Dirk M. Elston, MD

Identification

The Hymenoptera order of insects includes Apidae (bees), Vespidae (wasps, yellow jackets, hornets), and Formicidae (fire ants). All 3 of these families of insects inject venom into their prey or as a defense mechanism via ovipositors in their abdomen. Vespids are the most aggressive and are found in each of the United States.¹ They have membranous wings, broad antennae, and a nonbarbed stinger (Figure 1).² The nonbarbed stinger of Vespidae differentiates them from Apidae and allows these insects to sting their prey multiple times. Vespids can build nests in the ground (yellow jackets), trees (hornets), or areas of cover such as window shutters (mud wasps). Because only the queens survive winter, larger populations do not develop until late summer when the most stings take place. Stings most often take place near the nest of the vespid or while the victim is eating outdoors.³

Envenomation

When vespids sting their prey they inject venom via their ovipositors.¹ The venom is composed of a mixture of low-molecular-weight proteins, kinins, proteolytic enzymes, lipids, carbohydrates, and high-molecular-weight proteins that act as allergens.^1,4,5 The proteolytic enzymes degrade the surrounding tissue, basophils become activated, and histamine is released secondary to mast cell degranulation, which results in vasodilation and an inflammatory response characterized by edema, erythema, warmth, and pain.¹ The pain of the sting is immediate and can be intense; almost all victims are acutely aware of the discomforting sensation.⁴

Management of Reactions

Three types of reactions can be seen after a vespid sting: uncomplicated local reactions, large local reactions, and systemic reactions (SRs). The most common reaction is the self-limiting uncomplicated local reaction that includes a focal area of warmth, edema, erythema, induration, and tenderness.¹ Treatment of this kind of reaction is supportive, with ice, nonsteroidal anti-inflammatory drugs, and H₁ and H₂ blockers being commonly used methods. Large local reactions (Figure 2) are similar to uncomplicated local reactions but are greater than 10 cm in diameter and last longer. The same symptomatic treatment may be used along with possible short (3–5 days) oral glucocorticoid (40–60 mg prednisone) or potent topical steroid administration if symptoms persist. Systemic reactions involve IgE-mediated generalized urticaria, angioedema, face swelling, stridor, bronchospasm, nausea, vomiting, flushing, and respiratory distress.¹ Emergency management includes maintenance of airway, breathing, and circulation. Epinephrine injection commonly is employed and should be given via intramuscular injection into the anterolateral thigh; a dose of 0.3 to 0.5 mg can be repeatedly injected every 5 to 15 minutes, as needed.¹

If an individual has an SR, it is recommended to go to an emergency department after stabilization for monitoring. Referral to an allergist for desensitization is appropriate. A radioallergosorbent test to measure allergen-specific IgE can be helpful to confirm an allergy.⁴ This test also should be done weeks after the incident because during the first few days IgE may be too low to measure. Once the allergy is confirmed, the desensitization with venom immunotherapy (VIT) can begin. Venom immunotherapy is effective and reduces a patient’s risk for recurrent SRs to less than 5% to 20%.⁶ A 2015 study recommended longer duration of VIT therapy due to risk for repeat SRs after discontinuing therapy. This study concluded that VIT is to be administered for 5 years, unless the patient is at high risk for SRs after VIT therapy—risk factors include older age, cardiopulmonary disease, SR during VIT treatment, mast cell disorders, and elevated serum tryptase—in which case VIT may have to be continued indefinitely. It is recommended that all patients with history of SR carry an epinephrine autoinjector in case of emergency.⁶

Epidemiologic data show a prevalence of 0.3% to 7.5% for self-reported SRs due to stings, with lower prevalence in children (0.15%–0.3%).^4,7 An additional study looking at data from an allergy practice determined 24% of all cases of anaphylaxis were due to insect stings.⁵

Conclusion

Although many vespid stings can be managed symptomatically, it is imperative for patients and providers to be aware of the possible severe reactions that can take place. It is essential for providers to be aware of how to care for and treat large local reactions and SRs, as symptom recognition and timely treatment can improve patient safety and result in better outcomes.

Identification

The Hymenoptera order of insects includes Apidae (bees), Vespidae (wasps, yellow jackets, hornets), and Formicidae (fire ants). All 3 of these families of insects inject venom into their prey or as a defense mechanism via ovipositors in their abdomen. Vespids are the most aggressive and are found in each of the United States.¹ They have membranous wings, broad antennae, and a nonbarbed stinger (Figure 1).² The nonbarbed stinger of Vespidae differentiates them from Apidae and allows these insects to sting their prey multiple times. Vespids can build nests in the ground (yellow jackets), trees (hornets), or areas of cover such as window shutters (mud wasps). Because only the queens survive winter, larger populations do not develop until late summer when the most stings take place. Stings most often take place near the nest of the vespid or while the victim is eating outdoors.³

Envenomation

When vespids sting their prey they inject venom via their ovipositors.¹ The venom is composed of a mixture of low-molecular-weight proteins, kinins, proteolytic enzymes, lipids, carbohydrates, and high-molecular-weight proteins that act as allergens.^1,4,5 The proteolytic enzymes degrade the surrounding tissue, basophils become activated, and histamine is released secondary to mast cell degranulation, which results in vasodilation and an inflammatory response characterized by edema, erythema, warmth, and pain.¹ The pain of the sting is immediate and can be intense; almost all victims are acutely aware of the discomforting sensation.⁴

Management of Reactions

Three types of reactions can be seen after a vespid sting: uncomplicated local reactions, large local reactions, and systemic reactions (SRs). The most common reaction is the self-limiting uncomplicated local reaction that includes a focal area of warmth, edema, erythema, induration, and tenderness.¹ Treatment of this kind of reaction is supportive, with ice, nonsteroidal anti-inflammatory drugs, and H₁ and H₂ blockers being commonly used methods. Large local reactions (Figure 2) are similar to uncomplicated local reactions but are greater than 10 cm in diameter and last longer. The same symptomatic treatment may be used along with possible short (3–5 days) oral glucocorticoid (40–60 mg prednisone) or potent topical steroid administration if symptoms persist. Systemic reactions involve IgE-mediated generalized urticaria, angioedema, face swelling, stridor, bronchospasm, nausea, vomiting, flushing, and respiratory distress.¹ Emergency management includes maintenance of airway, breathing, and circulation. Epinephrine injection commonly is employed and should be given via intramuscular injection into the anterolateral thigh; a dose of 0.3 to 0.5 mg can be repeatedly injected every 5 to 15 minutes, as needed.¹

If an individual has an SR, it is recommended to go to an emergency department after stabilization for monitoring. Referral to an allergist for desensitization is appropriate. A radioallergosorbent test to measure allergen-specific IgE can be helpful to confirm an allergy.⁴ This test also should be done weeks after the incident because during the first few days IgE may be too low to measure. Once the allergy is confirmed, the desensitization with venom immunotherapy (VIT) can begin. Venom immunotherapy is effective and reduces a patient’s risk for recurrent SRs to less than 5% to 20%.⁶ A 2015 study recommended longer duration of VIT therapy due to risk for repeat SRs after discontinuing therapy. This study concluded that VIT is to be administered for 5 years, unless the patient is at high risk for SRs after VIT therapy—risk factors include older age, cardiopulmonary disease, SR during VIT treatment, mast cell disorders, and elevated serum tryptase—in which case VIT may have to be continued indefinitely. It is recommended that all patients with history of SR carry an epinephrine autoinjector in case of emergency.⁶

Epidemiologic data show a prevalence of 0.3% to 7.5% for self-reported SRs due to stings, with lower prevalence in children (0.15%–0.3%).^4,7 An additional study looking at data from an allergy practice determined 24% of all cases of anaphylaxis were due to insect stings.⁵

Conclusion

Although many vespid stings can be managed symptomatically, it is imperative for patients and providers to be aware of the possible severe reactions that can take place. It is essential for providers to be aware of how to care for and treat large local reactions and SRs, as symptom recognition and timely treatment can improve patient safety and result in better outcomes.

Identification

The Hymenoptera order of insects includes Apidae (bees), Vespidae (wasps, yellow jackets, hornets), and Formicidae (fire ants). All 3 of these families of insects inject venom into their prey or as a defense mechanism via ovipositors in their abdomen. Vespids are the most aggressive and are found in each of the United States.¹ They have membranous wings, broad antennae, and a nonbarbed stinger (Figure 1).² The nonbarbed stinger of Vespidae differentiates them from Apidae and allows these insects to sting their prey multiple times. Vespids can build nests in the ground (yellow jackets), trees (hornets), or areas of cover such as window shutters (mud wasps). Because only the queens survive winter, larger populations do not develop until late summer when the most stings take place. Stings most often take place near the nest of the vespid or while the victim is eating outdoors.³

Envenomation

When vespids sting their prey they inject venom via their ovipositors.¹ The venom is composed of a mixture of low-molecular-weight proteins, kinins, proteolytic enzymes, lipids, carbohydrates, and high-molecular-weight proteins that act as allergens.^1,4,5 The proteolytic enzymes degrade the surrounding tissue, basophils become activated, and histamine is released secondary to mast cell degranulation, which results in vasodilation and an inflammatory response characterized by edema, erythema, warmth, and pain.¹ The pain of the sting is immediate and can be intense; almost all victims are acutely aware of the discomforting sensation.⁴

Management of Reactions

Three types of reactions can be seen after a vespid sting: uncomplicated local reactions, large local reactions, and systemic reactions (SRs). The most common reaction is the self-limiting uncomplicated local reaction that includes a focal area of warmth, edema, erythema, induration, and tenderness.¹ Treatment of this kind of reaction is supportive, with ice, nonsteroidal anti-inflammatory drugs, and H₁ and H₂ blockers being commonly used methods. Large local reactions (Figure 2) are similar to uncomplicated local reactions but are greater than 10 cm in diameter and last longer. The same symptomatic treatment may be used along with possible short (3–5 days) oral glucocorticoid (40–60 mg prednisone) or potent topical steroid administration if symptoms persist. Systemic reactions involve IgE-mediated generalized urticaria, angioedema, face swelling, stridor, bronchospasm, nausea, vomiting, flushing, and respiratory distress.¹ Emergency management includes maintenance of airway, breathing, and circulation. Epinephrine injection commonly is employed and should be given via intramuscular injection into the anterolateral thigh; a dose of 0.3 to 0.5 mg can be repeatedly injected every 5 to 15 minutes, as needed.¹

If an individual has an SR, it is recommended to go to an emergency department after stabilization for monitoring. Referral to an allergist for desensitization is appropriate. A radioallergosorbent test to measure allergen-specific IgE can be helpful to confirm an allergy.⁴ This test also should be done weeks after the incident because during the first few days IgE may be too low to measure. Once the allergy is confirmed, the desensitization with venom immunotherapy (VIT) can begin. Venom immunotherapy is effective and reduces a patient’s risk for recurrent SRs to less than 5% to 20%.⁶ A 2015 study recommended longer duration of VIT therapy due to risk for repeat SRs after discontinuing therapy. This study concluded that VIT is to be administered for 5 years, unless the patient is at high risk for SRs after VIT therapy—risk factors include older age, cardiopulmonary disease, SR during VIT treatment, mast cell disorders, and elevated serum tryptase—in which case VIT may have to be continued indefinitely. It is recommended that all patients with history of SR carry an epinephrine autoinjector in case of emergency.⁶

Epidemiologic data show a prevalence of 0.3% to 7.5% for self-reported SRs due to stings, with lower prevalence in children (0.15%–0.3%).^4,7 An additional study looking at data from an allergy practice determined 24% of all cases of anaphylaxis were due to insect stings.⁵

Conclusion

Although many vespid stings can be managed symptomatically, it is imperative for patients and providers to be aware of the possible severe reactions that can take place. It is essential for providers to be aware of how to care for and treat large local reactions and SRs, as symptom recognition and timely treatment can improve patient safety and result in better outcomes.

Classification

Blister beetles are both a scourge and the source of medical cantharidin (Figure 1). The term blister beetle refers to 3 families of the order Coleoptera: Meloidae, Oedemeridae, and Staphylinidae (Figure 2).

Meloidae is the most well-known family of blister beetles, with more than 200 species worldwide identified as a cause of blistering dermatitis.¹ The most notorious is Lytta vesicatoria, also known as the Spanish fly. Although some blister beetles are inconspicuous in appearance, most are brightly colored and easily spotted, making them attractive to small children.² They may be attracted to fluorescent lighting and commonly enter through open windows.³ Blister beetles do not bite or sting; rather, they release cantharidin via hemolymph, an oily yellow substance that is copiously expressed from the leg joints when disturbed by rubbing or pressing.^1,3-5 Blistering also is associated with exposure to the contents of crushed beetles, which is the source of pharmacologic cantharidin.^2,4,6

Oedemeridae are the smallest and least known beetles within the Coleoptera family. They often are called false blister beetles, which is a misnomer. Oedemeridae beetles also produce cantharidin, similar to Meloidae beetles; however, because Oedemeridae beetles are smaller, the vesiculobullous eruptions also are less pronounced.¹

A third well-known family of blister beetles is the Staphylinidae family. Rove beetles (genus Paederus) differ from the Meloidae and Oedemeridae families in that they produce the vesicant pederin rather than cantharidin. Pederin causes a more violent eruption called dermatitis linearis, which often is associated with intense urticaria prior to blistering.¹ Rove beetles are found in moist environments and tend to favor tropical and subtropical climates. They may emerge in large numbers after heavy rainfall.

