Cutis

Tick-borne disease in the United States continues to be a threat as people interact with their natural surroundings. We present a case of an 8-year-old boy with a larval tick infestation. Ticks within the United States can carry Lyme disease, Rocky Mountain spotted fever (RMSF), ehrlichiosis, babesiosis, tularemia, tick-borne relapsing fever, and tick paralysis. These preventable diseases are treatable when accurately recognized and diagnosed; however, if left untreated, they can cause substantial morbidity and mortality. This article highlights the knowledge necessary to recognize, treat, and prevent tick-borne disease.

Case Report
An 8-year-old boy presented to a pediatrician's office. The patient's father was concerned that his son had crabs. Because of the sensitivity of such a diagnosis, the pediatrician immediately consulted the dermatology department for more expert identification of possible crab lice. The father reported that the family had spent the weekend at a farm. Approximately 24 hours after leaving the farm, the child started to complain of itching and bugs on his genitalia. The child and family members denied any sexual abuse or sexual contact. The child did not have a fever, rash, joint pain, headache, or other complaints or concerns. Overall, the child was feeling well. Physical examination of genitalia revealed one 2- to 3-mm tick near the glans penis and 40 to 50 ticks measuring 0.5 mm in diameter located on the shaft of the penis and scrotum (Figure). A single tick was plucked as it was running across the child's leg and was identified by the local public health department as a nymphal deer tick (Ixodes dammini).

Comment
Biology of Ticks—More than 800 species of ticks exist worldwide.1 The 2 large families of ticks include hard ticks (Ixodidae) and soft ticks (Argasidae). Ixodidae ticks are the main disease vectors of concern in the United States (Table). Ixodidae genera include Ixodes, Amblyomma, and Dermacentor, each with important disease vectors.3 Hard ticks inhabit both open grassy and wooded environments, though competing arthropods may limit their range.3,4 In the southern United States, Amblyomma ticks were common in grassy areas. However, the introduction of imported fire ants, which forage for tick eggs, has limited Amblyomma ticks to wooded areas. The 2-year life cycle of ticks consists of 4 stages: egg, larva, nymph, and adult. Larvae (sometimes referred to as seed ticks) measure from 0.5 to 0.8 mm in diameter and often are difficult to recognize because of their small size.4,5 Nymphs are approximately 1.5 mm in diameter and adults can be 5 mm in diameter. Both the nymphs and adults are 8 legged, while larvae have 6 legs.3,4 A blood meal is consumed during each stage of a tick's life cycle.6

Studies have reviewed the importance of the duration of tick attachment and its relationship to disease transmission.7,8 It has been shown that maximal transmission of Borrelia burgdorferi occurred following 48 to 72 hours of tick attachment. However, transmission of Ehrlichia phagocytophila from infected Ixodes scapularis nymphs occurred within 24 hours of tick attachment.7 Another study focused on the length of time I scapularis ticks fed on human hosts before being detected and removed, and compared the duration of attachment for nymphs and adult female ticks.8 Results showed the attachment time significantly increased with age of the host (P40°C) with an irregular pattern, chills, headache, myalgia, arthralgia, and fatigue. Additional associated symptoms are a macular rash at the end of a febrile episode, conjunctival injection, hepatosplenomegaly, epistaxis, and meningeal signs.6 The initial febrile period spontaneously resolves within 3 days and is followed by an afebrile period, after which the fever will relapse. Each relapse of the fever becomes progressively more mild than the preceding episode. The diagnosis of tick-borne relapsing fever can be made by visualizing the spirochetes on the peripheral blood smear with a Giemsa or Wright stain. Detection is most likely if the smear is taken during a febrile episode. Leukocytosis and thrombocytopenia may be observed on laboratory test results. The treatment of choice is oral doxycycline 100 mg twice daily for 5 to 10 days. As an alternative therapy, erythromycin 500 mg orally 4 times daily for 5 to 7 days can be used. Penicillin G also has been proven to be effective. A Jarisch-Herxheimer reaction has been noted in some patients following initiation of therapy. Administering acetaminophen before and after antibiotic therapy may help decrease the severity of this reaction.3,12 Tick Paralysis—Tick paralysis is a toxin-mediated illness that typically occurs in children and can cause substantial morbidity and mortality if not appropriately recognized.3 In the United States, most cases have been reported in the Rocky Mountains and northwestern states.21,22 In animals, tick paralysis is caused by 43 different species of ticks, though D variabilis and D andersoni are the only ticks substantially associated with human tick paralysis in the United States.3 Because these ticks tend to attach to the scalp, they often are not identified and are most commonly found postmortem. Paralysis occurs 4 to 7 days following tick attachment. It is characterized as an acute, ascending, flaccid paralysis that often is confused with neurologic disorders, Guillain-Barré syndrome, botulism, and myasthenia gravis. The paralysis is thought to be caused by a neurotoxin that is secreted in the tick saliva during the feeding process23 and causes a presynaptic neuromuscular blockade.22,23 If the tick is not removed, dysarthria, dysphagia, and death from respiratory failure in 10% of patients is possible.22 Prevention—Prevention of tick exposure is the optimal way to decrease the amount of tick-borne disease seen in the United States. By applying N,N-diethyl-m-toluamide (or DEET) to exposed skin, treating clothing with permethrin, and wearing protective clothing while walking through grassy vegetation, individuals can minimize their tick exposure. N,N-diethyl-m-toluamide often is found in over-the-counter insect repellents and can be applied to the skin. Sustained-release formulas are preferred; efficacy plateaus at a 30% concentration of these formulations. Permethrin is an acaricide that is available as a spray. It should be applied to clothing and remains stable through many cycles of laundry.24 Garments pretreated with permethrin also are available. Prompt removal of an attached tick is critical to the prevention of tick-borne disease. Vertical traction with blunt forceps near the site of attachment can be effective. Various tick removal devices are available that are slipped under the tick to allow traction without tearing the body of the tick. It is advised to discourage patients from removing ticks with isopropyl alcohol, fingernail polish, petroleum jelly, or hot matches, or in chlorine swimming pools.12,14,23

