Cutis

The bite of the brown recluse spider, also known as Loxosceles reclusa, usually causes a local hemorrhagic lesion characterized by areas of red, white, and blue discoloration.1 Rarely, the venom from this spider may cause a systemic response characterized by fever, malaise, myalgia, hemolysis, acute renal failure, disseminated intravascular coagulation, or even death. The condition is called systemic loxoscelism and can be particularly dangerous in childhood, when most deaths from loxoscelism occur. The hemolysis in patients with systemic loxoscelism is not completely understood, despite extensive research into the components of this deadly spider's venom.2-4 Why this venom results in systemic symptoms in some patients and local reactions in others also is not completely understood. This variation in symptomatology likely has to do with the location of the initial spider bite and a possible predisposition of some individuals to environmental red blood cell toxins. The treatment of necrotic arachnidism is as controversial as the pathophysiology of the hemolysis. No standard of care exists for the more severe or anatomically vital spider bites. Several systemic medications have been tried with extensive anecdotal support, but no large controlled trials have been performed in humans to prove these agents are more effective than aggressive and meticulous wound care. Previous studies have shown that patients treated with early surgery resulted in prolonged healing times and increased negative outcomes compared with patients treated with supportive wound care.5,6 Patients generally do very well with only supportive measures, which should remain the treatment of choice until larger studies elucidate the role of systemic medications. We report 2 cases of systemic loxoscelism causing a Coombs-positive intravascular hemolysis requiring blood transfusion and review the treatment options of this condition.

Case Reports

Patient 1—A 19-year-old African American woman with a medical history significant only for asthma presented to her primary care physician 2 days after a painless bite from a "brown spider" in her bed. At this initial evaluation, she had a diffuse maculopapular rash with mild systemic symptoms including malaise and arthralgia. No laboratory workups were done, and she was started on a 5-day steroid dose pack. The patient was seen in our urgent care department 2 days later with documentation of a 2X2-cm ecchymotic area on her right posterior thigh with surrounding erythema and a diffuse maculopapular rash. Her laboratory workup at this time showed a mildly elevated total bilirubin level, mild leukocytosis, anemia with a hemoglobin level of 11.7 mg/dL, elevated reticulocyte count, and normal coagulation profile. She was given intramuscular methylprednisolone 125 mg, acetaminophen for pain, and hydroxyzine for pruritus, with plans for follow-up in urgent care the next day. The patient did not follow-up until 2 days later, at which time she reported worsening systemic symptoms including nausea, peripheral edema, lymphadenopathy, fever, and dysuria, along with worsening pain and erythema at the bite site. She was febrile, and her anemia progressed when her hemoglobin level fell to 8.3 mg/dL. She was admitted for hematologic monitoring and supportive measures. At the time of admission, her skin examination results were pertinent for a diffuse, faint maculopapular rash and a 3X3-cm necrotic eschar with surrounding erythema (Figure 1).

The day after admission, the patient continued to be febrile, and her hemoglobin level dropped to 6.9 mg/dL. She was transfused with 2 units of packed red blood cells, and the hematology department was consulted to assist with the progressing anemia. The dermatology department also was consulted to assist with wound care and treatment. The hematologist recommended performing an indirect and direct Coombs test. The indirect Coombs test results were negative, but the direct Coombs test results were positive for complement 3 and negative for immunoglobulin G (IgG). The patient's anemia and systemic symptoms continued to progress (hemoglobin nadir level, 5.7 mg/dL), requiring 2 more units of blood. The hematologist recommended starting intravenous steroids to improve the patient's "immunohemolytic anemia secondary to spider bite with positive Coombs test." The patient was started on methylprednisolone 125 mg/d intravenously. Per dermatology's recommendation, wound care was initiated along with elevation and ice to the affected extremity. The patient's clinical status began to improve on hospital day 4, with absence of systemic symptoms and regression of her lesional erythema. She was discharged on a quick-taper oral steroid regimen, per the hematologist's recommendation, and was instructed to continue her wound care. At the patient's hospital follow-up visit, her bite site was healing well, and she had no further evidence of anemia. Patient 2—A 9-year-old African American girl in otherwise excellent health was transferred from an outside emergency department one week after being bitten by "a brown spider" while lying in bed. Initially, the bite was painless, but she later developed swelling and warmth in the area. Due to increased pain, swelling, and blister formation, her primary physician saw her several days later and prescribed an oral cephalosporin for presumed cellulitis. Fever, fatigue, and malaise continued throughout the week. Two days prior to presentation at our hospital, she developed scleral icterus and vomiting. During the patient's evaluation at the transferring emergency department, her laboratory workup revealed a profound anemia with a hemoglobin level of 5.2 mg/dL, elevated white blood cell count, indirect hyperbilirubinemia, and mildly prolonged international normalized ratio value. Her examination was significant for a tachycardia, holosystolic murmur, scleral icterus, and 5X2-cm necrotic eschar on her left flank with a surrounding area of erythema that was exquisitely tender to palpation (Figure 2). She was immediately admitted for close observation and treatment of her anemia. She was transfused with 2 units of packed red blood cells.

The patient's hemoglobin level rebounded to 8.2 mg/dL on hospital day 2, at which time the dermatology department was consulted for assistance with wound care management. Elevation of the extremity and continuing wound care was recommended, and debridement or systemic therapy was advised against. Results of the patient's direct Coombs test were positive for IgG and negative for complement 3. No specific treatment changes were made based on the Coombs test result. The patient continued to improve with wound care and hemodynamic support and displayed improved erythema with less tenderness at the bite site after several days of hospitalization. She was sent home on hospital day 4 in improved condition. She was seen by a dermatologist at her follow-up visit, and her eschar was treated with hydrocolloid dressing changes and eventual debridement of the eschar with follow-up occlusive dressings until the lesion was completely healed.

Comment

Brown Recluse-Induced Hemolysis—Brown recluse spider bites are common in the Midwest, Southeast, and south central United States.7 Although there are more than 70 species of Loxosceles found throughout the world, only approximately 15 species inhabit North America, with L reclusa being the most common encountered by humans.8 Patients affected by this malady are often seen by physicians in various specialties, including primary care providers, emergency physicians, dermatologists, general surgeons, and surgical subspecialists. It is important that physicians in these specialties recognize and treat this condition appropriately.

Although these bites usually cause a local necrotic lesion, sometimes a more serious systemic syndrome, known as systemic loxoscelism, occurs. This can result in high fever, significant intravascular hemolysis, renal failure, disseminated intravascular coagulation, and even death. Although most fatalities have been reported in children, 2 cases of adult deaths have been reported.9,10 The hemolytic anemia that accompanies systemic loxoscelism has been only partially described, and the full mechanism by which the venom of the brown recluse causes this syndrome is still a mystery. The prevailing theory for the cause of hemolysis has incriminated the phospholipase sphingomyelin D, an enzyme isolated from brown recluse venom, because of its effect on cell walls in vivo to cause lysis.11 It was thought that sphingomyelinase disrupted cell membranes either directly or indirectly and resulted in the release of phospholipid-derived substances that bound complement and resulted in tissue hypoxia and necrosis.12-14 Because such a small amount of venom and toxin actually enter the body after a bite, another mechanism is likely taking place to produce the symptoms involved in systemic loxoscelism. Activation and propagation of the immune system by a toxin in the venom could explain such a reaction.

A study on another member of the Loxosceles family, Loxosceles intermedia, may help elucidate the factors involved in the overwhelming reaction to the Loxosceles venom in some people.¹⁵ In this study, it was found that the sphingomyelinase in the spider toxin did not directly affect glycophorins on red blood cell membranes but instead activated an endogenous metalloproteinase that then cleaved these glycophorins. The authors proposed that the altered glycophorins destabilized the red blood cell membrane, rendering the glycophorins vulnerable for complement-mediated lysis. The authors also observed that the hemolysis-inducing and glycophorin-cleaving activity of this activated metalloproteinase could be transferred from one erythrocyte to another, thereby propagating the hemolyzing response.15 This type of transfer of sphingomyelinase and metalloproteinase activity between cells has been described before and could explain the overwhelming systemic response of the Loxosceles toxin in some individuals.16

Historically, most cases of massive hemolysis due to brown recluse bites documented in the literature have been Coombs negative.17 This also has been the case at our institution until recently.11 We report 2 cases of life-threatening hemolytic anemia with positive direct Coombs testing in a span of 9 months. These results are a rarity but may help us understand the pathophysiology of systemic loxoscelism. To our knowledge, these are the fifth and sixth reported cases of a Coombs-positive hemolytic anemia from a brown recluse spider bite. The first case was documented by Nance18 in 1961, but there was no mention of whether complement or immunoglobulin was involved. Eichner¹⁷ reported the second and third cases of Coombs-positive anemia in loxoscelism, with both cases involving complement-mediated hemolysis. The fourth case of Coombs-positive anemia was reported by William et al9 in 1995, and the Coombs test was positive for both IgG and complement. Our cases affirm that both IgG and complement can be involved in Coombs-positive hemolytic anemia. It is likely that the venom of the brown recluse is able to activate both IgG and complement in predisposed individuals by activation of an unknown endogenous mediator (eg, metalloproteinase) to cause massive intravascular hemolysis. Investigations into which patients may be predisposed to develop this complication are warranted.

Treatment—The treatment of local and systemic brown recluse spider bites also has been a source of controversy over the years. Several treatment regimens, including early and late surgical excision and debridement, systemic steroids, hyperbaric oxygen therapy, cryproheptadine, electric shock therapy, and dapsone, have been anecdotally described in the literature; however, none of these treatments have prospective human trials to back up this anecdotal evidence. With conservative wound management, ice, elevation, and analgesics, almost all patients exhibit a full recovery with minimal scarring that rarely needs surgical revision.19

Dapsone has been the most controversial of the treatments for brown recluse bites. Dapsone makes theoretical sense in the treatment of these lesions because of its ability to inhibit polymorphonuclear leukocytes from entering the wound area and causing local destruction. There are many anecdotal reports supporting the use of dapsone for more severe bites, the most famous being the King and Rees²⁰ case report of a patient with a brown recluse bite of the leg that was seen 24 hours after the bite had occurred. They reported that 2 days after prescribing dapsone 100 mg twice daily along with ice and local wound care, the bite site was pain free with marked reduction in induration and erythema. Their argument was based on an assumption that the lesion "probably would have developed an indolent ulcer." They supported their use of dapsone with an animal model of guinea pigs that were pretreated with dapsone before being injected with Loxosceles venom. The authors reported that pretreated guinea pigs showed a reduction in lesion size at 24 hours compared with those without treatment.20 The methods of this study have come into question primarily due to the rarity of patients with brown recluse bites pretreated with dapsone. Also, follow-up animal studies have conflicted with the benefit of dapsone for this indication.21,22

Although the benefit of dapsone is controversial, the side effects of this medicine are protean and well known. The development of hemolytic anemia has long been attributed to this medication and will occur to some degree in all patients.23 This predictable hemolysis can sometimes become confused with the direct effects of the brown recluse venom, which can delay definitive diagnosis of the etiology of the hemolysis and expose patients to an unproven drug with multiple toxicities. Severe hemolysis can be expected in patients with glucose-6-phosphate dehydrogenase deficiency; therefore, dapsone is absolutely contraindicated in this patient population.