Clinical Presentation

Blistering dermatitis—caused by exposure to cantharidin (families Meloidae and Oedemeridae) or pederin (genus Paederus)—begins as burning and tingling within minutes of exposure. Bullae later develop, often in a linear fashion, with subsequent bursting and crust formation.^1,3 Secondary infection can occur.⁵ Exposure occurring on the elbows, knees, or mirroring skin folds results in lesions on opposing surfaces that come into contact, otherwise known as kissing lesions.^1,3 Acantholysis of suprabasal keratinocytes can be seen on histologic sections of blisters (Figure 3)^1,7 due to cantharidin activation of the serine/threonine protein phosphatases that cause detachment of tonofilaments from desmosomes.^1,8 Washing of exposed sites with soap or alcohol can potentially prevent development of blistering dermatitis; however, lesions usually heal without complication when treated with topical antibiotics.³

If blister beetles are ingested, they can cause poisoning characterized by abdominal pain and hematuria.^1,3,9,10 In fact, blister beetle ingestion by animals consuming baled hay is an important agricultural and economical implication. Several cases of fatal farm animal ingestion resulting in gastrointestinal erosion have been reported.^4,6

Medicinal Properties

Medicinal use of cantharidin has been recorded as early as the 19th century and is believed to have been part of ancient medicinal practices in China, Spain, South Africa, and pre-Columbian America for its vesicant, abortifacient, and supposed aphrodisiac properties.^2,4,8

Toxicity from internal ingestion has been well documented.^1,3,9,10 The Mylabris and Epicauta genera of the family Meloidae, most commonly the Spanish fly, are used for modern extraction of cantharidin. Up to 5% of the dry weight of a blister beetle can be constituted by cantharidin.⁴

Although its use has diminished due to limited availability, cantharidin is still used for treatment of common warts, periungual warts, and molluscum contagiosum. It is a favorable choice for treating pediatric patients because of the tolerability and painlessness of application. Due to its acantholytic properties, warts generally slough with the cantharidin-induced blister.¹¹

In recent years, cantharidin has been studied for its anticancer properties. It has been shown to weaken cancer cell antioxidant properties by interfering with glutathione-related enzymes, thus inducing oxidative damage. Additionally, cantharidin is associated with decreased mitochondrial cytochrome C and increased cytosolic cytochrome C, an important signal for apoptosis.¹² Furthermore, cantharidin recently was shown to increase expression of proapoptotic proteins and decrease expression of antiapoptotic proteins causing cell death in nasopharyngeal carcinoma, making it a potential anticancer treatment.¹³

Conclusion

Blister beetles, long known for their production of vesicant agents, are both a cause of as well as a potential treatment of dermatologic disease. The blistering associated with exposure to a disturbed beetle generally is mild and heals without scarring if vital areas such as the eyelids are not affected.

Classification

Blister beetles are both a scourge and the source of medical cantharidin (Figure 1). The term blister beetle refers to 3 families of the order Coleoptera: Meloidae, Oedemeridae, and Staphylinidae (Figure 2).

Meloidae is the most well-known family of blister beetles, with more than 200 species worldwide identified as a cause of blistering dermatitis.¹ The most notorious is Lytta vesicatoria, also known as the Spanish fly. Although some blister beetles are inconspicuous in appearance, most are brightly colored and easily spotted, making them attractive to small children.² They may be attracted to fluorescent lighting and commonly enter through open windows.³ Blister beetles do not bite or sting; rather, they release cantharidin via hemolymph, an oily yellow substance that is copiously expressed from the leg joints when disturbed by rubbing or pressing.^1,3-5 Blistering also is associated with exposure to the contents of crushed beetles, which is the source of pharmacologic cantharidin.^2,4,6

Oedemeridae are the smallest and least known beetles within the Coleoptera family. They often are called false blister beetles, which is a misnomer. Oedemeridae beetles also produce cantharidin, similar to Meloidae beetles; however, because Oedemeridae beetles are smaller, the vesiculobullous eruptions also are less pronounced.¹

A third well-known family of blister beetles is the Staphylinidae family. Rove beetles (genus Paederus) differ from the Meloidae and Oedemeridae families in that they produce the vesicant pederin rather than cantharidin. Pederin causes a more violent eruption called dermatitis linearis, which often is associated with intense urticaria prior to blistering.¹ Rove beetles are found in moist environments and tend to favor tropical and subtropical climates. They may emerge in large numbers after heavy rainfall.

Clinical Presentation

Blistering dermatitis—caused by exposure to cantharidin (families Meloidae and Oedemeridae) or pederin (genus Paederus)—begins as burning and tingling within minutes of exposure. Bullae later develop, often in a linear fashion, with subsequent bursting and crust formation.^1,3 Secondary infection can occur.⁵ Exposure occurring on the elbows, knees, or mirroring skin folds results in lesions on opposing surfaces that come into contact, otherwise known as kissing lesions.^1,3 Acantholysis of suprabasal keratinocytes can be seen on histologic sections of blisters (Figure 3)^1,7 due to cantharidin activation of the serine/threonine protein phosphatases that cause detachment of tonofilaments from desmosomes.^1,8 Washing of exposed sites with soap or alcohol can potentially prevent development of blistering dermatitis; however, lesions usually heal without complication when treated with topical antibiotics.³

If blister beetles are ingested, they can cause poisoning characterized by abdominal pain and hematuria.^1,3,9,10 In fact, blister beetle ingestion by animals consuming baled hay is an important agricultural and economical implication. Several cases of fatal farm animal ingestion resulting in gastrointestinal erosion have been reported.^4,6

Medicinal Properties

Medicinal use of cantharidin has been recorded as early as the 19th century and is believed to have been part of ancient medicinal practices in China, Spain, South Africa, and pre-Columbian America for its vesicant, abortifacient, and supposed aphrodisiac properties.^2,4,8

Toxicity from internal ingestion has been well documented.^1,3,9,10 The Mylabris and Epicauta genera of the family Meloidae, most commonly the Spanish fly, are used for modern extraction of cantharidin. Up to 5% of the dry weight of a blister beetle can be constituted by cantharidin.⁴

Although its use has diminished due to limited availability, cantharidin is still used for treatment of common warts, periungual warts, and molluscum contagiosum. It is a favorable choice for treating pediatric patients because of the tolerability and painlessness of application. Due to its acantholytic properties, warts generally slough with the cantharidin-induced blister.¹¹

In recent years, cantharidin has been studied for its anticancer properties. It has been shown to weaken cancer cell antioxidant properties by interfering with glutathione-related enzymes, thus inducing oxidative damage. Additionally, cantharidin is associated with decreased mitochondrial cytochrome C and increased cytosolic cytochrome C, an important signal for apoptosis.¹² Furthermore, cantharidin recently was shown to increase expression of proapoptotic proteins and decrease expression of antiapoptotic proteins causing cell death in nasopharyngeal carcinoma, making it a potential anticancer treatment.¹³

Conclusion

Blister beetles, long known for their production of vesicant agents, are both a cause of as well as a potential treatment of dermatologic disease. The blistering associated with exposure to a disturbed beetle generally is mild and heals without scarring if vital areas such as the eyelids are not affected.

Classification

Blister beetles are both a scourge and the source of medical cantharidin (Figure 1). The term blister beetle refers to 3 families of the order Coleoptera: Meloidae, Oedemeridae, and Staphylinidae (Figure 2).

Meloidae is the most well-known family of blister beetles, with more than 200 species worldwide identified as a cause of blistering dermatitis.¹ The most notorious is Lytta vesicatoria, also known as the Spanish fly. Although some blister beetles are inconspicuous in appearance, most are brightly colored and easily spotted, making them attractive to small children.² They may be attracted to fluorescent lighting and commonly enter through open windows.³ Blister beetles do not bite or sting; rather, they release cantharidin via hemolymph, an oily yellow substance that is copiously expressed from the leg joints when disturbed by rubbing or pressing.^1,3-5 Blistering also is associated with exposure to the contents of crushed beetles, which is the source of pharmacologic cantharidin.^2,4,6

Oedemeridae are the smallest and least known beetles within the Coleoptera family. They often are called false blister beetles, which is a misnomer. Oedemeridae beetles also produce cantharidin, similar to Meloidae beetles; however, because Oedemeridae beetles are smaller, the vesiculobullous eruptions also are less pronounced.¹

A third well-known family of blister beetles is the Staphylinidae family. Rove beetles (genus Paederus) differ from the Meloidae and Oedemeridae families in that they produce the vesicant pederin rather than cantharidin. Pederin causes a more violent eruption called dermatitis linearis, which often is associated with intense urticaria prior to blistering.¹ Rove beetles are found in moist environments and tend to favor tropical and subtropical climates. They may emerge in large numbers after heavy rainfall.

Clinical Presentation

Blistering dermatitis—caused by exposure to cantharidin (families Meloidae and Oedemeridae) or pederin (genus Paederus)—begins as burning and tingling within minutes of exposure. Bullae later develop, often in a linear fashion, with subsequent bursting and crust formation.^1,3 Secondary infection can occur.⁵ Exposure occurring on the elbows, knees, or mirroring skin folds results in lesions on opposing surfaces that come into contact, otherwise known as kissing lesions.^1,3 Acantholysis of suprabasal keratinocytes can be seen on histologic sections of blisters (Figure 3)^1,7 due to cantharidin activation of the serine/threonine protein phosphatases that cause detachment of tonofilaments from desmosomes.^1,8 Washing of exposed sites with soap or alcohol can potentially prevent development of blistering dermatitis; however, lesions usually heal without complication when treated with topical antibiotics.³

If blister beetles are ingested, they can cause poisoning characterized by abdominal pain and hematuria.^1,3,9,10 In fact, blister beetle ingestion by animals consuming baled hay is an important agricultural and economical implication. Several cases of fatal farm animal ingestion resulting in gastrointestinal erosion have been reported.^4,6

Medicinal Properties

Medicinal use of cantharidin has been recorded as early as the 19th century and is believed to have been part of ancient medicinal practices in China, Spain, South Africa, and pre-Columbian America for its vesicant, abortifacient, and supposed aphrodisiac properties.^2,4,8

Toxicity from internal ingestion has been well documented.^1,3,9,10 The Mylabris and Epicauta genera of the family Meloidae, most commonly the Spanish fly, are used for modern extraction of cantharidin. Up to 5% of the dry weight of a blister beetle can be constituted by cantharidin.⁴

Although its use has diminished due to limited availability, cantharidin is still used for treatment of common warts, periungual warts, and molluscum contagiosum. It is a favorable choice for treating pediatric patients because of the tolerability and painlessness of application. Due to its acantholytic properties, warts generally slough with the cantharidin-induced blister.¹¹

In recent years, cantharidin has been studied for its anticancer properties. It has been shown to weaken cancer cell antioxidant properties by interfering with glutathione-related enzymes, thus inducing oxidative damage. Additionally, cantharidin is associated with decreased mitochondrial cytochrome C and increased cytosolic cytochrome C, an important signal for apoptosis.¹² Furthermore, cantharidin recently was shown to increase expression of proapoptotic proteins and decrease expression of antiapoptotic proteins causing cell death in nasopharyngeal carcinoma, making it a potential anticancer treatment.¹³

Conclusion

Blister beetles, long known for their production of vesicant agents, are both a cause of as well as a potential treatment of dermatologic disease. The blistering associated with exposure to a disturbed beetle generally is mild and heals without scarring if vital areas such as the eyelids are not affected.

The Diagnosis: Sclerosing Perineurioma 

Sclerosing perineurioma, first described in 1997 by Fetsch and Miettinen,¹ is a subtype of perineurioma with a strong predilection for the fingers and palms of young adults. Rare cases involving extra-acral sites including the forearm, elbow, axilla, back, neck, lower leg, thigh, knee, lips, nose, and mouth have been reported.^2-4 Perineurioma is a relatively uncommon and benign peripheral nerve sheath tumor with exclusive perineurial differentiation.⁵ Perineurioma is divided into intraneural and extraneural types; the latter are further subclassified into soft tissue, sclerosing, reticular, and plexiform types. Other rare forms include the sclerosing, Pacinian corpuscle-like perineurioma, lipomatous perineurioma, perineurioma with xanthomatous areas, and perineurioma with granular cells.^6,7  

Clinically, sclerosing perineurioma usually presents as a solitary lesion; however, rare cases of multiple lesions have been reported.⁸ Our patient presented with a solitary papule on the nose. Histopathologically, sclerosing perineurioma demonstrates slender spindle cells in a whorled growth pattern (onion skin) embedded in a hyalinized, lamellar, and dense collagenous stroma with intervening cleftlike spaces. Immunohistochemically, the spindle cells of our case stained positive for epithelial membrane antigen (quiz images). Other positive immunostains for perineurioma include claudin-1 and glucose transporter 1 (GLUT1). Perineurioma lacks expression of S-100 but can express CD34.² As a benign tumor, the prognosis of sclerosing perineurioma is excellent. Complete local excision is considered curative.¹  

Angiofibroma, also known as fibrous papule, is a common and benign lesion located primarily on or in close proximity to the nose.⁹ Angiofibromas can be associated with genodermatoses such as tuberous sclerosis, multiple endocrine neoplasia type 1, or Birt-Hogg-Dubé syndrome. When angiofibromas involve the penis, they are called pearly penile papules. Ungual angiofibroma, also known as Koenen tumor, occurs underneath the nail.^10-12 Both facial angiofibromas (>3) and ungual angiofibromas (>2) are independent major criteria for tuberous sclerosis.¹³ Clinically, angiofibroma presents as a small, dome-shaped, pink papule arising on the lower portion of the nose or nearby area of the central face. Histopathologically, angiofibromas classically demonstrate increased dilated vessels and fibrosis in the dermis. Stellate, plump, spindle-shaped, and multinucleated cells can be seen in the collagenous stroma. The collagen fibers around hair follicles are arranged concentrically, resulting in an onion skin-like appearance. The epidermal rete ridges can be effaced (Figure 1). Increased numbers of single-unit melanocytes along the dermoepidermal junction can be seen in some cases. Immunohistochemically, a variable number of spindled and multinucleated cells in the dermis stain with factor XIIIa. There are at least 7 histologic variants of angiofibroma including hypercellular, pigmented, inflammatory, pleomorphic, clear cell, granular cell, and epithelioid.^9,14 

