the patient did not obtain this for unknown reasons. Histology demonstrated pseudoepitheliomatous hyperplasia and necrotizing granulomas, which suggested an infectious etiology, but no organisms were identified on tissue staining and all cultures were negative for growth at 6 weeks. The patient was asked to return at that point, and 4 additional scouting biopsies were performed and sent for routine histology, M tuberculosis nucleic acid amplification testing, and microbiologic cultures (ie, bacterial, mycobacterial, fungal, nocardia, actinomycetes). Within 1 week, a filamentous organism with pigmentation visible on the front and back of a Sabouraud dextrose agar plate was identified on fungal culture (Figure 2). Microscopic evaluation of this mold with lactophenol blue stain revealed thin septate hyphae with conidiophores arising at right angles that bore clusters of microconidia (Figure 3). Sequencing analysis ultimately identified this organism as Sporothrix schenckii. Routine histology demonstrated pseudoepitheliomatous hyperplasia with scattered intraepidermal collections of neutrophils (Figure 4). The dermis showed a dense, superficial, and deep infiltrate composed of lymphocytes, histiocytes, and plasma cells with occasional neutrophils and eosinophils. A Grocott-Gomori methenamine-silver stain revealed a cluster of ovoid yeast forms within the stratum corneum (Figure 5). The patient was referred to infectious disease for follow-up and treatment.

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The patient later visited a community clinic providing dermatologic care for patients without insurance. He was started on itraconazole 200 mg daily for a total of 6 months until dermatologic clearance of the cutaneous lesions was observed. He was followed by the clinic with laboratory tests including a liver function test. At follow-up 8 months later, a repeat biopsy was performed to ensure histologic clearance of the sporotrichosis, which revealed a dermal scar and no evidence of residual infection.

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Sporothrix schenckii was first isolated in 1898 by Benjamin Schenck, a student at Johns Hopkins Medicine (Baltimore, Maryland), and identified by a mycologist as sporotricha.¹ Species within the genus Sporothrix are unique in that the fungi are both dimorphic (growing as a mold at 25 °C but as a yeast at 37 °C) and dematiaceous (dark pigmentation from melanin is visible on inspection of the anterior and reverse sides of culture plates). Infection usually occurs when cutaneous or subcutaneous tissues are exposed to the fungus via microabrasions; activities thought to contribute to exposure include gardening, agricultural work, animal husbandry, and feline scratches.² Although skin trauma frequently is considered the primary route of infection, patient recall is variable, with one study noting that only 37.7% of patients recalled trauma and another study similarly demonstrating a patient recall rate of 25%.^3,4

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Lymphocutaneous sporotrichosis is the most common presentation of the fungal infection,⁵ and clinical cases may be classified into 1 of 4 categories: (1) lymphangitic lesions—papules at the site of inoculation with spread along the lymphatic channels; (2) localized (fixed) cutaneous lesions—1 or 2 lesions at the inoculation site; (3) disseminated (multifocal) cutaneous lesions; and (4) extracutaneous lesions.⁶ Extracutaneous manifestations of this infection most notably have been reported as pulmonary disease through inhalation of conidia or through dissemination in immunocompromised hosts.⁷ Our patient’s infection was categorized as lymphangitic lesions due to spread from the lower to upper leg, albeit in a highly atypical, annular fashion. A review of systems was otherwise negative, and CT ruled out osteoarticular involvement.

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In addition to socioeconomic barriers, several factors contributed to a delayed diagnosis in this patient including the annular presentation with central hypopigmentation and atrophy, negative initial microbiological cultures and lack of visualization of organisms on histopathology, and the consequent need for repeat biopsies. For lymphocutaneous sporotrichosis, the typical presentation consists of a papule or ulcerated nodule at the site of inoculation with subsequent linear spread along lymphatic channels. This classic sporotrichoid pattern is a key diagnostic clue for identifying sporotrichosis but was absent at the time our patient presented for medical care. Rather, the sporotrichoid spread seemed to have occurred in a centrifugal fashion up the leg. Few case reports have documented an annular presentation of lymphocutaneous sporotrichosis,^8-13 and one report described central atrophy and hypopigmentation.¹⁰ Pain and pruritus, which were present in our patient, rarely are documented.⁹ Finally, the diagnosis of cutaneous fungal infections may require multiple biopsies due to the variable abundance of viable organisms in tissue specimens as well as the fastidious growth characteristics of these organisms. Furthermore, sensitivity often is low for both fungal and mycobacterial cultures, and cultures may take days to weeks to yield growth.^14,15 For these reasons, empiric therapy and repeat biopsies often are pursued if clinical suspicion is high enough.¹⁶ Our patient returned for multiple scouting biopsies after the initial tissue culture was negative and was even considered for empiric treatment against Mycobacterium prior to positive fungal cultures.

Another unique aspect of our case was the presence of a keloid. It is difficult to know if this keloid was secondary to the trauma the patient sustained in the inciting incident or formed from the fungal infection. Interestingly, it has been hypothesized that fungal infections may contribute to keloid and hypertrophic scar formation.¹⁷ In a case series of 3 patients with either keloids or hypertrophic scars and concomitant tinea infection, there was notable improvement in the appearance of the scars 2 weeks after beginning itraconazole therapy.¹⁷ However, it is not yet known if a fungal infection can contribute to the pathogenesis of keloid formation.

As with other aspects of this case, the length of time the patient went without diagnosis and treatment was unusual and may help explain the atypical presentation. Although the incubation period for S schenckii can vary, most reports identify patients as seeking medical attention within 1 year of rash onset.^18-20 In our case, the patient was not diagnosed until 8 years after his symptoms began, requiring multiple referrals, multiple health system touchpoints, and an institution-specific financial aid program. As such, this case also highlights the potential need for a multidisciplinary team approach when caring for patients with poor access to health care.

In conclusion, this case illustrates a unique presentation of lymphocutaneous sporotrichosis that may mimic other chronic infections and result in delayed diagnosis. Although lymphangitic sporotrichosis generally is recognized as having a linear distribution, mounting evidence from this report and others suggests an annular presentation also is possible. Pruritus or pain is rare but should not preclude a diagnosis of sporotrichosis if present. For patients with limited access to health care resources, it is especially important to involve multiple members of the health care team, including social workers and specialists, to prevent a protracted and severe course of disease.

To the Editor:

Sporotrichosis refers to a subacute to chronic fungal infection that usually involves the cutaneous and subcutaneous tissues and is caused by the introduction of Sporothrix, a dimorphic fungus, through the skin. We present a case of chronic atypical lymphocutaneous sporotrichosis.

A 46-year-old man presented to the outpatient dermatology clinic for follow-up for a rash on the right leg that spread to the thigh and became painful and pruritic. It initially developed 8 years prior to the current presentation after he sustained trauma to the leg from an electroshock weapon. One year prior to the current presentation, he had presented to the emergency department and was prescribed doxycycline 100 mg twice daily for 7 days as well as bacitracin ointment. He also was instructed to follow up with dermatology, but a lack of health insurance and other socioeconomic barriers prevented him from seeking dermatologic care. Nine months later, he again presented to the emergency department due to a motor vehicle accident. Computed tomography (CT) of the right leg revealed exophytic dermal masses, inflammatory stranding of the subcutaneous tissue, and right inguinal lymph nodes measuring up to 1.4 cm; there was no osteoarticular involvement. At that time, the patient was applying gentian violet to the skin lesions and taking hydroxyzine 50 mg 3 times daily as needed for pruritus with minimal relief. Financial support was provided for follow-up with dermatology, which occurred almost 5 months later.

At the current presentation, physical examination revealed a large annular plaque with verrucous, scaly, erythematous borders and a hypopigmented atrophic center extending from the medial aspect of the right leg to the posterior thigh. Numerous pink, scaly, crusted nodules were scattered primarily along the periphery, with some evidence of draining sinus tracts. In addition, a fibrotic pink linear plaque extended from the medial right leg to the popliteal fossa, consistent with a keloid. Violet staining along the periphery of the lesion also was appreciated secondary to the application of topical gentian violet (Figure 1).

CT113004006_e_Fig1_AB.jpg

Based on the chronic history and morphology, a diagnosis of a chronic fungal or atypical mycobacterial infection was favored. In particular, chromoblastomycosis, cutaneous tuberculosis (eg, scrofuloderma, lupus vulgaris, tuberculosis verrucosa cutis), and atypical mycobacterial infection were highest on the differential, as these conditions often exhibit annular, nodular, verrucous, and/or atrophic lesions. The nodularity, crusting, and draining sinus tracts also raised the possibility of mycetoma. Given the extension of the lesion from the lower to upper leg, a sporotrichoid infection also was considered but was thought to be less likely based on the annular configuration.

Two 4-mm punch biopsies were taken from a peripheral nodule—one for routine histology and another for bacterial, fungal, and mycobacterial cultures. An ­interferon-gamma release assay also was ordered to evaluate for immune responses indicative of prior Mycobacterium tuberculosis infection, but the patient did not obtain this for unknown reasons. Histology demonstrated pseudoepitheliomatous hyperplasia and necrotizing granulomas, which suggested an infectious etiology, but no organisms were identified on tissue staining and all cultures were negative for growth at 6 weeks. The patient was asked to return at that point, and 4 additional scouting biopsies were performed and sent for routine histology, M tuberculosis nucleic acid amplification testing, and microbiologic cultures (ie, bacterial, mycobacterial, fungal, nocardia, actinomycetes). Within 1 week, a filamentous organism with pigmentation visible on the front and back of a Sabouraud dextrose agar plate was identified on fungal culture (Figure 2). Microscopic evaluation of this mold with lactophenol blue stain revealed thin septate hyphae with conidiophores arising at right angles that bore clusters of microconidia (Figure 3). Sequencing analysis ultimately identified this organism as Sporothrix schenckii. Routine histology demonstrated pseudoepitheliomatous hyperplasia with scattered intraepidermal collections of neutrophils (Figure 4). The dermis showed a dense, superficial, and deep infiltrate composed of lymphocytes, histiocytes, and plasma cells with occasional neutrophils and eosinophils. A Grocott-Gomori methenamine-silver stain revealed a cluster of ovoid yeast forms within the stratum corneum (Figure 5). The patient was referred to infectious disease for follow-up and treatment.

Aggarwal_2.jpg

The patient later visited a community clinic providing dermatologic care for patients without insurance. He was started on itraconazole 200 mg daily for a total of 6 months until dermatologic clearance of the cutaneous lesions was observed. He was followed by the clinic with laboratory tests including a liver function test. At follow-up 8 months later, a repeat biopsy was performed to ensure histologic clearance of the sporotrichosis, which revealed a dermal scar and no evidence of residual infection.

Aggarwal_3.jpg

Sporothrix schenckii was first isolated in 1898 by Benjamin Schenck, a student at Johns Hopkins Medicine (Baltimore, Maryland), and identified by a mycologist as sporotricha.¹ Species within the genus Sporothrix are unique in that the fungi are both dimorphic (growing as a mold at 25 °C but as a yeast at 37 °C) and dematiaceous (dark pigmentation from melanin is visible on inspection of the anterior and reverse sides of culture plates). Infection usually occurs when cutaneous or subcutaneous tissues are exposed to the fungus via microabrasions; activities thought to contribute to exposure include gardening, agricultural work, animal husbandry, and feline scratches.² Although skin trauma frequently is considered the primary route of infection, patient recall is variable, with one study noting that only 37.7% of patients recalled trauma and another study similarly demonstrating a patient recall rate of 25%.^3,4

Aggarwal_4.jpg

Lymphocutaneous sporotrichosis is the most common presentation of the fungal infection,⁵ and clinical cases may be classified into 1 of 4 categories: (1) lymphangitic lesions—papules at the site of inoculation with spread along the lymphatic channels; (2) localized (fixed) cutaneous lesions—1 or 2 lesions at the inoculation site; (3) disseminated (multifocal) cutaneous lesions; and (4) extracutaneous lesions.⁶ Extracutaneous manifestations of this infection most notably have been reported as pulmonary disease through inhalation of conidia or through dissemination in immunocompromised hosts.⁷ Our patient’s infection was categorized as lymphangitic lesions due to spread from the lower to upper leg, albeit in a highly atypical, annular fashion. A review of systems was otherwise negative, and CT ruled out osteoarticular involvement.

Aggarwal_5.jpg

In addition to socioeconomic barriers, several factors contributed to a delayed diagnosis in this patient including the annular presentation with central hypopigmentation and atrophy, negative initial microbiological cultures and lack of visualization of organisms on histopathology, and the consequent need for repeat biopsies. For lymphocutaneous sporotrichosis, the typical presentation consists of a papule or ulcerated nodule at the site of inoculation with subsequent linear spread along lymphatic channels. This classic sporotrichoid pattern is a key diagnostic clue for identifying sporotrichosis but was absent at the time our patient presented for medical care. Rather, the sporotrichoid spread seemed to have occurred in a centrifugal fashion up the leg. Few case reports have documented an annular presentation of lymphocutaneous sporotrichosis,^8-13 and one report described central atrophy and hypopigmentation.¹⁰ Pain and pruritus, which were present in our patient, rarely are documented.⁹ Finally, the diagnosis of cutaneous fungal infections may require multiple biopsies due to the variable abundance of viable organisms in tissue specimens as well as the fastidious growth characteristics of these organisms. Furthermore, sensitivity often is low for both fungal and mycobacterial cultures, and cultures may take days to weeks to yield growth.^14,15 For these reasons, empiric therapy and repeat biopsies often are pursued if clinical suspicion is high enough.¹⁶ Our patient returned for multiple scouting biopsies after the initial tissue culture was negative and was even considered for empiric treatment against Mycobacterium prior to positive fungal cultures.