Conclusion
Tick-borne disease continues to be a problem commonly encountered in the United States. With many people regularly enjoying the outdoors and spending more time exploring their surroundings, it is important for practitioners to recognize the signs and symptoms of tick-borne disease. Tick-borne disease within the United States includes Lyme disease, RMSF, ehrlichiosis, babesiosis, tularemia, tick-borne relapsing fever, and tick paralysis. With prompt removal and treatment, disease prognosis is generally good.

Tick-borne disease in the United States continues to be a threat as people interact with their natural surroundings. We present a case of an 8-year-old boy with a larval tick infestation. Ticks within the United States can carry Lyme disease, Rocky Mountain spotted fever (RMSF), ehrlichiosis, babesiosis, tularemia, tick-borne relapsing fever, and tick paralysis. These preventable diseases are treatable when accurately recognized and diagnosed; however, if left untreated, they can cause substantial morbidity and mortality. This article highlights the knowledge necessary to recognize, treat, and prevent tick-borne disease.

Case Report
An 8-year-old boy presented to a pediatrician's office. The patient's father was concerned that his son had crabs. Because of the sensitivity of such a diagnosis, the pediatrician immediately consulted the dermatology department for more expert identification of possible crab lice. The father reported that the family had spent the weekend at a farm. Approximately 24 hours after leaving the farm, the child started to complain of itching and bugs on his genitalia. The child and family members denied any sexual abuse or sexual contact. The child did not have a fever, rash, joint pain, headache, or other complaints or concerns. Overall, the child was feeling well. Physical examination of genitalia revealed one 2- to 3-mm tick near the glans penis and 40 to 50 ticks measuring 0.5 mm in diameter located on the shaft of the penis and scrotum (Figure). A single tick was plucked as it was running across the child's leg and was identified by the local public health department as a nymphal deer tick (Ixodes dammini).

Comment
Biology of Ticks—More than 800 species of ticks exist worldwide.1 The 2 large families of ticks include hard ticks (Ixodidae) and soft ticks (Argasidae). Ixodidae ticks are the main disease vectors of concern in the United States (Table). Ixodidae genera include Ixodes, Amblyomma, and Dermacentor, each with important disease vectors.3 Hard ticks inhabit both open grassy and wooded environments, though competing arthropods may limit their range.3,4 In the southern United States, Amblyomma ticks were common in grassy areas. However, the introduction of imported fire ants, which forage for tick eggs, has limited Amblyomma ticks to wooded areas. The 2-year life cycle of ticks consists of 4 stages: egg, larva, nymph, and adult. Larvae (sometimes referred to as seed ticks) measure from 0.5 to 0.8 mm in diameter and often are difficult to recognize because of their small size.4,5 Nymphs are approximately 1.5 mm in diameter and adults can be 5 mm in diameter. Both the nymphs and adults are 8 legged, while larvae have 6 legs.3,4 A blood meal is consumed during each stage of a tick's life cycle.6