Palisaded encapsulated neuroma, also referred to as solitary circumscribed neuroma, was first described by Reed et al²¹ in 1972. It is a benign and solitary, firm, dome-shaped, flesh-colored papule that occurs in middle-aged adults, predominately near mucocutaneous junctions of the face. Other locations include the oral mucosa, eyelid, nasal fossa, shoulder, arm, hand, foot, and glans penis.^22,23 Histopathologically, palisaded encapsulated neuroma demonstrates a solitary, well-circumscribed, partially encapsulated, intradermal nodule composed of interweaving fascicles of spindle cells with prominent clefts (Figure 3). Rarely, palisaded encapsulated neuroma may have a plexiform or multinodular architecture.²⁴ Immunohistochemically, tumor cells stain positively for S-100 protein, type IV collagen, and vimentin. The capsule, composed of perineural cells, stains positive for epithelial membrane antigen. A neurofilament stain will highlight axons within the tumor.^24,25 Currently, palisaded encapsulated neuroma does not have a well-established link to known neurocutaneous or inherited syndromes. Excision is curative with a low risk of recurrence.²⁶ 

Sclerotic fibromas (SFs) were first reported by Weary et al²⁷ as multiple tumors involving the tongues of patients with Cowden syndrome. Sporadic or solitary SFs of the skin in patients without Cowden syndrome have been reported, and both multiple and solitary SFs present with similar pathologic changes.^28-30 Clinically, the solitary variant manifests as a well-demarcated, flesh-colored to erythematous, waxy papule or nodule with no site or sex predilection.^30,31 Histologically, SF demonstrates a well-demarcated, nonencapsulated dermal nodule composed of hypocellular and sclerotic collagen bundles with scattered spindled cells and prominent clefts resembling Vincent van Gogh's Starry Night or plywood (Figure 4). Immunohistochemically, the spindled cells strongly express CD34. Factor XIIIa and markers of melanocytic, neural, and muscular differentiation are negative. When rendering a diagnosis in a patient with multiple SFs, a comment regarding the possibility of Cowden syndrome should be mentioned.³² 

The Diagnosis: Sclerosing Perineurioma 

Sclerosing perineurioma, first described in 1997 by Fetsch and Miettinen,¹ is a subtype of perineurioma with a strong predilection for the fingers and palms of young adults. Rare cases involving extra-acral sites including the forearm, elbow, axilla, back, neck, lower leg, thigh, knee, lips, nose, and mouth have been reported.^2-4 Perineurioma is a relatively uncommon and benign peripheral nerve sheath tumor with exclusive perineurial differentiation.⁵ Perineurioma is divided into intraneural and extraneural types; the latter are further subclassified into soft tissue, sclerosing, reticular, and plexiform types. Other rare forms include the sclerosing, Pacinian corpuscle-like perineurioma, lipomatous perineurioma, perineurioma with xanthomatous areas, and perineurioma with granular cells.^6,7  

Clinically, sclerosing perineurioma usually presents as a solitary lesion; however, rare cases of multiple lesions have been reported.⁸ Our patient presented with a solitary papule on the nose. Histopathologically, sclerosing perineurioma demonstrates slender spindle cells in a whorled growth pattern (onion skin) embedded in a hyalinized, lamellar, and dense collagenous stroma with intervening cleftlike spaces. Immunohistochemically, the spindle cells of our case stained positive for epithelial membrane antigen (quiz images). Other positive immunostains for perineurioma include claudin-1 and glucose transporter 1 (GLUT1). Perineurioma lacks expression of S-100 but can express CD34.² As a benign tumor, the prognosis of sclerosing perineurioma is excellent. Complete local excision is considered curative.¹  

Angiofibroma, also known as fibrous papule, is a common and benign lesion located primarily on or in close proximity to the nose.⁹ Angiofibromas can be associated with genodermatoses such as tuberous sclerosis, multiple endocrine neoplasia type 1, or Birt-Hogg-Dubé syndrome. When angiofibromas involve the penis, they are called pearly penile papules. Ungual angiofibroma, also known as Koenen tumor, occurs underneath the nail.^10-12 Both facial angiofibromas (>3) and ungual angiofibromas (>2) are independent major criteria for tuberous sclerosis.¹³ Clinically, angiofibroma presents as a small, dome-shaped, pink papule arising on the lower portion of the nose or nearby area of the central face. Histopathologically, angiofibromas classically demonstrate increased dilated vessels and fibrosis in the dermis. Stellate, plump, spindle-shaped, and multinucleated cells can be seen in the collagenous stroma. The collagen fibers around hair follicles are arranged concentrically, resulting in an onion skin-like appearance. The epidermal rete ridges can be effaced (Figure 1). Increased numbers of single-unit melanocytes along the dermoepidermal junction can be seen in some cases. Immunohistochemically, a variable number of spindled and multinucleated cells in the dermis stain with factor XIIIa. There are at least 7 histologic variants of angiofibroma including hypercellular, pigmented, inflammatory, pleomorphic, clear cell, granular cell, and epithelioid.^9,14 

Palisaded encapsulated neuroma, also referred to as solitary circumscribed neuroma, was first described by Reed et al²¹ in 1972. It is a benign and solitary, firm, dome-shaped, flesh-colored papule that occurs in middle-aged adults, predominately near mucocutaneous junctions of the face. Other locations include the oral mucosa, eyelid, nasal fossa, shoulder, arm, hand, foot, and glans penis.^22,23 Histopathologically, palisaded encapsulated neuroma demonstrates a solitary, well-circumscribed, partially encapsulated, intradermal nodule composed of interweaving fascicles of spindle cells with prominent clefts (Figure 3). Rarely, palisaded encapsulated neuroma may have a plexiform or multinodular architecture.²⁴ Immunohistochemically, tumor cells stain positively for S-100 protein, type IV collagen, and vimentin. The capsule, composed of perineural cells, stains positive for epithelial membrane antigen. A neurofilament stain will highlight axons within the tumor.^24,25 Currently, palisaded encapsulated neuroma does not have a well-established link to known neurocutaneous or inherited syndromes. Excision is curative with a low risk of recurrence.²⁶ 

Sclerotic fibromas (SFs) were first reported by Weary et al²⁷ as multiple tumors involving the tongues of patients with Cowden syndrome. Sporadic or solitary SFs of the skin in patients without Cowden syndrome have been reported, and both multiple and solitary SFs present with similar pathologic changes.^28-30 Clinically, the solitary variant manifests as a well-demarcated, flesh-colored to erythematous, waxy papule or nodule with no site or sex predilection.^30,31 Histologically, SF demonstrates a well-demarcated, nonencapsulated dermal nodule composed of hypocellular and sclerotic collagen bundles with scattered spindled cells and prominent clefts resembling Vincent van Gogh's Starry Night or plywood (Figure 4). Immunohistochemically, the spindled cells strongly express CD34. Factor XIIIa and markers of melanocytic, neural, and muscular differentiation are negative. When rendering a diagnosis in a patient with multiple SFs, a comment regarding the possibility of Cowden syndrome should be mentioned.³² 

The Diagnosis: Sclerosing Perineurioma 

Sclerosing perineurioma, first described in 1997 by Fetsch and Miettinen,¹ is a subtype of perineurioma with a strong predilection for the fingers and palms of young adults. Rare cases involving extra-acral sites including the forearm, elbow, axilla, back, neck, lower leg, thigh, knee, lips, nose, and mouth have been reported.^2-4 Perineurioma is a relatively uncommon and benign peripheral nerve sheath tumor with exclusive perineurial differentiation.⁵ Perineurioma is divided into intraneural and extraneural types; the latter are further subclassified into soft tissue, sclerosing, reticular, and plexiform types. Other rare forms include the sclerosing, Pacinian corpuscle-like perineurioma, lipomatous perineurioma, perineurioma with xanthomatous areas, and perineurioma with granular cells.^6,7  

Clinically, sclerosing perineurioma usually presents as a solitary lesion; however, rare cases of multiple lesions have been reported.⁸ Our patient presented with a solitary papule on the nose. Histopathologically, sclerosing perineurioma demonstrates slender spindle cells in a whorled growth pattern (onion skin) embedded in a hyalinized, lamellar, and dense collagenous stroma with intervening cleftlike spaces. Immunohistochemically, the spindle cells of our case stained positive for epithelial membrane antigen (quiz images). Other positive immunostains for perineurioma include claudin-1 and glucose transporter 1 (GLUT1). Perineurioma lacks expression of S-100 but can express CD34.² As a benign tumor, the prognosis of sclerosing perineurioma is excellent. Complete local excision is considered curative.¹  

Angiofibroma, also known as fibrous papule, is a common and benign lesion located primarily on or in close proximity to the nose.⁹ Angiofibromas can be associated with genodermatoses such as tuberous sclerosis, multiple endocrine neoplasia type 1, or Birt-Hogg-Dubé syndrome. When angiofibromas involve the penis, they are called pearly penile papules. Ungual angiofibroma, also known as Koenen tumor, occurs underneath the nail.^10-12 Both facial angiofibromas (>3) and ungual angiofibromas (>2) are independent major criteria for tuberous sclerosis.¹³ Clinically, angiofibroma presents as a small, dome-shaped, pink papule arising on the lower portion of the nose or nearby area of the central face. Histopathologically, angiofibromas classically demonstrate increased dilated vessels and fibrosis in the dermis. Stellate, plump, spindle-shaped, and multinucleated cells can be seen in the collagenous stroma. The collagen fibers around hair follicles are arranged concentrically, resulting in an onion skin-like appearance. The epidermal rete ridges can be effaced (Figure 1). Increased numbers of single-unit melanocytes along the dermoepidermal junction can be seen in some cases. Immunohistochemically, a variable number of spindled and multinucleated cells in the dermis stain with factor XIIIa. There are at least 7 histologic variants of angiofibroma including hypercellular, pigmented, inflammatory, pleomorphic, clear cell, granular cell, and epithelioid.^9,14 

Palisaded encapsulated neuroma, also referred to as solitary circumscribed neuroma, was first described by Reed et al²¹ in 1972. It is a benign and solitary, firm, dome-shaped, flesh-colored papule that occurs in middle-aged adults, predominately near mucocutaneous junctions of the face. Other locations include the oral mucosa, eyelid, nasal fossa, shoulder, arm, hand, foot, and glans penis.^22,23 Histopathologically, palisaded encapsulated neuroma demonstrates a solitary, well-circumscribed, partially encapsulated, intradermal nodule composed of interweaving fascicles of spindle cells with prominent clefts (Figure 3). Rarely, palisaded encapsulated neuroma may have a plexiform or multinodular architecture.²⁴ Immunohistochemically, tumor cells stain positively for S-100 protein, type IV collagen, and vimentin. The capsule, composed of perineural cells, stains positive for epithelial membrane antigen. A neurofilament stain will highlight axons within the tumor.^24,25 Currently, palisaded encapsulated neuroma does not have a well-established link to known neurocutaneous or inherited syndromes. Excision is curative with a low risk of recurrence.²⁶ 

Sclerotic fibromas (SFs) were first reported by Weary et al²⁷ as multiple tumors involving the tongues of patients with Cowden syndrome. Sporadic or solitary SFs of the skin in patients without Cowden syndrome have been reported, and both multiple and solitary SFs present with similar pathologic changes.^28-30 Clinically, the solitary variant manifests as a well-demarcated, flesh-colored to erythematous, waxy papule or nodule with no site or sex predilection.^30,31 Histologically, SF demonstrates a well-demarcated, nonencapsulated dermal nodule composed of hypocellular and sclerotic collagen bundles with scattered spindled cells and prominent clefts resembling Vincent van Gogh's Starry Night or plywood (Figure 4). Immunohistochemically, the spindled cells strongly express CD34. Factor XIIIa and markers of melanocytic, neural, and muscular differentiation are negative. When rendering a diagnosis in a patient with multiple SFs, a comment regarding the possibility of Cowden syndrome should be mentioned.³² 

Case Report

A 7-year-old Chinese boy presented with multiple painful oral and tongue ulcers of 2 weeks’ duration as well as acute onset of moderate to high fever (highest temperature, 39.3°C) for 5 days. The fever was reported to have run a relapsing course, accompanied by rigors but without convulsions or cognitive changes. At times, the patient had nasal congestion, nasal discharge, and cough. He also had a transient eruption on the back and hands as well as an indurated red nodule on the left forearm.

Before the patient was hospitalized, antibiotic therapy was administered by other physicians, but the condition of fever and oral ulcers did not improve. After the patient was hospitalized, new tender nodules emerged on the scalp, buttocks, and lower extremities. New ulcers also appeared on the palate.

History
Two months earlier, the patient had presented with a painful perioral skin ulcer that resolved after being treated as contagious eczema. Another dermatologist previously had considered a diagnosis of hand-foot-and-mouth disease.

The patient was born by normal spontaneous vaginal delivery, without abnormality. He was breastfed; feeding, growth, and the developmental history showed no abnormality. He was the family’s eldest child, with a healthy brother and sister. There was no history of familial illness. He received bacillus Calmette-Guérin and poliomyelitis vaccines after birth; the rest of the vaccine history was unclear. There was no history of immunologic abnormality.

Physical Examination
A 1.5×1.5-cm, warm, red nodule with a central black crust was noted on the left forearm (Figure 1A). Several similar lesions were noted on the buttocks, scalp, and lower extremities. Multiple ulcers, as large as 1 cm, were present on the tongue, palate, and left angle of the mouth (Figure 1B). The pharynx was congested, and the tonsils were mildly enlarged. Multiple enlarged, movable, nontender lymph nodes could be palpated in the cervical basins, axillae, and groin. No purpura or ecchymosis was detected.