Another unique aspect of our case was the presence of a keloid. It is difficult to know if this keloid was secondary to the trauma the patient sustained in the inciting incident or formed from the fungal infection. Interestingly, it has been hypothesized that fungal infections may contribute to keloid and hypertrophic scar formation.¹⁷ In a case series of 3 patients with either keloids or hypertrophic scars and concomitant tinea infection, there was notable improvement in the appearance of the scars 2 weeks after beginning itraconazole therapy.¹⁷ However, it is not yet known if a fungal infection can contribute to the pathogenesis of keloid formation.

As with other aspects of this case, the length of time the patient went without diagnosis and treatment was unusual and may help explain the atypical presentation. Although the incubation period for S schenckii can vary, most reports identify patients as seeking medical attention within 1 year of rash onset.^18-20 In our case, the patient was not diagnosed until 8 years after his symptoms began, requiring multiple referrals, multiple health system touchpoints, and an institution-specific financial aid program. As such, this case also highlights the potential need for a multidisciplinary team approach when caring for patients with poor access to health care.

In conclusion, this case illustrates a unique presentation of lymphocutaneous sporotrichosis that may mimic other chronic infections and result in delayed diagnosis. Although lymphangitic sporotrichosis generally is recognized as having a linear distribution, mounting evidence from this report and others suggests an annular presentation also is possible. Pruritus or pain is rare but should not preclude a diagnosis of sporotrichosis if present. For patients with limited access to health care resources, it is especially important to involve multiple members of the health care team, including social workers and specialists, to prevent a protracted and severe course of disease.

To the Editor:

Sporotrichosis refers to a subacute to chronic fungal infection that usually involves the cutaneous and subcutaneous tissues and is caused by the introduction of Sporothrix, a dimorphic fungus, through the skin. We present a case of chronic atypical lymphocutaneous sporotrichosis.

A 46-year-old man presented to the outpatient dermatology clinic for follow-up for a rash on the right leg that spread to the thigh and became painful and pruritic. It initially developed 8 years prior to the current presentation after he sustained trauma to the leg from an electroshock weapon. One year prior to the current presentation, he had presented to the emergency department and was prescribed doxycycline 100 mg twice daily for 7 days as well as bacitracin ointment. He also was instructed to follow up with dermatology, but a lack of health insurance and other socioeconomic barriers prevented him from seeking dermatologic care. Nine months later, he again presented to the emergency department due to a motor vehicle accident. Computed tomography (CT) of the right leg revealed exophytic dermal masses, inflammatory stranding of the subcutaneous tissue, and right inguinal lymph nodes measuring up to 1.4 cm; there was no osteoarticular involvement. At that time, the patient was applying gentian violet to the skin lesions and taking hydroxyzine 50 mg 3 times daily as needed for pruritus with minimal relief. Financial support was provided for follow-up with dermatology, which occurred almost 5 months later.

At the current presentation, physical examination revealed a large annular plaque with verrucous, scaly, erythematous borders and a hypopigmented atrophic center extending from the medial aspect of the right leg to the posterior thigh. Numerous pink, scaly, crusted nodules were scattered primarily along the periphery, with some evidence of draining sinus tracts. In addition, a fibrotic pink linear plaque extended from the medial right leg to the popliteal fossa, consistent with a keloid. Violet staining along the periphery of the lesion also was appreciated secondary to the application of topical gentian violet (Figure 1).

CT113004006_e_Fig1_AB.jpg

Based on the chronic history and morphology, a diagnosis of a chronic fungal or atypical mycobacterial infection was favored. In particular, chromoblastomycosis, cutaneous tuberculosis (eg, scrofuloderma, lupus vulgaris, tuberculosis verrucosa cutis), and atypical mycobacterial infection were highest on the differential, as these conditions often exhibit annular, nodular, verrucous, and/or atrophic lesions. The nodularity, crusting, and draining sinus tracts also raised the possibility of mycetoma. Given the extension of the lesion from the lower to upper leg, a sporotrichoid infection also was considered but was thought to be less likely based on the annular configuration.

Two 4-mm punch biopsies were taken from a peripheral nodule—one for routine histology and another for bacterial, fungal, and mycobacterial cultures. An ­interferon-gamma release assay also was ordered to evaluate for immune responses indicative of prior Mycobacterium tuberculosis infection, but the patient did not obtain this for unknown reasons. Histology demonstrated pseudoepitheliomatous hyperplasia and necrotizing granulomas, which suggested an infectious etiology, but no organisms were identified on tissue staining and all cultures were negative for growth at 6 weeks. The patient was asked to return at that point, and 4 additional scouting biopsies were performed and sent for routine histology, M tuberculosis nucleic acid amplification testing, and microbiologic cultures (ie, bacterial, mycobacterial, fungal, nocardia, actinomycetes). Within 1 week, a filamentous organism with pigmentation visible on the front and back of a Sabouraud dextrose agar plate was identified on fungal culture (Figure 2). Microscopic evaluation of this mold with lactophenol blue stain revealed thin septate hyphae with conidiophores arising at right angles that bore clusters of microconidia (Figure 3). Sequencing analysis ultimately identified this organism as Sporothrix schenckii. Routine histology demonstrated pseudoepitheliomatous hyperplasia with scattered intraepidermal collections of neutrophils (Figure 4). The dermis showed a dense, superficial, and deep infiltrate composed of lymphocytes, histiocytes, and plasma cells with occasional neutrophils and eosinophils. A Grocott-Gomori methenamine-silver stain revealed a cluster of ovoid yeast forms within the stratum corneum (Figure 5). The patient was referred to infectious disease for follow-up and treatment.

Aggarwal_2.jpg

The patient later visited a community clinic providing dermatologic care for patients without insurance. He was started on itraconazole 200 mg daily for a total of 6 months until dermatologic clearance of the cutaneous lesions was observed. He was followed by the clinic with laboratory tests including a liver function test. At follow-up 8 months later, a repeat biopsy was performed to ensure histologic clearance of the sporotrichosis, which revealed a dermal scar and no evidence of residual infection.

Aggarwal_3.jpg

Sporothrix schenckii was first isolated in 1898 by Benjamin Schenck, a student at Johns Hopkins Medicine (Baltimore, Maryland), and identified by a mycologist as sporotricha.¹ Species within the genus Sporothrix are unique in that the fungi are both dimorphic (growing as a mold at 25 °C but as a yeast at 37 °C) and dematiaceous (dark pigmentation from melanin is visible on inspection of the anterior and reverse sides of culture plates). Infection usually occurs when cutaneous or subcutaneous tissues are exposed to the fungus via microabrasions; activities thought to contribute to exposure include gardening, agricultural work, animal husbandry, and feline scratches.² Although skin trauma frequently is considered the primary route of infection, patient recall is variable, with one study noting that only 37.7% of patients recalled trauma and another study similarly demonstrating a patient recall rate of 25%.^3,4

Aggarwal_4.jpg

Lymphocutaneous sporotrichosis is the most common presentation of the fungal infection,⁵ and clinical cases may be classified into 1 of 4 categories: (1) lymphangitic lesions—papules at the site of inoculation with spread along the lymphatic channels; (2) localized (fixed) cutaneous lesions—1 or 2 lesions at the inoculation site; (3) disseminated (multifocal) cutaneous lesions; and (4) extracutaneous lesions.⁶ Extracutaneous manifestations of this infection most notably have been reported as pulmonary disease through inhalation of conidia or through dissemination in immunocompromised hosts.⁷ Our patient’s infection was categorized as lymphangitic lesions due to spread from the lower to upper leg, albeit in a highly atypical, annular fashion. A review of systems was otherwise negative, and CT ruled out osteoarticular involvement.

Aggarwal_5.jpg

In addition to socioeconomic barriers, several factors contributed to a delayed diagnosis in this patient including the annular presentation with central hypopigmentation and atrophy, negative initial microbiological cultures and lack of visualization of organisms on histopathology, and the consequent need for repeat biopsies. For lymphocutaneous sporotrichosis, the typical presentation consists of a papule or ulcerated nodule at the site of inoculation with subsequent linear spread along lymphatic channels. This classic sporotrichoid pattern is a key diagnostic clue for identifying sporotrichosis but was absent at the time our patient presented for medical care. Rather, the sporotrichoid spread seemed to have occurred in a centrifugal fashion up the leg. Few case reports have documented an annular presentation of lymphocutaneous sporotrichosis,^8-13 and one report described central atrophy and hypopigmentation.¹⁰ Pain and pruritus, which were present in our patient, rarely are documented.⁹ Finally, the diagnosis of cutaneous fungal infections may require multiple biopsies due to the variable abundance of viable organisms in tissue specimens as well as the fastidious growth characteristics of these organisms. Furthermore, sensitivity often is low for both fungal and mycobacterial cultures, and cultures may take days to weeks to yield growth.^14,15 For these reasons, empiric therapy and repeat biopsies often are pursued if clinical suspicion is high enough.¹⁶ Our patient returned for multiple scouting biopsies after the initial tissue culture was negative and was even considered for empiric treatment against Mycobacterium prior to positive fungal cultures.

Another unique aspect of our case was the presence of a keloid. It is difficult to know if this keloid was secondary to the trauma the patient sustained in the inciting incident or formed from the fungal infection. Interestingly, it has been hypothesized that fungal infections may contribute to keloid and hypertrophic scar formation.¹⁷ In a case series of 3 patients with either keloids or hypertrophic scars and concomitant tinea infection, there was notable improvement in the appearance of the scars 2 weeks after beginning itraconazole therapy.¹⁷ However, it is not yet known if a fungal infection can contribute to the pathogenesis of keloid formation.

As with other aspects of this case, the length of time the patient went without diagnosis and treatment was unusual and may help explain the atypical presentation. Although the incubation period for S schenckii can vary, most reports identify patients as seeking medical attention within 1 year of rash onset.^18-20 In our case, the patient was not diagnosed until 8 years after his symptoms began, requiring multiple referrals, multiple health system touchpoints, and an institution-specific financial aid program. As such, this case also highlights the potential need for a multidisciplinary team approach when caring for patients with poor access to health care.

In conclusion, this case illustrates a unique presentation of lymphocutaneous sporotrichosis that may mimic other chronic infections and result in delayed diagnosis. Although lymphangitic sporotrichosis generally is recognized as having a linear distribution, mounting evidence from this report and others suggests an annular presentation also is possible. Pruritus or pain is rare but should not preclude a diagnosis of sporotrichosis if present. For patients with limited access to health care resources, it is especially important to involve multiple members of the health care team, including social workers and specialists, to prevent a protracted and severe course of disease.

To the Editor:

Cases of primary varicella-zoster virus (VZV) are relatively uncommon in the United States since the introduction of the varicella vaccine in 1995, with an overall decline in cases of more than 97%.¹ Prior to the vaccine, 70% of hospitalizations occurred in children; subsequently, hospitalizations among the pediatric population (aged ≤20 years) declined by 97%. Compared to children, adults and immunocompromised patients with VZV infection may present with more severe disease and experience more complications.¹

Most children in the United States are vaccinated against VZV, with 90.3% receiving at least 1 dose by 24 months of age.² However, many countries do not implement universal varicella vaccination for infants.³ As a result, physicians should remember to include primary varicella in the differential when clinically correlated, especially when evaluating patients who have immigrated to the United States or who may be living in unvaccinated communities. We report 2 cases of primary VZV manifesting in adults to remind readers of the salient clinical features of this disease and how dermatologists play a critical role in early and accurate identification of diseases that can have wide-reaching public health implications.

A 26-year-old man with no relevant medical history presented to the emergency department with an itchy and painful rash of 5 days’ duration that began on the trunk and spread to the face, lips, feet, hands, arms, and legs. He also reported shortness of breath, cough, and chills, and he had a temperature of 100.8 °F (38.2 °C). Physical examination revealed numerous erythematous papules and vesiculopustules, some with central umbilication and some with overlying gold crusts (Figure 1).

Richards_Varicella_1.jpg

Later that day, a 47-year-old man with no relevant medical history presented to the same emergency department with a rash along with self-reported fever and sore throat of 3 days’ duration. Physical examination found innumerable erythematous vesicopustules scattered on the face, scalp, neck, trunk, arms, and legs, some with a “dew drop on a rose petal” appearance and some with overlying hemorrhagic crust (Figure 2).

Richards_Varicella_2.jpg

Although infection was of primary concern for the first patient, the presentation of the second patient prompted specific concern for primary VZV infection in both patients, who were placed on airborne and contact isolation precautions.