Studies have reviewed the importance of the duration of tick attachment and its relationship to disease transmission.7,8 It has been shown that maximal transmission of Borrelia burgdorferi occurred following 48 to 72 hours of tick attachment. However, transmission of Ehrlichia phagocytophila from infected Ixodes scapularis nymphs occurred within 24 hours of tick attachment.7 Another study focused on the length of time I scapularis ticks fed on human hosts before being detected and removed, and compared the duration of attachment for nymphs and adult female ticks.8 Results showed the attachment time significantly increased with age of the host (P40°C) with an irregular pattern, chills, headache, myalgia, arthralgia, and fatigue. Additional associated symptoms are a macular rash at the end of a febrile episode, conjunctival injection, hepatosplenomegaly, epistaxis, and meningeal signs.6 The initial febrile period spontaneously resolves within 3 days and is followed by an afebrile period, after which the fever will relapse. Each relapse of the fever becomes progressively more mild than the preceding episode. The diagnosis of tick-borne relapsing fever can be made by visualizing the spirochetes on the peripheral blood smear with a Giemsa or Wright stain. Detection is most likely if the smear is taken during a febrile episode. Leukocytosis and thrombocytopenia may be observed on laboratory test results. The treatment of choice is oral doxycycline 100 mg twice daily for 5 to 10 days. As an alternative therapy, erythromycin 500 mg orally 4 times daily for 5 to 7 days can be used. Penicillin G also has been proven to be effective. A Jarisch-Herxheimer reaction has been noted in some patients following initiation of therapy. Administering acetaminophen before and after antibiotic therapy may help decrease the severity of this reaction.3,12 Tick Paralysis—Tick paralysis is a toxin-mediated illness that typically occurs in children and can cause substantial morbidity and mortality if not appropriately recognized.3 In the United States, most cases have been reported in the Rocky Mountains and northwestern states.21,22 In animals, tick paralysis is caused by 43 different species of ticks, though D variabilis and D andersoni are the only ticks substantially associated with human tick paralysis in the United States.3 Because these ticks tend to attach to the scalp, they often are not identified and are most commonly found postmortem. Paralysis occurs 4 to 7 days following tick attachment. It is characterized as an acute, ascending, flaccid paralysis that often is confused with neurologic disorders, Guillain-Barré syndrome, botulism, and myasthenia gravis. The paralysis is thought to be caused by a neurotoxin that is secreted in the tick saliva during the feeding process23 and causes a presynaptic neuromuscular blockade.22,23 If the tick is not removed, dysarthria, dysphagia, and death from respiratory failure in 10% of patients is possible.22 Prevention—Prevention of tick exposure is the optimal way to decrease the amount of tick-borne disease seen in the United States. By applying N,N-diethyl-m-toluamide (or DEET) to exposed skin, treating clothing with permethrin, and wearing protective clothing while walking through grassy vegetation, individuals can minimize their tick exposure. N,N-diethyl-m-toluamide often is found in over-the-counter insect repellents and can be applied to the skin. Sustained-release formulas are preferred; efficacy plateaus at a 30% concentration of these formulations. Permethrin is an acaricide that is available as a spray. It should be applied to clothing and remains stable through many cycles of laundry.24 Garments pretreated with permethrin also are available. Prompt removal of an attached tick is critical to the prevention of tick-borne disease. Vertical traction with blunt forceps near the site of attachment can be effective. Various tick removal devices are available that are slipped under the tick to allow traction without tearing the body of the tick. It is advised to discourage patients from removing ticks with isopropyl alcohol, fingernail polish, petroleum jelly, or hot matches, or in chlorine swimming pools.12,14,23

Conclusion
Tick-borne disease continues to be a problem commonly encountered in the United States. With many people regularly enjoying the outdoors and spending more time exploring their surroundings, it is important for practitioners to recognize the signs and symptoms of tick-borne disease. Tick-borne disease within the United States includes Lyme disease, RMSF, ehrlichiosis, babesiosis, tularemia, tick-borne relapsing fever, and tick paralysis. With prompt removal and treatment, disease prognosis is generally good.

Tick-borne disease in the United States continues to be a threat as people interact with their natural surroundings. We present a case of an 8-year-old boy with a larval tick infestation. Ticks within the United States can carry Lyme disease, Rocky Mountain spotted fever (RMSF), ehrlichiosis, babesiosis, tularemia, tick-borne relapsing fever, and tick paralysis. These preventable diseases are treatable when accurately recognized and diagnosed; however, if left untreated, they can cause substantial morbidity and mortality. This article highlights the knowledge necessary to recognize, treat, and prevent tick-borne disease.

Case Report
An 8-year-old boy presented to a pediatrician's office. The patient's father was concerned that his son had crabs. Because of the sensitivity of such a diagnosis, the pediatrician immediately consulted the dermatology department for more expert identification of possible crab lice. The father reported that the family had spent the weekend at a farm. Approximately 24 hours after leaving the farm, the child started to complain of itching and bugs on his genitalia. The child and family members denied any sexual abuse or sexual contact. The child did not have a fever, rash, joint pain, headache, or other complaints or concerns. Overall, the child was feeling well. Physical examination of genitalia revealed one 2- to 3-mm tick near the glans penis and 40 to 50 ticks measuring 0.5 mm in diameter located on the shaft of the penis and scrotum (Figure). A single tick was plucked as it was running across the child's leg and was identified by the local public health department as a nymphal deer tick (Ixodes dammini).