Laboratory Results
Laboratory testing revealed a normal total white blood cell count (4.26×10⁹/L [reference range, 4.0–12.0×10⁹/L]), with normal neutrophils (1.36×10⁹/L [reference range, 1.32–7.90×10⁹/L]), lymphocytes (2.77×10⁹/L [reference range, 1.20–6.00×10⁹/L]), and monocytes (0.13×10⁹/L [reference range, 0.08–0.80×10⁹/L]); a mildly decreased hemoglobin level (115 g/L [reference range, 120–160 g/L]); a normal platelet count (102×10⁹/L [reference range, 100–380×10⁹/L]); an elevated lactate dehydrogenase level (614 U/L [reference range, 110–330 U/L]); an elevated α-hydroxybutyrate dehydrogenase level (483 U/L [reference range, 120–270 U/L]); elevated prothrombin time (15.3 s [reference range, 9–14 s]); elevated activated partial thromboplastin time (59.8 s [reference range, 20.6–39.6 s]); and an elevated D-dimer level (1.51 mg/L [reference range, <0.73 mg/L]). In addition, autoantibody testing revealed a positive antinuclear antibody titer of 1:320 and a strong positive anti–Ro-52 level.

The peripheral blood lymphocyte classification demonstrated a prominent elevated percentage of T lymphocytes, with predominantly CD8⁺ cells (CD3, 94.87%; CD8, 71.57%; CD4, 24.98%; CD4:CD8 ratio, 0.35) and a diminished percentage of B lymphocytes and natural killer (NK) cells. Epstein-Barr virus (EBV) antibody testing was positive for anti–viral capsid antigen (VCA) IgG and negative for anti-VCA IgM.

Smears of the ulcer on the tongue demonstrated gram-positive cocci, gram-negative bacilli, and diplococci. Culture of sputum showed methicillin-resistant Staphylococcus aureus. Inspection for acid-fast bacilli in sputum yielded negative results 3 times. A purified protein derivative skin test for Mycobacterium tuberculosis infection was negative.

Imaging and Other Studies
Computed tomography of the chest and abdomen demonstrated 2 nodular opacities on the lower right lung; spotted opacities on the upper right lung; floccular opacities on the rest area of the lung; mild pleural effusion; enlargement of lymph nodes on the mediastinum, the bilateral hilum of the lung, and mesentery; and hepatosplenomegaly. Electrocardiography showed sinus tachycardia. Nasal cavity endoscopy showed sinusitis. Fundus examination showed vasculopathy of the left retina. A colonoscopy showed normal mucosa.

Histopathology
Biopsy of the nodule on the left arm showed dense, superficial to deep perivascular, periadnexal, perineural, and panniculitislike lymphoid infiltrates, as well as a sparse interstitial infiltrate with irregular and pleomorphic medium to large nuclei. Lymphoid cells showed mild epidermotropism, with tagging to the basal layer. Some vessel walls were infiltrated by similar cells (Figure 2). Infiltrative atypical lymphoid cells expressed CD3 and CD7 and were mostly CD8⁺, with a few CD4⁺ cells and most cells negative for CD5, CD20, CD30, CD56, and anaplastic lymphoma kinase. Cytotoxic markers granzyme B and T-cell intracellular antigen protein 1 were scattered positive. Immunostaining for Ki-67 protein highlighted an increased proliferative rate of 80% in malignant cells. In situ hybridization for EBV-encoded RNA (EBER) demonstrated EBV-positive atypical lymphoid cells (Figure 3). Analysis for T-cell receptor (TCR) γ gene rearrangement revealed a monoclonal pattern. Bone marrow aspirate showed proliferation of the 3 cell lines. The percentage of T lymphocytes was increased (20% of all nucleated cells). No hemophagocytic activity was found.

The patient’s parents refused to accept chemotherapy for him. Instead, they chose herbal therapy only; 5 months later, they reported that all of his symptoms had resolved; however, the disease suddenly relapsed after another 7 months, with multiple skin nodules and fever. The patient died, even with chemotherapy in another hospital.

Comment

Prevalence and Presentation
Epstein-Barr virus is a ubiquitous γ-herpesvirus with tropism for B cells, affecting more than 90% of the adult population worldwide. In addition to infecting B cells, EBV is capable of infecting T and NK cells, leading to various EBV-related lymphoproliferative disorders (LPDs). The frequency and clinical presentation of infection varies based on the type of EBV-infected cells and the state of host immunity.^1-3

Primary infection usually is asymptomatic and occurs early in life; when symptomatic, the disease usually presents as infectious mononucleosis (IM), characterized by polyclonal expansion of infected B cells and subsequent cytotoxic T-cell response. A diagnosis of EBV infection can be made by testing for specific IgM and IgG antibodies against VCA, early antigens, and EBV nuclear antigen proteins.^3,4

Associated LPDs
Although most symptoms associated with IM resolve within weeks or months, persistent or recurrent IM-like symptoms or even lasting disease occasionally occur, particularly in children and young adults. This complication is known as chronic active EBV infection (CAEBV), frequently associated with EBV-infected T-cell or NK-cell proliferation, especially in East Asian populations.^3,5

Epstein-Barr virus–positive T-cell and NK-cell LPDs of childhood include CAEBV infection of T-cell and NK-cell types and systemic EBV-positive T-cell lymphoma of childhood. The former includes hydroa vacciniforme–like LPD and severe mosquito bite allergy.³

Systemic EBV-Positive T-cell Lymphoma of Childhood
This entity occurs not only in children but also in adolescents and young adults. A fulminant illness characterized by clonal proliferation of EBV-infected cytotoxic T cells, it can develop shortly after primary EBV infection or is linked to CAEBV infection. The disorder is rare and has a racial predilection for Asian (ie, Japanese, Chinese, Korean) populations and indigenous populations of Mexico and Central and South America.^6-8

Complications
Systemic EBV-positive T-cell lymphoma of childhood is often complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. Other signs and symptoms include high fever, rash, jaundice, diarrhea, pancytopenia, and hepatosplenomegaly. The liver, spleen, lymph nodes, and bone marrow are commonly involved, and the disease can involve skin, the heart, and the lungs.^9,10

Diagnosis
When systemic EBV-positive T-cell lymphoma occurs shortly after IM, serology shows low or absent anti-VCA IgM and positive anti-VCA IgG. Infiltrating T cells usually are small and lack cytologic atypia; however, cases with pleomorphic, medium to large lymphoid cells, irregular nuclei, and frequent mitoses have been described. Hemophagocytosis can be seen in the liver, spleen, and bone marrow.^3,11

The most typical phenotype of systemic EBV-positive T-cell lymphoma is CD2⁺CD3⁺CD8⁺CD20⁻CD56⁻, with expression of the cytotoxic granules known as T-cell intracellular antigen 1 and granzyme B. Rare cases of CD4⁺ and mixed CD4⁺/CD8⁺ phenotypes have been described, usually in the setting of CAEBV infection.^3,12 Neoplastic cells have monoclonally rearranged TCR-γ genes and consistent EBER positivity with in situ hybridization.¹³ A final diagnosis is based on a comprehensive analysis of clinical, morphological, immunohistochemical, and molecular biological aspects.

Clinical Course and Prognosis
Most patients with systemic EBV-positive T-cell lymphoma have an aggressive clinical course with high mortality. In a few cases, patients were reported to respond to a regimen of etoposide and dexamethasone, followed by allogeneic hematopoietic stem cell transplantation.³

In recognition of the aggressive clinical behavior and desire to clearly distinguish systemic EBV-positive T-cell lymphoma from CAEBV infection, the older term systemic EBV-positive T-cell LPD of childhood, which had been introduced in 2008 to the World Health Organization classification, was changed to systemic EBV-positive T-cell lymphoma of childhood in the revised 2016 World Health Organization classification.^6,12 However, Kim et al¹⁴ reported a case with excellent response to corticosteroid administration, suggesting that systemic EBV-positive T-cell lymphoma of childhood may be more heterogeneous in terms of prognosis.

Our patient presented with acute IM-like symptoms, including high fever, tonsillar enlargement, lymphadenopathy, and hepatosplenomegaly, as well as uncommon oral ulcers and skin lesions, including indurated nodules. Histopathologic changes in the skin nodule, proliferation in bone marrow, immunohistochemical phenotype, and positivity of EBER and TCR-γ monoclonal rearrangement were all consistent with systemic EBV-positive T-cell lymphoma of childhood. The patient was positive for VCA IgG and negative for VCA IgM, compatible with systemic EBV-positive T-cell lymphoma of childhood occurring shortly after IM. Neither pancytopenia, hemophagocytic syndrome, nor multiorgan failure occurred during the course.

Differential Diagnosis
It is important to distinguish IM from systemic EBV-positive T-cell lymphoma of childhood and CAEBV infection. Detection of anti–VCA IgM in the early stage, its disappearance during the clinical course, and appearance of anti-EBV–determined nuclear antigen is useful to distinguish IM from the neoplasms, as systemic EBV-positive T-cell lymphoma of childhood is negative for anti-EBV–determined nuclear antigen. Carefully following the clinical course also is important.^3,15

Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis can occur in association with systemic EBV-positive T-cell lymphoma of childhood and might represent a continuum of disease rather than distinct entities.¹⁴ The most useful marker for differentiating EBV-associated hemophagocytic lymphohistiocytosis and systemic EBV-positive T-cell lymphoma of childhood is an abnormal karyotype rather than molecular clonality.¹⁶

Outcome
Mortality risk in EBV-associated T-cell and NK-cell LPD is not primarily dependent on whether the lesion has progressed to lymphoma but instead is related to associated complications.¹⁷

Conclusion

Although systemic EBV-positive T-cell lymphoma of childhood is a rare disorder and has race predilection, dermatologists should be aware due to the aggressive clinical source and poor prognosis. Histopathology and in situ hybridization for EBER and TCR gene rearrangements are critical for final diagnosis. Although rare cases can show temporary resolution, the final outcome of this disease is not optimistic.

Case Report

A 7-year-old Chinese boy presented with multiple painful oral and tongue ulcers of 2 weeks’ duration as well as acute onset of moderate to high fever (highest temperature, 39.3°C) for 5 days. The fever was reported to have run a relapsing course, accompanied by rigors but without convulsions or cognitive changes. At times, the patient had nasal congestion, nasal discharge, and cough. He also had a transient eruption on the back and hands as well as an indurated red nodule on the left forearm.

Before the patient was hospitalized, antibiotic therapy was administered by other physicians, but the condition of fever and oral ulcers did not improve. After the patient was hospitalized, new tender nodules emerged on the scalp, buttocks, and lower extremities. New ulcers also appeared on the palate.

History
Two months earlier, the patient had presented with a painful perioral skin ulcer that resolved after being treated as contagious eczema. Another dermatologist previously had considered a diagnosis of hand-foot-and-mouth disease.

The patient was born by normal spontaneous vaginal delivery, without abnormality. He was breastfed; feeding, growth, and the developmental history showed no abnormality. He was the family’s eldest child, with a healthy brother and sister. There was no history of familial illness. He received bacillus Calmette-Guérin and poliomyelitis vaccines after birth; the rest of the vaccine history was unclear. There was no history of immunologic abnormality.

Physical Examination
A 1.5×1.5-cm, warm, red nodule with a central black crust was noted on the left forearm (Figure 1A). Several similar lesions were noted on the buttocks, scalp, and lower extremities. Multiple ulcers, as large as 1 cm, were present on the tongue, palate, and left angle of the mouth (Figure 1B). The pharynx was congested, and the tonsils were mildly enlarged. Multiple enlarged, movable, nontender lymph nodes could be palpated in the cervical basins, axillae, and groin. No purpura or ecchymosis was detected.

Laboratory Results
Laboratory testing revealed a normal total white blood cell count (4.26×10⁹/L [reference range, 4.0–12.0×10⁹/L]), with normal neutrophils (1.36×10⁹/L [reference range, 1.32–7.90×10⁹/L]), lymphocytes (2.77×10⁹/L [reference range, 1.20–6.00×10⁹/L]), and monocytes (0.13×10⁹/L [reference range, 0.08–0.80×10⁹/L]); a mildly decreased hemoglobin level (115 g/L [reference range, 120–160 g/L]); a normal platelet count (102×10⁹/L [reference range, 100–380×10⁹/L]); an elevated lactate dehydrogenase level (614 U/L [reference range, 110–330 U/L]); an elevated α-hydroxybutyrate dehydrogenase level (483 U/L [reference range, 120–270 U/L]); elevated prothrombin time (15.3 s [reference range, 9–14 s]); elevated activated partial thromboplastin time (59.8 s [reference range, 20.6–39.6 s]); and an elevated D-dimer level (1.51 mg/L [reference range, <0.73 mg/L]). In addition, autoantibody testing revealed a positive antinuclear antibody titer of 1:320 and a strong positive anti–Ro-52 level.

The peripheral blood lymphocyte classification demonstrated a prominent elevated percentage of T lymphocytes, with predominantly CD8⁺ cells (CD3, 94.87%; CD8, 71.57%; CD4, 24.98%; CD4:CD8 ratio, 0.35) and a diminished percentage of B lymphocytes and natural killer (NK) cells. Epstein-Barr virus (EBV) antibody testing was positive for anti–viral capsid antigen (VCA) IgG and negative for anti-VCA IgM.

Smears of the ulcer on the tongue demonstrated gram-positive cocci, gram-negative bacilli, and diplococci. Culture of sputum showed methicillin-resistant Staphylococcus aureus. Inspection for acid-fast bacilli in sputum yielded negative results 3 times. A purified protein derivative skin test for Mycobacterium tuberculosis infection was negative.

Imaging and Other Studies
Computed tomography of the chest and abdomen demonstrated 2 nodular opacities on the lower right lung; spotted opacities on the upper right lung; floccular opacities on the rest area of the lung; mild pleural effusion; enlargement of lymph nodes on the mediastinum, the bilateral hilum of the lung, and mesentery; and hepatosplenomegaly. Electrocardiography showed sinus tachycardia. Nasal cavity endoscopy showed sinusitis. Fundus examination showed vasculopathy of the left retina. A colonoscopy showed normal mucosa.