Skin biopsies from both patients showed acantholytic blisters, hair follicle necrosis, and marked dermal inflammation (Figure 3). Herpetic viral changes were seen in keratinocytes, with steel-grey nuclei, multinucleated keratinocytes, and chromatin margination. An immunostain for VZV was diffusely positive, and VZV antibody IgG was positive (Figure 4).

CT113003016_e_Fig3_AB.jpg

Upon additional questioning, both patients reported recent exposure to VZV-like illnesses in family members without a history of international travel. Neither of the patients was sure of their vaccination status or prior infection history. Both patients received intravenous acyclovir 10 mg/kg administered every 8 hours. Both patients experienced improvement and were discharged after 3 days on oral valacyclovir (1 g 3 times daily for a 7-day treatment course).

Richards_Varicella_4.jpg

The similar presentation and timing of these 2 VZV cases caused concern for an unidentified community outbreak. The infection control team was notified; additionally, per hospital protocol the state health department was alerted as well as the clinicians and staff of the hospital with a request to be vigilant for further cases.

Despite high vaccination rates in the United States, outbreaks of varicella still occur, particularly among unvaccinated individuals, and a robust and efficient response is necessary to control the spread of such outbreaks.⁴ Many states, including Arkansas where our cases occurred, have laws mandating report of VZV cases to the department of health.⁵ Dermatologists play an important role in reporting cases, aiding in diagnosis through recognition of the physical examination findings, obtaining appropriate biopsy, and recommending additional laboratory testing.

Typical skin manifestations include a pruritic rash of macules, papules, vesicles, and crusted lesions distributed throughout the trunk, face, arms, and legs. Because new lesions appear over several days, they will be in different stages of healing, resulting in the simultaneous presence of papules, vesicles, and crusted lesions.⁶ This unique characteristic helps distinguish VZV from other skin diseases such as smallpox or mpox (monkeypox), which generally show lesions in similar stages of evolution.

Biopsy also can aid in identification. Viruses in the herpes family reveal similar histopathologic characteristics, including acantholysis and vesicle formation, intranuclear inclusions with margination of chromatin, multinucleation, and nuclear molding.⁷ Immunohistochemistry can be used to differentiate VZV from herpes simplex virus; however, neither microscopic examination nor immunohistochemistry distinguish primary VZV infection from herpes zoster (HZ).⁸

The mpox rash progresses more slowly than a VZV rash and has a centrifugal rather than central distribution that can involve the palms and soles. Lymphadenopathy is a characteristic finding in mpox.⁹ Rickettsialpox is distinguished from VZV primarily by the appearance of brown or black eschar after the original papulovesicular lesions dry out.¹⁰ Atypical hand, foot, and mouth disease can manifest in adults as widespread papulovesicular lesions. This form is associated with coxsackievirus A6 and may require direct fluorescent antibody assay or polymerase chain reaction of keratinocytes to rule out VZV.¹¹

Herpes zoster occurs in older adults with a history of primary VZV.⁶ It manifests as vesicular lesions confined to 1 or 2 adjacent dermatomes vs the diffuse spread of VZV over the entire body. However, HZ can become disseminated in immunocompromised individuals, making it difficult to clinically distinguish from VZV.⁶ Serology can be helpful, as high IgM titers indicate an acute primary VZV infection. Subsequently increased IgG titers steadily wane over time and spike during reactivation.¹²

Dermatology and infectious disease consultations in our cases yielded a preliminary diagnosis through physical examination that was confirmed by biopsy and subsequent laboratory testing, which allowed for a swift response by the infection control team including isolation precautions to control a potential outbreak. Patients with VZV should remain in respiratory isolation until all lesions have crusted over.⁶

Individuals who had face-to-face indoor contact for at least 5 minutes or who shared a living space with an infected individual should be assessed for VZV immunity, which is defined as confirmed prior immunization or infection.^5,13 Lack of VZV immunity requires postexposure prophylaxis—active immunization for the immunocompetent and passive immunization for the immunocompromised.¹³ Ultimately, no additional cases were reported in the community where our patients resided.

Immunocompetent children with primary VZV require supportive care only. Oral antiviral therapy is the treatment of choice for immunocompetent adults or anyone at increased risk for complications, while intravenous antivirals are recommended for the immunocompromised or those with VZV-related complications.¹⁴ A similar approach is used for HZ. Uncomplicated cases are treated with oral antivirals, and complicated cases (eg, HZ ophthalmicus) are treated with intravenous antivirals.¹⁵ Commonly used antivirals include acyclovir, valacyclovir, and famciclovir.¹⁴

Our cases highlight the ongoing risk for varicella outbreaks in unvaccinated or undervaccinated communities. Physician vigilance is necessary, and dermatology plays a particularly important role in swift and accurate detection of VZV, as demonstrated in our cases by the recognition of classic physical examination findings of erythematous and vesicular papules in each of the patients. Because primary VZV infection can result in life-threatening complications including hepatitis, encephalitis, and pancreatitis, prompt identification and initiation of therapy is important.⁶ Similarly, quick notification of public health officials about detected primary VZV cases is vital to containing potential community outbreaks.

To the Editor:

Cases of primary varicella-zoster virus (VZV) are relatively uncommon in the United States since the introduction of the varicella vaccine in 1995, with an overall decline in cases of more than 97%.¹ Prior to the vaccine, 70% of hospitalizations occurred in children; subsequently, hospitalizations among the pediatric population (aged ≤20 years) declined by 97%. Compared to children, adults and immunocompromised patients with VZV infection may present with more severe disease and experience more complications.¹

Most children in the United States are vaccinated against VZV, with 90.3% receiving at least 1 dose by 24 months of age.² However, many countries do not implement universal varicella vaccination for infants.³ As a result, physicians should remember to include primary varicella in the differential when clinically correlated, especially when evaluating patients who have immigrated to the United States or who may be living in unvaccinated communities. We report 2 cases of primary VZV manifesting in adults to remind readers of the salient clinical features of this disease and how dermatologists play a critical role in early and accurate identification of diseases that can have wide-reaching public health implications.

A 26-year-old man with no relevant medical history presented to the emergency department with an itchy and painful rash of 5 days’ duration that began on the trunk and spread to the face, lips, feet, hands, arms, and legs. He also reported shortness of breath, cough, and chills, and he had a temperature of 100.8 °F (38.2 °C). Physical examination revealed numerous erythematous papules and vesiculopustules, some with central umbilication and some with overlying gold crusts (Figure 1).

Richards_Varicella_1.jpg

Later that day, a 47-year-old man with no relevant medical history presented to the same emergency department with a rash along with self-reported fever and sore throat of 3 days’ duration. Physical examination found innumerable erythematous vesicopustules scattered on the face, scalp, neck, trunk, arms, and legs, some with a “dew drop on a rose petal” appearance and some with overlying hemorrhagic crust (Figure 2).

Richards_Varicella_2.jpg

Although infection was of primary concern for the first patient, the presentation of the second patient prompted specific concern for primary VZV infection in both patients, who were placed on airborne and contact isolation precautions.

Skin biopsies from both patients showed acantholytic blisters, hair follicle necrosis, and marked dermal inflammation (Figure 3). Herpetic viral changes were seen in keratinocytes, with steel-grey nuclei, multinucleated keratinocytes, and chromatin margination. An immunostain for VZV was diffusely positive, and VZV antibody IgG was positive (Figure 4).

CT113003016_e_Fig3_AB.jpg

Upon additional questioning, both patients reported recent exposure to VZV-like illnesses in family members without a history of international travel. Neither of the patients was sure of their vaccination status or prior infection history. Both patients received intravenous acyclovir 10 mg/kg administered every 8 hours. Both patients experienced improvement and were discharged after 3 days on oral valacyclovir (1 g 3 times daily for a 7-day treatment course).

Richards_Varicella_4.jpg

The similar presentation and timing of these 2 VZV cases caused concern for an unidentified community outbreak. The infection control team was notified; additionally, per hospital protocol the state health department was alerted as well as the clinicians and staff of the hospital with a request to be vigilant for further cases.

Despite high vaccination rates in the United States, outbreaks of varicella still occur, particularly among unvaccinated individuals, and a robust and efficient response is necessary to control the spread of such outbreaks.⁴ Many states, including Arkansas where our cases occurred, have laws mandating report of VZV cases to the department of health.⁵ Dermatologists play an important role in reporting cases, aiding in diagnosis through recognition of the physical examination findings, obtaining appropriate biopsy, and recommending additional laboratory testing.

Typical skin manifestations include a pruritic rash of macules, papules, vesicles, and crusted lesions distributed throughout the trunk, face, arms, and legs. Because new lesions appear over several days, they will be in different stages of healing, resulting in the simultaneous presence of papules, vesicles, and crusted lesions.⁶ This unique characteristic helps distinguish VZV from other skin diseases such as smallpox or mpox (monkeypox), which generally show lesions in similar stages of evolution.

Biopsy also can aid in identification. Viruses in the herpes family reveal similar histopathologic characteristics, including acantholysis and vesicle formation, intranuclear inclusions with margination of chromatin, multinucleation, and nuclear molding.⁷ Immunohistochemistry can be used to differentiate VZV from herpes simplex virus; however, neither microscopic examination nor immunohistochemistry distinguish primary VZV infection from herpes zoster (HZ).⁸

The mpox rash progresses more slowly than a VZV rash and has a centrifugal rather than central distribution that can involve the palms and soles. Lymphadenopathy is a characteristic finding in mpox.⁹ Rickettsialpox is distinguished from VZV primarily by the appearance of brown or black eschar after the original papulovesicular lesions dry out.¹⁰ Atypical hand, foot, and mouth disease can manifest in adults as widespread papulovesicular lesions. This form is associated with coxsackievirus A6 and may require direct fluorescent antibody assay or polymerase chain reaction of keratinocytes to rule out VZV.¹¹

Herpes zoster occurs in older adults with a history of primary VZV.⁶ It manifests as vesicular lesions confined to 1 or 2 adjacent dermatomes vs the diffuse spread of VZV over the entire body. However, HZ can become disseminated in immunocompromised individuals, making it difficult to clinically distinguish from VZV.⁶ Serology can be helpful, as high IgM titers indicate an acute primary VZV infection. Subsequently increased IgG titers steadily wane over time and spike during reactivation.¹²

Dermatology and infectious disease consultations in our cases yielded a preliminary diagnosis through physical examination that was confirmed by biopsy and subsequent laboratory testing, which allowed for a swift response by the infection control team including isolation precautions to control a potential outbreak. Patients with VZV should remain in respiratory isolation until all lesions have crusted over.⁶

Individuals who had face-to-face indoor contact for at least 5 minutes or who shared a living space with an infected individual should be assessed for VZV immunity, which is defined as confirmed prior immunization or infection.^5,13 Lack of VZV immunity requires postexposure prophylaxis—active immunization for the immunocompetent and passive immunization for the immunocompromised.¹³ Ultimately, no additional cases were reported in the community where our patients resided.

Immunocompetent children with primary VZV require supportive care only. Oral antiviral therapy is the treatment of choice for immunocompetent adults or anyone at increased risk for complications, while intravenous antivirals are recommended for the immunocompromised or those with VZV-related complications.¹⁴ A similar approach is used for HZ. Uncomplicated cases are treated with oral antivirals, and complicated cases (eg, HZ ophthalmicus) are treated with intravenous antivirals.¹⁵ Commonly used antivirals include acyclovir, valacyclovir, and famciclovir.¹⁴

Our cases highlight the ongoing risk for varicella outbreaks in unvaccinated or undervaccinated communities. Physician vigilance is necessary, and dermatology plays a particularly important role in swift and accurate detection of VZV, as demonstrated in our cases by the recognition of classic physical examination findings of erythematous and vesicular papules in each of the patients. Because primary VZV infection can result in life-threatening complications including hepatitis, encephalitis, and pancreatitis, prompt identification and initiation of therapy is important.⁶ Similarly, quick notification of public health officials about detected primary VZV cases is vital to containing potential community outbreaks.

To the Editor:

Cases of primary varicella-zoster virus (VZV) are relatively uncommon in the United States since the introduction of the varicella vaccine in 1995, with an overall decline in cases of more than 97%.¹ Prior to the vaccine, 70% of hospitalizations occurred in children; subsequently, hospitalizations among the pediatric population (aged ≤20 years) declined by 97%. Compared to children, adults and immunocompromised patients with VZV infection may present with more severe disease and experience more complications.¹

Most children in the United States are vaccinated against VZV, with 90.3% receiving at least 1 dose by 24 months of age.² However, many countries do not implement universal varicella vaccination for infants.³ As a result, physicians should remember to include primary varicella in the differential when clinically correlated, especially when evaluating patients who have immigrated to the United States or who may be living in unvaccinated communities. We report 2 cases of primary VZV manifesting in adults to remind readers of the salient clinical features of this disease and how dermatologists play a critical role in early and accurate identification of diseases that can have wide-reaching public health implications.

A 26-year-old man with no relevant medical history presented to the emergency department with an itchy and painful rash of 5 days’ duration that began on the trunk and spread to the face, lips, feet, hands, arms, and legs. He also reported shortness of breath, cough, and chills, and he had a temperature of 100.8 °F (38.2 °C). Physical examination revealed numerous erythematous papules and vesiculopustules, some with central umbilication and some with overlying gold crusts (Figure 1).