Methemoglobinemia is another feared side effect of dapsone. Although mostly asymptomatic and usually undetectable, sometimes elevated levels of methemoglobin can cause severe systemic symptoms requiring hospitalization.24 Unfortunately, it is impossible to predict who will experience this complication because of a lack of simple blood testing such as that available for patients with subclinical glucose-6-phosphate dehydrogenase deficiency. Because of these serious and sometimes common adverse events attributed to dapsone, and the lack of solid evidence to support its effectiveness, there is no place for dapsone in the treatment of loxoscelism at this time.

The role of early surgical excision has changed over the past few decades. Reports prior to 1975 often suggested early surgical excision of bites with grafting as the treatment of choice.25,26 Since then, multiple reports have shown that early surgical excision often does more harm than good in the treatment of brown recluse bites.5,6 Early surgical excision is contraindicated because of the rapid spread of the toxin through the wound in the first weeks following a bite. The toxin may continue to spread for at least 4 weeks, which makes demarcation between envenomed and healthy tissue difficult.27 DeLozier et al6 suggested that the added surgical trauma from early excision may potentiate the inflammatory response to the brown recluse venom, prolonging healing time.

Conservative debridement may be performed to prevent secondary infection, but surgery should generally be withheld for 4 to 6 weeks. Early local wound care during this time followed by late surgical excision and grafting are more successful than early surgical excision. However, most wounds, if treated with supportive therapy alone, will ultimately heal with minimal scarring.28 A retrospective study of 149 patients with brown recluse bites showed that nearly half of all bites healed within 2 weeks and only 13% of bites left a visible scar. None of these patients were treated with surgery.29

Corticosteroids also have been used extensively for more serious reactions after envenomation from a brown recluse spider, but documentation in the literature is sparse. In a white rabbit model, Jansen et al30 did not find any treatment value for either intramuscular or intralesional methylprednisolone in the prevention of dermonecrosis after a brown recluse spider bite. Berger et al31 also concluded that large doses of steroids had no effect on the progression or development of necrotic arachnidism. Despite this evidence, there are many who still advocate the use of steroids for more serious bites and for those associated with systemic symptoms.32 Given the extensive use of corticosteroids in patients with autoimmune hemolytic anemia, this treatment may be of use in patients with Coombs-positive hemolytic anemia secondary to brown recluse envenomation.33,34 For this reason, direct Coombs testing in patients with hemolytic anemia due to brown recluse bites could provide useful information in the inpatient management of these patients.

Other treatments also have been reported, including colchicine, hyperbaric oxygen, cyproheptadine, electrical shock treatment, and brown recluse specific antivenin.7,21,35 Despite early promise, all of these treatments have been met with mixed results in subsequent studies. In one study, the early use of intradermal injection of polyclonal antiloxosceles Fab fragments was shown to attenuate necrosis in an animal model up to 4 hours after envenomation.36 Unfortunately, it is difficult to predict which patients would benefit from the antivenin. Additionally, the antivenin has to be administered in the first 24 hours after a bite, before most patients are seen by a physician.

In our cases, both patients were young and presented with a recent history of a bite by a brown spider consistent with a brown recluse. They were both systemically ill with a profound hemolytic anemia. They were both treated with aggressive wound management, hematologic monitoring with blood transfusion, and expectant care. Patient 1 was given intravenous corticosteroids, and patient 2 was treated with aggressive wound management only. It is not known whether the corticosteroids given in our first patient affected her clinical course because both patients experienced a complete recovery. Like other case reports of treatment in brown recluse spider bites, it is difficult to tell what effect, if any, the treatment has on clinical outcome because most patients, even those with serious systemic symptoms, make a complete recovery. This routine excellent outcome with supportive care only suggests that the use of systemic treatment or surgery is unnecessary and exposes the patient to risks of treatments with unproven efficacies. 

Conclusion

Brown recluse spider bites usually cause a local dermonecrotic reaction but can cause a serious systemic illness and rarely death. We report the fifth and sixth cases of Coombs-positive hemolytic anemia associated with presumed L reclusa envenomation. The first 4 reported cases of Coombs-positive hemolysis were positive for IgG and/or complement. This was confirmed in our cases. The treatment of loxoscelism is controversial in the literature and in practice. We must keep in mind to "first, do no harm" when choosing treatments for patients with brown recluse bites. Many of the treatments previously described, including dapsone, have only anecdotal support for their use. Others, such as early surgery, have been shown to actually delay healing and worsen outcomes. Patients with brown recluse bites typically do well with conservative management alone and agents such as dapsone and systemic corticosteroids can have serious adverse reactions. It is our view that patients with local dermonecrotic skin lesions should be treated with aggressive wound care only. For patients who develop systemic loxoscelism, hemodynamic support and blood transfusion should remain the mainstay of therapy. Further study is needed to determine the benefits of systemic corticosteroid use in patients with Coombs-positive hemolytic anemia secondary to systemic loxoscelism. 

The bite of the brown recluse spider, also known as Loxosceles reclusa, usually causes a local hemorrhagic lesion characterized by areas of red, white, and blue discoloration.1 Rarely, the venom from this spider may cause a systemic response characterized by fever, malaise, myalgia, hemolysis, acute renal failure, disseminated intravascular coagulation, or even death. The condition is called systemic loxoscelism and can be particularly dangerous in childhood, when most deaths from loxoscelism occur. The hemolysis in patients with systemic loxoscelism is not completely understood, despite extensive research into the components of this deadly spider's venom.2-4 Why this venom results in systemic symptoms in some patients and local reactions in others also is not completely understood. This variation in symptomatology likely has to do with the location of the initial spider bite and a possible predisposition of some individuals to environmental red blood cell toxins. The treatment of necrotic arachnidism is as controversial as the pathophysiology of the hemolysis. No standard of care exists for the more severe or anatomically vital spider bites. Several systemic medications have been tried with extensive anecdotal support, but no large controlled trials have been performed in humans to prove these agents are more effective than aggressive and meticulous wound care. Previous studies have shown that patients treated with early surgery resulted in prolonged healing times and increased negative outcomes compared with patients treated with supportive wound care.5,6 Patients generally do very well with only supportive measures, which should remain the treatment of choice until larger studies elucidate the role of systemic medications. We report 2 cases of systemic loxoscelism causing a Coombs-positive intravascular hemolysis requiring blood transfusion and review the treatment options of this condition.

Case Reports

Patient 1—A 19-year-old African American woman with a medical history significant only for asthma presented to her primary care physician 2 days after a painless bite from a "brown spider" in her bed. At this initial evaluation, she had a diffuse maculopapular rash with mild systemic symptoms including malaise and arthralgia. No laboratory workups were done, and she was started on a 5-day steroid dose pack. The patient was seen in our urgent care department 2 days later with documentation of a 2X2-cm ecchymotic area on her right posterior thigh with surrounding erythema and a diffuse maculopapular rash. Her laboratory workup at this time showed a mildly elevated total bilirubin level, mild leukocytosis, anemia with a hemoglobin level of 11.7 mg/dL, elevated reticulocyte count, and normal coagulation profile. She was given intramuscular methylprednisolone 125 mg, acetaminophen for pain, and hydroxyzine for pruritus, with plans for follow-up in urgent care the next day. The patient did not follow-up until 2 days later, at which time she reported worsening systemic symptoms including nausea, peripheral edema, lymphadenopathy, fever, and dysuria, along with worsening pain and erythema at the bite site. She was febrile, and her anemia progressed when her hemoglobin level fell to 8.3 mg/dL. She was admitted for hematologic monitoring and supportive measures. At the time of admission, her skin examination results were pertinent for a diffuse, faint maculopapular rash and a 3X3-cm necrotic eschar with surrounding erythema (Figure 1).

The day after admission, the patient continued to be febrile, and her hemoglobin level dropped to 6.9 mg/dL. She was transfused with 2 units of packed red blood cells, and the hematology department was consulted to assist with the progressing anemia. The dermatology department also was consulted to assist with wound care and treatment. The hematologist recommended performing an indirect and direct Coombs test. The indirect Coombs test results were negative, but the direct Coombs test results were positive for complement 3 and negative for immunoglobulin G (IgG). The patient's anemia and systemic symptoms continued to progress (hemoglobin nadir level, 5.7 mg/dL), requiring 2 more units of blood. The hematologist recommended starting intravenous steroids to improve the patient's "immunohemolytic anemia secondary to spider bite with positive Coombs test." The patient was started on methylprednisolone 125 mg/d intravenously. Per dermatology's recommendation, wound care was initiated along with elevation and ice to the affected extremity. The patient's clinical status began to improve on hospital day 4, with absence of systemic symptoms and regression of her lesional erythema. She was discharged on a quick-taper oral steroid regimen, per the hematologist's recommendation, and was instructed to continue her wound care. At the patient's hospital follow-up visit, her bite site was healing well, and she had no further evidence of anemia. Patient 2—A 9-year-old African American girl in otherwise excellent health was transferred from an outside emergency department one week after being bitten by "a brown spider" while lying in bed. Initially, the bite was painless, but she later developed swelling and warmth in the area. Due to increased pain, swelling, and blister formation, her primary physician saw her several days later and prescribed an oral cephalosporin for presumed cellulitis. Fever, fatigue, and malaise continued throughout the week. Two days prior to presentation at our hospital, she developed scleral icterus and vomiting. During the patient's evaluation at the transferring emergency department, her laboratory workup revealed a profound anemia with a hemoglobin level of 5.2 mg/dL, elevated white blood cell count, indirect hyperbilirubinemia, and mildly prolonged international normalized ratio value. Her examination was significant for a tachycardia, holosystolic murmur, scleral icterus, and 5X2-cm necrotic eschar on her left flank with a surrounding area of erythema that was exquisitely tender to palpation (Figure 2). She was immediately admitted for close observation and treatment of her anemia. She was transfused with 2 units of packed red blood cells.