Comment
Biology of Ticks—More than 800 species of ticks exist worldwide.1 The 2 large families of ticks include hard ticks (Ixodidae) and soft ticks (Argasidae). Ixodidae ticks are the main disease vectors of concern in the United States (Table). Ixodidae genera include Ixodes, Amblyomma, and Dermacentor, each with important disease vectors.3 Hard ticks inhabit both open grassy and wooded environments, though competing arthropods may limit their range.3,4 In the southern United States, Amblyomma ticks were common in grassy areas. However, the introduction of imported fire ants, which forage for tick eggs, has limited Amblyomma ticks to wooded areas. The 2-year life cycle of ticks consists of 4 stages: egg, larva, nymph, and adult. Larvae (sometimes referred to as seed ticks) measure from 0.5 to 0.8 mm in diameter and often are difficult to recognize because of their small size.4,5 Nymphs are approximately 1.5 mm in diameter and adults can be 5 mm in diameter. Both the nymphs and adults are 8 legged, while larvae have 6 legs.3,4 A blood meal is consumed during each stage of a tick's life cycle.6

Studies have reviewed the importance of the duration of tick attachment and its relationship to disease transmission.7,8 It has been shown that maximal transmission of Borrelia burgdorferi occurred following 48 to 72 hours of tick attachment. However, transmission of Ehrlichia phagocytophila from infected Ixodes scapularis nymphs occurred within 24 hours of tick attachment.7 Another study focused on the length of time I scapularis ticks fed on human hosts before being detected and removed, and compared the duration of attachment for nymphs and adult female ticks.8 Results showed the attachment time significantly increased with age of the host (P40°C) with an irregular pattern, chills, headache, myalgia, arthralgia, and fatigue. Additional associated symptoms are a macular rash at the end of a febrile episode, conjunctival injection, hepatosplenomegaly, epistaxis, and meningeal signs.6 The initial febrile period spontaneously resolves within 3 days and is followed by an afebrile period, after which the fever will relapse. Each relapse of the fever becomes progressively more mild than the preceding episode. The diagnosis of tick-borne relapsing fever can be made by visualizing the spirochetes on the peripheral blood smear with a Giemsa or Wright stain. Detection is most likely if the smear is taken during a febrile episode. Leukocytosis and thrombocytopenia may be observed on laboratory test results. The treatment of choice is oral doxycycline 100 mg twice daily for 5 to 10 days. As an alternative therapy, erythromycin 500 mg orally 4 times daily for 5 to 7 days can be used. Penicillin G also has been proven to be effective. A Jarisch-Herxheimer reaction has been noted in some patients following initiation of therapy. Administering acetaminophen before and after antibiotic therapy may help decrease the severity of this reaction.3,12 Tick Paralysis—Tick paralysis is a toxin-mediated illness that typically occurs in children and can cause substantial morbidity and mortality if not appropriately recognized.3 In the United States, most cases have been reported in the Rocky Mountains and northwestern states.21,22 In animals, tick paralysis is caused by 43 different species of ticks, though D variabilis and D andersoni are the only ticks substantially associated with human tick paralysis in the United States.3 Because these ticks tend to attach to the scalp, they often are not identified and are most commonly found postmortem. Paralysis occurs 4 to 7 days following tick attachment. It is characterized as an acute, ascending, flaccid paralysis that often is confused with neurologic disorders, Guillain-Barré syndrome, botulism, and myasthenia gravis. The paralysis is thought to be caused by a neurotoxin that is secreted in the tick saliva during the feeding process23 and causes a presynaptic neuromuscular blockade.22,23 If the tick is not removed, dysarthria, dysphagia, and death from respiratory failure in 10% of patients is possible.22 Prevention—Prevention of tick exposure is the optimal way to decrease the amount of tick-borne disease seen in the United States. By applying N,N-diethyl-m-toluamide (or DEET) to exposed skin, treating clothing with permethrin, and wearing protective clothing while walking through grassy vegetation, individuals can minimize their tick exposure. N,N-diethyl-m-toluamide often is found in over-the-counter insect repellents and can be applied to the skin. Sustained-release formulas are preferred; efficacy plateaus at a 30% concentration of these formulations. Permethrin is an acaricide that is available as a spray. It should be applied to clothing and remains stable through many cycles of laundry.24 Garments pretreated with permethrin also are available. Prompt removal of an attached tick is critical to the prevention of tick-borne disease. Vertical traction with blunt forceps near the site of attachment can be effective. Various tick removal devices are available that are slipped under the tick to allow traction without tearing the body of the tick. It is advised to discourage patients from removing ticks with isopropyl alcohol, fingernail polish, petroleum jelly, or hot matches, or in chlorine swimming pools.12,14,23

Conclusion
Tick-borne disease continues to be a problem commonly encountered in the United States. With many people regularly enjoying the outdoors and spending more time exploring their surroundings, it is important for practitioners to recognize the signs and symptoms of tick-borne disease. Tick-borne disease within the United States includes Lyme disease, RMSF, ehrlichiosis, babesiosis, tularemia, tick-borne relapsing fever, and tick paralysis. With prompt removal and treatment, disease prognosis is generally good.