Richards_Varicella_1.jpg

Later that day, a 47-year-old man with no relevant medical history presented to the same emergency department with a rash along with self-reported fever and sore throat of 3 days’ duration. Physical examination found innumerable erythematous vesicopustules scattered on the face, scalp, neck, trunk, arms, and legs, some with a “dew drop on a rose petal” appearance and some with overlying hemorrhagic crust (Figure 2).

Richards_Varicella_2.jpg

Although infection was of primary concern for the first patient, the presentation of the second patient prompted specific concern for primary VZV infection in both patients, who were placed on airborne and contact isolation precautions.

Skin biopsies from both patients showed acantholytic blisters, hair follicle necrosis, and marked dermal inflammation (Figure 3). Herpetic viral changes were seen in keratinocytes, with steel-grey nuclei, multinucleated keratinocytes, and chromatin margination. An immunostain for VZV was diffusely positive, and VZV antibody IgG was positive (Figure 4).

CT113003016_e_Fig3_AB.jpg

Upon additional questioning, both patients reported recent exposure to VZV-like illnesses in family members without a history of international travel. Neither of the patients was sure of their vaccination status or prior infection history. Both patients received intravenous acyclovir 10 mg/kg administered every 8 hours. Both patients experienced improvement and were discharged after 3 days on oral valacyclovir (1 g 3 times daily for a 7-day treatment course).

Richards_Varicella_4.jpg

The similar presentation and timing of these 2 VZV cases caused concern for an unidentified community outbreak. The infection control team was notified; additionally, per hospital protocol the state health department was alerted as well as the clinicians and staff of the hospital with a request to be vigilant for further cases.

Despite high vaccination rates in the United States, outbreaks of varicella still occur, particularly among unvaccinated individuals, and a robust and efficient response is necessary to control the spread of such outbreaks.⁴ Many states, including Arkansas where our cases occurred, have laws mandating report of VZV cases to the department of health.⁵ Dermatologists play an important role in reporting cases, aiding in diagnosis through recognition of the physical examination findings, obtaining appropriate biopsy, and recommending additional laboratory testing.

Typical skin manifestations include a pruritic rash of macules, papules, vesicles, and crusted lesions distributed throughout the trunk, face, arms, and legs. Because new lesions appear over several days, they will be in different stages of healing, resulting in the simultaneous presence of papules, vesicles, and crusted lesions.⁶ This unique characteristic helps distinguish VZV from other skin diseases such as smallpox or mpox (monkeypox), which generally show lesions in similar stages of evolution.

Biopsy also can aid in identification. Viruses in the herpes family reveal similar histopathologic characteristics, including acantholysis and vesicle formation, intranuclear inclusions with margination of chromatin, multinucleation, and nuclear molding.⁷ Immunohistochemistry can be used to differentiate VZV from herpes simplex virus; however, neither microscopic examination nor immunohistochemistry distinguish primary VZV infection from herpes zoster (HZ).⁸

The mpox rash progresses more slowly than a VZV rash and has a centrifugal rather than central distribution that can involve the palms and soles. Lymphadenopathy is a characteristic finding in mpox.⁹ Rickettsialpox is distinguished from VZV primarily by the appearance of brown or black eschar after the original papulovesicular lesions dry out.¹⁰ Atypical hand, foot, and mouth disease can manifest in adults as widespread papulovesicular lesions. This form is associated with coxsackievirus A6 and may require direct fluorescent antibody assay or polymerase chain reaction of keratinocytes to rule out VZV.¹¹

Herpes zoster occurs in older adults with a history of primary VZV.⁶ It manifests as vesicular lesions confined to 1 or 2 adjacent dermatomes vs the diffuse spread of VZV over the entire body. However, HZ can become disseminated in immunocompromised individuals, making it difficult to clinically distinguish from VZV.⁶ Serology can be helpful, as high IgM titers indicate an acute primary VZV infection. Subsequently increased IgG titers steadily wane over time and spike during reactivation.¹²

Dermatology and infectious disease consultations in our cases yielded a preliminary diagnosis through physical examination that was confirmed by biopsy and subsequent laboratory testing, which allowed for a swift response by the infection control team including isolation precautions to control a potential outbreak. Patients with VZV should remain in respiratory isolation until all lesions have crusted over.⁶

Individuals who had face-to-face indoor contact for at least 5 minutes or who shared a living space with an infected individual should be assessed for VZV immunity, which is defined as confirmed prior immunization or infection.^5,13 Lack of VZV immunity requires postexposure prophylaxis—active immunization for the immunocompetent and passive immunization for the immunocompromised.¹³ Ultimately, no additional cases were reported in the community where our patients resided.

Immunocompetent children with primary VZV require supportive care only. Oral antiviral therapy is the treatment of choice for immunocompetent adults or anyone at increased risk for complications, while intravenous antivirals are recommended for the immunocompromised or those with VZV-related complications.¹⁴ A similar approach is used for HZ. Uncomplicated cases are treated with oral antivirals, and complicated cases (eg, HZ ophthalmicus) are treated with intravenous antivirals.¹⁵ Commonly used antivirals include acyclovir, valacyclovir, and famciclovir.¹⁴

Our cases highlight the ongoing risk for varicella outbreaks in unvaccinated or undervaccinated communities. Physician vigilance is necessary, and dermatology plays a particularly important role in swift and accurate detection of VZV, as demonstrated in our cases by the recognition of classic physical examination findings of erythematous and vesicular papules in each of the patients. Because primary VZV infection can result in life-threatening complications including hepatitis, encephalitis, and pancreatitis, prompt identification and initiation of therapy is important.⁶ Similarly, quick notification of public health officials about detected primary VZV cases is vital to containing potential community outbreaks.

A retrospective analysis of Medicare data revealed that between 2000 and 2017, immunohistochemistry (IHC) claims associated with melanoma diagnoses grew from 11% to 51%. Rising utilization — and substantial geographic variation in practice patterns — argue for further research to optimize IHC use in the diagnoses of melanoma, according to the authors.

But with sparse guidance regarding best practices for IHC in melanoma diagnosis, concerns for appropriate use are rising, they wrote in their report, recently published in JAMA Dermatology.

Kenechukwu Ojukwu, MD, MPP, of the department of pathology and laboratory medicine, University of California, Los Angeles, and coinvestigators, searched the Surveillance, Epidemiology, and End Results (SEER)–Medicare database for incident in situ or invasive cutaneous melanoma in patients 65 years and older and accompanying IHC claims made during the month of diagnosis through 14 days afterward.

Among 132,547 melanomas in 116,117 patients, 43,396 (33%) had accompanying IHC claims. Such claims were less common with increasing age, declining from 44% in patients aged 65-74 years to 18% in patients 85 aged years and older. Although melanoma incidence increased throughout the period studied, melanoma mortality rates remained relatively stable.

By summary stage at diagnosis, IHC utilization ranged from 29% of in situ cases to 75% of distant cases. After the researchers controlled for year of diagnosis, IHC use was statistically significantly associated with all demographic, tumor, and geographic characteristics examined, except race and ethnicity. Across all the years of the study, regional usage ranged from a low of 22% in Detroit to a high of 44% in both Louisiana and San Jose-Monterey, California. Figures for 2017 ranged from 39% of cases in Kentucky and Atlanta to 68% in New Mexico.

[embed:render:related:node:268401]

“Given the extensive use of IHC in clinical practice,” the authors concluded, “studies examining the resulting outcomes of IHC on different domains, such as symptom burden, quality of life, and mortality, are crucial.”

The “notable” regional variation in IHC utilization suggests uncertainty about its optimal employment in clinical practice, and, they wrote, “these findings highlight the need for research to identify where IHC provides the most value and to develop guidelines regarding the appropriate use of IHC.”

In an accompanying JAMA Dermatology editorial, Alexandra Flamm, MD, wrote, “now is an exciting time to practice dermatopathology, with an increased number of ancillary tests, such as IHC, that can be used to diagnose malignant neoplasms more precisely and to more accurately determine prognosis and therapeutic options in this age of precision medicine”.

However, added Dr. Flamm, a dermatologist and dermatopathologist at New York University, New York City, the increasing number of ancillary tests is fueling awareness of appropriate use and the importance of ensuring high-quality, value-based healthcare. “With this increased scrutiny on the appropriateness of ancillary histopathologic testing within dermatopathology,” she wrote, “the need is growing for parameters that can be used to guide when to use IHC testing and other ancillary testing.” And using dermatopathologist-developed tools such as American Society of Dermatopathology guidelines for 11 IHC tests can help ensure that appropriate medical decision-making is taken into account when creating these tools, she added.

IHC Usage Growing

“The paper confirms what I already knew,” said Whitney High, MD, JD, who was not involved with the study and was asked to comment on the results. “Use of IHC in dermatopathology has increased substantially, and probably will continue to increase over time.” The societal burden of IHC costs represents a legitimate concern, said Dr. High, professor of dermatology and pathology and director of dermatopathology at the University of Colorado, Aurora.

“However,” he told this news organization, “the histologic diagnosis of melanoma is sometimes substantially subjective — and all physicians, including pathologists, even though they are not providing care in the physical presence of the patient, are fiduciaries.” If an IHC stain would meaningfully improve a patient’s care, he said, physicians should attempt to provide it, unless strictly disallowed by a payer. Controlling medical-care costs might be better left to professional societies to guide care standards over time, he noted.

High_Whitney_COLO_web.jpg

A retrospective analysis of Medicare data revealed that between 2000 and 2017, immunohistochemistry (IHC) claims associated with melanoma diagnoses grew from 11% to 51%. Rising utilization — and substantial geographic variation in practice patterns — argue for further research to optimize IHC use in the diagnoses of melanoma, according to the authors.

But with sparse guidance regarding best practices for IHC in melanoma diagnosis, concerns for appropriate use are rising, they wrote in their report, recently published in JAMA Dermatology.

Kenechukwu Ojukwu, MD, MPP, of the department of pathology and laboratory medicine, University of California, Los Angeles, and coinvestigators, searched the Surveillance, Epidemiology, and End Results (SEER)–Medicare database for incident in situ or invasive cutaneous melanoma in patients 65 years and older and accompanying IHC claims made during the month of diagnosis through 14 days afterward.

Among 132,547 melanomas in 116,117 patients, 43,396 (33%) had accompanying IHC claims. Such claims were less common with increasing age, declining from 44% in patients aged 65-74 years to 18% in patients 85 aged years and older. Although melanoma incidence increased throughout the period studied, melanoma mortality rates remained relatively stable.

By summary stage at diagnosis, IHC utilization ranged from 29% of in situ cases to 75% of distant cases. After the researchers controlled for year of diagnosis, IHC use was statistically significantly associated with all demographic, tumor, and geographic characteristics examined, except race and ethnicity. Across all the years of the study, regional usage ranged from a low of 22% in Detroit to a high of 44% in both Louisiana and San Jose-Monterey, California. Figures for 2017 ranged from 39% of cases in Kentucky and Atlanta to 68% in New Mexico.

[embed:render:related:node:268401]

“Given the extensive use of IHC in clinical practice,” the authors concluded, “studies examining the resulting outcomes of IHC on different domains, such as symptom burden, quality of life, and mortality, are crucial.”

The “notable” regional variation in IHC utilization suggests uncertainty about its optimal employment in clinical practice, and, they wrote, “these findings highlight the need for research to identify where IHC provides the most value and to develop guidelines regarding the appropriate use of IHC.”

In an accompanying JAMA Dermatology editorial, Alexandra Flamm, MD, wrote, “now is an exciting time to practice dermatopathology, with an increased number of ancillary tests, such as IHC, that can be used to diagnose malignant neoplasms more precisely and to more accurately determine prognosis and therapeutic options in this age of precision medicine”.

However, added Dr. Flamm, a dermatologist and dermatopathologist at New York University, New York City, the increasing number of ancillary tests is fueling awareness of appropriate use and the importance of ensuring high-quality, value-based healthcare. “With this increased scrutiny on the appropriateness of ancillary histopathologic testing within dermatopathology,” she wrote, “the need is growing for parameters that can be used to guide when to use IHC testing and other ancillary testing.” And using dermatopathologist-developed tools such as American Society of Dermatopathology guidelines for 11 IHC tests can help ensure that appropriate medical decision-making is taken into account when creating these tools, she added.

IHC Usage Growing

“The paper confirms what I already knew,” said Whitney High, MD, JD, who was not involved with the study and was asked to comment on the results. “Use of IHC in dermatopathology has increased substantially, and probably will continue to increase over time.” The societal burden of IHC costs represents a legitimate concern, said Dr. High, professor of dermatology and pathology and director of dermatopathology at the University of Colorado, Aurora.

“However,” he told this news organization, “the histologic diagnosis of melanoma is sometimes substantially subjective — and all physicians, including pathologists, even though they are not providing care in the physical presence of the patient, are fiduciaries.” If an IHC stain would meaningfully improve a patient’s care, he said, physicians should attempt to provide it, unless strictly disallowed by a payer. Controlling medical-care costs might be better left to professional societies to guide care standards over time, he noted.