The patient's hemoglobin level rebounded to 8.2 mg/dL on hospital day 2, at which time the dermatology department was consulted for assistance with wound care management. Elevation of the extremity and continuing wound care was recommended, and debridement or systemic therapy was advised against. Results of the patient's direct Coombs test were positive for IgG and negative for complement 3. No specific treatment changes were made based on the Coombs test result. The patient continued to improve with wound care and hemodynamic support and displayed improved erythema with less tenderness at the bite site after several days of hospitalization. She was sent home on hospital day 4 in improved condition. She was seen by a dermatologist at her follow-up visit, and her eschar was treated with hydrocolloid dressing changes and eventual debridement of the eschar with follow-up occlusive dressings until the lesion was completely healed.

Comment

Brown Recluse-Induced Hemolysis—Brown recluse spider bites are common in the Midwest, Southeast, and south central United States.7 Although there are more than 70 species of Loxosceles found throughout the world, only approximately 15 species inhabit North America, with L reclusa being the most common encountered by humans.8 Patients affected by this malady are often seen by physicians in various specialties, including primary care providers, emergency physicians, dermatologists, general surgeons, and surgical subspecialists. It is important that physicians in these specialties recognize and treat this condition appropriately.

Although these bites usually cause a local necrotic lesion, sometimes a more serious systemic syndrome, known as systemic loxoscelism, occurs. This can result in high fever, significant intravascular hemolysis, renal failure, disseminated intravascular coagulation, and even death. Although most fatalities have been reported in children, 2 cases of adult deaths have been reported.9,10 The hemolytic anemia that accompanies systemic loxoscelism has been only partially described, and the full mechanism by which the venom of the brown recluse causes this syndrome is still a mystery. The prevailing theory for the cause of hemolysis has incriminated the phospholipase sphingomyelin D, an enzyme isolated from brown recluse venom, because of its effect on cell walls in vivo to cause lysis.11 It was thought that sphingomyelinase disrupted cell membranes either directly or indirectly and resulted in the release of phospholipid-derived substances that bound complement and resulted in tissue hypoxia and necrosis.12-14 Because such a small amount of venom and toxin actually enter the body after a bite, another mechanism is likely taking place to produce the symptoms involved in systemic loxoscelism. Activation and propagation of the immune system by a toxin in the venom could explain such a reaction.

A study on another member of the Loxosceles family, Loxosceles intermedia, may help elucidate the factors involved in the overwhelming reaction to the Loxosceles venom in some people.¹⁵ In this study, it was found that the sphingomyelinase in the spider toxin did not directly affect glycophorins on red blood cell membranes but instead activated an endogenous metalloproteinase that then cleaved these glycophorins. The authors proposed that the altered glycophorins destabilized the red blood cell membrane, rendering the glycophorins vulnerable for complement-mediated lysis. The authors also observed that the hemolysis-inducing and glycophorin-cleaving activity of this activated metalloproteinase could be transferred from one erythrocyte to another, thereby propagating the hemolyzing response.15 This type of transfer of sphingomyelinase and metalloproteinase activity between cells has been described before and could explain the overwhelming systemic response of the Loxosceles toxin in some individuals.16

Historically, most cases of massive hemolysis due to brown recluse bites documented in the literature have been Coombs negative.17 This also has been the case at our institution until recently.11 We report 2 cases of life-threatening hemolytic anemia with positive direct Coombs testing in a span of 9 months. These results are a rarity but may help us understand the pathophysiology of systemic loxoscelism. To our knowledge, these are the fifth and sixth reported cases of a Coombs-positive hemolytic anemia from a brown recluse spider bite. The first case was documented by Nance18 in 1961, but there was no mention of whether complement or immunoglobulin was involved. Eichner¹⁷ reported the second and third cases of Coombs-positive anemia in loxoscelism, with both cases involving complement-mediated hemolysis. The fourth case of Coombs-positive anemia was reported by William et al9 in 1995, and the Coombs test was positive for both IgG and complement. Our cases affirm that both IgG and complement can be involved in Coombs-positive hemolytic anemia. It is likely that the venom of the brown recluse is able to activate both IgG and complement in predisposed individuals by activation of an unknown endogenous mediator (eg, metalloproteinase) to cause massive intravascular hemolysis. Investigations into which patients may be predisposed to develop this complication are warranted.

Treatment—The treatment of local and systemic brown recluse spider bites also has been a source of controversy over the years. Several treatment regimens, including early and late surgical excision and debridement, systemic steroids, hyperbaric oxygen therapy, cryproheptadine, electric shock therapy, and dapsone, have been anecdotally described in the literature; however, none of these treatments have prospective human trials to back up this anecdotal evidence. With conservative wound management, ice, elevation, and analgesics, almost all patients exhibit a full recovery with minimal scarring that rarely needs surgical revision.19

Dapsone has been the most controversial of the treatments for brown recluse bites. Dapsone makes theoretical sense in the treatment of these lesions because of its ability to inhibit polymorphonuclear leukocytes from entering the wound area and causing local destruction. There are many anecdotal reports supporting the use of dapsone for more severe bites, the most famous being the King and Rees²⁰ case report of a patient with a brown recluse bite of the leg that was seen 24 hours after the bite had occurred. They reported that 2 days after prescribing dapsone 100 mg twice daily along with ice and local wound care, the bite site was pain free with marked reduction in induration and erythema. Their argument was based on an assumption that the lesion "probably would have developed an indolent ulcer." They supported their use of dapsone with an animal model of guinea pigs that were pretreated with dapsone before being injected with Loxosceles venom. The authors reported that pretreated guinea pigs showed a reduction in lesion size at 24 hours compared with those without treatment.20 The methods of this study have come into question primarily due to the rarity of patients with brown recluse bites pretreated with dapsone. Also, follow-up animal studies have conflicted with the benefit of dapsone for this indication.21,22

Although the benefit of dapsone is controversial, the side effects of this medicine are protean and well known. The development of hemolytic anemia has long been attributed to this medication and will occur to some degree in all patients.23 This predictable hemolysis can sometimes become confused with the direct effects of the brown recluse venom, which can delay definitive diagnosis of the etiology of the hemolysis and expose patients to an unproven drug with multiple toxicities. Severe hemolysis can be expected in patients with glucose-6-phosphate dehydrogenase deficiency; therefore, dapsone is absolutely contraindicated in this patient population.

Methemoglobinemia is another feared side effect of dapsone. Although mostly asymptomatic and usually undetectable, sometimes elevated levels of methemoglobin can cause severe systemic symptoms requiring hospitalization.24 Unfortunately, it is impossible to predict who will experience this complication because of a lack of simple blood testing such as that available for patients with subclinical glucose-6-phosphate dehydrogenase deficiency. Because of these serious and sometimes common adverse events attributed to dapsone, and the lack of solid evidence to support its effectiveness, there is no place for dapsone in the treatment of loxoscelism at this time.

The role of early surgical excision has changed over the past few decades. Reports prior to 1975 often suggested early surgical excision of bites with grafting as the treatment of choice.25,26 Since then, multiple reports have shown that early surgical excision often does more harm than good in the treatment of brown recluse bites.5,6 Early surgical excision is contraindicated because of the rapid spread of the toxin through the wound in the first weeks following a bite. The toxin may continue to spread for at least 4 weeks, which makes demarcation between envenomed and healthy tissue difficult.27 DeLozier et al6 suggested that the added surgical trauma from early excision may potentiate the inflammatory response to the brown recluse venom, prolonging healing time.

Conservative debridement may be performed to prevent secondary infection, but surgery should generally be withheld for 4 to 6 weeks. Early local wound care during this time followed by late surgical excision and grafting are more successful than early surgical excision. However, most wounds, if treated with supportive therapy alone, will ultimately heal with minimal scarring.28 A retrospective study of 149 patients with brown recluse bites showed that nearly half of all bites healed within 2 weeks and only 13% of bites left a visible scar. None of these patients were treated with surgery.29

Corticosteroids also have been used extensively for more serious reactions after envenomation from a brown recluse spider, but documentation in the literature is sparse. In a white rabbit model, Jansen et al30 did not find any treatment value for either intramuscular or intralesional methylprednisolone in the prevention of dermonecrosis after a brown recluse spider bite. Berger et al31 also concluded that large doses of steroids had no effect on the progression or development of necrotic arachnidism. Despite this evidence, there are many who still advocate the use of steroids for more serious bites and for those associated with systemic symptoms.32 Given the extensive use of corticosteroids in patients with autoimmune hemolytic anemia, this treatment may be of use in patients with Coombs-positive hemolytic anemia secondary to brown recluse envenomation.33,34 For this reason, direct Coombs testing in patients with hemolytic anemia due to brown recluse bites could provide useful information in the inpatient management of these patients.

Other treatments also have been reported, including colchicine, hyperbaric oxygen, cyproheptadine, electrical shock treatment, and brown recluse specific antivenin.7,21,35 Despite early promise, all of these treatments have been met with mixed results in subsequent studies. In one study, the early use of intradermal injection of polyclonal antiloxosceles Fab fragments was shown to attenuate necrosis in an animal model up to 4 hours after envenomation.36 Unfortunately, it is difficult to predict which patients would benefit from the antivenin. Additionally, the antivenin has to be administered in the first 24 hours after a bite, before most patients are seen by a physician.

In our cases, both patients were young and presented with a recent history of a bite by a brown spider consistent with a brown recluse. They were both systemically ill with a profound hemolytic anemia. They were both treated with aggressive wound management, hematologic monitoring with blood transfusion, and expectant care. Patient 1 was given intravenous corticosteroids, and patient 2 was treated with aggressive wound management only. It is not known whether the corticosteroids given in our first patient affected her clinical course because both patients experienced a complete recovery. Like other case reports of treatment in brown recluse spider bites, it is difficult to tell what effect, if any, the treatment has on clinical outcome because most patients, even those with serious systemic symptoms, make a complete recovery. This routine excellent outcome with supportive care only suggests that the use of systemic treatment or surgery is unnecessary and exposes the patient to risks of treatments with unproven efficacies. 

Conclusion

Brown recluse spider bites usually cause a local dermonecrotic reaction but can cause a serious systemic illness and rarely death. We report the fifth and sixth cases of Coombs-positive hemolytic anemia associated with presumed L reclusa envenomation. The first 4 reported cases of Coombs-positive hemolysis were positive for IgG and/or complement. This was confirmed in our cases. The treatment of loxoscelism is controversial in the literature and in practice. We must keep in mind to "first, do no harm" when choosing treatments for patients with brown recluse bites. Many of the treatments previously described, including dapsone, have only anecdotal support for their use. Others, such as early surgery, have been shown to actually delay healing and worsen outcomes. Patients with brown recluse bites typically do well with conservative management alone and agents such as dapsone and systemic corticosteroids can have serious adverse reactions. It is our view that patients with local dermonecrotic skin lesions should be treated with aggressive wound care only. For patients who develop systemic loxoscelism, hemodynamic support and blood transfusion should remain the mainstay of therapy. Further study is needed to determine the benefits of systemic corticosteroid use in patients with Coombs-positive hemolytic anemia secondary to systemic loxoscelism. 