Histopathology
Biopsy of the nodule on the left arm showed dense, superficial to deep perivascular, periadnexal, perineural, and panniculitislike lymphoid infiltrates, as well as a sparse interstitial infiltrate with irregular and pleomorphic medium to large nuclei. Lymphoid cells showed mild epidermotropism, with tagging to the basal layer. Some vessel walls were infiltrated by similar cells (Figure 2). Infiltrative atypical lymphoid cells expressed CD3 and CD7 and were mostly CD8⁺, with a few CD4⁺ cells and most cells negative for CD5, CD20, CD30, CD56, and anaplastic lymphoma kinase. Cytotoxic markers granzyme B and T-cell intracellular antigen protein 1 were scattered positive. Immunostaining for Ki-67 protein highlighted an increased proliferative rate of 80% in malignant cells. In situ hybridization for EBV-encoded RNA (EBER) demonstrated EBV-positive atypical lymphoid cells (Figure 3). Analysis for T-cell receptor (TCR) γ gene rearrangement revealed a monoclonal pattern. Bone marrow aspirate showed proliferation of the 3 cell lines. The percentage of T lymphocytes was increased (20% of all nucleated cells). No hemophagocytic activity was found.

The patient’s parents refused to accept chemotherapy for him. Instead, they chose herbal therapy only; 5 months later, they reported that all of his symptoms had resolved; however, the disease suddenly relapsed after another 7 months, with multiple skin nodules and fever. The patient died, even with chemotherapy in another hospital.

Comment

Prevalence and Presentation
Epstein-Barr virus is a ubiquitous γ-herpesvirus with tropism for B cells, affecting more than 90% of the adult population worldwide. In addition to infecting B cells, EBV is capable of infecting T and NK cells, leading to various EBV-related lymphoproliferative disorders (LPDs). The frequency and clinical presentation of infection varies based on the type of EBV-infected cells and the state of host immunity.^1-3

Primary infection usually is asymptomatic and occurs early in life; when symptomatic, the disease usually presents as infectious mononucleosis (IM), characterized by polyclonal expansion of infected B cells and subsequent cytotoxic T-cell response. A diagnosis of EBV infection can be made by testing for specific IgM and IgG antibodies against VCA, early antigens, and EBV nuclear antigen proteins.^3,4

Associated LPDs
Although most symptoms associated with IM resolve within weeks or months, persistent or recurrent IM-like symptoms or even lasting disease occasionally occur, particularly in children and young adults. This complication is known as chronic active EBV infection (CAEBV), frequently associated with EBV-infected T-cell or NK-cell proliferation, especially in East Asian populations.^3,5

Epstein-Barr virus–positive T-cell and NK-cell LPDs of childhood include CAEBV infection of T-cell and NK-cell types and systemic EBV-positive T-cell lymphoma of childhood. The former includes hydroa vacciniforme–like LPD and severe mosquito bite allergy.³

Systemic EBV-Positive T-cell Lymphoma of Childhood
This entity occurs not only in children but also in adolescents and young adults. A fulminant illness characterized by clonal proliferation of EBV-infected cytotoxic T cells, it can develop shortly after primary EBV infection or is linked to CAEBV infection. The disorder is rare and has a racial predilection for Asian (ie, Japanese, Chinese, Korean) populations and indigenous populations of Mexico and Central and South America.^6-8

Complications
Systemic EBV-positive T-cell lymphoma of childhood is often complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. Other signs and symptoms include high fever, rash, jaundice, diarrhea, pancytopenia, and hepatosplenomegaly. The liver, spleen, lymph nodes, and bone marrow are commonly involved, and the disease can involve skin, the heart, and the lungs.^9,10

Diagnosis
When systemic EBV-positive T-cell lymphoma occurs shortly after IM, serology shows low or absent anti-VCA IgM and positive anti-VCA IgG. Infiltrating T cells usually are small and lack cytologic atypia; however, cases with pleomorphic, medium to large lymphoid cells, irregular nuclei, and frequent mitoses have been described. Hemophagocytosis can be seen in the liver, spleen, and bone marrow.^3,11

The most typical phenotype of systemic EBV-positive T-cell lymphoma is CD2⁺CD3⁺CD8⁺CD20⁻CD56⁻, with expression of the cytotoxic granules known as T-cell intracellular antigen 1 and granzyme B. Rare cases of CD4⁺ and mixed CD4⁺/CD8⁺ phenotypes have been described, usually in the setting of CAEBV infection.^3,12 Neoplastic cells have monoclonally rearranged TCR-γ genes and consistent EBER positivity with in situ hybridization.¹³ A final diagnosis is based on a comprehensive analysis of clinical, morphological, immunohistochemical, and molecular biological aspects.

Clinical Course and Prognosis
Most patients with systemic EBV-positive T-cell lymphoma have an aggressive clinical course with high mortality. In a few cases, patients were reported to respond to a regimen of etoposide and dexamethasone, followed by allogeneic hematopoietic stem cell transplantation.³

In recognition of the aggressive clinical behavior and desire to clearly distinguish systemic EBV-positive T-cell lymphoma from CAEBV infection, the older term systemic EBV-positive T-cell LPD of childhood, which had been introduced in 2008 to the World Health Organization classification, was changed to systemic EBV-positive T-cell lymphoma of childhood in the revised 2016 World Health Organization classification.^6,12 However, Kim et al¹⁴ reported a case with excellent response to corticosteroid administration, suggesting that systemic EBV-positive T-cell lymphoma of childhood may be more heterogeneous in terms of prognosis.

Our patient presented with acute IM-like symptoms, including high fever, tonsillar enlargement, lymphadenopathy, and hepatosplenomegaly, as well as uncommon oral ulcers and skin lesions, including indurated nodules. Histopathologic changes in the skin nodule, proliferation in bone marrow, immunohistochemical phenotype, and positivity of EBER and TCR-γ monoclonal rearrangement were all consistent with systemic EBV-positive T-cell lymphoma of childhood. The patient was positive for VCA IgG and negative for VCA IgM, compatible with systemic EBV-positive T-cell lymphoma of childhood occurring shortly after IM. Neither pancytopenia, hemophagocytic syndrome, nor multiorgan failure occurred during the course.

Differential Diagnosis
It is important to distinguish IM from systemic EBV-positive T-cell lymphoma of childhood and CAEBV infection. Detection of anti–VCA IgM in the early stage, its disappearance during the clinical course, and appearance of anti-EBV–determined nuclear antigen is useful to distinguish IM from the neoplasms, as systemic EBV-positive T-cell lymphoma of childhood is negative for anti-EBV–determined nuclear antigen. Carefully following the clinical course also is important.^3,15

Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis can occur in association with systemic EBV-positive T-cell lymphoma of childhood and might represent a continuum of disease rather than distinct entities.¹⁴ The most useful marker for differentiating EBV-associated hemophagocytic lymphohistiocytosis and systemic EBV-positive T-cell lymphoma of childhood is an abnormal karyotype rather than molecular clonality.¹⁶

Outcome
Mortality risk in EBV-associated T-cell and NK-cell LPD is not primarily dependent on whether the lesion has progressed to lymphoma but instead is related to associated complications.¹⁷

Conclusion

Although systemic EBV-positive T-cell lymphoma of childhood is a rare disorder and has race predilection, dermatologists should be aware due to the aggressive clinical source and poor prognosis. Histopathology and in situ hybridization for EBER and TCR gene rearrangements are critical for final diagnosis. Although rare cases can show temporary resolution, the final outcome of this disease is not optimistic.

Case Report

A 7-year-old Chinese boy presented with multiple painful oral and tongue ulcers of 2 weeks’ duration as well as acute onset of moderate to high fever (highest temperature, 39.3°C) for 5 days. The fever was reported to have run a relapsing course, accompanied by rigors but without convulsions or cognitive changes. At times, the patient had nasal congestion, nasal discharge, and cough. He also had a transient eruption on the back and hands as well as an indurated red nodule on the left forearm.

Before the patient was hospitalized, antibiotic therapy was administered by other physicians, but the condition of fever and oral ulcers did not improve. After the patient was hospitalized, new tender nodules emerged on the scalp, buttocks, and lower extremities. New ulcers also appeared on the palate.

History
Two months earlier, the patient had presented with a painful perioral skin ulcer that resolved after being treated as contagious eczema. Another dermatologist previously had considered a diagnosis of hand-foot-and-mouth disease.

The patient was born by normal spontaneous vaginal delivery, without abnormality. He was breastfed; feeding, growth, and the developmental history showed no abnormality. He was the family’s eldest child, with a healthy brother and sister. There was no history of familial illness. He received bacillus Calmette-Guérin and poliomyelitis vaccines after birth; the rest of the vaccine history was unclear. There was no history of immunologic abnormality.

Physical Examination
A 1.5×1.5-cm, warm, red nodule with a central black crust was noted on the left forearm (Figure 1A). Several similar lesions were noted on the buttocks, scalp, and lower extremities. Multiple ulcers, as large as 1 cm, were present on the tongue, palate, and left angle of the mouth (Figure 1B). The pharynx was congested, and the tonsils were mildly enlarged. Multiple enlarged, movable, nontender lymph nodes could be palpated in the cervical basins, axillae, and groin. No purpura or ecchymosis was detected.

Laboratory Results
Laboratory testing revealed a normal total white blood cell count (4.26×10⁹/L [reference range, 4.0–12.0×10⁹/L]), with normal neutrophils (1.36×10⁹/L [reference range, 1.32–7.90×10⁹/L]), lymphocytes (2.77×10⁹/L [reference range, 1.20–6.00×10⁹/L]), and monocytes (0.13×10⁹/L [reference range, 0.08–0.80×10⁹/L]); a mildly decreased hemoglobin level (115 g/L [reference range, 120–160 g/L]); a normal platelet count (102×10⁹/L [reference range, 100–380×10⁹/L]); an elevated lactate dehydrogenase level (614 U/L [reference range, 110–330 U/L]); an elevated α-hydroxybutyrate dehydrogenase level (483 U/L [reference range, 120–270 U/L]); elevated prothrombin time (15.3 s [reference range, 9–14 s]); elevated activated partial thromboplastin time (59.8 s [reference range, 20.6–39.6 s]); and an elevated D-dimer level (1.51 mg/L [reference range, <0.73 mg/L]). In addition, autoantibody testing revealed a positive antinuclear antibody titer of 1:320 and a strong positive anti–Ro-52 level.

The peripheral blood lymphocyte classification demonstrated a prominent elevated percentage of T lymphocytes, with predominantly CD8⁺ cells (CD3, 94.87%; CD8, 71.57%; CD4, 24.98%; CD4:CD8 ratio, 0.35) and a diminished percentage of B lymphocytes and natural killer (NK) cells. Epstein-Barr virus (EBV) antibody testing was positive for anti–viral capsid antigen (VCA) IgG and negative for anti-VCA IgM.

Smears of the ulcer on the tongue demonstrated gram-positive cocci, gram-negative bacilli, and diplococci. Culture of sputum showed methicillin-resistant Staphylococcus aureus. Inspection for acid-fast bacilli in sputum yielded negative results 3 times. A purified protein derivative skin test for Mycobacterium tuberculosis infection was negative.

Imaging and Other Studies
Computed tomography of the chest and abdomen demonstrated 2 nodular opacities on the lower right lung; spotted opacities on the upper right lung; floccular opacities on the rest area of the lung; mild pleural effusion; enlargement of lymph nodes on the mediastinum, the bilateral hilum of the lung, and mesentery; and hepatosplenomegaly. Electrocardiography showed sinus tachycardia. Nasal cavity endoscopy showed sinusitis. Fundus examination showed vasculopathy of the left retina. A colonoscopy showed normal mucosa.

Histopathology
Biopsy of the nodule on the left arm showed dense, superficial to deep perivascular, periadnexal, perineural, and panniculitislike lymphoid infiltrates, as well as a sparse interstitial infiltrate with irregular and pleomorphic medium to large nuclei. Lymphoid cells showed mild epidermotropism, with tagging to the basal layer. Some vessel walls were infiltrated by similar cells (Figure 2). Infiltrative atypical lymphoid cells expressed CD3 and CD7 and were mostly CD8⁺, with a few CD4⁺ cells and most cells negative for CD5, CD20, CD30, CD56, and anaplastic lymphoma kinase. Cytotoxic markers granzyme B and T-cell intracellular antigen protein 1 were scattered positive. Immunostaining for Ki-67 protein highlighted an increased proliferative rate of 80% in malignant cells. In situ hybridization for EBV-encoded RNA (EBER) demonstrated EBV-positive atypical lymphoid cells (Figure 3). Analysis for T-cell receptor (TCR) γ gene rearrangement revealed a monoclonal pattern. Bone marrow aspirate showed proliferation of the 3 cell lines. The percentage of T lymphocytes was increased (20% of all nucleated cells). No hemophagocytic activity was found.

The patient’s parents refused to accept chemotherapy for him. Instead, they chose herbal therapy only; 5 months later, they reported that all of his symptoms had resolved; however, the disease suddenly relapsed after another 7 months, with multiple skin nodules and fever. The patient died, even with chemotherapy in another hospital.