Cutaneous leiomyomas are benign tumors of smooth muscle bundles. Of the 5 subtypes of cutaneous leiomyomas, multiple piloleiomyomas (pilar leiomyomas) are the most common.1 Originating from arrector pili muscles of hair follicles, they usually present as small, red-brown, firm papules on the extremities or trunk of young adults. Solitary piloleiomyomas occur more commonly in women as larger nodules, measuring up to 2 cm. Occasionally, lesions can be symmetrical, Blaschkoid, diffuse (disseminated), or segmental (zosteriform).2 Multiple eruptive lesions have been described in patients with chronic lymphocytic leukemia, erythrocytosis, and human immunodeficiency virus infection. Patients may have a history of spontaneous burning, pinching, or stabbing pain. In addition, pain may be triggered by pressure, cold temperature, trauma, or emotional stress.3 Although the pathophysiology of pain is still unknown, it may be caused by pressure of the nerve fibers within the tumors upon contraction of the smooth muscles.4 Pain tends to occur more frequently in diffuse and segmental forms of leiomyomas.5 Multiple cutaneous leiomyomas may occur in conjunction with uterine leiomyomas, also known as multiple cutaneous and uterine leiomyomatosis (MCUL), familial leiomyomatosis cutis et uteri, Reed syndrome, or multiple leiomyomatosis.6 An autosomal dominant mode of transmission with incomplete penetrance occurs with MCUL. In this syndrome, multiple piloleiomyomas usually occur in both sexes. However, affected women also have severely symptomatic uterine leiomyomas or fibroids that usually require early hysterectomy for symptom control. Some patients with MCUL also were found to have uncommon and aggressive forms of renal cell carcinoma, especially papillary renal cell carcinoma type 2 or renal collecting duct carcinoma, which also is known as hereditary leiomyomatosis and renal cell cancer (HLRCC).7

Case Report An 81-year-old man presented with a 50-year history of multiple red-brown papules and nodules on both sides of his back. He denied any pruritus, tenderness, or burning sensation. His medical history included type 2 diabetes mellitus, cardiomyopathy, peripheral neuropathy, peripheral vascular disease, and benign prostatic hypertrophy. A thorough family history was unremarkable for any neoplasm including kidney cancer or uterine fibroids. On examination, there were multiple red-brown flattopped papules and nodules coalescing into plaques in a segmental distribution on both sides of his back (Figure 1). These papules were not tender on palpation. Upon stroking, there was no accentuation or piloerection.

Histopathologic findings showed a poorly circumscribed spindle cell proliferation with blunt-ended cigar-shaped nuclei and abundant pink cytoplasm in the deep papillary and reticular dermis. Perinuclear vacuolization was present in the cross-section of the smooth muscle bundles (Figure 2). There was no cytologic atypia or mitotic activity. Immunohistochemistry stains were positive for vimentin, smooth muscle actin, and desmin. The diagnosis of bilateral segmental leiomyomas (piloleiomyomas) was confirmed. Further history did not reveal any cancer or neoplasm. Radiographic and genetic studies were offered, but the patient and his family declined.

Comment
There are 5 subtypes of cutaneous leiomyomas: multiple piloleiomyomas, solitary piloleiomyomas, solitary genital leiomyomas, solitary angioleiomyomas, and leiomyomas with mesenchymal elements.¹ Solitary genital leiomyomas usually are asymptomatic. They originate from the superficial smooth muscles of the scrotum, labia majora, and nipples. Solitary angioleiomyomas present with painful solitary nodules deep in the mid-dermis or subcutaneous tissues and are derived from vascular smooth muscles. They most commonly present on the lower extremities in women aged 30 to 60 years. Rarely, mature adipocytes are found within the nodules as seen in angiolipoleiomyomas. Although they most likely represent metaplastic change, the presence of adipocytes is now accepted to be a hamartomatous process.8 Cutaneous angiolipoleiomyomas are more common in men and, contrary to renal angiomyolipomas, have no association with tuberous sclerosis.1 Histologically, piloleiomyomas and genital leiomyomas are composed of poorly demarcated, well-differentiated, interlacing bundles of smooth muscle fibers. The centrally located nuclei are long and thin with blunt ends in a cigar or eel shape (Figure 2). Angioleiomyomas are more sharply circumscribed. Round, slitlike, or stellate lumina also may be seen. Differential diagnosis may include other spindle cell proliferative tumors such as neurofibroma, dermatofibroma, schwannoma, and leiomyosarcoma. Nuclear pleomorphism and atypical mitoses are abundant in leiomyosarcomas. Immunohistochemistry also may help to confirm the diagnosis of leiomyomas and differentiate them from other similar entities. Genetic defects in MCUL and HLRCC were colocalized to band 1q42.3-43.9 Heterozygous germ line mutations in the fumarate hydratase gene, FH, that resulted in either decreased or absent FH enzymatic activity were subsequently identified in 42 patients affected with leiomyomatosis.10 The FH gene comprises 22 kilobases with 10 exons11 and encodes both the cytosolic and mitochondrial isoforms. Fumarate hydratase functions within the Krebs cycle by converting fumarate to L-malate. While the pathway by which tumorigenesis occurs in MCUL and HLRCC is still unknown, it is postulated that mutations in the FH gene exert a tumor suppressive effect by altering Krebs cycle activity.12 To date, there have been approximately 70 different mutations of the FH gene reported. Although the incidence of FH gene mutations in patients with uterine leiomyomas and papillary renal cell carcinoma type 2 remains unknown, 90% (80/89) of patients with cutaneous leiomyomas have FH gene mutations, determined by either DNA analysis or decreased enzymatic activity.13 Apoptotic and antiapoptotic factors also may play a role in the pathogenesis of leiomyomas. Wortham et al14 reported increased expressions of antiapoptotic BCL2 and the proliferation factor proliferating cell nuclear antigen in uterine leiomyomas from both sporadic patients and patients with HLRCC. Furthermore, an increase in antiapoptotic BCLX with a simultaneous decrease in proapoptotic Bak (BCL2 antagonist/killer) protein also has been reported.14 It is controversial if patients presenting with multiple cutaneous or uterine leiomyomas should be screened for MCUL and HLRCC.13 However, a thorough personal and family history of cutaneous leiomyomas, fibroids, and renal cell carcinoma should be performed. If needed, a computed tomographic scan with contrast or magnetic resonance imaging should be performed. Both modalities are sensitive to detect smaller lesions and some types of papillary renal cell carcinoma that may be isoechoic and undetectable on ultrasound.15 