High_Whitney_COLO_web.jpg

A retrospective analysis of Medicare data revealed that between 2000 and 2017, immunohistochemistry (IHC) claims associated with melanoma diagnoses grew from 11% to 51%. Rising utilization — and substantial geographic variation in practice patterns — argue for further research to optimize IHC use in the diagnoses of melanoma, according to the authors.

But with sparse guidance regarding best practices for IHC in melanoma diagnosis, concerns for appropriate use are rising, they wrote in their report, recently published in JAMA Dermatology.

Kenechukwu Ojukwu, MD, MPP, of the department of pathology and laboratory medicine, University of California, Los Angeles, and coinvestigators, searched the Surveillance, Epidemiology, and End Results (SEER)–Medicare database for incident in situ or invasive cutaneous melanoma in patients 65 years and older and accompanying IHC claims made during the month of diagnosis through 14 days afterward.

Among 132,547 melanomas in 116,117 patients, 43,396 (33%) had accompanying IHC claims. Such claims were less common with increasing age, declining from 44% in patients aged 65-74 years to 18% in patients 85 aged years and older. Although melanoma incidence increased throughout the period studied, melanoma mortality rates remained relatively stable.

By summary stage at diagnosis, IHC utilization ranged from 29% of in situ cases to 75% of distant cases. After the researchers controlled for year of diagnosis, IHC use was statistically significantly associated with all demographic, tumor, and geographic characteristics examined, except race and ethnicity. Across all the years of the study, regional usage ranged from a low of 22% in Detroit to a high of 44% in both Louisiana and San Jose-Monterey, California. Figures for 2017 ranged from 39% of cases in Kentucky and Atlanta to 68% in New Mexico.

[embed:render:related:node:268401]

“Given the extensive use of IHC in clinical practice,” the authors concluded, “studies examining the resulting outcomes of IHC on different domains, such as symptom burden, quality of life, and mortality, are crucial.”

The “notable” regional variation in IHC utilization suggests uncertainty about its optimal employment in clinical practice, and, they wrote, “these findings highlight the need for research to identify where IHC provides the most value and to develop guidelines regarding the appropriate use of IHC.”

In an accompanying JAMA Dermatology editorial, Alexandra Flamm, MD, wrote, “now is an exciting time to practice dermatopathology, with an increased number of ancillary tests, such as IHC, that can be used to diagnose malignant neoplasms more precisely and to more accurately determine prognosis and therapeutic options in this age of precision medicine”.

However, added Dr. Flamm, a dermatologist and dermatopathologist at New York University, New York City, the increasing number of ancillary tests is fueling awareness of appropriate use and the importance of ensuring high-quality, value-based healthcare. “With this increased scrutiny on the appropriateness of ancillary histopathologic testing within dermatopathology,” she wrote, “the need is growing for parameters that can be used to guide when to use IHC testing and other ancillary testing.” And using dermatopathologist-developed tools such as American Society of Dermatopathology guidelines for 11 IHC tests can help ensure that appropriate medical decision-making is taken into account when creating these tools, she added.

IHC Usage Growing

“The paper confirms what I already knew,” said Whitney High, MD, JD, who was not involved with the study and was asked to comment on the results. “Use of IHC in dermatopathology has increased substantially, and probably will continue to increase over time.” The societal burden of IHC costs represents a legitimate concern, said Dr. High, professor of dermatology and pathology and director of dermatopathology at the University of Colorado, Aurora.

“However,” he told this news organization, “the histologic diagnosis of melanoma is sometimes substantially subjective — and all physicians, including pathologists, even though they are not providing care in the physical presence of the patient, are fiduciaries.” If an IHC stain would meaningfully improve a patient’s care, he said, physicians should attempt to provide it, unless strictly disallowed by a payer. Controlling medical-care costs might be better left to professional societies to guide care standards over time, he noted.

High_Whitney_COLO_web.jpg

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

Cutaneous plasmacytoma initially was suspected because of the patient’s history of monoclonal gammopathy as well as angiosarcoma due to the purpuric vascular appearance of the lesions. However, histopathology revealed a pleomorphic cellular dermal infiltrate characterized by atypical cells with mediumlarge nuclei, fine chromatin, and small nucleoli; the cells also had little cytoplasm (Figure). The infiltrate did not involve the epidermis but extended into the subcutaneous tissue. Immunohistochemistry revealed that the cells were positive for CD45, CD43, CD4, CD7, CD56, CD123, CD33, T-cell leukemia/lymphoma protein 1, and CD68. The cells were negative for CD2, CD3, CD5, CD8, T-cell intracellular antigen 1, CD13, CD15, CD19, CD20, CD21, CD23, cyclin D1, Bcl-2, Bcl-6, CD10, PAX5, MUM1, lysozyme, myeloperoxidase, perforin, granzyme B, CD57, CD34, CD117, terminal deoxynucleotidyl transferase, activin receptorlike kinase 1 βF1, Epstein-Barr virus– encoded small RNA, CD30, CD163, and pancytokeratin. Thus, the clinical and histopathologic findings led to a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy.

CT113003025_e_FigAB.jpg

Blastic plasmacytoid dendritic cell neoplasm affects males older than 60 years.¹ It is characterized by the clonal proliferation of precursor plasmacytoid dendritic cells—otherwise known as professional type I interferonproducing cells or plasmacytoid monocytes—of myeloid origin. Plasmacytoid dendritic cells have been renamed on several occasions, reflecting uncertainties of their histogenesis. The diagnosis of BPDCN requires a biopsy showing the morphology of plasmacytoid dendritic blast cells and immunophenotypic criteria established by either immunohistochemistry or flow cytometry.^2,3 Tumor cells morphologically show an immature blastic appearance, and the diagnosis rests upon the demonstration of CD4 and CD56, together with markers more restricted to plasmacytoid dendritic cells (eg, BDCA-2, CD123, T-cell leukemia/lymphoma protein 1, CD2AP, BCL11A) and negativity for lymphoid and myeloid lineage–associated antigens.^1,4

Blastic plasmacytoid dendritic cell neoplasms account for less than 1% of all hematopoietic neoplasms. Cutaneous lesions occur in 64% of patients with the disease and often are the reason patients seek medical care.⁵ Clinical findings include numerous erythematous and violaceous papules, nodules, and plaques that resemble purpura or vasculitis. Cutaneous lesions can vary in size from a few millimeters to 10 cm and vary in color. Moreover, patients often present with bruiselike patches, disseminated lesions, or mucosal lesions.¹ Extracutaneous involvement includes lymphadenopathy, splenomegaly, and cytopenia caused by bone marrow infiltration, which may be present at diagnosis or during disease progression. Bone marrow involvement often is present with thrombocytopenia, anemia, and neutropenia. One-third of patients with BPDCN have central nervous system involvement and no disease relapse.⁶ Other affected sites include the liver, lungs, tonsils, soft tissues, and eyes. Patients with BPDCN may present with a history of myeloid neoplasms, such as acute/chronic myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome.⁴ Our case highlights the importance of skin biopsy for making the correct diagnosis, as BPDCN manifests with cutaneous lesions that are nonspecific for neoplastic or nonneoplastic etiologies.

Given the aggressive nature of BPDCN, along with its potential for acute leukemic transformation, treatment has been challenging due to both poor response rates and lack of consensus and treatment strategies. Historically, patients who have received high-dose acute leukemia–based chemotherapy followed by an allogeneic stem cell transplant during the first remission appeared to have the best outcomes.⁷ Conventional treatments have included surgical excision with radiation and various leukemia-based chemotherapy regimens, with hyper- CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone-methotrexate, and cytarabine) being the most commonly used regimen.^7,8 Venetoclax, a B-cell lymphoma 2 protein inhibitor, has shown promise when used in combination with hyper-CVAD. For older patients who may not tolerate aggressive chemotherapy, hypomethylating agents are preferred for their tolerability. Although tagraxofusp, a CD123-directed cytotoxin, has been utilized, Sapienza et al⁹ demonstrated an association with capillary leak syndrome.

Leukemia cutis is characterized by infiltration of the skin by malignant leukocytes, often associated with a prior diagnosis of systemic leukemia or myelodysplasia. Extramedullary accumulation of leukemic cells typically is referred to as myeloid sarcoma, while leukemia cutis serves as a general term for specific skin involvement.¹⁰ In rare instances, cutaneous lesions may manifest as the initial sign of systemic disease.

Cutaneous T-cell lymphomas comprise a diverse group of non-Hodgkin lymphomas that manifest as malignant monoclonal T-lymphocyte infiltration in the skin. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T-cell lymphomas are among the key subtypes. Histologically, differentiating these conditions from benign inflammatory disorders can be challenging due to subtle features such as haloed lymphocytes, epidermotropism, and Pautrier microabscesses seen in mycosis fungoides.¹¹

Multiple myeloma involves monoclonal plasma cell proliferation, primarily affecting bone and bone marrow. Extramedullary plasmacytomas can occur outside these sites through hematogenous spread or adjacent infiltration, while metastatic plasmacytomas result from metastasis. Cutaneous plasmacytomas may arise from hematogenous dissemination or infiltration from neighboring structures.¹²

Extranodal natural killer/T-cell lymphoma, nasal type, manifests as aggressive mid-facial necrotizing lesions with extranodal involvement, notably in the nasal/paranasal area. These lesions can cause local destruction of cartilage, bone, and soft tissues and may progress through stages or arise de novo. Diagnostic challenges arise from the historical variety of terms used to describe extranodal natural killer/T-cell lymphoma, including midline lethal granuloma and lymphomatoid granulomatosis.¹³

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

Cutaneous plasmacytoma initially was suspected because of the patient’s history of monoclonal gammopathy as well as angiosarcoma due to the purpuric vascular appearance of the lesions. However, histopathology revealed a pleomorphic cellular dermal infiltrate characterized by atypical cells with mediumlarge nuclei, fine chromatin, and small nucleoli; the cells also had little cytoplasm (Figure). The infiltrate did not involve the epidermis but extended into the subcutaneous tissue. Immunohistochemistry revealed that the cells were positive for CD45, CD43, CD4, CD7, CD56, CD123, CD33, T-cell leukemia/lymphoma protein 1, and CD68. The cells were negative for CD2, CD3, CD5, CD8, T-cell intracellular antigen 1, CD13, CD15, CD19, CD20, CD21, CD23, cyclin D1, Bcl-2, Bcl-6, CD10, PAX5, MUM1, lysozyme, myeloperoxidase, perforin, granzyme B, CD57, CD34, CD117, terminal deoxynucleotidyl transferase, activin receptorlike kinase 1 βF1, Epstein-Barr virus– encoded small RNA, CD30, CD163, and pancytokeratin. Thus, the clinical and histopathologic findings led to a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy.

CT113003025_e_FigAB.jpg

Blastic plasmacytoid dendritic cell neoplasm affects males older than 60 years.¹ It is characterized by the clonal proliferation of precursor plasmacytoid dendritic cells—otherwise known as professional type I interferonproducing cells or plasmacytoid monocytes—of myeloid origin. Plasmacytoid dendritic cells have been renamed on several occasions, reflecting uncertainties of their histogenesis. The diagnosis of BPDCN requires a biopsy showing the morphology of plasmacytoid dendritic blast cells and immunophenotypic criteria established by either immunohistochemistry or flow cytometry.^2,3 Tumor cells morphologically show an immature blastic appearance, and the diagnosis rests upon the demonstration of CD4 and CD56, together with markers more restricted to plasmacytoid dendritic cells (eg, BDCA-2, CD123, T-cell leukemia/lymphoma protein 1, CD2AP, BCL11A) and negativity for lymphoid and myeloid lineage–associated antigens.^1,4

Blastic plasmacytoid dendritic cell neoplasms account for less than 1% of all hematopoietic neoplasms. Cutaneous lesions occur in 64% of patients with the disease and often are the reason patients seek medical care.⁵ Clinical findings include numerous erythematous and violaceous papules, nodules, and plaques that resemble purpura or vasculitis. Cutaneous lesions can vary in size from a few millimeters to 10 cm and vary in color. Moreover, patients often present with bruiselike patches, disseminated lesions, or mucosal lesions.¹ Extracutaneous involvement includes lymphadenopathy, splenomegaly, and cytopenia caused by bone marrow infiltration, which may be present at diagnosis or during disease progression. Bone marrow involvement often is present with thrombocytopenia, anemia, and neutropenia. One-third of patients with BPDCN have central nervous system involvement and no disease relapse.⁶ Other affected sites include the liver, lungs, tonsils, soft tissues, and eyes. Patients with BPDCN may present with a history of myeloid neoplasms, such as acute/chronic myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome.⁴ Our case highlights the importance of skin biopsy for making the correct diagnosis, as BPDCN manifests with cutaneous lesions that are nonspecific for neoplastic or nonneoplastic etiologies.