Comment

Prevalence and Presentation
Epstein-Barr virus is a ubiquitous γ-herpesvirus with tropism for B cells, affecting more than 90% of the adult population worldwide. In addition to infecting B cells, EBV is capable of infecting T and NK cells, leading to various EBV-related lymphoproliferative disorders (LPDs). The frequency and clinical presentation of infection varies based on the type of EBV-infected cells and the state of host immunity.^1-3

Primary infection usually is asymptomatic and occurs early in life; when symptomatic, the disease usually presents as infectious mononucleosis (IM), characterized by polyclonal expansion of infected B cells and subsequent cytotoxic T-cell response. A diagnosis of EBV infection can be made by testing for specific IgM and IgG antibodies against VCA, early antigens, and EBV nuclear antigen proteins.^3,4

Associated LPDs
Although most symptoms associated with IM resolve within weeks or months, persistent or recurrent IM-like symptoms or even lasting disease occasionally occur, particularly in children and young adults. This complication is known as chronic active EBV infection (CAEBV), frequently associated with EBV-infected T-cell or NK-cell proliferation, especially in East Asian populations.^3,5

Epstein-Barr virus–positive T-cell and NK-cell LPDs of childhood include CAEBV infection of T-cell and NK-cell types and systemic EBV-positive T-cell lymphoma of childhood. The former includes hydroa vacciniforme–like LPD and severe mosquito bite allergy.³

Systemic EBV-Positive T-cell Lymphoma of Childhood
This entity occurs not only in children but also in adolescents and young adults. A fulminant illness characterized by clonal proliferation of EBV-infected cytotoxic T cells, it can develop shortly after primary EBV infection or is linked to CAEBV infection. The disorder is rare and has a racial predilection for Asian (ie, Japanese, Chinese, Korean) populations and indigenous populations of Mexico and Central and South America.^6-8

Complications
Systemic EBV-positive T-cell lymphoma of childhood is often complicated by hemophagocytic syndrome, coagulopathy, sepsis, and multiorgan failure. Other signs and symptoms include high fever, rash, jaundice, diarrhea, pancytopenia, and hepatosplenomegaly. The liver, spleen, lymph nodes, and bone marrow are commonly involved, and the disease can involve skin, the heart, and the lungs.^9,10

Diagnosis
When systemic EBV-positive T-cell lymphoma occurs shortly after IM, serology shows low or absent anti-VCA IgM and positive anti-VCA IgG. Infiltrating T cells usually are small and lack cytologic atypia; however, cases with pleomorphic, medium to large lymphoid cells, irregular nuclei, and frequent mitoses have been described. Hemophagocytosis can be seen in the liver, spleen, and bone marrow.^3,11

The most typical phenotype of systemic EBV-positive T-cell lymphoma is CD2⁺CD3⁺CD8⁺CD20⁻CD56⁻, with expression of the cytotoxic granules known as T-cell intracellular antigen 1 and granzyme B. Rare cases of CD4⁺ and mixed CD4⁺/CD8⁺ phenotypes have been described, usually in the setting of CAEBV infection.^3,12 Neoplastic cells have monoclonally rearranged TCR-γ genes and consistent EBER positivity with in situ hybridization.¹³ A final diagnosis is based on a comprehensive analysis of clinical, morphological, immunohistochemical, and molecular biological aspects.

Clinical Course and Prognosis
Most patients with systemic EBV-positive T-cell lymphoma have an aggressive clinical course with high mortality. In a few cases, patients were reported to respond to a regimen of etoposide and dexamethasone, followed by allogeneic hematopoietic stem cell transplantation.³

In recognition of the aggressive clinical behavior and desire to clearly distinguish systemic EBV-positive T-cell lymphoma from CAEBV infection, the older term systemic EBV-positive T-cell LPD of childhood, which had been introduced in 2008 to the World Health Organization classification, was changed to systemic EBV-positive T-cell lymphoma of childhood in the revised 2016 World Health Organization classification.^6,12 However, Kim et al¹⁴ reported a case with excellent response to corticosteroid administration, suggesting that systemic EBV-positive T-cell lymphoma of childhood may be more heterogeneous in terms of prognosis.

Our patient presented with acute IM-like symptoms, including high fever, tonsillar enlargement, lymphadenopathy, and hepatosplenomegaly, as well as uncommon oral ulcers and skin lesions, including indurated nodules. Histopathologic changes in the skin nodule, proliferation in bone marrow, immunohistochemical phenotype, and positivity of EBER and TCR-γ monoclonal rearrangement were all consistent with systemic EBV-positive T-cell lymphoma of childhood. The patient was positive for VCA IgG and negative for VCA IgM, compatible with systemic EBV-positive T-cell lymphoma of childhood occurring shortly after IM. Neither pancytopenia, hemophagocytic syndrome, nor multiorgan failure occurred during the course.

Differential Diagnosis
It is important to distinguish IM from systemic EBV-positive T-cell lymphoma of childhood and CAEBV infection. Detection of anti–VCA IgM in the early stage, its disappearance during the clinical course, and appearance of anti-EBV–determined nuclear antigen is useful to distinguish IM from the neoplasms, as systemic EBV-positive T-cell lymphoma of childhood is negative for anti-EBV–determined nuclear antigen. Carefully following the clinical course also is important.^3,15

Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis can occur in association with systemic EBV-positive T-cell lymphoma of childhood and might represent a continuum of disease rather than distinct entities.¹⁴ The most useful marker for differentiating EBV-associated hemophagocytic lymphohistiocytosis and systemic EBV-positive T-cell lymphoma of childhood is an abnormal karyotype rather than molecular clonality.¹⁶

Outcome
Mortality risk in EBV-associated T-cell and NK-cell LPD is not primarily dependent on whether the lesion has progressed to lymphoma but instead is related to associated complications.¹⁷

Conclusion

Although systemic EBV-positive T-cell lymphoma of childhood is a rare disorder and has race predilection, dermatologists should be aware due to the aggressive clinical source and poor prognosis. Histopathology and in situ hybridization for EBER and TCR gene rearrangements are critical for final diagnosis. Although rare cases can show temporary resolution, the final outcome of this disease is not optimistic.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

The Diagnosis: Epithelioid Histiocytoma 

Epithelioid histiocytoma (EH), also known as epithelioid cell histiocytoma or epithelioid fibrous histiocytoma, is a rare benign fibrohistiocytic tumor first described in 1989.¹ Epithelioid histiocytoma commonly presents in middle-aged adults with a slight predilection for males.² The most frequently affected site is the lower extremity. The arms, trunk, head and neck, groin, and tongue also can be involved.^3,4 It usually presents as a solitary asymptomatic papule or nodule, though cases with multiple lesions have been reported.⁵ Anaplastic lymphoma kinase rearrangement and overexpression have been confirmed and suggest that EH is distinct from conventional cutaneous fibrous histiocytoma.⁵  

Histologically, EH appears as an exophytic, symmetric, and well-demarcated dermal nodule with a classic epidermal collarette. Prominent vascularity with perivascular accentuation of the epithelioid tumor cells is common. Older lesions may be hyalinized and sclerotic. Epithelioid cells commonly account for more than 50% of the tumor and are characterized by eosinophilic cytoplasm, vesicular nuclei, and small eosinophilic nucleoli. A small population of lymphocytes and mast cells are variably present (quiz image, bottom).^1-3,7 A predominantly spindle cell variant has been reported.⁸ Other histopathologic variants include granular cell,⁹ cellular,¹⁰ and EH with perineuriomalike growth.¹¹ Immunohistochemical staining shows anaplastic lymphoma kinase positivity in most cases, and more than half of cases stain positive for factor XIIIa and epithelial membrane antigen. Tumor cells consistently are negative for desmin and cytokeratins.^6,10,12 Excision is curative.⁸  

Polypoid Spitz nevus (PSN) is a benign nevus with a conspicuous polypoid or papillary exophytic architecture. The term was coined in 2000 by Fabrizi and Massi.¹³ Spitz nevus is a benign acquired melanocytic tumor that typically presents in children and adolescents and has a wide histologic spectrum.¹⁴ There is some debate on this entity, as some authors do not regard PSN as a distinct histologic variant; thus, it seems underreported in the literature.¹⁵ In a review of 349 cases of Spitz nevi, the authors found 7 cases of PSN.¹⁶ In another review of 74 cases of intradermal Spitz nevi, 14 cases of PSN were identified.¹⁴ This polypoid variant is easily mistaken for a polypoid melanoma because it can show cytologic atypia with large nuclei. Polypoid Spitz nevus usually lacks mitoses, notable pleomorphism, and sheetlike growth, unlike melanoma (Figure 1).^13,14  

Myopericytoma is an uncommon benign mesenchymal neoplasm that typically presents as a solitary, slowly enlarging and painless nodule with a predilection for the lower extremities, usually in adult males.^17-20 Histologically, it consists of a well-circumscribed nodule with numerous thin-walled vessels and a proliferation of ovoid to spindled myopericytes exhibiting a concentric perivascular growth pattern (Figure 2). Myopericytoma usually is positive for smooth muscle actin and h-caldesmon but is negative or only focally positive for desmin. The prognosis is good with rare recurrence, despite incomplete excision.^17,18 

Solitary reticulohistiocytoma is a rare benign form of non-Langerhans cell histiocytosis.^21,22 Unlike its multicentric counterpart, solitary reticulohistiocytoma rarely is associated with systemic disease. It presents as a small, dome-shaped, painless papule or nodule that can affect any part of the body.^22,23 Solitary reticulohistiocytoma characteristically demonstrates cells with a ground glass-like appearance and 2-toned cytoplasm. A mixed inflammatory infiltrate including neutrophils, eosinophils, and lymphocytes commonly is present (Figure 3). The epithelioid histiocytes are positive for vimentin and histiocytic markers including CD68 and CD163.²²  

Solitary fibrous tumor (SFT) is an uncommon mesenchymal fibroblastic neoplasm that can arise at almost any anatomic site.²⁴ Cutaneous SFTs are more common in women, most often involve the head, and appear to behave in an indolent manner.²⁵ Solitary fibrous tumors are translocation-associated neoplasms with a NAB2-STAT6 gene fusion.²⁶ The classic histology of SFT is a spindled fibroblastic proliferation arranged in a "patternless pattern" with interspersed stag horn-like, thin-walled blood vessels (Figure 4). Tumor cells usually are positive for CD34, CD99, and Bcl-2.²⁷ In addition, STAT6 immunoreactivity is useful in diagnosis of SFT.²⁵

The Diagnosis: Epithelioid Histiocytoma 

Epithelioid histiocytoma (EH), also known as epithelioid cell histiocytoma or epithelioid fibrous histiocytoma, is a rare benign fibrohistiocytic tumor first described in 1989.¹ Epithelioid histiocytoma commonly presents in middle-aged adults with a slight predilection for males.² The most frequently affected site is the lower extremity. The arms, trunk, head and neck, groin, and tongue also can be involved.^3,4 It usually presents as a solitary asymptomatic papule or nodule, though cases with multiple lesions have been reported.⁵ Anaplastic lymphoma kinase rearrangement and overexpression have been confirmed and suggest that EH is distinct from conventional cutaneous fibrous histiocytoma.⁵  

Histologically, EH appears as an exophytic, symmetric, and well-demarcated dermal nodule with a classic epidermal collarette. Prominent vascularity with perivascular accentuation of the epithelioid tumor cells is common. Older lesions may be hyalinized and sclerotic. Epithelioid cells commonly account for more than 50% of the tumor and are characterized by eosinophilic cytoplasm, vesicular nuclei, and small eosinophilic nucleoli. A small population of lymphocytes and mast cells are variably present (quiz image, bottom).^1-3,7 A predominantly spindle cell variant has been reported.⁸ Other histopathologic variants include granular cell,⁹ cellular,¹⁰ and EH with perineuriomalike growth.¹¹ Immunohistochemical staining shows anaplastic lymphoma kinase positivity in most cases, and more than half of cases stain positive for factor XIIIa and epithelial membrane antigen. Tumor cells consistently are negative for desmin and cytokeratins.^6,10,12 Excision is curative.⁸  

Polypoid Spitz nevus (PSN) is a benign nevus with a conspicuous polypoid or papillary exophytic architecture. The term was coined in 2000 by Fabrizi and Massi.¹³ Spitz nevus is a benign acquired melanocytic tumor that typically presents in children and adolescents and has a wide histologic spectrum.¹⁴ There is some debate on this entity, as some authors do not regard PSN as a distinct histologic variant; thus, it seems underreported in the literature.¹⁵ In a review of 349 cases of Spitz nevi, the authors found 7 cases of PSN.¹⁶ In another review of 74 cases of intradermal Spitz nevi, 14 cases of PSN were identified.¹⁴ This polypoid variant is easily mistaken for a polypoid melanoma because it can show cytologic atypia with large nuclei. Polypoid Spitz nevus usually lacks mitoses, notable pleomorphism, and sheetlike growth, unlike melanoma (Figure 1).^13,14  

Myopericytoma is an uncommon benign mesenchymal neoplasm that typically presents as a solitary, slowly enlarging and painless nodule with a predilection for the lower extremities, usually in adult males.^17-20 Histologically, it consists of a well-circumscribed nodule with numerous thin-walled vessels and a proliferation of ovoid to spindled myopericytes exhibiting a concentric perivascular growth pattern (Figure 2). Myopericytoma usually is positive for smooth muscle actin and h-caldesmon but is negative or only focally positive for desmin. The prognosis is good with rare recurrence, despite incomplete excision.^17,18 

Solitary reticulohistiocytoma is a rare benign form of non-Langerhans cell histiocytosis.^21,22 Unlike its multicentric counterpart, solitary reticulohistiocytoma rarely is associated with systemic disease. It presents as a small, dome-shaped, painless papule or nodule that can affect any part of the body.^22,23 Solitary reticulohistiocytoma characteristically demonstrates cells with a ground glass-like appearance and 2-toned cytoplasm. A mixed inflammatory infiltrate including neutrophils, eosinophils, and lymphocytes commonly is present (Figure 3). The epithelioid histiocytes are positive for vimentin and histiocytic markers including CD68 and CD163.²²  