Cutaneous leiomyomas are benign tumors of smooth muscle bundles. Of the 5 subtypes of cutaneous leiomyomas, multiple piloleiomyomas (pilar leiomyomas) are the most common.1 Originating from arrector pili muscles of hair follicles, they usually present as small, red-brown, firm papules on the extremities or trunk of young adults. Solitary piloleiomyomas occur more commonly in women as larger nodules, measuring up to 2 cm. Occasionally, lesions can be symmetrical, Blaschkoid, diffuse (disseminated), or segmental (zosteriform).2 Multiple eruptive lesions have been described in patients with chronic lymphocytic leukemia, erythrocytosis, and human immunodeficiency virus infection. Patients may have a history of spontaneous burning, pinching, or stabbing pain. In addition, pain may be triggered by pressure, cold temperature, trauma, or emotional stress.3 Although the pathophysiology of pain is still unknown, it may be caused by pressure of the nerve fibers within the tumors upon contraction of the smooth muscles.4 Pain tends to occur more frequently in diffuse and segmental forms of leiomyomas.5 Multiple cutaneous leiomyomas may occur in conjunction with uterine leiomyomas, also known as multiple cutaneous and uterine leiomyomatosis (MCUL), familial leiomyomatosis cutis et uteri, Reed syndrome, or multiple leiomyomatosis.6 An autosomal dominant mode of transmission with incomplete penetrance occurs with MCUL. In this syndrome, multiple piloleiomyomas usually occur in both sexes. However, affected women also have severely symptomatic uterine leiomyomas or fibroids that usually require early hysterectomy for symptom control. Some patients with MCUL also were found to have uncommon and aggressive forms of renal cell carcinoma, especially papillary renal cell carcinoma type 2 or renal collecting duct carcinoma, which also is known as hereditary leiomyomatosis and renal cell cancer (HLRCC).7

Case Report An 81-year-old man presented with a 50-year history of multiple red-brown papules and nodules on both sides of his back. He denied any pruritus, tenderness, or burning sensation. His medical history included type 2 diabetes mellitus, cardiomyopathy, peripheral neuropathy, peripheral vascular disease, and benign prostatic hypertrophy. A thorough family history was unremarkable for any neoplasm including kidney cancer or uterine fibroids. On examination, there were multiple red-brown flattopped papules and nodules coalescing into plaques in a segmental distribution on both sides of his back (Figure 1). These papules were not tender on palpation. Upon stroking, there was no accentuation or piloerection.

Histopathologic findings showed a poorly circumscribed spindle cell proliferation with blunt-ended cigar-shaped nuclei and abundant pink cytoplasm in the deep papillary and reticular dermis. Perinuclear vacuolization was present in the cross-section of the smooth muscle bundles (Figure 2). There was no cytologic atypia or mitotic activity. Immunohistochemistry stains were positive for vimentin, smooth muscle actin, and desmin. The diagnosis of bilateral segmental leiomyomas (piloleiomyomas) was confirmed. Further history did not reveal any cancer or neoplasm. Radiographic and genetic studies were offered, but the patient and his family declined.