Given the aggressive nature of BPDCN, along with its potential for acute leukemic transformation, treatment has been challenging due to both poor response rates and lack of consensus and treatment strategies. Historically, patients who have received high-dose acute leukemia–based chemotherapy followed by an allogeneic stem cell transplant during the first remission appeared to have the best outcomes.⁷ Conventional treatments have included surgical excision with radiation and various leukemia-based chemotherapy regimens, with hyper- CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone-methotrexate, and cytarabine) being the most commonly used regimen.^7,8 Venetoclax, a B-cell lymphoma 2 protein inhibitor, has shown promise when used in combination with hyper-CVAD. For older patients who may not tolerate aggressive chemotherapy, hypomethylating agents are preferred for their tolerability. Although tagraxofusp, a CD123-directed cytotoxin, has been utilized, Sapienza et al⁹ demonstrated an association with capillary leak syndrome.

Leukemia cutis is characterized by infiltration of the skin by malignant leukocytes, often associated with a prior diagnosis of systemic leukemia or myelodysplasia. Extramedullary accumulation of leukemic cells typically is referred to as myeloid sarcoma, while leukemia cutis serves as a general term for specific skin involvement.¹⁰ In rare instances, cutaneous lesions may manifest as the initial sign of systemic disease.

Cutaneous T-cell lymphomas comprise a diverse group of non-Hodgkin lymphomas that manifest as malignant monoclonal T-lymphocyte infiltration in the skin. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T-cell lymphomas are among the key subtypes. Histologically, differentiating these conditions from benign inflammatory disorders can be challenging due to subtle features such as haloed lymphocytes, epidermotropism, and Pautrier microabscesses seen in mycosis fungoides.¹¹

Multiple myeloma involves monoclonal plasma cell proliferation, primarily affecting bone and bone marrow. Extramedullary plasmacytomas can occur outside these sites through hematogenous spread or adjacent infiltration, while metastatic plasmacytomas result from metastasis. Cutaneous plasmacytomas may arise from hematogenous dissemination or infiltration from neighboring structures.¹²

Extranodal natural killer/T-cell lymphoma, nasal type, manifests as aggressive mid-facial necrotizing lesions with extranodal involvement, notably in the nasal/paranasal area. These lesions can cause local destruction of cartilage, bone, and soft tissues and may progress through stages or arise de novo. Diagnostic challenges arise from the historical variety of terms used to describe extranodal natural killer/T-cell lymphoma, including midline lethal granuloma and lymphomatoid granulomatosis.¹³

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

Cutaneous plasmacytoma initially was suspected because of the patient’s history of monoclonal gammopathy as well as angiosarcoma due to the purpuric vascular appearance of the lesions. However, histopathology revealed a pleomorphic cellular dermal infiltrate characterized by atypical cells with mediumlarge nuclei, fine chromatin, and small nucleoli; the cells also had little cytoplasm (Figure). The infiltrate did not involve the epidermis but extended into the subcutaneous tissue. Immunohistochemistry revealed that the cells were positive for CD45, CD43, CD4, CD7, CD56, CD123, CD33, T-cell leukemia/lymphoma protein 1, and CD68. The cells were negative for CD2, CD3, CD5, CD8, T-cell intracellular antigen 1, CD13, CD15, CD19, CD20, CD21, CD23, cyclin D1, Bcl-2, Bcl-6, CD10, PAX5, MUM1, lysozyme, myeloperoxidase, perforin, granzyme B, CD57, CD34, CD117, terminal deoxynucleotidyl transferase, activin receptorlike kinase 1 βF1, Epstein-Barr virus– encoded small RNA, CD30, CD163, and pancytokeratin. Thus, the clinical and histopathologic findings led to a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy.

CT113003025_e_FigAB.jpg

Blastic plasmacytoid dendritic cell neoplasm affects males older than 60 years.¹ It is characterized by the clonal proliferation of precursor plasmacytoid dendritic cells—otherwise known as professional type I interferonproducing cells or plasmacytoid monocytes—of myeloid origin. Plasmacytoid dendritic cells have been renamed on several occasions, reflecting uncertainties of their histogenesis. The diagnosis of BPDCN requires a biopsy showing the morphology of plasmacytoid dendritic blast cells and immunophenotypic criteria established by either immunohistochemistry or flow cytometry.^2,3 Tumor cells morphologically show an immature blastic appearance, and the diagnosis rests upon the demonstration of CD4 and CD56, together with markers more restricted to plasmacytoid dendritic cells (eg, BDCA-2, CD123, T-cell leukemia/lymphoma protein 1, CD2AP, BCL11A) and negativity for lymphoid and myeloid lineage–associated antigens.^1,4

Blastic plasmacytoid dendritic cell neoplasms account for less than 1% of all hematopoietic neoplasms. Cutaneous lesions occur in 64% of patients with the disease and often are the reason patients seek medical care.⁵ Clinical findings include numerous erythematous and violaceous papules, nodules, and plaques that resemble purpura or vasculitis. Cutaneous lesions can vary in size from a few millimeters to 10 cm and vary in color. Moreover, patients often present with bruiselike patches, disseminated lesions, or mucosal lesions.¹ Extracutaneous involvement includes lymphadenopathy, splenomegaly, and cytopenia caused by bone marrow infiltration, which may be present at diagnosis or during disease progression. Bone marrow involvement often is present with thrombocytopenia, anemia, and neutropenia. One-third of patients with BPDCN have central nervous system involvement and no disease relapse.⁶ Other affected sites include the liver, lungs, tonsils, soft tissues, and eyes. Patients with BPDCN may present with a history of myeloid neoplasms, such as acute/chronic myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome.⁴ Our case highlights the importance of skin biopsy for making the correct diagnosis, as BPDCN manifests with cutaneous lesions that are nonspecific for neoplastic or nonneoplastic etiologies.

Given the aggressive nature of BPDCN, along with its potential for acute leukemic transformation, treatment has been challenging due to both poor response rates and lack of consensus and treatment strategies. Historically, patients who have received high-dose acute leukemia–based chemotherapy followed by an allogeneic stem cell transplant during the first remission appeared to have the best outcomes.⁷ Conventional treatments have included surgical excision with radiation and various leukemia-based chemotherapy regimens, with hyper- CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone-methotrexate, and cytarabine) being the most commonly used regimen.^7,8 Venetoclax, a B-cell lymphoma 2 protein inhibitor, has shown promise when used in combination with hyper-CVAD. For older patients who may not tolerate aggressive chemotherapy, hypomethylating agents are preferred for their tolerability. Although tagraxofusp, a CD123-directed cytotoxin, has been utilized, Sapienza et al⁹ demonstrated an association with capillary leak syndrome.

Leukemia cutis is characterized by infiltration of the skin by malignant leukocytes, often associated with a prior diagnosis of systemic leukemia or myelodysplasia. Extramedullary accumulation of leukemic cells typically is referred to as myeloid sarcoma, while leukemia cutis serves as a general term for specific skin involvement.¹⁰ In rare instances, cutaneous lesions may manifest as the initial sign of systemic disease.

Cutaneous T-cell lymphomas comprise a diverse group of non-Hodgkin lymphomas that manifest as malignant monoclonal T-lymphocyte infiltration in the skin. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T-cell lymphomas are among the key subtypes. Histologically, differentiating these conditions from benign inflammatory disorders can be challenging due to subtle features such as haloed lymphocytes, epidermotropism, and Pautrier microabscesses seen in mycosis fungoides.¹¹

Multiple myeloma involves monoclonal plasma cell proliferation, primarily affecting bone and bone marrow. Extramedullary plasmacytomas can occur outside these sites through hematogenous spread or adjacent infiltration, while metastatic plasmacytomas result from metastasis. Cutaneous plasmacytomas may arise from hematogenous dissemination or infiltration from neighboring structures.¹²

Extranodal natural killer/T-cell lymphoma, nasal type, manifests as aggressive mid-facial necrotizing lesions with extranodal involvement, notably in the nasal/paranasal area. These lesions can cause local destruction of cartilage, bone, and soft tissues and may progress through stages or arise de novo. Diagnostic challenges arise from the historical variety of terms used to describe extranodal natural killer/T-cell lymphoma, including midline lethal granuloma and lymphomatoid granulomatosis.¹³

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

CT113003010_e_ABC.jpg

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

CT113003010_e_ABC.jpg

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

CT113003010_e_ABC.jpg

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Proliferating Pilar Cyst

Histopathology revealed an extensive lobulated epithelial proliferation in a characteristic “rolls and scrolls” pattern (Figure 1). This finding along with the patient’s prior diagnosis of keratitis-ichthyosisdeafness (KID) syndrome supported the diagnosis of a proliferating pilar cyst.

Chou_1.jpg

Pilar (or trichilemmal) cysts are common dermal cysts typically found on the outer root sheath of hair follicles. They clinically manifest as multiple yellow dome-shaped nodules without central puncta. They are slow growing and histologically are characterized as cysts with a stratified squamous epithelium demonstrating lack of a granular layer (trichilemmal keratinization) with bright red keratin contents and central focal calcification (Figure 2). Pilar cysts are more common in adult women and may be inherited through an autosomal-dominant pattern.¹

Chou_2.jpg

Proliferating pilar cysts represent less than 3% of all pilar cysts.² In addition to the characteristic features of a pilar cyst, proliferating pilar cysts generally are larger (can be >6-cm wide) and are more ulcerative.³ Histopathology of proliferating pilar cysts reveals a more extensive epithelial proliferation, yielding a rolls and scrolls appearance, and may demonstrate nuclear atypia.⁴ Proliferating pilar cysts classically manifest as large, raised, smooth and/or ulcerated nodules on the scalp accompanied by areas of excessive hair growth in older women. They generally arise from pre-existing pilar cysts but also may occur sporadically.⁴

The development of multiple proliferating pilar cysts has been observed in patients with KID syndrome, a rare congenital ectodermal disorder characterized by a triad of vascularizing keratitis, hyperkeratosis, and sensorineural deafness.^5,6 It is caused by a missense mutation of the GJB2 gene encoding for connexin 26, a gap junction that facilitates intercellular signaling and is expressed in a variety of structures including the cochlea, cornea, sweat glands, and inner and outer root sheaths of hair follicles.⁷

The differential diagnosis for proliferating pilar cysts includes pilomatrixomas, squamous cell carcinomas, and malignant proliferating pilar tumors. Pilomatrixomas (or calcifying epitheliomas of Malherbe) are the most common adnexal skin tumors in the pediatric population and most commonly present on the head, neck, and arms.⁸ They also can manifest in adults. Pilomatrixomas are benign dermal-subcutaneous tumors encapsulated by connective tissue that are found on the hair matrix and are histologically characterized by basaloid cells, shadow (or ghost) cells, dystrophic calcifications, and giant cells.⁹ The amount of basaloid cells and shadow cells can vary. Tumor progression results in the enucleation of the basaloid cells to form eosinophilic shadow cells in which calcification can occur. Giant cell granulomas may form contiguous with the calcifications. Both proliferating pilar cysts and pilomatrixomas have a rolls and scrolls appearance on low-power microscopy, but the latter are differentiated by their shadow cells and basaloid areas (Figure 3).

Chou_3.jpg

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer and more commonly affects men. Risk factors for SCC include immunosuppression and exposure to UV radiation. Histopathology of well-differentiated SCCs reveals invasive squamous cells with larger nuclei and a glassy appearance in addition to possible mitotic figures and keratin pearls (Figure 4). They typically manifest in sun-exposed areas such as the scalp, face, forearms, dorsal aspects of the hands, and lower legs.¹⁰ Proliferating pilar tumors often lack the nuclear atypia and invasive architecture of a well-differentiated SCC.

Chou_4.jpg

Features of malignant proliferating pilar tumors overlap with proliferating pilar cysts. In addition to the proliferative epithelium with abrupt trichilemmal keratinization that is typical of a proliferating pilar cyst, a malignant proliferating pilar tumor will demonstrate invasion into the surrounding tissue and lymph nodes, mitotic and architectural atypia, and necrosis (Figure 5).¹¹ Malignant proliferating pilar tumors grow rapidly, ranging in size from 1 to 10 cm, and may develop from pre-existing or proliferating pilar cysts or de novo.

Chou_5.jpg

The development of multiple proliferating pilar cysts and thus increased risk for progression to malignant proliferating pilar tumors has been observed in patients with KID syndrome.⁶ Our case highlights the importance of early screening and recognition of proliferating pilar tumors in patients with this condition.

The Diagnosis: Proliferating Pilar Cyst

Histopathology revealed an extensive lobulated epithelial proliferation in a characteristic “rolls and scrolls” pattern (Figure 1). This finding along with the patient’s prior diagnosis of keratitis-ichthyosisdeafness (KID) syndrome supported the diagnosis of a proliferating pilar cyst.

