Case Reports

Scleromyxedema (SM) is a generalized papular and sclerodermoid form of lichen myxedematosus (LM), commonly referred to as papular mucinosis. It is a rare progressive disease of unknown etiology with systemic manifestations that cause serious morbidity and mortality. Diagnostic criteria were initially created by Montgomery and Underwood¹ in 1953 and revised by Rongioletti and Rebora² in 2001 as follows: (1) generalized papular and sclerodermoid eruption; (2) histologic triad of mucin deposition, fibroblast proliferation, and fibrosis; (3) monoclonal gammopathy; and (4) absence of thyroid disease. There are several reports of LM in association with hypothyroidism, most of which can be characterized as atypical.^3-8 We present a case of SM in a patient with Hashimoto thyroiditis and propose that the presence of thyroid disease should not preclude the diagnosis of SM.

Case Report

A 44-year-old woman presented with a progressive eruption of thickened skin and papules spanning many months. The papules ranged from flesh colored to erythematous and covered more than 80% of the body surface area, most notably involving the face, neck, ears, arms, chest, abdomen, and thighs (Figures 1A and 2A). Review of systems was notable for pruritus, muscle pain but no weakness, dysphagia, and constipation. Her medical history included childhood atopic dermatitis and Hashimoto thyroiditis. Hypothyroidism was diagnosed with support of a thyroid ultrasound and thyroid peroxidase antibodies. It was treated with oral levothyroxine for 2 years prior to the skin eruption. Thyroid biopsy was not performed. Her thyroid-stimulating hormone levels notably fluctuated in the year prior to presentation despite close clinical and laboratory monitoring by an endocrinologist. Laboratory results are summarized in Table 1. Both skin and muscle⁹ biopsies were consistent with SM (Figure 3) and are summarized in Table 1.

Shortly after presentation to our clinic the patient developed acute concerns of confusion and muscle weakness. She was admitted for further inpatient management due to concern for dermato-neuro syndrome, a rare but potentially fatal decline in neurological status that can progress to coma and death, rather than myxedema coma. On admission, a thyroid function test showed subclinical hypothyroidism with a thyroid-stimulating hormone level of 6.35 uU/mL (reference range, 0.3–4.35 uU/mL) and free thyroxine (FT₄) level of 1.5 ng/dL (reference range, 0.8–2.8 ng/dL). While hospitalized she was started on intravenous levothyroxine, systemic steroids, and a course of intravenous immunoglobulin (IVIg) treatment consisting of 2 g/kg divided over 5 days. On this regimen, her mental status quickly returned to baseline and other symptoms improved, including the skin eruption (Figures 1B and 2B). She has been maintained on lenalidomide 25 mg/d for the first 3 weeks of each month as well as monthly IVIg infusions. Her thyroid levels have persistently fluctuated despite intramuscular levothyroxine dosing, but her skin has remained clear with continued SM-directed therapy.

Comment

Classification
Lichen myxedematosus is differentiated into localized and generalized forms. The former is limited to the skin and lacks monoclonal gammopathy. The latter, also known as SM, is associated with monoclonal gammopathy and systemic symptoms. Atypical LM is an umbrella term for intermediate cases.

Clinical Presentation
Skin manifestations of SM are described as 1- to 3-mm, firm, waxy, dome-shaped papules that commonly affect the hands, forearms, face, neck, trunk, and thighs. The surrounding skin may be reddish brown and edematous with evidence of skin thickening. Extracutaneous manifestations in SM are numerous and unpredictable. Any organ system can be involved, but gastrointestinal, rheumatologic, pulmonary, and cardiovascular complications are most common.¹⁰ A comprehensive multidisciplinary evaluation is necessary based on clinical symptoms and laboratory findings.

Management
Many treatments have been proposed for SM in case reports and case series. Prior treatments have had little success. Most recently, in one of the largest case series on SM, Rongioletti et al¹⁰ demonstrated IVIg to be a safe and effective treatment modality.