Solitary fibrous tumor (SFT) is an uncommon mesenchymal fibroblastic neoplasm that can arise at almost any anatomic site.²⁴ Cutaneous SFTs are more common in women, most often involve the head, and appear to behave in an indolent manner.²⁵ Solitary fibrous tumors are translocation-associated neoplasms with a NAB2-STAT6 gene fusion.²⁶ The classic histology of SFT is a spindled fibroblastic proliferation arranged in a "patternless pattern" with interspersed stag horn-like, thin-walled blood vessels (Figure 4). Tumor cells usually are positive for CD34, CD99, and Bcl-2.²⁷ In addition, STAT6 immunoreactivity is useful in diagnosis of SFT.²⁵

The Diagnosis: Epithelioid Histiocytoma 

Epithelioid histiocytoma (EH), also known as epithelioid cell histiocytoma or epithelioid fibrous histiocytoma, is a rare benign fibrohistiocytic tumor first described in 1989.¹ Epithelioid histiocytoma commonly presents in middle-aged adults with a slight predilection for males.² The most frequently affected site is the lower extremity. The arms, trunk, head and neck, groin, and tongue also can be involved.^3,4 It usually presents as a solitary asymptomatic papule or nodule, though cases with multiple lesions have been reported.⁵ Anaplastic lymphoma kinase rearrangement and overexpression have been confirmed and suggest that EH is distinct from conventional cutaneous fibrous histiocytoma.⁵  

Histologically, EH appears as an exophytic, symmetric, and well-demarcated dermal nodule with a classic epidermal collarette. Prominent vascularity with perivascular accentuation of the epithelioid tumor cells is common. Older lesions may be hyalinized and sclerotic. Epithelioid cells commonly account for more than 50% of the tumor and are characterized by eosinophilic cytoplasm, vesicular nuclei, and small eosinophilic nucleoli. A small population of lymphocytes and mast cells are variably present (quiz image, bottom).^1-3,7 A predominantly spindle cell variant has been reported.⁸ Other histopathologic variants include granular cell,⁹ cellular,¹⁰ and EH with perineuriomalike growth.¹¹ Immunohistochemical staining shows anaplastic lymphoma kinase positivity in most cases, and more than half of cases stain positive for factor XIIIa and epithelial membrane antigen. Tumor cells consistently are negative for desmin and cytokeratins.^6,10,12 Excision is curative.⁸  

Polypoid Spitz nevus (PSN) is a benign nevus with a conspicuous polypoid or papillary exophytic architecture. The term was coined in 2000 by Fabrizi and Massi.¹³ Spitz nevus is a benign acquired melanocytic tumor that typically presents in children and adolescents and has a wide histologic spectrum.¹⁴ There is some debate on this entity, as some authors do not regard PSN as a distinct histologic variant; thus, it seems underreported in the literature.¹⁵ In a review of 349 cases of Spitz nevi, the authors found 7 cases of PSN.¹⁶ In another review of 74 cases of intradermal Spitz nevi, 14 cases of PSN were identified.¹⁴ This polypoid variant is easily mistaken for a polypoid melanoma because it can show cytologic atypia with large nuclei. Polypoid Spitz nevus usually lacks mitoses, notable pleomorphism, and sheetlike growth, unlike melanoma (Figure 1).^13,14  

Myopericytoma is an uncommon benign mesenchymal neoplasm that typically presents as a solitary, slowly enlarging and painless nodule with a predilection for the lower extremities, usually in adult males.^17-20 Histologically, it consists of a well-circumscribed nodule with numerous thin-walled vessels and a proliferation of ovoid to spindled myopericytes exhibiting a concentric perivascular growth pattern (Figure 2). Myopericytoma usually is positive for smooth muscle actin and h-caldesmon but is negative or only focally positive for desmin. The prognosis is good with rare recurrence, despite incomplete excision.^17,18 

Solitary reticulohistiocytoma is a rare benign form of non-Langerhans cell histiocytosis.^21,22 Unlike its multicentric counterpart, solitary reticulohistiocytoma rarely is associated with systemic disease. It presents as a small, dome-shaped, painless papule or nodule that can affect any part of the body.^22,23 Solitary reticulohistiocytoma characteristically demonstrates cells with a ground glass-like appearance and 2-toned cytoplasm. A mixed inflammatory infiltrate including neutrophils, eosinophils, and lymphocytes commonly is present (Figure 3). The epithelioid histiocytes are positive for vimentin and histiocytic markers including CD68 and CD163.²²  

Solitary fibrous tumor (SFT) is an uncommon mesenchymal fibroblastic neoplasm that can arise at almost any anatomic site.²⁴ Cutaneous SFTs are more common in women, most often involve the head, and appear to behave in an indolent manner.²⁵ Solitary fibrous tumors are translocation-associated neoplasms with a NAB2-STAT6 gene fusion.²⁶ The classic histology of SFT is a spindled fibroblastic proliferation arranged in a "patternless pattern" with interspersed stag horn-like, thin-walled blood vessels (Figure 4). Tumor cells usually are positive for CD34, CD99, and Bcl-2.²⁷ In addition, STAT6 immunoreactivity is useful in diagnosis of SFT.²⁵

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

The Diagnosis: Thallium-Induced Alopecia 

At the time of presentation, a punch biopsy specimen of the scalp revealed nonscarring alopecia with increased catagen hairs; follicular miniaturization; peribulbar lymphoid infiltrates; and fibrous tract remnants containing melanin, lymphocytes, and occasional mast cells (Figure 1). The differential diagnosis included alopecia areata, syphilis, and toxin-mediated anagen effluvium (AE). Given the abrupt onset affecting multiple individuals in an industrial environment, heavy metal poisoning was suspected. Blood and urine testing was negative, but a few months had elapsed since exposure. Several months after his initial presentation, the patient reported problems with his teeth, thin brittle nails, and resolution of the visual changes. Photographs sent by the patient revealed darkening and degeneration of the gingival margin (Figure 2). 

Environmental review revealed the patient was working on a demolition site of a 150-year-old electrical plant near a river. Inundation of rainfall caused a river swell and subsequent flooding of the work site. The patient reported working for more than 2 months in knee-deep muddy water, and he noted that water for consumption and showers was procured on-site from a well-based source that may have been contaminated by the floodwaters.  

Acute nonscarring alopecia can be an AE or telogen effluvium (TE), also known as telogen defluvium. The key distinguishing factor is the mode of injury.¹ In TE, medications, stress, hormonal shifts, or inflammation induce a synchronized and abrupt transition of hairs from anagen phase to catagen phase, a committed step that then must fully cycle through the telogen phase, culminating in the simultaneous shedding of numerous telogen hairs approximately 3 to 4 months later. Conversely, AE is caused by a sudden insult to the metabolic machinery of the hair matrix. Affected follicles rapidly produce thinner weaker shafts yielding Pohl-Pinkus constrictions or pencil point-shaped fractures that shed approximately 1 to 2 months after injury. The 10% of scalp hairs in the resting telogen phase have no matrix and thus are unaffected. Some etiologies can cause either AE or TE, depending on the dose and intensity of the insult. Common causes of AE include alopecia areata and syphilis, both consisting of abrupt severe bulbar inflammation.¹ Other causes include chemotherapy, particularly antimetabolites, alkylating agents, and mitotic inhibitors; radiation; medications (eg, isoniazid); severe protein malnutrition; toxic chemicals (eg, boron/boric acid); and heavy metals (eg, thallium, mercury).  

Thallium is one of the most common causes of heavy metal poisoning and is particularly dangerous due to its colorless, tasteless, and odorless characteristics. Although its common use as a rodenticide has dramatically decreased in the United States after it was banned in 1965, it is still used in this fashion in other countries and has a notable industrial presence, particularly in electronics, superconductors, and low-temperature thermometers. Accidental poisoning of a graduate chemistry student during copper research has been reported,² highlighting that thallium can be inhaled, ingested, or absorbed through the skin. Thallium is even present in mycoplasma agar plates, the ingestion of which has resulted in poisoning.³  

Systemic symptoms of thallium poisoning include somnolence, weakness, nausea, vomiting, stomatitis, abdominal pain, diarrhea, tachycardia, hypertension, and polyneuropathy.^4-7 Neuropathy often manifests as painful acral dysesthesia and paresthesia, perioral numbness, optic neuropathy causing visual changes, and encephalopathy. Cutaneous findings include diffuse alopecia of the scalp and eyebrows, perioral dermatitis, glossitis, diffuse hyperpigmentation, oral hyperpigmentation (often as a stippled lead line along the gingival margin with subsequent alveolar damage and resorption), melanonychia, palmoplantar keratoderma, acneform or pustular eruption, and nail changes including Mees lines.^2,4,5,7-9 Rarely, major organ failure and death may result.¹⁰ 

Toxin panels may not include thallium, and urine and serum tests may be negative if too much time has transpired since the acute exposure. Hair or nail analysis has proved useful in subacute cases¹¹; however, most laboratories require a pencil-thick segment of hair cut at the roots and bundled, weighing at least 500 mg. Thallium poisoning is treated with activated charcoal, Prussian blue, and blood purification therapies (eg, hemodialysis, hemoperfusion, hemofiltration).^4,7 Cutaneous findings typically resolve, but neuropathic changes may persist.

The Diagnosis: Thallium-Induced Alopecia 

At the time of presentation, a punch biopsy specimen of the scalp revealed nonscarring alopecia with increased catagen hairs; follicular miniaturization; peribulbar lymphoid infiltrates; and fibrous tract remnants containing melanin, lymphocytes, and occasional mast cells (Figure 1). The differential diagnosis included alopecia areata, syphilis, and toxin-mediated anagen effluvium (AE). Given the abrupt onset affecting multiple individuals in an industrial environment, heavy metal poisoning was suspected. Blood and urine testing was negative, but a few months had elapsed since exposure. Several months after his initial presentation, the patient reported problems with his teeth, thin brittle nails, and resolution of the visual changes. Photographs sent by the patient revealed darkening and degeneration of the gingival margin (Figure 2). 

Environmental review revealed the patient was working on a demolition site of a 150-year-old electrical plant near a river. Inundation of rainfall caused a river swell and subsequent flooding of the work site. The patient reported working for more than 2 months in knee-deep muddy water, and he noted that water for consumption and showers was procured on-site from a well-based source that may have been contaminated by the floodwaters.  

Acute nonscarring alopecia can be an AE or telogen effluvium (TE), also known as telogen defluvium. The key distinguishing factor is the mode of injury.¹ In TE, medications, stress, hormonal shifts, or inflammation induce a synchronized and abrupt transition of hairs from anagen phase to catagen phase, a committed step that then must fully cycle through the telogen phase, culminating in the simultaneous shedding of numerous telogen hairs approximately 3 to 4 months later. Conversely, AE is caused by a sudden insult to the metabolic machinery of the hair matrix. Affected follicles rapidly produce thinner weaker shafts yielding Pohl-Pinkus constrictions or pencil point-shaped fractures that shed approximately 1 to 2 months after injury. The 10% of scalp hairs in the resting telogen phase have no matrix and thus are unaffected. Some etiologies can cause either AE or TE, depending on the dose and intensity of the insult. Common causes of AE include alopecia areata and syphilis, both consisting of abrupt severe bulbar inflammation.¹ Other causes include chemotherapy, particularly antimetabolites, alkylating agents, and mitotic inhibitors; radiation; medications (eg, isoniazid); severe protein malnutrition; toxic chemicals (eg, boron/boric acid); and heavy metals (eg, thallium, mercury).  

Thallium is one of the most common causes of heavy metal poisoning and is particularly dangerous due to its colorless, tasteless, and odorless characteristics. Although its common use as a rodenticide has dramatically decreased in the United States after it was banned in 1965, it is still used in this fashion in other countries and has a notable industrial presence, particularly in electronics, superconductors, and low-temperature thermometers. Accidental poisoning of a graduate chemistry student during copper research has been reported,² highlighting that thallium can be inhaled, ingested, or absorbed through the skin. Thallium is even present in mycoplasma agar plates, the ingestion of which has resulted in poisoning.³  

Systemic symptoms of thallium poisoning include somnolence, weakness, nausea, vomiting, stomatitis, abdominal pain, diarrhea, tachycardia, hypertension, and polyneuropathy.^4-7 Neuropathy often manifests as painful acral dysesthesia and paresthesia, perioral numbness, optic neuropathy causing visual changes, and encephalopathy. Cutaneous findings include diffuse alopecia of the scalp and eyebrows, perioral dermatitis, glossitis, diffuse hyperpigmentation, oral hyperpigmentation (often as a stippled lead line along the gingival margin with subsequent alveolar damage and resorption), melanonychia, palmoplantar keratoderma, acneform or pustular eruption, and nail changes including Mees lines.^2,4,5,7-9 Rarely, major organ failure and death may result.¹⁰ 

Toxin panels may not include thallium, and urine and serum tests may be negative if too much time has transpired since the acute exposure. Hair or nail analysis has proved useful in subacute cases¹¹; however, most laboratories require a pencil-thick segment of hair cut at the roots and bundled, weighing at least 500 mg. Thallium poisoning is treated with activated charcoal, Prussian blue, and blood purification therapies (eg, hemodialysis, hemoperfusion, hemofiltration).^4,7 Cutaneous findings typically resolve, but neuropathic changes may persist.

The Diagnosis: Thallium-Induced Alopecia 

At the time of presentation, a punch biopsy specimen of the scalp revealed nonscarring alopecia with increased catagen hairs; follicular miniaturization; peribulbar lymphoid infiltrates; and fibrous tract remnants containing melanin, lymphocytes, and occasional mast cells (Figure 1). The differential diagnosis included alopecia areata, syphilis, and toxin-mediated anagen effluvium (AE). Given the abrupt onset affecting multiple individuals in an industrial environment, heavy metal poisoning was suspected. Blood and urine testing was negative, but a few months had elapsed since exposure. Several months after his initial presentation, the patient reported problems with his teeth, thin brittle nails, and resolution of the visual changes. Photographs sent by the patient revealed darkening and degeneration of the gingival margin (Figure 2). 