Chou_1.jpg

Pilar (or trichilemmal) cysts are common dermal cysts typically found on the outer root sheath of hair follicles. They clinically manifest as multiple yellow dome-shaped nodules without central puncta. They are slow growing and histologically are characterized as cysts with a stratified squamous epithelium demonstrating lack of a granular layer (trichilemmal keratinization) with bright red keratin contents and central focal calcification (Figure 2). Pilar cysts are more common in adult women and may be inherited through an autosomal-dominant pattern.¹

Chou_2.jpg

Proliferating pilar cysts represent less than 3% of all pilar cysts.² In addition to the characteristic features of a pilar cyst, proliferating pilar cysts generally are larger (can be >6-cm wide) and are more ulcerative.³ Histopathology of proliferating pilar cysts reveals a more extensive epithelial proliferation, yielding a rolls and scrolls appearance, and may demonstrate nuclear atypia.⁴ Proliferating pilar cysts classically manifest as large, raised, smooth and/or ulcerated nodules on the scalp accompanied by areas of excessive hair growth in older women. They generally arise from pre-existing pilar cysts but also may occur sporadically.⁴

The development of multiple proliferating pilar cysts has been observed in patients with KID syndrome, a rare congenital ectodermal disorder characterized by a triad of vascularizing keratitis, hyperkeratosis, and sensorineural deafness.^5,6 It is caused by a missense mutation of the GJB2 gene encoding for connexin 26, a gap junction that facilitates intercellular signaling and is expressed in a variety of structures including the cochlea, cornea, sweat glands, and inner and outer root sheaths of hair follicles.⁷

The differential diagnosis for proliferating pilar cysts includes pilomatrixomas, squamous cell carcinomas, and malignant proliferating pilar tumors. Pilomatrixomas (or calcifying epitheliomas of Malherbe) are the most common adnexal skin tumors in the pediatric population and most commonly present on the head, neck, and arms.⁸ They also can manifest in adults. Pilomatrixomas are benign dermal-subcutaneous tumors encapsulated by connective tissue that are found on the hair matrix and are histologically characterized by basaloid cells, shadow (or ghost) cells, dystrophic calcifications, and giant cells.⁹ The amount of basaloid cells and shadow cells can vary. Tumor progression results in the enucleation of the basaloid cells to form eosinophilic shadow cells in which calcification can occur. Giant cell granulomas may form contiguous with the calcifications. Both proliferating pilar cysts and pilomatrixomas have a rolls and scrolls appearance on low-power microscopy, but the latter are differentiated by their shadow cells and basaloid areas (Figure 3).

Chou_3.jpg

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer and more commonly affects men. Risk factors for SCC include immunosuppression and exposure to UV radiation. Histopathology of well-differentiated SCCs reveals invasive squamous cells with larger nuclei and a glassy appearance in addition to possible mitotic figures and keratin pearls (Figure 4). They typically manifest in sun-exposed areas such as the scalp, face, forearms, dorsal aspects of the hands, and lower legs.¹⁰ Proliferating pilar tumors often lack the nuclear atypia and invasive architecture of a well-differentiated SCC.

Chou_4.jpg

Features of malignant proliferating pilar tumors overlap with proliferating pilar cysts. In addition to the proliferative epithelium with abrupt trichilemmal keratinization that is typical of a proliferating pilar cyst, a malignant proliferating pilar tumor will demonstrate invasion into the surrounding tissue and lymph nodes, mitotic and architectural atypia, and necrosis (Figure 5).¹¹ Malignant proliferating pilar tumors grow rapidly, ranging in size from 1 to 10 cm, and may develop from pre-existing or proliferating pilar cysts or de novo.

Chou_5.jpg

The development of multiple proliferating pilar cysts and thus increased risk for progression to malignant proliferating pilar tumors has been observed in patients with KID syndrome.⁶ Our case highlights the importance of early screening and recognition of proliferating pilar tumors in patients with this condition.

The Diagnosis: Proliferating Pilar Cyst

Histopathology revealed an extensive lobulated epithelial proliferation in a characteristic “rolls and scrolls” pattern (Figure 1). This finding along with the patient’s prior diagnosis of keratitis-ichthyosisdeafness (KID) syndrome supported the diagnosis of a proliferating pilar cyst.

Chou_1.jpg

Pilar (or trichilemmal) cysts are common dermal cysts typically found on the outer root sheath of hair follicles. They clinically manifest as multiple yellow dome-shaped nodules without central puncta. They are slow growing and histologically are characterized as cysts with a stratified squamous epithelium demonstrating lack of a granular layer (trichilemmal keratinization) with bright red keratin contents and central focal calcification (Figure 2). Pilar cysts are more common in adult women and may be inherited through an autosomal-dominant pattern.¹

Chou_2.jpg

Proliferating pilar cysts represent less than 3% of all pilar cysts.² In addition to the characteristic features of a pilar cyst, proliferating pilar cysts generally are larger (can be >6-cm wide) and are more ulcerative.³ Histopathology of proliferating pilar cysts reveals a more extensive epithelial proliferation, yielding a rolls and scrolls appearance, and may demonstrate nuclear atypia.⁴ Proliferating pilar cysts classically manifest as large, raised, smooth and/or ulcerated nodules on the scalp accompanied by areas of excessive hair growth in older women. They generally arise from pre-existing pilar cysts but also may occur sporadically.⁴

The development of multiple proliferating pilar cysts has been observed in patients with KID syndrome, a rare congenital ectodermal disorder characterized by a triad of vascularizing keratitis, hyperkeratosis, and sensorineural deafness.^5,6 It is caused by a missense mutation of the GJB2 gene encoding for connexin 26, a gap junction that facilitates intercellular signaling and is expressed in a variety of structures including the cochlea, cornea, sweat glands, and inner and outer root sheaths of hair follicles.⁷

The differential diagnosis for proliferating pilar cysts includes pilomatrixomas, squamous cell carcinomas, and malignant proliferating pilar tumors. Pilomatrixomas (or calcifying epitheliomas of Malherbe) are the most common adnexal skin tumors in the pediatric population and most commonly present on the head, neck, and arms.⁸ They also can manifest in adults. Pilomatrixomas are benign dermal-subcutaneous tumors encapsulated by connective tissue that are found on the hair matrix and are histologically characterized by basaloid cells, shadow (or ghost) cells, dystrophic calcifications, and giant cells.⁹ The amount of basaloid cells and shadow cells can vary. Tumor progression results in the enucleation of the basaloid cells to form eosinophilic shadow cells in which calcification can occur. Giant cell granulomas may form contiguous with the calcifications. Both proliferating pilar cysts and pilomatrixomas have a rolls and scrolls appearance on low-power microscopy, but the latter are differentiated by their shadow cells and basaloid areas (Figure 3).

Chou_3.jpg

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer and more commonly affects men. Risk factors for SCC include immunosuppression and exposure to UV radiation. Histopathology of well-differentiated SCCs reveals invasive squamous cells with larger nuclei and a glassy appearance in addition to possible mitotic figures and keratin pearls (Figure 4). They typically manifest in sun-exposed areas such as the scalp, face, forearms, dorsal aspects of the hands, and lower legs.¹⁰ Proliferating pilar tumors often lack the nuclear atypia and invasive architecture of a well-differentiated SCC.

Chou_4.jpg

Features of malignant proliferating pilar tumors overlap with proliferating pilar cysts. In addition to the proliferative epithelium with abrupt trichilemmal keratinization that is typical of a proliferating pilar cyst, a malignant proliferating pilar tumor will demonstrate invasion into the surrounding tissue and lymph nodes, mitotic and architectural atypia, and necrosis (Figure 5).¹¹ Malignant proliferating pilar tumors grow rapidly, ranging in size from 1 to 10 cm, and may develop from pre-existing or proliferating pilar cysts or de novo.

Chou_5.jpg

The development of multiple proliferating pilar cysts and thus increased risk for progression to malignant proliferating pilar tumors has been observed in patients with KID syndrome.⁶ Our case highlights the importance of early screening and recognition of proliferating pilar tumors in patients with this condition.

To the Editor:

Necrotizing myositis (NM) is an exceedingly rare necrotizing soft-tissue infection (NSTI) that is characterized by skeletal muscle involvement. β -Hemolytic streptococci, such as Streptococcus pyogenes , are the most common causative organisms. The overall prevalence and incidence of NM is unknown. A review of the literature by Adams et al ² identified only 21 cases between 1900 and 1985.

Timely treatment of this infection leads to improved outcomes, but diagnosis can be challenging due to the ambiguous presentation of NM and lack of specific cutaneous changes.³ Clinical manifestations including bullae, blisters, vesicles, and petechiae become more prominent as infection progresses.⁴ If NM is suspected due to cutaneous manifestations, it is imperative that the underlying cause be identified; for example, NM must be distinguished from the overlapping presentation of pyoderma gangrenosum (PG). Because NM has nearly 100% mortality without prompt surgical intervention, early identification is critical.⁵ Herein, we report a case of NM that illustrates the correlation of clinical, histological, and imaging findings required to diagnose this potentially fatal infection.

An 80-year-old man presented to the emergency department with worsening pain, edema, and spreading redness of the right wrist over the last 5 weeks. He had a history of atopic dermatitis that was refractory to topical steroids and methotrexate; he was dependent on an oral steroid (prednisone 30 mg/d) for symptom control. The patient reported minor trauma to the area after performing home renovations. He received numerous rounds of oral antibiotics as an outpatient for presumed cellulitis and reported he was “getting better” but that the signs and symptoms of the condition grew worse after outpatient arthrocentesis. Dermatology was consulted to evaluate for a necrotizing neutrophilic dermatosis such as PG.

At the current presentation, the patient was tachycardic and afebrile (temperature, 98.2 °F [36.8 °C]). Physical examination revealed large, exquisitely tender, ill-defined necrotic ulceration of the right wrist with purulent debris and diffuse edema (Figure 1). Sequential evaluation at 6-hour intervals revealed notably increasing purulence, edema, and tenderness. Interconnected sinus tracts that extended to the fascial plane were observed.

Jensen_1.jpg

Laboratory workup was notable for a markedly elevated C-reactive protein level of 18.9 mg/dL (reference range, 0–0.8 mg/dL) and an elevated white blood cell count of 19.92×10⁹/L (reference range, 4.5–11.0×10⁹/L). Blood and tissue cultures were positive for methicillin-sensitive Staphylococcus aureus. Computed tomography and magnetic resonance imaging (MRI) prior to biopsy demonstrated findings consistent with extensive subcutaneous and intramuscular areas of loculation and foci of gas (Figure 2). These findings were consistent with intramuscular involvement. A punch biopsy revealed a necrotic epidermis filled with neutrophilic pustules and a dense dermal infiltrate of neutrophilic inflammation consistent with infection (Figure 3).

Jensen_2.jpg

Emergency surgery was performed with debridement of necrotic tissue and muscle. Postoperatively, he became more clinically stable after being placed on cefazolin through a peripherally inserted central catheter. He underwent 4 additional washouts over the ensuing month, as well as tendon reconstructions, a radial forearm flap, and reverse radial forearm flap reconstruction of the forearm. At the time of publication, there has been no recurrence. The patient’s atopic dermatitis is well controlled on dupilumab and topical fluocinonide alone, with a recent IgA level of 1 g/L and a body surface area measurement of 2%. Dupilumab was started 3 months after surgery.

Jensen_3.jpg

Necrotizing myositis is a rare, rapidly progressive infection involving muscle that can manifest as superficial cutaneous involvement. The clinical manifestation of NM is harder to recognize than other NSTIs such as necrotizing fasciitis, likely due to the initial prodromal phase of NM, which consists of nonspecific constitutional symptoms.³ Systemic findings such as tachycardia, fever, hypotension, and shock occur in only 10% to 40% of NM patients.^4,5

In our patient, clues of NM included fulfillment of criteria for systemic inflammatory response syndrome at admission and a presumed source of infection; taken together, these findings should lead to a diagnosis of sepsis until otherwise proven. The patient also reported pain that was not proportional to the skin findings, which suggested an NSTI. His lack of constitutional symptoms may have been due to the effects of prednisone, which was changed to dupilumab during hospitalization.

The clinical and histological findings of NM are nonspecific. Clinical findings include skin discoloration with bullae, blisters, vesicles, or petechiae.⁴ Our case adds to the descriptive morphology by including marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane. Histologic findings can include confluent necrosis extending from the epidermis to the underlying muscle with dense neutrophilic inflammation. Notably, these findings can mirror necrotizing neutrophilic dermatoses in the absence of an infectious cause. Failure to recognize simple systemic inflammatory response syndrome criteria in NM patients due to slow treatment response or incorrect treatment can can lead to loss of a limb or death.

Workup reveals overlap with necrotizing neutrophilic dermatoses including PG, which is the prototypical neutrophilic dermatosis. Morphologically, PG presents as an ulcer with a purple and undermined border, often having developed from an initial papule, vesicle, or pustule. A neutrophilic infiltrate of the ulcer edge is the major criterion required to diagnose PG⁶; minor criteria include a positive pathergy test, history of inflammatory arthritis or inflammatory bowel disease, and exclusion of infection.⁶ When compared directly to an NSTI such as NM, the most important variable that sets PG apart is the absence of bacterial growth on blood and tissue cultures.⁷

Imaging studies can aid in the clinical diagnosis of NM and help distinguish the disease from PG. Computed tomography and MRI may demonstrate hallmarks of extensive necrotizing infection, such as gas formation and consequent fascial swelling, thickening and edema of involved muscle, and subfascial fluid collection.^3,4 Distinct from NM, imaging findings in PG are more subtle, suggesting cellulitic inflammation with edema.⁸ A defining radiographic feature of NM can be foci of gas within muscle or fascia, though absence of this finding does not exclude NM.^1,4

In conclusion, NM is a rare intramuscular infection that can be difficult to diagnose due to its nonspecific presentation and lack of constitutional symptoms. Dermatologists should maintain a high level of suspicion for NM in the setting of rapidly progressive clinical findings; accurate diagnosis requires a multimodal approach with complete correlation of clinical, histological, and imaging findings. Computed tomography and MRI can heighten the approach, even when necrotizing neutrophilic dermatoses and NM have similar clinical and histological appearances. Once a diagnosis of NM is established, prompt surgical and medical intervention improves the prognosis.