Differential Diagnosis
An important differential diagnosis is generalized myxedema, which is seen in long-standing hypothyroidism and may present with cutaneous mucinosis and systemic symptoms that resemble SM. Hypothyroid myxedema is associated with a widespread slowing of the body’s metabolic processes and deposition of mucin in various organs, including the skin, creating a generalized nonpitting edema. Classic clinical signs include macroglossia, periorbital puffiness, thick lips, and acral swelling. The skin tends to be cold, dry, and pale. Hair is characterized as being coarse, dry, and brittle with diffuse partial alopecia. Histologically, there is hyperkeratosis with follicular plugging and diffuse mucin and edema splaying between collagen fibers spanning the entire dermis.¹¹ In contradistinction with SM, there is no fibroblast proliferation. The treatment is thyroid replacement therapy. Hyperthyroidism has distinct clinical and histologic changes. Clinically, there is moist and smooth skin with soft, fine, and sometimes alopecic hair. Graves disease, the most common cause of hyperthyroidism, is further characterized by Graves ophthalmopathy and pretibial myxedema, or pink to brown, raised, firm, indurated, asymmetric plaques most commonly affecting the shins. Histologically there is increased mucin in the lower to mid dermis without fibroblast proliferation. The epidermis can be hyperkeratotic, which will clinically correlate with verrucous lesions.¹²

Hypothyroid encephalopathy is a rare disorder that can cause a change in mental status. It is a steroid-responsive autoimmune process characterized by encephalopathy that is associated with cognitive impairment and psychiatric features. It is a diagnosis of exclusion and should be suspected in women with a history of autoimmune disease, especially antithyroid peroxidase antibodies, a negative infectious workup, and encephalitis with behavioral changes. Although typically highly responsive to systemic steroids, IVIg also has shown efficacy.¹³

Presence of Thyroid Disease
According to a PubMed search of articles indexed for MEDLINE using the terms scleromyxedema and lichen myxedematosus, there are 7 cases in the literature that potentially describe LM associated with hypothyroidism (Table 2).^3-8 The majority of these cases lack monoclonal gammopathy; improved with thyroid replacement therapy; or had severely atypical clinical presentations, rendering them cases of atypical LM or atypical thyroid dermopathy.^3-6 Macnab and Kenny⁷ presented a case of subclinical hypothyroidism with a generalized papular eruption, monoclonal gammopathy, and consistent histologic changes that responded to IVIg therapy. These findings are suggestive of SM, but limited to the current diagnostic criteria, the patient was diagnosed with atypical LM.⁷ Shenoy et al⁸ described 2 cases of LM with hypothyroidism. One patient had biopsy-proven SM that was responsive to IVIg as well as Hashimoto thyroiditis with delayed onset of monoclonal gammopathy. The second patient had a medical history of hypothyroidism and Hodgkin lymphoma with active rheumatoid arthritis and biopsy-proven LM that was responsive to systemic steroids.⁸

Current literature states that thyroid disorder precludes the diagnosis of SM. However, historic literature would suggest otherwise. Because of inconsistent reports and theories regarding the pathogenesis of various sclerodermoid and mucin deposition diseases, in 1953 Montgomery and Underwood¹ sought to differentiate LM from scleroderma and generalized myxedema. They stressed clinical appearance and proposed diagnostic criteria for LM as generalized papular mucinosis in which “[n]o relation to disturbance of the thyroid or other endocrine glands is apparent,” whereas generalized myxedema was defined as a “[t]rue cutaneous myxedema, with diffuse edema and the usual commonly recognized changes” in patients with endocrine abnormalities.¹ With this classification, the authors made a clear distinction between mucinosis caused by thyroid abnormalities and LM, which is not caused by a thyroid disorder. Since this original description was published, associations with monoclonal gammopathy and fibroblast proliferation have been made, ultimately culminating into the current 2001 criteria that incorporate the absence of thyroid disease.²

Conclusion

We believe our case is consistent with the classification initially proposed by Montgomery and Underwood¹ and is strengthened with the more recent associations with monoclonal gammopathy and specific histopathologic findings. Although there is no definitive way to rule out myxedema coma or Hashimoto encephalopathy to describe our patient’s transient neurologic decline, her clinical symptoms, laboratory findings, and biopsy results all supported the diagnosis of SM. Furthermore, her response to SM-directed therapy, despite fluctuating thyroid function test results, also supported the diagnosis. In the setting of cutaneous mucinosis with conflicting findings for hypothyroid myxedema, LM should be ruled out. Given the features presented in this report and others, diagnostic criteria should allow for SM and thyroid dysfunction to be concurrent diagnoses. Most importantly, we believe it is essential to identify and diagnose SM in a timely manner to facilitate SM-directed therapy, namely IVIg, to potentially minimize the disease’s notable morbidity and mortality.