The bite of the brown recluse spider, also known as Loxosceles reclusa, usually causes a local hemorrhagic lesion characterized by areas of red, white, and blue discoloration.1 Rarely, the venom from this spider may cause a systemic response characterized by fever, malaise, myalgia, hemolysis, acute renal failure, disseminated intravascular coagulation, or even death. The condition is called systemic loxoscelism and can be particularly dangerous in childhood, when most deaths from loxoscelism occur. The hemolysis in patients with systemic loxoscelism is not completely understood, despite extensive research into the components of this deadly spider's venom.2-4 Why this venom results in systemic symptoms in some patients and local reactions in others also is not completely understood. This variation in symptomatology likely has to do with the location of the initial spider bite and a possible predisposition of some individuals to environmental red blood cell toxins. The treatment of necrotic arachnidism is as controversial as the pathophysiology of the hemolysis. No standard of care exists for the more severe or anatomically vital spider bites. Several systemic medications have been tried with extensive anecdotal support, but no large controlled trials have been performed in humans to prove these agents are more effective than aggressive and meticulous wound care. Previous studies have shown that patients treated with early surgery resulted in prolonged healing times and increased negative outcomes compared with patients treated with supportive wound care.5,6 Patients generally do very well with only supportive measures, which should remain the treatment of choice until larger studies elucidate the role of systemic medications. We report 2 cases of systemic loxoscelism causing a Coombs-positive intravascular hemolysis requiring blood transfusion and review the treatment options of this condition.

Case Reports

Patient 1—A 19-year-old African American woman with a medical history significant only for asthma presented to her primary care physician 2 days after a painless bite from a "brown spider" in her bed. At this initial evaluation, she had a diffuse maculopapular rash with mild systemic symptoms including malaise and arthralgia. No laboratory workups were done, and she was started on a 5-day steroid dose pack. The patient was seen in our urgent care department 2 days later with documentation of a 2X2-cm ecchymotic area on her right posterior thigh with surrounding erythema and a diffuse maculopapular rash. Her laboratory workup at this time showed a mildly elevated total bilirubin level, mild leukocytosis, anemia with a hemoglobin level of 11.7 mg/dL, elevated reticulocyte count, and normal coagulation profile. She was given intramuscular methylprednisolone 125 mg, acetaminophen for pain, and hydroxyzine for pruritus, with plans for follow-up in urgent care the next day. The patient did not follow-up until 2 days later, at which time she reported worsening systemic symptoms including nausea, peripheral edema, lymphadenopathy, fever, and dysuria, along with worsening pain and erythema at the bite site. She was febrile, and her anemia progressed when her hemoglobin level fell to 8.3 mg/dL. She was admitted for hematologic monitoring and supportive measures. At the time of admission, her skin examination results were pertinent for a diffuse, faint maculopapular rash and a 3X3-cm necrotic eschar with surrounding erythema (Figure 1).

The day after admission, the patient continued to be febrile, and her hemoglobin level dropped to 6.9 mg/dL. She was transfused with 2 units of packed red blood cells, and the hematology department was consulted to assist with the progressing anemia. The dermatology department also was consulted to assist with wound care and treatment. The hematologist recommended performing an indirect and direct Coombs test. The indirect Coombs test results were negative, but the direct Coombs test results were positive for complement 3 and negative for immunoglobulin G (IgG). The patient's anemia and systemic symptoms continued to progress (hemoglobin nadir level, 5.7 mg/dL), requiring 2 more units of blood. The hematologist recommended starting intravenous steroids to improve the patient's "immunohemolytic anemia secondary to spider bite with positive Coombs test." The patient was started on methylprednisolone 125 mg/d intravenously. Per dermatology's recommendation, wound care was initiated along with elevation and ice to the affected extremity. The patient's clinical status began to improve on hospital day 4, with absence of systemic symptoms and regression of her lesional erythema. She was discharged on a quick-taper oral steroid regimen, per the hematologist's recommendation, and was instructed to continue her wound care. At the patient's hospital follow-up visit, her bite site was healing well, and she had no further evidence of anemia. Patient 2—A 9-year-old African American girl in otherwise excellent health was transferred from an outside emergency department one week after being bitten by "a brown spider" while lying in bed. Initially, the bite was painless, but she later developed swelling and warmth in the area. Due to increased pain, swelling, and blister formation, her primary physician saw her several days later and prescribed an oral cephalosporin for presumed cellulitis. Fever, fatigue, and malaise continued throughout the week. Two days prior to presentation at our hospital, she developed scleral icterus and vomiting. During the patient's evaluation at the transferring emergency department, her laboratory workup revealed a profound anemia with a hemoglobin level of 5.2 mg/dL, elevated white blood cell count, indirect hyperbilirubinemia, and mildly prolonged international normalized ratio value. Her examination was significant for a tachycardia, holosystolic murmur, scleral icterus, and 5X2-cm necrotic eschar on her left flank with a surrounding area of erythema that was exquisitely tender to palpation (Figure 2). She was immediately admitted for close observation and treatment of her anemia. She was transfused with 2 units of packed red blood cells.

The patient's hemoglobin level rebounded to 8.2 mg/dL on hospital day 2, at which time the dermatology department was consulted for assistance with wound care management. Elevation of the extremity and continuing wound care was recommended, and debridement or systemic therapy was advised against. Results of the patient's direct Coombs test were positive for IgG and negative for complement 3. No specific treatment changes were made based on the Coombs test result. The patient continued to improve with wound care and hemodynamic support and displayed improved erythema with less tenderness at the bite site after several days of hospitalization. She was sent home on hospital day 4 in improved condition. She was seen by a dermatologist at her follow-up visit, and her eschar was treated with hydrocolloid dressing changes and eventual debridement of the eschar with follow-up occlusive dressings until the lesion was completely healed.

Comment

Brown Recluse-Induced Hemolysis—Brown recluse spider bites are common in the Midwest, Southeast, and south central United States.7 Although there are more than 70 species of Loxosceles found throughout the world, only approximately 15 species inhabit North America, with L reclusa being the most common encountered by humans.8 Patients affected by this malady are often seen by physicians in various specialties, including primary care providers, emergency physicians, dermatologists, general surgeons, and surgical subspecialists. It is important that physicians in these specialties recognize and treat this condition appropriately.

Although these bites usually cause a local necrotic lesion, sometimes a more serious systemic syndrome, known as systemic loxoscelism, occurs. This can result in high fever, significant intravascular hemolysis, renal failure, disseminated intravascular coagulation, and even death. Although most fatalities have been reported in children, 2 cases of adult deaths have been reported.9,10 The hemolytic anemia that accompanies systemic loxoscelism has been only partially described, and the full mechanism by which the venom of the brown recluse causes this syndrome is still a mystery. The prevailing theory for the cause of hemolysis has incriminated the phospholipase sphingomyelin D, an enzyme isolated from brown recluse venom, because of its effect on cell walls in vivo to cause lysis.11 It was thought that sphingomyelinase disrupted cell membranes either directly or indirectly and resulted in the release of phospholipid-derived substances that bound complement and resulted in tissue hypoxia and necrosis.12-14 Because such a small amount of venom and toxin actually enter the body after a bite, another mechanism is likely taking place to produce the symptoms involved in systemic loxoscelism. Activation and propagation of the immune system by a toxin in the venom could explain such a reaction.

A study on another member of the Loxosceles family, Loxosceles intermedia, may help elucidate the factors involved in the overwhelming reaction to the Loxosceles venom in some people.¹⁵ In this study, it was found that the sphingomyelinase in the spider toxin did not directly affect glycophorins on red blood cell membranes but instead activated an endogenous metalloproteinase that then cleaved these glycophorins. The authors proposed that the altered glycophorins destabilized the red blood cell membrane, rendering the glycophorins vulnerable for complement-mediated lysis. The authors also observed that the hemolysis-inducing and glycophorin-cleaving activity of this activated metalloproteinase could be transferred from one erythrocyte to another, thereby propagating the hemolyzing response.15 This type of transfer of sphingomyelinase and metalloproteinase activity between cells has been described before and could explain the overwhelming systemic response of the Loxosceles toxin in some individuals.16

Historically, most cases of massive hemolysis due to brown recluse bites documented in the literature have been Coombs negative.17 This also has been the case at our institution until recently.11 We report 2 cases of life-threatening hemolytic anemia with positive direct Coombs testing in a span of 9 months. These results are a rarity but may help us understand the pathophysiology of systemic loxoscelism. To our knowledge, these are the fifth and sixth reported cases of a Coombs-positive hemolytic anemia from a brown recluse spider bite. The first case was documented by Nance18 in 1961, but there was no mention of whether complement or immunoglobulin was involved. Eichner¹⁷ reported the second and third cases of Coombs-positive anemia in loxoscelism, with both cases involving complement-mediated hemolysis. The fourth case of Coombs-positive anemia was reported by William et al9 in 1995, and the Coombs test was positive for both IgG and complement. Our cases affirm that both IgG and complement can be involved in Coombs-positive hemolytic anemia. It is likely that the venom of the brown recluse is able to activate both IgG and complement in predisposed individuals by activation of an unknown endogenous mediator (eg, metalloproteinase) to cause massive intravascular hemolysis. Investigations into which patients may be predisposed to develop this complication are warranted.

Treatment—The treatment of local and systemic brown recluse spider bites also has been a source of controversy over the years. Several treatment regimens, including early and late surgical excision and debridement, systemic steroids, hyperbaric oxygen therapy, cryproheptadine, electric shock therapy, and dapsone, have been anecdotally described in the literature; however, none of these treatments have prospective human trials to back up this anecdotal evidence. With conservative wound management, ice, elevation, and analgesics, almost all patients exhibit a full recovery with minimal scarring that rarely needs surgical revision.19

Dapsone has been the most controversial of the treatments for brown recluse bites. Dapsone makes theoretical sense in the treatment of these lesions because of its ability to inhibit polymorphonuclear leukocytes from entering the wound area and causing local destruction. There are many anecdotal reports supporting the use of dapsone for more severe bites, the most famous being the King and Rees²⁰ case report of a patient with a brown recluse bite of the leg that was seen 24 hours after the bite had occurred. They reported that 2 days after prescribing dapsone 100 mg twice daily along with ice and local wound care, the bite site was pain free with marked reduction in induration and erythema. Their argument was based on an assumption that the lesion "probably would have developed an indolent ulcer." They supported their use of dapsone with an animal model of guinea pigs that were pretreated with dapsone before being injected with Loxosceles venom. The authors reported that pretreated guinea pigs showed a reduction in lesion size at 24 hours compared with those without treatment.20 The methods of this study have come into question primarily due to the rarity of patients with brown recluse bites pretreated with dapsone. Also, follow-up animal studies have conflicted with the benefit of dapsone for this indication.21,22

Although the benefit of dapsone is controversial, the side effects of this medicine are protean and well known. The development of hemolytic anemia has long been attributed to this medication and will occur to some degree in all patients.23 This predictable hemolysis can sometimes become confused with the direct effects of the brown recluse venom, which can delay definitive diagnosis of the etiology of the hemolysis and expose patients to an unproven drug with multiple toxicities. Severe hemolysis can be expected in patients with glucose-6-phosphate dehydrogenase deficiency; therefore, dapsone is absolutely contraindicated in this patient population.