Environmental review revealed the patient was working on a demolition site of a 150-year-old electrical plant near a river. Inundation of rainfall caused a river swell and subsequent flooding of the work site. The patient reported working for more than 2 months in knee-deep muddy water, and he noted that water for consumption and showers was procured on-site from a well-based source that may have been contaminated by the floodwaters.  

Acute nonscarring alopecia can be an AE or telogen effluvium (TE), also known as telogen defluvium. The key distinguishing factor is the mode of injury.¹ In TE, medications, stress, hormonal shifts, or inflammation induce a synchronized and abrupt transition of hairs from anagen phase to catagen phase, a committed step that then must fully cycle through the telogen phase, culminating in the simultaneous shedding of numerous telogen hairs approximately 3 to 4 months later. Conversely, AE is caused by a sudden insult to the metabolic machinery of the hair matrix. Affected follicles rapidly produce thinner weaker shafts yielding Pohl-Pinkus constrictions or pencil point-shaped fractures that shed approximately 1 to 2 months after injury. The 10% of scalp hairs in the resting telogen phase have no matrix and thus are unaffected. Some etiologies can cause either AE or TE, depending on the dose and intensity of the insult. Common causes of AE include alopecia areata and syphilis, both consisting of abrupt severe bulbar inflammation.¹ Other causes include chemotherapy, particularly antimetabolites, alkylating agents, and mitotic inhibitors; radiation; medications (eg, isoniazid); severe protein malnutrition; toxic chemicals (eg, boron/boric acid); and heavy metals (eg, thallium, mercury).  

Thallium is one of the most common causes of heavy metal poisoning and is particularly dangerous due to its colorless, tasteless, and odorless characteristics. Although its common use as a rodenticide has dramatically decreased in the United States after it was banned in 1965, it is still used in this fashion in other countries and has a notable industrial presence, particularly in electronics, superconductors, and low-temperature thermometers. Accidental poisoning of a graduate chemistry student during copper research has been reported,² highlighting that thallium can be inhaled, ingested, or absorbed through the skin. Thallium is even present in mycoplasma agar plates, the ingestion of which has resulted in poisoning.³  

Systemic symptoms of thallium poisoning include somnolence, weakness, nausea, vomiting, stomatitis, abdominal pain, diarrhea, tachycardia, hypertension, and polyneuropathy.^4-7 Neuropathy often manifests as painful acral dysesthesia and paresthesia, perioral numbness, optic neuropathy causing visual changes, and encephalopathy. Cutaneous findings include diffuse alopecia of the scalp and eyebrows, perioral dermatitis, glossitis, diffuse hyperpigmentation, oral hyperpigmentation (often as a stippled lead line along the gingival margin with subsequent alveolar damage and resorption), melanonychia, palmoplantar keratoderma, acneform or pustular eruption, and nail changes including Mees lines.^2,4,5,7-9 Rarely, major organ failure and death may result.¹⁰ 

Toxin panels may not include thallium, and urine and serum tests may be negative if too much time has transpired since the acute exposure. Hair or nail analysis has proved useful in subacute cases¹¹; however, most laboratories require a pencil-thick segment of hair cut at the roots and bundled, weighing at least 500 mg. Thallium poisoning is treated with activated charcoal, Prussian blue, and blood purification therapies (eg, hemodialysis, hemoperfusion, hemofiltration).^4,7 Cutaneous findings typically resolve, but neuropathic changes may persist.

The Diagnosis: Bimatoprost-Induced Hypertrichosis 

Latanoprost, a prostaglandin analogue, typically is prescribed by ophthalmologists as eye drops to reduce intraocular pressure in open-angle glaucoma.¹ Common adverse reactions of latanoprost drops include blurred vision, ocular irritation, darkening of the eyelid skin, and pigmentation of the iris. 

In 1997, Johnstone² reported hypertrichosis and increased pigmentation of the eyelashes of both eyes and adjacent skin after latanoprost drops were used in glaucoma patients. Subsequently, topical latanoprost and bimatoprost, a similar analogue, are now utilized for the cosmetic purpose of thickening and lengthening the eyelashes due to the hypertrichosis effect. Travoprost, another prostaglandin analogue used to treat glaucoma, also has been associated with periocular hypertrichosis.³ Concomitant poliosis of the eyelashes with hypertrichosis from latanoprost also has been reported.⁴ Our patient specifically purchased the eye drops (marketed as generic bimatoprost) to lengthen her eyelashes and had noticed an increase in length. She denied a family history of increased facial hair in females. 

Along with gingival hyperplasia, systemic cyclosporine may cause generalized hypertrichosis consisting of terminal hair growth, particularly on the face and forearms. However, hypertrichosis from cyclosporine ophthalmic emulsion 0.05% rarely has been reported⁵ but would be more likely to occur in a patient reporting a history of chronic dry eye. Oral acetazolamide, not eye drops, is prescribed for glaucoma and typically is not associated with hypertrichosis. Betamethasone and timolol eye drops may cause burning, stinging, redness, or watering of the eyes, but they do not typically cause hypertrichosis.  

Other systemic medications (eg, zidovudine, phenytoin, minoxidil, danazol, anabolic steroids) may cause hypertrichosis but not typically localized to the periocular area. Phenytoin usually causes hair growth on the limbs but not on the face and trunk. Oral minoxidil causes hypertrichosis, predominately on the face, lower legs, and forearms. 

Systemic conditions such as endocrine abnormalities or porphyria cutanea tarda also may cause hypertrichosis; however, it typically does not present in small focal areas, and other stigmata often are present such as signs of virilization in hirsutism (ie, deepening of voice, pattern alopecia, acne) or liver disease with photosensitive erosions and bullae that leave scars and milia in porphyria cutanea tarda. Acquired hypertrichosis lanuginosa deserves consideration, in part due to its association with lung and colon cancers; however, it consists of softer, downy, nonterminal hairs (malignant down) and is more generalized on the face. Malnutrition from anorexia nervosa may similarly induce hypertrichosis lanuginose.  

The molecular mechanism for latanoprost-induced hypertrichosis is unknown; however, it may promote anagen growth as well as hypertrophic changes in the affected follicles.⁶ Patients should use extreme caution when purchasing unregulated medications due to the risk for impurities, less stable formulation, or inaccurate concentrations. Comparison between brand name and approved generic latanoprost has found notable differences, including variations in active-ingredient concentration, poor stability in warmer temperatures, and higher levels of particulate matter.⁷ Some cosmetic eyelash enhancers sold over-the-counter or online may contain prostaglandin analogues, but they may not be listed as ingredients.⁸ One report noted a bimatoprost product with a concentration level double that of brand-name bimatoprost that was discovered using high-performance liquid chromatography-tandem mass spectrometry.⁹ 

Treatment options for eliminating the excess hairs include discontinuing the prostaglandin analogue or applying it only to the eyelid margin with an appropriate applicator. Waxing, manual extraction, laser hair removal, electrolysis, and depilatory creams are alternative treatments. 

The Diagnosis: Bimatoprost-Induced Hypertrichosis 

Latanoprost, a prostaglandin analogue, typically is prescribed by ophthalmologists as eye drops to reduce intraocular pressure in open-angle glaucoma.¹ Common adverse reactions of latanoprost drops include blurred vision, ocular irritation, darkening of the eyelid skin, and pigmentation of the iris. 

In 1997, Johnstone² reported hypertrichosis and increased pigmentation of the eyelashes of both eyes and adjacent skin after latanoprost drops were used in glaucoma patients. Subsequently, topical latanoprost and bimatoprost, a similar analogue, are now utilized for the cosmetic purpose of thickening and lengthening the eyelashes due to the hypertrichosis effect. Travoprost, another prostaglandin analogue used to treat glaucoma, also has been associated with periocular hypertrichosis.³ Concomitant poliosis of the eyelashes with hypertrichosis from latanoprost also has been reported.⁴ Our patient specifically purchased the eye drops (marketed as generic bimatoprost) to lengthen her eyelashes and had noticed an increase in length. She denied a family history of increased facial hair in females. 

Along with gingival hyperplasia, systemic cyclosporine may cause generalized hypertrichosis consisting of terminal hair growth, particularly on the face and forearms. However, hypertrichosis from cyclosporine ophthalmic emulsion 0.05% rarely has been reported⁵ but would be more likely to occur in a patient reporting a history of chronic dry eye. Oral acetazolamide, not eye drops, is prescribed for glaucoma and typically is not associated with hypertrichosis. Betamethasone and timolol eye drops may cause burning, stinging, redness, or watering of the eyes, but they do not typically cause hypertrichosis.  

Other systemic medications (eg, zidovudine, phenytoin, minoxidil, danazol, anabolic steroids) may cause hypertrichosis but not typically localized to the periocular area. Phenytoin usually causes hair growth on the limbs but not on the face and trunk. Oral minoxidil causes hypertrichosis, predominately on the face, lower legs, and forearms. 

Systemic conditions such as endocrine abnormalities or porphyria cutanea tarda also may cause hypertrichosis; however, it typically does not present in small focal areas, and other stigmata often are present such as signs of virilization in hirsutism (ie, deepening of voice, pattern alopecia, acne) or liver disease with photosensitive erosions and bullae that leave scars and milia in porphyria cutanea tarda. Acquired hypertrichosis lanuginosa deserves consideration, in part due to its association with lung and colon cancers; however, it consists of softer, downy, nonterminal hairs (malignant down) and is more generalized on the face. Malnutrition from anorexia nervosa may similarly induce hypertrichosis lanuginose.  

The molecular mechanism for latanoprost-induced hypertrichosis is unknown; however, it may promote anagen growth as well as hypertrophic changes in the affected follicles.⁶ Patients should use extreme caution when purchasing unregulated medications due to the risk for impurities, less stable formulation, or inaccurate concentrations. Comparison between brand name and approved generic latanoprost has found notable differences, including variations in active-ingredient concentration, poor stability in warmer temperatures, and higher levels of particulate matter.⁷ Some cosmetic eyelash enhancers sold over-the-counter or online may contain prostaglandin analogues, but they may not be listed as ingredients.⁸ One report noted a bimatoprost product with a concentration level double that of brand-name bimatoprost that was discovered using high-performance liquid chromatography-tandem mass spectrometry.⁹ 

Treatment options for eliminating the excess hairs include discontinuing the prostaglandin analogue or applying it only to the eyelid margin with an appropriate applicator. Waxing, manual extraction, laser hair removal, electrolysis, and depilatory creams are alternative treatments. 

The Diagnosis: Bimatoprost-Induced Hypertrichosis 

Latanoprost, a prostaglandin analogue, typically is prescribed by ophthalmologists as eye drops to reduce intraocular pressure in open-angle glaucoma.¹ Common adverse reactions of latanoprost drops include blurred vision, ocular irritation, darkening of the eyelid skin, and pigmentation of the iris. 

In 1997, Johnstone² reported hypertrichosis and increased pigmentation of the eyelashes of both eyes and adjacent skin after latanoprost drops were used in glaucoma patients. Subsequently, topical latanoprost and bimatoprost, a similar analogue, are now utilized for the cosmetic purpose of thickening and lengthening the eyelashes due to the hypertrichosis effect. Travoprost, another prostaglandin analogue used to treat glaucoma, also has been associated with periocular hypertrichosis.³ Concomitant poliosis of the eyelashes with hypertrichosis from latanoprost also has been reported.⁴ Our patient specifically purchased the eye drops (marketed as generic bimatoprost) to lengthen her eyelashes and had noticed an increase in length. She denied a family history of increased facial hair in females. 

Along with gingival hyperplasia, systemic cyclosporine may cause generalized hypertrichosis consisting of terminal hair growth, particularly on the face and forearms. However, hypertrichosis from cyclosporine ophthalmic emulsion 0.05% rarely has been reported⁵ but would be more likely to occur in a patient reporting a history of chronic dry eye. Oral acetazolamide, not eye drops, is prescribed for glaucoma and typically is not associated with hypertrichosis. Betamethasone and timolol eye drops may cause burning, stinging, redness, or watering of the eyes, but they do not typically cause hypertrichosis.  

Other systemic medications (eg, zidovudine, phenytoin, minoxidil, danazol, anabolic steroids) may cause hypertrichosis but not typically localized to the periocular area. Phenytoin usually causes hair growth on the limbs but not on the face and trunk. Oral minoxidil causes hypertrichosis, predominately on the face, lower legs, and forearms. 

Systemic conditions such as endocrine abnormalities or porphyria cutanea tarda also may cause hypertrichosis; however, it typically does not present in small focal areas, and other stigmata often are present such as signs of virilization in hirsutism (ie, deepening of voice, pattern alopecia, acne) or liver disease with photosensitive erosions and bullae that leave scars and milia in porphyria cutanea tarda. Acquired hypertrichosis lanuginosa deserves consideration, in part due to its association with lung and colon cancers; however, it consists of softer, downy, nonterminal hairs (malignant down) and is more generalized on the face. Malnutrition from anorexia nervosa may similarly induce hypertrichosis lanuginose.  

The molecular mechanism for latanoprost-induced hypertrichosis is unknown; however, it may promote anagen growth as well as hypertrophic changes in the affected follicles.⁶ Patients should use extreme caution when purchasing unregulated medications due to the risk for impurities, less stable formulation, or inaccurate concentrations. Comparison between brand name and approved generic latanoprost has found notable differences, including variations in active-ingredient concentration, poor stability in warmer temperatures, and higher levels of particulate matter.⁷ Some cosmetic eyelash enhancers sold over-the-counter or online may contain prostaglandin analogues, but they may not be listed as ingredients.⁸ One report noted a bimatoprost product with a concentration level double that of brand-name bimatoprost that was discovered using high-performance liquid chromatography-tandem mass spectrometry.⁹ 

Treatment options for eliminating the excess hairs include discontinuing the prostaglandin analogue or applying it only to the eyelid margin with an appropriate applicator. Waxing, manual extraction, laser hair removal, electrolysis, and depilatory creams are alternative treatments. 

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.