Comment
There are 5 subtypes of cutaneous leiomyomas: multiple piloleiomyomas, solitary piloleiomyomas, solitary genital leiomyomas, solitary angioleiomyomas, and leiomyomas with mesenchymal elements.¹ Solitary genital leiomyomas usually are asymptomatic. They originate from the superficial smooth muscles of the scrotum, labia majora, and nipples. Solitary angioleiomyomas present with painful solitary nodules deep in the mid-dermis or subcutaneous tissues and are derived from vascular smooth muscles. They most commonly present on the lower extremities in women aged 30 to 60 years. Rarely, mature adipocytes are found within the nodules as seen in angiolipoleiomyomas. Although they most likely represent metaplastic change, the presence of adipocytes is now accepted to be a hamartomatous process.8 Cutaneous angiolipoleiomyomas are more common in men and, contrary to renal angiomyolipomas, have no association with tuberous sclerosis.1 Histologically, piloleiomyomas and genital leiomyomas are composed of poorly demarcated, well-differentiated, interlacing bundles of smooth muscle fibers. The centrally located nuclei are long and thin with blunt ends in a cigar or eel shape (Figure 2). Angioleiomyomas are more sharply circumscribed. Round, slitlike, or stellate lumina also may be seen. Differential diagnosis may include other spindle cell proliferative tumors such as neurofibroma, dermatofibroma, schwannoma, and leiomyosarcoma. Nuclear pleomorphism and atypical mitoses are abundant in leiomyosarcomas. Immunohistochemistry also may help to confirm the diagnosis of leiomyomas and differentiate them from other similar entities. Genetic defects in MCUL and HLRCC were colocalized to band 1q42.3-43.9 Heterozygous germ line mutations in the fumarate hydratase gene, FH, that resulted in either decreased or absent FH enzymatic activity were subsequently identified in 42 patients affected with leiomyomatosis.10 The FH gene comprises 22 kilobases with 10 exons11 and encodes both the cytosolic and mitochondrial isoforms. Fumarate hydratase functions within the Krebs cycle by converting fumarate to L-malate. While the pathway by which tumorigenesis occurs in MCUL and HLRCC is still unknown, it is postulated that mutations in the FH gene exert a tumor suppressive effect by altering Krebs cycle activity.12 To date, there have been approximately 70 different mutations of the FH gene reported. Although the incidence of FH gene mutations in patients with uterine leiomyomas and papillary renal cell carcinoma type 2 remains unknown, 90% (80/89) of patients with cutaneous leiomyomas have FH gene mutations, determined by either DNA analysis or decreased enzymatic activity.13 Apoptotic and antiapoptotic factors also may play a role in the pathogenesis of leiomyomas. Wortham et al14 reported increased expressions of antiapoptotic BCL2 and the proliferation factor proliferating cell nuclear antigen in uterine leiomyomas from both sporadic patients and patients with HLRCC. Furthermore, an increase in antiapoptotic BCLX with a simultaneous decrease in proapoptotic Bak (BCL2 antagonist/killer) protein also has been reported.14 It is controversial if patients presenting with multiple cutaneous or uterine leiomyomas should be screened for MCUL and HLRCC.13 However, a thorough personal and family history of cutaneous leiomyomas, fibroids, and renal cell carcinoma should be performed. If needed, a computed tomographic scan with contrast or magnetic resonance imaging should be performed. Both modalities are sensitive to detect smaller lesions and some types of papillary renal cell carcinoma that may be isoechoic and undetectable on ultrasound.15 

Cutaneous leiomyomas are benign tumors of smooth muscle bundles. Of the 5 subtypes of cutaneous leiomyomas, multiple piloleiomyomas (pilar leiomyomas) are the most common.1 Originating from arrector pili muscles of hair follicles, they usually present as small, red-brown, firm papules on the extremities or trunk of young adults. Solitary piloleiomyomas occur more commonly in women as larger nodules, measuring up to 2 cm. Occasionally, lesions can be symmetrical, Blaschkoid, diffuse (disseminated), or segmental (zosteriform).2 Multiple eruptive lesions have been described in patients with chronic lymphocytic leukemia, erythrocytosis, and human immunodeficiency virus infection. Patients may have a history of spontaneous burning, pinching, or stabbing pain. In addition, pain may be triggered by pressure, cold temperature, trauma, or emotional stress.3 Although the pathophysiology of pain is still unknown, it may be caused by pressure of the nerve fibers within the tumors upon contraction of the smooth muscles.4 Pain tends to occur more frequently in diffuse and segmental forms of leiomyomas.5 Multiple cutaneous leiomyomas may occur in conjunction with uterine leiomyomas, also known as multiple cutaneous and uterine leiomyomatosis (MCUL), familial leiomyomatosis cutis et uteri, Reed syndrome, or multiple leiomyomatosis.6 An autosomal dominant mode of transmission with incomplete penetrance occurs with MCUL. In this syndrome, multiple piloleiomyomas usually occur in both sexes. However, affected women also have severely symptomatic uterine leiomyomas or fibroids that usually require early hysterectomy for symptom control. Some patients with MCUL also were found to have uncommon and aggressive forms of renal cell carcinoma, especially papillary renal cell carcinoma type 2 or renal collecting duct carcinoma, which also is known as hereditary leiomyomatosis and renal cell cancer (HLRCC).7