Methemoglobinemia is another feared side effect of dapsone. Although mostly asymptomatic and usually undetectable, sometimes elevated levels of methemoglobin can cause severe systemic symptoms requiring hospitalization.24 Unfortunately, it is impossible to predict who will experience this complication because of a lack of simple blood testing such as that available for patients with subclinical glucose-6-phosphate dehydrogenase deficiency. Because of these serious and sometimes common adverse events attributed to dapsone, and the lack of solid evidence to support its effectiveness, there is no place for dapsone in the treatment of loxoscelism at this time.

The role of early surgical excision has changed over the past few decades. Reports prior to 1975 often suggested early surgical excision of bites with grafting as the treatment of choice.25,26 Since then, multiple reports have shown that early surgical excision often does more harm than good in the treatment of brown recluse bites.5,6 Early surgical excision is contraindicated because of the rapid spread of the toxin through the wound in the first weeks following a bite. The toxin may continue to spread for at least 4 weeks, which makes demarcation between envenomed and healthy tissue difficult.27 DeLozier et al6 suggested that the added surgical trauma from early excision may potentiate the inflammatory response to the brown recluse venom, prolonging healing time.

Conservative debridement may be performed to prevent secondary infection, but surgery should generally be withheld for 4 to 6 weeks. Early local wound care during this time followed by late surgical excision and grafting are more successful than early surgical excision. However, most wounds, if treated with supportive therapy alone, will ultimately heal with minimal scarring.28 A retrospective study of 149 patients with brown recluse bites showed that nearly half of all bites healed within 2 weeks and only 13% of bites left a visible scar. None of these patients were treated with surgery.29

Corticosteroids also have been used extensively for more serious reactions after envenomation from a brown recluse spider, but documentation in the literature is sparse. In a white rabbit model, Jansen et al30 did not find any treatment value for either intramuscular or intralesional methylprednisolone in the prevention of dermonecrosis after a brown recluse spider bite. Berger et al31 also concluded that large doses of steroids had no effect on the progression or development of necrotic arachnidism. Despite this evidence, there are many who still advocate the use of steroids for more serious bites and for those associated with systemic symptoms.32 Given the extensive use of corticosteroids in patients with autoimmune hemolytic anemia, this treatment may be of use in patients with Coombs-positive hemolytic anemia secondary to brown recluse envenomation.33,34 For this reason, direct Coombs testing in patients with hemolytic anemia due to brown recluse bites could provide useful information in the inpatient management of these patients.

Other treatments also have been reported, including colchicine, hyperbaric oxygen, cyproheptadine, electrical shock treatment, and brown recluse specific antivenin.7,21,35 Despite early promise, all of these treatments have been met with mixed results in subsequent studies. In one study, the early use of intradermal injection of polyclonal antiloxosceles Fab fragments was shown to attenuate necrosis in an animal model up to 4 hours after envenomation.36 Unfortunately, it is difficult to predict which patients would benefit from the antivenin. Additionally, the antivenin has to be administered in the first 24 hours after a bite, before most patients are seen by a physician.

In our cases, both patients were young and presented with a recent history of a bite by a brown spider consistent with a brown recluse. They were both systemically ill with a profound hemolytic anemia. They were both treated with aggressive wound management, hematologic monitoring with blood transfusion, and expectant care. Patient 1 was given intravenous corticosteroids, and patient 2 was treated with aggressive wound management only. It is not known whether the corticosteroids given in our first patient affected her clinical course because both patients experienced a complete recovery. Like other case reports of treatment in brown recluse spider bites, it is difficult to tell what effect, if any, the treatment has on clinical outcome because most patients, even those with serious systemic symptoms, make a complete recovery. This routine excellent outcome with supportive care only suggests that the use of systemic treatment or surgery is unnecessary and exposes the patient to risks of treatments with unproven efficacies. 

Conclusion

Brown recluse spider bites usually cause a local dermonecrotic reaction but can cause a serious systemic illness and rarely death. We report the fifth and sixth cases of Coombs-positive hemolytic anemia associated with presumed L reclusa envenomation. The first 4 reported cases of Coombs-positive hemolysis were positive for IgG and/or complement. This was confirmed in our cases. The treatment of loxoscelism is controversial in the literature and in practice. We must keep in mind to "first, do no harm" when choosing treatments for patients with brown recluse bites. Many of the treatments previously described, including dapsone, have only anecdotal support for their use. Others, such as early surgery, have been shown to actually delay healing and worsen outcomes. Patients with brown recluse bites typically do well with conservative management alone and agents such as dapsone and systemic corticosteroids can have serious adverse reactions. It is our view that patients with local dermonecrotic skin lesions should be treated with aggressive wound care only. For patients who develop systemic loxoscelism, hemodynamic support and blood transfusion should remain the mainstay of therapy. Further study is needed to determine the benefits of systemic corticosteroid use in patients with Coombs-positive hemolytic anemia secondary to systemic loxoscelism. 

Scars may become pigmented for a variety of reasons, including the persistence and/or recurrence of an incompletely removed melanocytic nevus. However, development of an intensely hyperpigmented scar not long after a surgical procedure, in the absence of a clear explanation, would be a distinctly uncommon event. We recently encountered such a lesion in an otherwise healthy 20-year-old patient. In this case, the histopathologic findings led to further questioning of the patient and revealed a cause that had not been previously suspected. 

Case Report

A 20-year-old woman was seen for evaluation of a lesion on the left lower abdomen. Six weeks earlier, the lesion had been shave excised by an outside physician; pathology results were not initially available. The patient reported that the lesion had quadrupled in size and darkened considerably since the time of the excision. Her grandmother had died of malignant melanoma. She reported that her only medication was birth control pills. On physical examination, there was a 13X8-mm brown-black nodule with discrete but irregular borders (Figure 1). The clinical impression was recurrent nevus in a shave excision scar. However, because of the rapid growth, dark color, and family history of melanoma, there also was concern about the possibility of an atypical nevus or malignant melanoma. Therefore, an elliptical excision was performed. A report of the initial biopsy specimen was received, with the interpretation benign compound nevus.

Results of histopathologic evaluation of the reexcision specimen showed no residual melanocytic lesion. There was a prominent pigmented, cellular scar occupying the superficial to mid dermis in the central portion of the specimen. The pigmented material consisted of refractile, golden brown granules within macrophages and extracellularly, having a resemblance to hemosiderin (Figure 2). These granules stained positively with Perls stain for iron and with Fontana-Masson stain (Figure 3). Fontana-Masson staining was negative when performed after a bleaching procedure that employed potassium permanganate solution at a concentration of 3 g/L.

The staining results suggested the possibility of minocycline-related hyperpigmentation. Subsequent questioning of the patient revealed that she had been taking minocycline 100 mg twice daily during the 2 years prior to her clinic visit. 

Comment

Pigmented scars can arise occasionally because of a number of factors. The sites of persistent and/or recurrent nevus are often pigmented. This pigment, confined to the scar, often shows irregular borders and may have a mottled appearance.1 Pigmented scars also are observed in spontaneously regressing malignant melanoma.2 In a related phenomenon called tumoral melanosis, sheets of melanophages may accompany either a regressed melanoma or epithelial neoplasm.3,4 Pigmentation of scars related to hemorrhage also could occur, eg, following postsurgical trauma or in association with clotting abnormalities, though it is difficult to find literature directly addressing this problem. Other reported associations with hyperpigmented scars include leishmaniasis,5 chickenpox,6 burns,7 Addison disease,8 and hemosiderin-related pigmentation in endometriosis arising in cesarean scars.9 Among other agents that cause cutaneous pigmentation and could potentially produce hyperpigmented scars are heavy metals (eg, gold) and drugs such as amiodarone, phenothiazines, and antimalarials.10,11 Biopsy results of oral hyperpigmentation due to long-term antimalarial therapy have shown macrophages that contain melanin and ferric iron,12 findings resembling those reported here. None of these causes was pertinent to our case.

Minocycline first became available for clinical use in 1967. An association between minocycline administration and black discoloration of thyroid gland follicles in animals was reported that same year.13,14 As early as 1972, Velasco et al15 reported a macular pigmentation of the legs in patients receiving minocycline for the treatment of venereal disease. Since that time, there have been a number of reports of minocycline-induced pigmentation of skin and mucous membranes. Journal articles and textbooks usually divide minocycline-related cutaneous pigmentation into 3 major types. The first, type I, is a blue-black pigmentation that develops in areas of inflammation and scar13,16-19; this is the type that we report here. The second, type II, is a blue-gray pigmentation that develops particularly over otherwise normal-appearing skin of the arms, legs, or face.18,20,21 The third, type III, is usually described as a diffuse or generalized "muddy brown" pigmentation,13,22-25 though in one report this type of pigmentation was actually described as dark blue-gray.24 The Table provides a summary of the clinical and histopathologic changes associated with the 3 major types of minocycline pigmentation. Pigmentation of the nails and nail beds also occurs19,26 and has coexisted with diffuse cutaneous and scleral pigmentation.25 A fourth type of pigmentation that is not specific to minocycline results from fixed drug eruption, as described by Chu et al27 and possibly also represented by the case of Tanzi and Hecker.28 Minocycline also has been associated with discoloration of teeth,23 pigmented conjunctival cysts,29 and black galactorrhea,30 as well as pigmentation of internal organs such as cardiac valves.31,32

The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25

As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26

The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.

The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37 

Conclusion

Minocycline therapy should be included in the differential diagnosis of hyperpigmented scars. Careful history taking and even repeated questioning may be necessary to elicit an accurate medication history. The pigmentation is most likely due to a minocycline metabolite, bound to iron; Fontana-Masson positivity may result from the action of reducing agents other than melanin. Slow resolution of the pigment can be expected following discontinuation of the drug. Nevertheless, biopsy is indicated when, as in this case, an atypical pigmented skin lesion raises concerns about malignant melanoma.