Scleromyxedema (SM) is a generalized papular and sclerodermoid form of lichen myxedematosus (LM), commonly referred to as papular mucinosis. It is a rare progressive disease of unknown etiology with systemic manifestations that cause serious morbidity and mortality. Diagnostic criteria were initially created by Montgomery and Underwood¹ in 1953 and revised by Rongioletti and Rebora² in 2001 as follows: (1) generalized papular and sclerodermoid eruption; (2) histologic triad of mucin deposition, fibroblast proliferation, and fibrosis; (3) monoclonal gammopathy; and (4) absence of thyroid disease. There are several reports of LM in association with hypothyroidism, most of which can be characterized as atypical.^3-8 We present a case of SM in a patient with Hashimoto thyroiditis and propose that the presence of thyroid disease should not preclude the diagnosis of SM.

Case Report

A 44-year-old woman presented with a progressive eruption of thickened skin and papules spanning many months. The papules ranged from flesh colored to erythematous and covered more than 80% of the body surface area, most notably involving the face, neck, ears, arms, chest, abdomen, and thighs (Figures 1A and 2A). Review of systems was notable for pruritus, muscle pain but no weakness, dysphagia, and constipation. Her medical history included childhood atopic dermatitis and Hashimoto thyroiditis. Hypothyroidism was diagnosed with support of a thyroid ultrasound and thyroid peroxidase antibodies. It was treated with oral levothyroxine for 2 years prior to the skin eruption. Thyroid biopsy was not performed. Her thyroid-stimulating hormone levels notably fluctuated in the year prior to presentation despite close clinical and laboratory monitoring by an endocrinologist. Laboratory results are summarized in Table 1. Both skin and muscle⁹ biopsies were consistent with SM (Figure 3) and are summarized in Table 1.

Shortly after presentation to our clinic the patient developed acute concerns of confusion and muscle weakness. She was admitted for further inpatient management due to concern for dermato-neuro syndrome, a rare but potentially fatal decline in neurological status that can progress to coma and death, rather than myxedema coma. On admission, a thyroid function test showed subclinical hypothyroidism with a thyroid-stimulating hormone level of 6.35 uU/mL (reference range, 0.3–4.35 uU/mL) and free thyroxine (FT₄) level of 1.5 ng/dL (reference range, 0.8–2.8 ng/dL). While hospitalized she was started on intravenous levothyroxine, systemic steroids, and a course of intravenous immunoglobulin (IVIg) treatment consisting of 2 g/kg divided over 5 days. On this regimen, her mental status quickly returned to baseline and other symptoms improved, including the skin eruption (Figures 1B and 2B). She has been maintained on lenalidomide 25 mg/d for the first 3 weeks of each month as well as monthly IVIg infusions. Her thyroid levels have persistently fluctuated despite intramuscular levothyroxine dosing, but her skin has remained clear with continued SM-directed therapy.

Comment

Classification
Lichen myxedematosus is differentiated into localized and generalized forms. The former is limited to the skin and lacks monoclonal gammopathy. The latter, also known as SM, is associated with monoclonal gammopathy and systemic symptoms. Atypical LM is an umbrella term for intermediate cases.

Clinical Presentation
Skin manifestations of SM are described as 1- to 3-mm, firm, waxy, dome-shaped papules that commonly affect the hands, forearms, face, neck, trunk, and thighs. The surrounding skin may be reddish brown and edematous with evidence of skin thickening. Extracutaneous manifestations in SM are numerous and unpredictable. Any organ system can be involved, but gastrointestinal, rheumatologic, pulmonary, and cardiovascular complications are most common.¹⁰ A comprehensive multidisciplinary evaluation is necessary based on clinical symptoms and laboratory findings.

Management
Many treatments have been proposed for SM in case reports and case series. Prior treatments have had little success. Most recently, in one of the largest case series on SM, Rongioletti et al¹⁰ demonstrated IVIg to be a safe and effective treatment modality.