To the Editor:

Necrotizing myositis (NM) is an exceedingly rare necrotizing soft-tissue infection (NSTI) that is characterized by skeletal muscle involvement. β -Hemolytic streptococci, such as Streptococcus pyogenes , are the most common causative organisms. The overall prevalence and incidence of NM is unknown. A review of the literature by Adams et al ² identified only 21 cases between 1900 and 1985.

Timely treatment of this infection leads to improved outcomes, but diagnosis can be challenging due to the ambiguous presentation of NM and lack of specific cutaneous changes.³ Clinical manifestations including bullae, blisters, vesicles, and petechiae become more prominent as infection progresses.⁴ If NM is suspected due to cutaneous manifestations, it is imperative that the underlying cause be identified; for example, NM must be distinguished from the overlapping presentation of pyoderma gangrenosum (PG). Because NM has nearly 100% mortality without prompt surgical intervention, early identification is critical.⁵ Herein, we report a case of NM that illustrates the correlation of clinical, histological, and imaging findings required to diagnose this potentially fatal infection.

An 80-year-old man presented to the emergency department with worsening pain, edema, and spreading redness of the right wrist over the last 5 weeks. He had a history of atopic dermatitis that was refractory to topical steroids and methotrexate; he was dependent on an oral steroid (prednisone 30 mg/d) for symptom control. The patient reported minor trauma to the area after performing home renovations. He received numerous rounds of oral antibiotics as an outpatient for presumed cellulitis and reported he was “getting better” but that the signs and symptoms of the condition grew worse after outpatient arthrocentesis. Dermatology was consulted to evaluate for a necrotizing neutrophilic dermatosis such as PG.

At the current presentation, the patient was tachycardic and afebrile (temperature, 98.2 °F [36.8 °C]). Physical examination revealed large, exquisitely tender, ill-defined necrotic ulceration of the right wrist with purulent debris and diffuse edema (Figure 1). Sequential evaluation at 6-hour intervals revealed notably increasing purulence, edema, and tenderness. Interconnected sinus tracts that extended to the fascial plane were observed.

Jensen_1.jpg

Laboratory workup was notable for a markedly elevated C-reactive protein level of 18.9 mg/dL (reference range, 0–0.8 mg/dL) and an elevated white blood cell count of 19.92×10⁹/L (reference range, 4.5–11.0×10⁹/L). Blood and tissue cultures were positive for methicillin-sensitive Staphylococcus aureus. Computed tomography and magnetic resonance imaging (MRI) prior to biopsy demonstrated findings consistent with extensive subcutaneous and intramuscular areas of loculation and foci of gas (Figure 2). These findings were consistent with intramuscular involvement. A punch biopsy revealed a necrotic epidermis filled with neutrophilic pustules and a dense dermal infiltrate of neutrophilic inflammation consistent with infection (Figure 3).

Jensen_2.jpg

Emergency surgery was performed with debridement of necrotic tissue and muscle. Postoperatively, he became more clinically stable after being placed on cefazolin through a peripherally inserted central catheter. He underwent 4 additional washouts over the ensuing month, as well as tendon reconstructions, a radial forearm flap, and reverse radial forearm flap reconstruction of the forearm. At the time of publication, there has been no recurrence. The patient’s atopic dermatitis is well controlled on dupilumab and topical fluocinonide alone, with a recent IgA level of 1 g/L and a body surface area measurement of 2%. Dupilumab was started 3 months after surgery.

Jensen_3.jpg

Necrotizing myositis is a rare, rapidly progressive infection involving muscle that can manifest as superficial cutaneous involvement. The clinical manifestation of NM is harder to recognize than other NSTIs such as necrotizing fasciitis, likely due to the initial prodromal phase of NM, which consists of nonspecific constitutional symptoms.³ Systemic findings such as tachycardia, fever, hypotension, and shock occur in only 10% to 40% of NM patients.^4,5

In our patient, clues of NM included fulfillment of criteria for systemic inflammatory response syndrome at admission and a presumed source of infection; taken together, these findings should lead to a diagnosis of sepsis until otherwise proven. The patient also reported pain that was not proportional to the skin findings, which suggested an NSTI. His lack of constitutional symptoms may have been due to the effects of prednisone, which was changed to dupilumab during hospitalization.

The clinical and histological findings of NM are nonspecific. Clinical findings include skin discoloration with bullae, blisters, vesicles, or petechiae.⁴ Our case adds to the descriptive morphology by including marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane. Histologic findings can include confluent necrosis extending from the epidermis to the underlying muscle with dense neutrophilic inflammation. Notably, these findings can mirror necrotizing neutrophilic dermatoses in the absence of an infectious cause. Failure to recognize simple systemic inflammatory response syndrome criteria in NM patients due to slow treatment response or incorrect treatment can can lead to loss of a limb or death.

Workup reveals overlap with necrotizing neutrophilic dermatoses including PG, which is the prototypical neutrophilic dermatosis. Morphologically, PG presents as an ulcer with a purple and undermined border, often having developed from an initial papule, vesicle, or pustule. A neutrophilic infiltrate of the ulcer edge is the major criterion required to diagnose PG⁶; minor criteria include a positive pathergy test, history of inflammatory arthritis or inflammatory bowel disease, and exclusion of infection.⁶ When compared directly to an NSTI such as NM, the most important variable that sets PG apart is the absence of bacterial growth on blood and tissue cultures.⁷

Imaging studies can aid in the clinical diagnosis of NM and help distinguish the disease from PG. Computed tomography and MRI may demonstrate hallmarks of extensive necrotizing infection, such as gas formation and consequent fascial swelling, thickening and edema of involved muscle, and subfascial fluid collection.^3,4 Distinct from NM, imaging findings in PG are more subtle, suggesting cellulitic inflammation with edema.⁸ A defining radiographic feature of NM can be foci of gas within muscle or fascia, though absence of this finding does not exclude NM.^1,4

In conclusion, NM is a rare intramuscular infection that can be difficult to diagnose due to its nonspecific presentation and lack of constitutional symptoms. Dermatologists should maintain a high level of suspicion for NM in the setting of rapidly progressive clinical findings; accurate diagnosis requires a multimodal approach with complete correlation of clinical, histological, and imaging findings. Computed tomography and MRI can heighten the approach, even when necrotizing neutrophilic dermatoses and NM have similar clinical and histological appearances. Once a diagnosis of NM is established, prompt surgical and medical intervention improves the prognosis.

To the Editor:

Necrotizing myositis (NM) is an exceedingly rare necrotizing soft-tissue infection (NSTI) that is characterized by skeletal muscle involvement. β -Hemolytic streptococci, such as Streptococcus pyogenes , are the most common causative organisms. The overall prevalence and incidence of NM is unknown. A review of the literature by Adams et al ² identified only 21 cases between 1900 and 1985.

Timely treatment of this infection leads to improved outcomes, but diagnosis can be challenging due to the ambiguous presentation of NM and lack of specific cutaneous changes.³ Clinical manifestations including bullae, blisters, vesicles, and petechiae become more prominent as infection progresses.⁴ If NM is suspected due to cutaneous manifestations, it is imperative that the underlying cause be identified; for example, NM must be distinguished from the overlapping presentation of pyoderma gangrenosum (PG). Because NM has nearly 100% mortality without prompt surgical intervention, early identification is critical.⁵ Herein, we report a case of NM that illustrates the correlation of clinical, histological, and imaging findings required to diagnose this potentially fatal infection.

An 80-year-old man presented to the emergency department with worsening pain, edema, and spreading redness of the right wrist over the last 5 weeks. He had a history of atopic dermatitis that was refractory to topical steroids and methotrexate; he was dependent on an oral steroid (prednisone 30 mg/d) for symptom control. The patient reported minor trauma to the area after performing home renovations. He received numerous rounds of oral antibiotics as an outpatient for presumed cellulitis and reported he was “getting better” but that the signs and symptoms of the condition grew worse after outpatient arthrocentesis. Dermatology was consulted to evaluate for a necrotizing neutrophilic dermatosis such as PG.

At the current presentation, the patient was tachycardic and afebrile (temperature, 98.2 °F [36.8 °C]). Physical examination revealed large, exquisitely tender, ill-defined necrotic ulceration of the right wrist with purulent debris and diffuse edema (Figure 1). Sequential evaluation at 6-hour intervals revealed notably increasing purulence, edema, and tenderness. Interconnected sinus tracts that extended to the fascial plane were observed.

Jensen_1.jpg

Laboratory workup was notable for a markedly elevated C-reactive protein level of 18.9 mg/dL (reference range, 0–0.8 mg/dL) and an elevated white blood cell count of 19.92×10⁹/L (reference range, 4.5–11.0×10⁹/L). Blood and tissue cultures were positive for methicillin-sensitive Staphylococcus aureus. Computed tomography and magnetic resonance imaging (MRI) prior to biopsy demonstrated findings consistent with extensive subcutaneous and intramuscular areas of loculation and foci of gas (Figure 2). These findings were consistent with intramuscular involvement. A punch biopsy revealed a necrotic epidermis filled with neutrophilic pustules and a dense dermal infiltrate of neutrophilic inflammation consistent with infection (Figure 3).

Jensen_2.jpg

Emergency surgery was performed with debridement of necrotic tissue and muscle. Postoperatively, he became more clinically stable after being placed on cefazolin through a peripherally inserted central catheter. He underwent 4 additional washouts over the ensuing month, as well as tendon reconstructions, a radial forearm flap, and reverse radial forearm flap reconstruction of the forearm. At the time of publication, there has been no recurrence. The patient’s atopic dermatitis is well controlled on dupilumab and topical fluocinonide alone, with a recent IgA level of 1 g/L and a body surface area measurement of 2%. Dupilumab was started 3 months after surgery.

Jensen_3.jpg

Necrotizing myositis is a rare, rapidly progressive infection involving muscle that can manifest as superficial cutaneous involvement. The clinical manifestation of NM is harder to recognize than other NSTIs such as necrotizing fasciitis, likely due to the initial prodromal phase of NM, which consists of nonspecific constitutional symptoms.³ Systemic findings such as tachycardia, fever, hypotension, and shock occur in only 10% to 40% of NM patients.^4,5

In our patient, clues of NM included fulfillment of criteria for systemic inflammatory response syndrome at admission and a presumed source of infection; taken together, these findings should lead to a diagnosis of sepsis until otherwise proven. The patient also reported pain that was not proportional to the skin findings, which suggested an NSTI. His lack of constitutional symptoms may have been due to the effects of prednisone, which was changed to dupilumab during hospitalization.

The clinical and histological findings of NM are nonspecific. Clinical findings include skin discoloration with bullae, blisters, vesicles, or petechiae.⁴ Our case adds to the descriptive morphology by including marked edema with ulceration, progressive purulence, and interconnected sinuses tracking to the fascial plane. Histologic findings can include confluent necrosis extending from the epidermis to the underlying muscle with dense neutrophilic inflammation. Notably, these findings can mirror necrotizing neutrophilic dermatoses in the absence of an infectious cause. Failure to recognize simple systemic inflammatory response syndrome criteria in NM patients due to slow treatment response or incorrect treatment can can lead to loss of a limb or death.

Workup reveals overlap with necrotizing neutrophilic dermatoses including PG, which is the prototypical neutrophilic dermatosis. Morphologically, PG presents as an ulcer with a purple and undermined border, often having developed from an initial papule, vesicle, or pustule. A neutrophilic infiltrate of the ulcer edge is the major criterion required to diagnose PG⁶; minor criteria include a positive pathergy test, history of inflammatory arthritis or inflammatory bowel disease, and exclusion of infection.⁶ When compared directly to an NSTI such as NM, the most important variable that sets PG apart is the absence of bacterial growth on blood and tissue cultures.⁷

Imaging studies can aid in the clinical diagnosis of NM and help distinguish the disease from PG. Computed tomography and MRI may demonstrate hallmarks of extensive necrotizing infection, such as gas formation and consequent fascial swelling, thickening and edema of involved muscle, and subfascial fluid collection.^3,4 Distinct from NM, imaging findings in PG are more subtle, suggesting cellulitic inflammation with edema.⁸ A defining radiographic feature of NM can be foci of gas within muscle or fascia, though absence of this finding does not exclude NM.^1,4

In conclusion, NM is a rare intramuscular infection that can be difficult to diagnose due to its nonspecific presentation and lack of constitutional symptoms. Dermatologists should maintain a high level of suspicion for NM in the setting of rapidly progressive clinical findings; accurate diagnosis requires a multimodal approach with complete correlation of clinical, histological, and imaging findings. Computed tomography and MRI can heighten the approach, even when necrotizing neutrophilic dermatoses and NM have similar clinical and histological appearances. Once a diagnosis of NM is established, prompt surgical and medical intervention improves the prognosis.