Scars may become pigmented for a variety of reasons, including the persistence and/or recurrence of an incompletely removed melanocytic nevus. However, development of an intensely hyperpigmented scar not long after a surgical procedure, in the absence of a clear explanation, would be a distinctly uncommon event. We recently encountered such a lesion in an otherwise healthy 20-year-old patient. In this case, the histopathologic findings led to further questioning of the patient and revealed a cause that had not been previously suspected. 

Case Report

A 20-year-old woman was seen for evaluation of a lesion on the left lower abdomen. Six weeks earlier, the lesion had been shave excised by an outside physician; pathology results were not initially available. The patient reported that the lesion had quadrupled in size and darkened considerably since the time of the excision. Her grandmother had died of malignant melanoma. She reported that her only medication was birth control pills. On physical examination, there was a 13X8-mm brown-black nodule with discrete but irregular borders (Figure 1). The clinical impression was recurrent nevus in a shave excision scar. However, because of the rapid growth, dark color, and family history of melanoma, there also was concern about the possibility of an atypical nevus or malignant melanoma. Therefore, an elliptical excision was performed. A report of the initial biopsy specimen was received, with the interpretation benign compound nevus.

Results of histopathologic evaluation of the reexcision specimen showed no residual melanocytic lesion. There was a prominent pigmented, cellular scar occupying the superficial to mid dermis in the central portion of the specimen. The pigmented material consisted of refractile, golden brown granules within macrophages and extracellularly, having a resemblance to hemosiderin (Figure 2). These granules stained positively with Perls stain for iron and with Fontana-Masson stain (Figure 3). Fontana-Masson staining was negative when performed after a bleaching procedure that employed potassium permanganate solution at a concentration of 3 g/L.

The staining results suggested the possibility of minocycline-related hyperpigmentation. Subsequent questioning of the patient revealed that she had been taking minocycline 100 mg twice daily during the 2 years prior to her clinic visit. 

Comment

Pigmented scars can arise occasionally because of a number of factors. The sites of persistent and/or recurrent nevus are often pigmented. This pigment, confined to the scar, often shows irregular borders and may have a mottled appearance.1 Pigmented scars also are observed in spontaneously regressing malignant melanoma.2 In a related phenomenon called tumoral melanosis, sheets of melanophages may accompany either a regressed melanoma or epithelial neoplasm.3,4 Pigmentation of scars related to hemorrhage also could occur, eg, following postsurgical trauma or in association with clotting abnormalities, though it is difficult to find literature directly addressing this problem. Other reported associations with hyperpigmented scars include leishmaniasis,5 chickenpox,6 burns,7 Addison disease,8 and hemosiderin-related pigmentation in endometriosis arising in cesarean scars.9 Among other agents that cause cutaneous pigmentation and could potentially produce hyperpigmented scars are heavy metals (eg, gold) and drugs such as amiodarone, phenothiazines, and antimalarials.10,11 Biopsy results of oral hyperpigmentation due to long-term antimalarial therapy have shown macrophages that contain melanin and ferric iron,12 findings resembling those reported here. None of these causes was pertinent to our case.

Minocycline first became available for clinical use in 1967. An association between minocycline administration and black discoloration of thyroid gland follicles in animals was reported that same year.13,14 As early as 1972, Velasco et al15 reported a macular pigmentation of the legs in patients receiving minocycline for the treatment of venereal disease. Since that time, there have been a number of reports of minocycline-induced pigmentation of skin and mucous membranes. Journal articles and textbooks usually divide minocycline-related cutaneous pigmentation into 3 major types. The first, type I, is a blue-black pigmentation that develops in areas of inflammation and scar13,16-19; this is the type that we report here. The second, type II, is a blue-gray pigmentation that develops particularly over otherwise normal-appearing skin of the arms, legs, or face.18,20,21 The third, type III, is usually described as a diffuse or generalized "muddy brown" pigmentation,13,22-25 though in one report this type of pigmentation was actually described as dark blue-gray.24 The Table provides a summary of the clinical and histopathologic changes associated with the 3 major types of minocycline pigmentation. Pigmentation of the nails and nail beds also occurs19,26 and has coexisted with diffuse cutaneous and scleral pigmentation.25 A fourth type of pigmentation that is not specific to minocycline results from fixed drug eruption, as described by Chu et al27 and possibly also represented by the case of Tanzi and Hecker.28 Minocycline also has been associated with discoloration of teeth,23 pigmented conjunctival cysts,29 and black galactorrhea,30 as well as pigmentation of internal organs such as cardiac valves.31,32

The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25

As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26

The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.

The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37 

Conclusion

Minocycline therapy should be included in the differential diagnosis of hyperpigmented scars. Careful history taking and even repeated questioning may be necessary to elicit an accurate medication history. The pigmentation is most likely due to a minocycline metabolite, bound to iron; Fontana-Masson positivity may result from the action of reducing agents other than melanin. Slow resolution of the pigment can be expected following discontinuation of the drug. Nevertheless, biopsy is indicated when, as in this case, an atypical pigmented skin lesion raises concerns about malignant melanoma.

Scars may become pigmented for a variety of reasons, including the persistence and/or recurrence of an incompletely removed melanocytic nevus. However, development of an intensely hyperpigmented scar not long after a surgical procedure, in the absence of a clear explanation, would be a distinctly uncommon event. We recently encountered such a lesion in an otherwise healthy 20-year-old patient. In this case, the histopathologic findings led to further questioning of the patient and revealed a cause that had not been previously suspected. 

Case Report

A 20-year-old woman was seen for evaluation of a lesion on the left lower abdomen. Six weeks earlier, the lesion had been shave excised by an outside physician; pathology results were not initially available. The patient reported that the lesion had quadrupled in size and darkened considerably since the time of the excision. Her grandmother had died of malignant melanoma. She reported that her only medication was birth control pills. On physical examination, there was a 13X8-mm brown-black nodule with discrete but irregular borders (Figure 1). The clinical impression was recurrent nevus in a shave excision scar. However, because of the rapid growth, dark color, and family history of melanoma, there also was concern about the possibility of an atypical nevus or malignant melanoma. Therefore, an elliptical excision was performed. A report of the initial biopsy specimen was received, with the interpretation benign compound nevus.

Results of histopathologic evaluation of the reexcision specimen showed no residual melanocytic lesion. There was a prominent pigmented, cellular scar occupying the superficial to mid dermis in the central portion of the specimen. The pigmented material consisted of refractile, golden brown granules within macrophages and extracellularly, having a resemblance to hemosiderin (Figure 2). These granules stained positively with Perls stain for iron and with Fontana-Masson stain (Figure 3). Fontana-Masson staining was negative when performed after a bleaching procedure that employed potassium permanganate solution at a concentration of 3 g/L.

The staining results suggested the possibility of minocycline-related hyperpigmentation. Subsequent questioning of the patient revealed that she had been taking minocycline 100 mg twice daily during the 2 years prior to her clinic visit. 

Comment

Pigmented scars can arise occasionally because of a number of factors. The sites of persistent and/or recurrent nevus are often pigmented. This pigment, confined to the scar, often shows irregular borders and may have a mottled appearance.1 Pigmented scars also are observed in spontaneously regressing malignant melanoma.2 In a related phenomenon called tumoral melanosis, sheets of melanophages may accompany either a regressed melanoma or epithelial neoplasm.3,4 Pigmentation of scars related to hemorrhage also could occur, eg, following postsurgical trauma or in association with clotting abnormalities, though it is difficult to find literature directly addressing this problem. Other reported associations with hyperpigmented scars include leishmaniasis,5 chickenpox,6 burns,7 Addison disease,8 and hemosiderin-related pigmentation in endometriosis arising in cesarean scars.9 Among other agents that cause cutaneous pigmentation and could potentially produce hyperpigmented scars are heavy metals (eg, gold) and drugs such as amiodarone, phenothiazines, and antimalarials.10,11 Biopsy results of oral hyperpigmentation due to long-term antimalarial therapy have shown macrophages that contain melanin and ferric iron,12 findings resembling those reported here. None of these causes was pertinent to our case.

Minocycline first became available for clinical use in 1967. An association between minocycline administration and black discoloration of thyroid gland follicles in animals was reported that same year.13,14 As early as 1972, Velasco et al15 reported a macular pigmentation of the legs in patients receiving minocycline for the treatment of venereal disease. Since that time, there have been a number of reports of minocycline-induced pigmentation of skin and mucous membranes. Journal articles and textbooks usually divide minocycline-related cutaneous pigmentation into 3 major types. The first, type I, is a blue-black pigmentation that develops in areas of inflammation and scar13,16-19; this is the type that we report here. The second, type II, is a blue-gray pigmentation that develops particularly over otherwise normal-appearing skin of the arms, legs, or face.18,20,21 The third, type III, is usually described as a diffuse or generalized "muddy brown" pigmentation,13,22-25 though in one report this type of pigmentation was actually described as dark blue-gray.24 The Table provides a summary of the clinical and histopathologic changes associated with the 3 major types of minocycline pigmentation. Pigmentation of the nails and nail beds also occurs19,26 and has coexisted with diffuse cutaneous and scleral pigmentation.25 A fourth type of pigmentation that is not specific to minocycline results from fixed drug eruption, as described by Chu et al27 and possibly also represented by the case of Tanzi and Hecker.28 Minocycline also has been associated with discoloration of teeth,23 pigmented conjunctival cysts,29 and black galactorrhea,30 as well as pigmentation of internal organs such as cardiac valves.31,32

The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25

As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26

The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.

The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37 

Conclusion

Minocycline therapy should be included in the differential diagnosis of hyperpigmented scars. Careful history taking and even repeated questioning may be necessary to elicit an accurate medication history. The pigmentation is most likely due to a minocycline metabolite, bound to iron; Fontana-Masson positivity may result from the action of reducing agents other than melanin. Slow resolution of the pigment can be expected following discontinuation of the drug. Nevertheless, biopsy is indicated when, as in this case, an atypical pigmented skin lesion raises concerns about malignant melanoma.

Psoriasiform dermatitis seen with Bazex syndrome may involve the nose and the helices of the ears in addition to the palms and soles. In most reported cases, the appearance of the characteristic psoriasiform lesions preceded the diagnosis of the associated underlying malignancy. Skin scrapings for potassium hydroxide and fungal cultures should be performed, and skin biopsy of keratotic plaques is recommended to exclude psoriasis.