Case Report An 81-year-old man presented with a 50-year history of multiple red-brown papules and nodules on both sides of his back. He denied any pruritus, tenderness, or burning sensation. His medical history included type 2 diabetes mellitus, cardiomyopathy, peripheral neuropathy, peripheral vascular disease, and benign prostatic hypertrophy. A thorough family history was unremarkable for any neoplasm including kidney cancer or uterine fibroids. On examination, there were multiple red-brown flattopped papules and nodules coalescing into plaques in a segmental distribution on both sides of his back (Figure 1). These papules were not tender on palpation. Upon stroking, there was no accentuation or piloerection.

Histopathologic findings showed a poorly circumscribed spindle cell proliferation with blunt-ended cigar-shaped nuclei and abundant pink cytoplasm in the deep papillary and reticular dermis. Perinuclear vacuolization was present in the cross-section of the smooth muscle bundles (Figure 2). There was no cytologic atypia or mitotic activity. Immunohistochemistry stains were positive for vimentin, smooth muscle actin, and desmin. The diagnosis of bilateral segmental leiomyomas (piloleiomyomas) was confirmed. Further history did not reveal any cancer or neoplasm. Radiographic and genetic studies were offered, but the patient and his family declined.

Comment
There are 5 subtypes of cutaneous leiomyomas: multiple piloleiomyomas, solitary piloleiomyomas, solitary genital leiomyomas, solitary angioleiomyomas, and leiomyomas with mesenchymal elements.¹ Solitary genital leiomyomas usually are asymptomatic. They originate from the superficial smooth muscles of the scrotum, labia majora, and nipples. Solitary angioleiomyomas present with painful solitary nodules deep in the mid-dermis or subcutaneous tissues and are derived from vascular smooth muscles. They most commonly present on the lower extremities in women aged 30 to 60 years. Rarely, mature adipocytes are found within the nodules as seen in angiolipoleiomyomas. Although they most likely represent metaplastic change, the presence of adipocytes is now accepted to be a hamartomatous process.8 Cutaneous angiolipoleiomyomas are more common in men and, contrary to renal angiomyolipomas, have no association with tuberous sclerosis.1 Histologically, piloleiomyomas and genital leiomyomas are composed of poorly demarcated, well-differentiated, interlacing bundles of smooth muscle fibers. The centrally located nuclei are long and thin with blunt ends in a cigar or eel shape (Figure 2). Angioleiomyomas are more sharply circumscribed. Round, slitlike, or stellate lumina also may be seen. Differential diagnosis may include other spindle cell proliferative tumors such as neurofibroma, dermatofibroma, schwannoma, and leiomyosarcoma. Nuclear pleomorphism and atypical mitoses are abundant in leiomyosarcomas. Immunohistochemistry also may help to confirm the diagnosis of leiomyomas and differentiate them from other similar entities. Genetic defects in MCUL and HLRCC were colocalized to band 1q42.3-43.9 Heterozygous germ line mutations in the fumarate hydratase gene, FH, that resulted in either decreased or absent FH enzymatic activity were subsequently identified in 42 patients affected with leiomyomatosis.10 The FH gene comprises 22 kilobases with 10 exons11 and encodes both the cytosolic and mitochondrial isoforms. Fumarate hydratase functions within the Krebs cycle by converting fumarate to L-malate. While the pathway by which tumorigenesis occurs in MCUL and HLRCC is still unknown, it is postulated that mutations in the FH gene exert a tumor suppressive effect by altering Krebs cycle activity.12 To date, there have been approximately 70 different mutations of the FH gene reported. Although the incidence of FH gene mutations in patients with uterine leiomyomas and papillary renal cell carcinoma type 2 remains unknown, 90% (80/89) of patients with cutaneous leiomyomas have FH gene mutations, determined by either DNA analysis or decreased enzymatic activity.13 Apoptotic and antiapoptotic factors also may play a role in the pathogenesis of leiomyomas. Wortham et al14 reported increased expressions of antiapoptotic BCL2 and the proliferation factor proliferating cell nuclear antigen in uterine leiomyomas from both sporadic patients and patients with HLRCC. Furthermore, an increase in antiapoptotic BCLX with a simultaneous decrease in proapoptotic Bak (BCL2 antagonist/killer) protein also has been reported.14 It is controversial if patients presenting with multiple cutaneous or uterine leiomyomas should be screened for MCUL and HLRCC.13 However, a thorough personal and family history of cutaneous leiomyomas, fibroids, and renal cell carcinoma should be performed. If needed, a computed tomographic scan with contrast or magnetic resonance imaging should be performed. Both modalities are sensitive to detect smaller lesions and some types of papillary renal cell carcinoma that may be isoechoic and undetectable on ultrasound.15