Case Report

A 70-year-old man with no personal or family history of psoriasis or other skin diseases developed psoriasiform dermatitis of the fingers, toes, and helices of the ears over a period of 3 months. He reported a history of cigarette smoking (1 pack per day) with significant consumption of alcoholic beverages over a period of 30 years. Results from a review of systems revealed progressive hoarseness and dysphagia, with a recent history of a 15-lb weight loss. On physical examination, psoriasiform plaques were seen on the palms and soles, as well as on the helices of the ears (Figure 1) and the tip and dorsum of the nose. There was a yellowish discoloration and dystrophy of all the fingernails and toenails (Figure 2). Results from potassium hydroxide preparations from scrapings of the palms and soles were negative, and fungal culture did not grow any pathogenic fungi.

Six weeks later, the patient developed bilateral cervical lymphadenopathy. Otolaryngologic examination consisted of direct laryngoscopy; imaging studies including magnetic resonance imaging and computed tomography scans; and laryngeal biopsy, which revealed a stage IV squamous cell carcinoma (SCC) confined to the head and neck area. Although the patient did not return for follow-up, management of the laryngeal SCC with surgery and postoperative chemotherapy completely cleared his skin and nail lesions without adjunct dermatologic treatments.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

Comment

Bazex syndrome (paraneoplastic acrokeratosis) was first described as a clinical entity by Gougerot and Rupp¹ more than 40 years prior to the coining of the disease's current widely used eponym of Bazex syndrome. In 1922, Gougerot and Grupper¹ described a patient with hyperkeratotic lesions on the nose, ears, palms, and soles in conjunction with an SCC on the tongue. Years later, Bazex and colleagues² described a patient with an SCC of the pyriform fossa and an associated psoriasiform dermatosis. Since that report, more than 110 cases of Bazex syndrome have been reported, most of which describe the condition as a cutaneous paraneoplastic syndrome characterized by psoriasiform lesions associated with an underlying malignancy of the upper aerodigestive tract (oropharynx, larynx, or esophagus), most often of the SCC subtype.^3-7

Bazex syndrome can be classified among the cutaneous paraneoplastic disorders that also include acanthosis nigricans maligna, erythema gyratum, necrolytic migratory erythema, and hypertrichosis lanuginosa acquisita.⁷ The cutaneous manifestations of Bazex syndrome are paraneoplastic in that the developing skin changes coevolve with an underlying malignancy; these cutaneous hallmarks of the syndrome do not, however, represent metastatic extensions of this malignancy. On the contrary, they may actually serve as harbingers of future oncologic progression.

The cutaneous changes observed in Bazex syndrome have been classified into 3 stages.³ In the first stage, psoriasiform changes of the fingers, toes, auricular helix, and nose are noted. In addition, the earliest stage of the syndrome is characterized by nail changes, including horizontal and vertical ridging, subungual hyperkeratosis, yellow discoloration, and nail dystrophy. During this stage, the primary tumor is considered asymptomatic. The second stage is primarily typified by proximal extension of the cutaneous changes observed in the first stage to involve the dorsum of the hands and feet, as well as the malar regions of the face. Local symptoms secondary to growth of the primary tumor also may surface during this stage. The third stage in the course of the syndrome is defined by progressive centripetal extension of the cutaneous disease process to affect regions of the arms and legs (nails, hands, elbows, knees, and feet), scalp, and trunk.^3-7 Other cutaneous changes that have been reported include hyperpigmentation, particularly in individuals with darker skin pigmentation,6 and development of bullous lesions.^5,8,9

Based on the initial dermatologic manifestations of Bazex syndrome, it is not surprising that the condition is often misdiagnosed as psoriasis or chronic dermatitis. Indeed, histopathologic examination of skin lesions in the syndrome is nonspecific and may mimic psoriasis or other more common dermatoses, demonstrating hyperkeratosis, parakeratosis, acanthosis, vacuolar degeneration of keratinocytes, and/or perivascular lymphohistiocytic infiltrate.^6,7,10 One potential distinguishing feature of Bazex syndrome, however, is specific psoriasiform involvement of the helix of the ear, as opposed to the entire ear, as would be more commonly expected in psoriasis.⁷ The tip of the nose also is involved in Bazex syndrome, which is an unusual location for psoriasis.

Extensive reviews of the literature reporting cases of Bazex syndrome demonstrate that most patients have been Caucasian, male, of French descent, and older than 40 years.^6,7 SCCs have accounted for nearly 60% of tumors found in patients with this syndrome, and adenocarcinomas have accounted for less than 10% of malignancies. Furthermore, the majority of the neoplasms have involved the oropharynx and larynx.⁷ These neoplasms may be silent and only present with lymph node metastases. Less commonly, primary tumors may occur in the lungs and esophagus. Rare cases of neoplasms of the prostate, liver, stomach, thymus, uterus, vulva, and lymphoid tissues also have been reported.¹¹ Numerous cases have been described in which the primary tumor could not be identified, and affected patients were diagnosed on the basis of metastases to cervical lymph nodes. In the vast majority of reported cases, the appearance of the characteristic psoriasiform lesions preceded the diagnosis of the associated malignancy.^6,7 Finally, the skin lesions either markedly improved or completely resolved in the great preponderance of patients in whom the underlying malignancy was either treated with chemotherapy and/or radiation therapy or surgical excision.^6,7,10-12 This was true of the patient presented in this report.

The pathogenesis of Bazex syndrome remains a mystery, though several authors have suggested an autoimmune etiology based on the common histologic finding of inflammatory infiltrates along the basal cell layer of affected skin regions.^5,8,9 The immune reaction may be humoral or cellular; the proposed mechanism states that cross reactivity between skin and tumor antigens may produce the characteristic cutaneous changes observed, because antitumor antibodies cross reacting with the epidermis or basement membrane zone could elicit an immunologic response resulting in basal cell layer damage.^13,14 Several authors also have proposed that the tumors may produce a host of growth factors that collectively lead to hyperkeratotic skin changes.^14,15

Ideal treatment of Bazex syndrome is eradication of the underlying malignancy. Unresectable or treatment-resistant tumors, however, pose a significant challenge for the clinician. Numerous studies have been conducted demonstrating equivocal efficacies of various standard dermatological therapies in the treatment of skin lesions occurring in this syndrome. Unfortunately, in the vast majority of patients, such treatment options as topical tar, topical and systemic corticosteroids, UVB irradiation, antifungals, and antibiotics have proven to be of little use.6,7 Gill and colleagues9 have reported that oral psoralen–UVA phototherapy may offer some promise of effective treatment in these patients. However, larger studies are required to further investigate the therapeutic benefits of this treatment option. Although the management of treatment-resistant cutaneous lesions in Bazex syndrome may prove problematic, it is clear that the clinician must be astute in recognizing this disease process in its earlier stages to identify and effectively treat any underlying malignancy as expeditiously as possible.

Acknowledgment—The authors wish to thank Dr. Eric Ehrsam for his assistance with the preparation of this manuscript.

Psoriasiform dermatitis seen with Bazex syndrome may involve the nose and the helices of the ears in addition to the palms and soles. In most reported cases, the appearance of the characteristic psoriasiform lesions preceded the diagnosis of the associated underlying malignancy. Skin scrapings for potassium hydroxide and fungal cultures should be performed, and skin biopsy of keratotic plaques is recommended to exclude psoriasis.

Case Report

A 70-year-old man with no personal or family history of psoriasis or other skin diseases developed psoriasiform dermatitis of the fingers, toes, and helices of the ears over a period of 3 months. He reported a history of cigarette smoking (1 pack per day) with significant consumption of alcoholic beverages over a period of 30 years. Results from a review of systems revealed progressive hoarseness and dysphagia, with a recent history of a 15-lb weight loss. On physical examination, psoriasiform plaques were seen on the palms and soles, as well as on the helices of the ears (Figure 1) and the tip and dorsum of the nose. There was a yellowish discoloration and dystrophy of all the fingernails and toenails (Figure 2). Results from potassium hydroxide preparations from scrapings of the palms and soles were negative, and fungal culture did not grow any pathogenic fungi.

Six weeks later, the patient developed bilateral cervical lymphadenopathy. Otolaryngologic examination consisted of direct laryngoscopy; imaging studies including magnetic resonance imaging and computed tomography scans; and laryngeal biopsy, which revealed a stage IV squamous cell carcinoma (SCC) confined to the head and neck area. Although the patient did not return for follow-up, management of the laryngeal SCC with surgery and postoperative chemotherapy completely cleared his skin and nail lesions without adjunct dermatologic treatments.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

Comment

Bazex syndrome (paraneoplastic acrokeratosis) was first described as a clinical entity by Gougerot and Rupp¹ more than 40 years prior to the coining of the disease's current widely used eponym of Bazex syndrome. In 1922, Gougerot and Grupper¹ described a patient with hyperkeratotic lesions on the nose, ears, palms, and soles in conjunction with an SCC on the tongue. Years later, Bazex and colleagues² described a patient with an SCC of the pyriform fossa and an associated psoriasiform dermatosis. Since that report, more than 110 cases of Bazex syndrome have been reported, most of which describe the condition as a cutaneous paraneoplastic syndrome characterized by psoriasiform lesions associated with an underlying malignancy of the upper aerodigestive tract (oropharynx, larynx, or esophagus), most often of the SCC subtype.^3-7

Bazex syndrome can be classified among the cutaneous paraneoplastic disorders that also include acanthosis nigricans maligna, erythema gyratum, necrolytic migratory erythema, and hypertrichosis lanuginosa acquisita.⁷ The cutaneous manifestations of Bazex syndrome are paraneoplastic in that the developing skin changes coevolve with an underlying malignancy; these cutaneous hallmarks of the syndrome do not, however, represent metastatic extensions of this malignancy. On the contrary, they may actually serve as harbingers of future oncologic progression.

The cutaneous changes observed in Bazex syndrome have been classified into 3 stages.³ In the first stage, psoriasiform changes of the fingers, toes, auricular helix, and nose are noted. In addition, the earliest stage of the syndrome is characterized by nail changes, including horizontal and vertical ridging, subungual hyperkeratosis, yellow discoloration, and nail dystrophy. During this stage, the primary tumor is considered asymptomatic. The second stage is primarily typified by proximal extension of the cutaneous changes observed in the first stage to involve the dorsum of the hands and feet, as well as the malar regions of the face. Local symptoms secondary to growth of the primary tumor also may surface during this stage. The third stage in the course of the syndrome is defined by progressive centripetal extension of the cutaneous disease process to affect regions of the arms and legs (nails, hands, elbows, knees, and feet), scalp, and trunk.^3-7 Other cutaneous changes that have been reported include hyperpigmentation, particularly in individuals with darker skin pigmentation,6 and development of bullous lesions.^5,8,9

Based on the initial dermatologic manifestations of Bazex syndrome, it is not surprising that the condition is often misdiagnosed as psoriasis or chronic dermatitis. Indeed, histopathologic examination of skin lesions in the syndrome is nonspecific and may mimic psoriasis or other more common dermatoses, demonstrating hyperkeratosis, parakeratosis, acanthosis, vacuolar degeneration of keratinocytes, and/or perivascular lymphohistiocytic infiltrate.^6,7,10 One potential distinguishing feature of Bazex syndrome, however, is specific psoriasiform involvement of the helix of the ear, as opposed to the entire ear, as would be more commonly expected in psoriasis.⁷ The tip of the nose also is involved in Bazex syndrome, which is an unusual location for psoriasis.

Extensive reviews of the literature reporting cases of Bazex syndrome demonstrate that most patients have been Caucasian, male, of French descent, and older than 40 years.^6,7 SCCs have accounted for nearly 60% of tumors found in patients with this syndrome, and adenocarcinomas have accounted for less than 10% of malignancies. Furthermore, the majority of the neoplasms have involved the oropharynx and larynx.⁷ These neoplasms may be silent and only present with lymph node metastases. Less commonly, primary tumors may occur in the lungs and esophagus. Rare cases of neoplasms of the prostate, liver, stomach, thymus, uterus, vulva, and lymphoid tissues also have been reported.¹¹ Numerous cases have been described in which the primary tumor could not be identified, and affected patients were diagnosed on the basis of metastases to cervical lymph nodes. In the vast majority of reported cases, the appearance of the characteristic psoriasiform lesions preceded the diagnosis of the associated malignancy.^6,7 Finally, the skin lesions either markedly improved or completely resolved in the great preponderance of patients in whom the underlying malignancy was either treated with chemotherapy and/or radiation therapy or surgical excision.^6,7,10-12 This was true of the patient presented in this report.

The pathogenesis of Bazex syndrome remains a mystery, though several authors have suggested an autoimmune etiology based on the common histologic finding of inflammatory infiltrates along the basal cell layer of affected skin regions.^5,8,9 The immune reaction may be humoral or cellular; the proposed mechanism states that cross reactivity between skin and tumor antigens may produce the characteristic cutaneous changes observed, because antitumor antibodies cross reacting with the epidermis or basement membrane zone could elicit an immunologic response resulting in basal cell layer damage.^13,14 Several authors also have proposed that the tumors may produce a host of growth factors that collectively lead to hyperkeratotic skin changes.^14,15

Ideal treatment of Bazex syndrome is eradication of the underlying malignancy. Unresectable or treatment-resistant tumors, however, pose a significant challenge for the clinician. Numerous studies have been conducted demonstrating equivocal efficacies of various standard dermatological therapies in the treatment of skin lesions occurring in this syndrome. Unfortunately, in the vast majority of patients, such treatment options as topical tar, topical and systemic corticosteroids, UVB irradiation, antifungals, and antibiotics have proven to be of little use.6,7 Gill and colleagues9 have reported that oral psoralen–UVA phototherapy may offer some promise of effective treatment in these patients. However, larger studies are required to further investigate the therapeutic benefits of this treatment option. Although the management of treatment-resistant cutaneous lesions in Bazex syndrome may prove problematic, it is clear that the clinician must be astute in recognizing this disease process in its earlier stages to identify and effectively treat any underlying malignancy as expeditiously as possible.

Acknowledgment—The authors wish to thank Dr. Eric Ehrsam for his assistance with the preparation of this manuscript.

Psoriasiform dermatitis seen with Bazex syndrome may involve the nose and the helices of the ears in addition to the palms and soles. In most reported cases, the appearance of the characteristic psoriasiform lesions preceded the diagnosis of the associated underlying malignancy. Skin scrapings for potassium hydroxide and fungal cultures should be performed, and skin biopsy of keratotic plaques is recommended to exclude psoriasis.

Case Report

A 70-year-old man with no personal or family history of psoriasis or other skin diseases developed psoriasiform dermatitis of the fingers, toes, and helices of the ears over a period of 3 months. He reported a history of cigarette smoking (1 pack per day) with significant consumption of alcoholic beverages over a period of 30 years. Results from a review of systems revealed progressive hoarseness and dysphagia, with a recent history of a 15-lb weight loss. On physical examination, psoriasiform plaques were seen on the palms and soles, as well as on the helices of the ears (Figure 1) and the tip and dorsum of the nose. There was a yellowish discoloration and dystrophy of all the fingernails and toenails (Figure 2). Results from potassium hydroxide preparations from scrapings of the palms and soles were negative, and fungal culture did not grow any pathogenic fungi.

Six weeks later, the patient developed bilateral cervical lymphadenopathy. Otolaryngologic examination consisted of direct laryngoscopy; imaging studies including magnetic resonance imaging and computed tomography scans; and laryngeal biopsy, which revealed a stage IV squamous cell carcinoma (SCC) confined to the head and neck area. Although the patient did not return for follow-up, management of the laryngeal SCC with surgery and postoperative chemotherapy completely cleared his skin and nail lesions without adjunct dermatologic treatments.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

Comment

Bazex syndrome (paraneoplastic acrokeratosis) was first described as a clinical entity by Gougerot and Rupp¹ more than 40 years prior to the coining of the disease's current widely used eponym of Bazex syndrome. In 1922, Gougerot and Grupper¹ described a patient with hyperkeratotic lesions on the nose, ears, palms, and soles in conjunction with an SCC on the tongue. Years later, Bazex and colleagues² described a patient with an SCC of the pyriform fossa and an associated psoriasiform dermatosis. Since that report, more than 110 cases of Bazex syndrome have been reported, most of which describe the condition as a cutaneous paraneoplastic syndrome characterized by psoriasiform lesions associated with an underlying malignancy of the upper aerodigestive tract (oropharynx, larynx, or esophagus), most often of the SCC subtype.^3-7

Bazex syndrome can be classified among the cutaneous paraneoplastic disorders that also include acanthosis nigricans maligna, erythema gyratum, necrolytic migratory erythema, and hypertrichosis lanuginosa acquisita.⁷ The cutaneous manifestations of Bazex syndrome are paraneoplastic in that the developing skin changes coevolve with an underlying malignancy; these cutaneous hallmarks of the syndrome do not, however, represent metastatic extensions of this malignancy. On the contrary, they may actually serve as harbingers of future oncologic progression.

The cutaneous changes observed in Bazex syndrome have been classified into 3 stages.³ In the first stage, psoriasiform changes of the fingers, toes, auricular helix, and nose are noted. In addition, the earliest stage of the syndrome is characterized by nail changes, including horizontal and vertical ridging, subungual hyperkeratosis, yellow discoloration, and nail dystrophy. During this stage, the primary tumor is considered asymptomatic. The second stage is primarily typified by proximal extension of the cutaneous changes observed in the first stage to involve the dorsum of the hands and feet, as well as the malar regions of the face. Local symptoms secondary to growth of the primary tumor also may surface during this stage. The third stage in the course of the syndrome is defined by progressive centripetal extension of the cutaneous disease process to affect regions of the arms and legs (nails, hands, elbows, knees, and feet), scalp, and trunk.^3-7 Other cutaneous changes that have been reported include hyperpigmentation, particularly in individuals with darker skin pigmentation,6 and development of bullous lesions.^5,8,9

Based on the initial dermatologic manifestations of Bazex syndrome, it is not surprising that the condition is often misdiagnosed as psoriasis or chronic dermatitis. Indeed, histopathologic examination of skin lesions in the syndrome is nonspecific and may mimic psoriasis or other more common dermatoses, demonstrating hyperkeratosis, parakeratosis, acanthosis, vacuolar degeneration of keratinocytes, and/or perivascular lymphohistiocytic infiltrate.^6,7,10 One potential distinguishing feature of Bazex syndrome, however, is specific psoriasiform involvement of the helix of the ear, as opposed to the entire ear, as would be more commonly expected in psoriasis.⁷ The tip of the nose also is involved in Bazex syndrome, which is an unusual location for psoriasis.

Extensive reviews of the literature reporting cases of Bazex syndrome demonstrate that most patients have been Caucasian, male, of French descent, and older than 40 years.^6,7 SCCs have accounted for nearly 60% of tumors found in patients with this syndrome, and adenocarcinomas have accounted for less than 10% of malignancies. Furthermore, the majority of the neoplasms have involved the oropharynx and larynx.⁷ These neoplasms may be silent and only present with lymph node metastases. Less commonly, primary tumors may occur in the lungs and esophagus. Rare cases of neoplasms of the prostate, liver, stomach, thymus, uterus, vulva, and lymphoid tissues also have been reported.¹¹ Numerous cases have been described in which the primary tumor could not be identified, and affected patients were diagnosed on the basis of metastases to cervical lymph nodes. In the vast majority of reported cases, the appearance of the characteristic psoriasiform lesions preceded the diagnosis of the associated malignancy.^6,7 Finally, the skin lesions either markedly improved or completely resolved in the great preponderance of patients in whom the underlying malignancy was either treated with chemotherapy and/or radiation therapy or surgical excision.^6,7,10-12 This was true of the patient presented in this report.

The pathogenesis of Bazex syndrome remains a mystery, though several authors have suggested an autoimmune etiology based on the common histologic finding of inflammatory infiltrates along the basal cell layer of affected skin regions.^5,8,9 The immune reaction may be humoral or cellular; the proposed mechanism states that cross reactivity between skin and tumor antigens may produce the characteristic cutaneous changes observed, because antitumor antibodies cross reacting with the epidermis or basement membrane zone could elicit an immunologic response resulting in basal cell layer damage.^13,14 Several authors also have proposed that the tumors may produce a host of growth factors that collectively lead to hyperkeratotic skin changes.^14,15

Ideal treatment of Bazex syndrome is eradication of the underlying malignancy. Unresectable or treatment-resistant tumors, however, pose a significant challenge for the clinician. Numerous studies have been conducted demonstrating equivocal efficacies of various standard dermatological therapies in the treatment of skin lesions occurring in this syndrome. Unfortunately, in the vast majority of patients, such treatment options as topical tar, topical and systemic corticosteroids, UVB irradiation, antifungals, and antibiotics have proven to be of little use.6,7 Gill and colleagues9 have reported that oral psoralen–UVA phototherapy may offer some promise of effective treatment in these patients. However, larger studies are required to further investigate the therapeutic benefits of this treatment option. Although the management of treatment-resistant cutaneous lesions in Bazex syndrome may prove problematic, it is clear that the clinician must be astute in recognizing this disease process in its earlier stages to identify and effectively treat any underlying malignancy as expeditiously as possible.

Acknowledgment—The authors wish to thank Dr. Eric Ehrsam for his assistance with the preparation of this manuscript.