Differential Diagnosis
An important differential diagnosis is generalized myxedema, which is seen in long-standing hypothyroidism and may present with cutaneous mucinosis and systemic symptoms that resemble SM. Hypothyroid myxedema is associated with a widespread slowing of the body’s metabolic processes and deposition of mucin in various organs, including the skin, creating a generalized nonpitting edema. Classic clinical signs include macroglossia, periorbital puffiness, thick lips, and acral swelling. The skin tends to be cold, dry, and pale. Hair is characterized as being coarse, dry, and brittle with diffuse partial alopecia. Histologically, there is hyperkeratosis with follicular plugging and diffuse mucin and edema splaying between collagen fibers spanning the entire dermis.¹¹ In contradistinction with SM, there is no fibroblast proliferation. The treatment is thyroid replacement therapy. Hyperthyroidism has distinct clinical and histologic changes. Clinically, there is moist and smooth skin with soft, fine, and sometimes alopecic hair. Graves disease, the most common cause of hyperthyroidism, is further characterized by Graves ophthalmopathy and pretibial myxedema, or pink to brown, raised, firm, indurated, asymmetric plaques most commonly affecting the shins. Histologically there is increased mucin in the lower to mid dermis without fibroblast proliferation. The epidermis can be hyperkeratotic, which will clinically correlate with verrucous lesions.¹²

Hypothyroid encephalopathy is a rare disorder that can cause a change in mental status. It is a steroid-responsive autoimmune process characterized by encephalopathy that is associated with cognitive impairment and psychiatric features. It is a diagnosis of exclusion and should be suspected in women with a history of autoimmune disease, especially antithyroid peroxidase antibodies, a negative infectious workup, and encephalitis with behavioral changes. Although typically highly responsive to systemic steroids, IVIg also has shown efficacy.¹³

Presence of Thyroid Disease
According to a PubMed search of articles indexed for MEDLINE using the terms scleromyxedema and lichen myxedematosus, there are 7 cases in the literature that potentially describe LM associated with hypothyroidism (Table 2).^3-8 The majority of these cases lack monoclonal gammopathy; improved with thyroid replacement therapy; or had severely atypical clinical presentations, rendering them cases of atypical LM or atypical thyroid dermopathy.^3-6 Macnab and Kenny⁷ presented a case of subclinical hypothyroidism with a generalized papular eruption, monoclonal gammopathy, and consistent histologic changes that responded to IVIg therapy. These findings are suggestive of SM, but limited to the current diagnostic criteria, the patient was diagnosed with atypical LM.⁷ Shenoy et al⁸ described 2 cases of LM with hypothyroidism. One patient had biopsy-proven SM that was responsive to IVIg as well as Hashimoto thyroiditis with delayed onset of monoclonal gammopathy. The second patient had a medical history of hypothyroidism and Hodgkin lymphoma with active rheumatoid arthritis and biopsy-proven LM that was responsive to systemic steroids.⁸

Current literature states that thyroid disorder precludes the diagnosis of SM. However, historic literature would suggest otherwise. Because of inconsistent reports and theories regarding the pathogenesis of various sclerodermoid and mucin deposition diseases, in 1953 Montgomery and Underwood¹ sought to differentiate LM from scleroderma and generalized myxedema. They stressed clinical appearance and proposed diagnostic criteria for LM as generalized papular mucinosis in which “[n]o relation to disturbance of the thyroid or other endocrine glands is apparent,” whereas generalized myxedema was defined as a “[t]rue cutaneous myxedema, with diffuse edema and the usual commonly recognized changes” in patients with endocrine abnormalities.¹ With this classification, the authors made a clear distinction between mucinosis caused by thyroid abnormalities and LM, which is not caused by a thyroid disorder. Since this original description was published, associations with monoclonal gammopathy and fibroblast proliferation have been made, ultimately culminating into the current 2001 criteria that incorporate the absence of thyroid disease.²

Conclusion

We believe our case is consistent with the classification initially proposed by Montgomery and Underwood¹ and is strengthened with the more recent associations with monoclonal gammopathy and specific histopathologic findings. Although there is no definitive way to rule out myxedema coma or Hashimoto encephalopathy to describe our patient’s transient neurologic decline, her clinical symptoms, laboratory findings, and biopsy results all supported the diagnosis of SM. Furthermore, her response to SM-directed therapy, despite fluctuating thyroid function test results, also supported the diagnosis. In the setting of cutaneous mucinosis with conflicting findings for hypothyroid myxedema, LM should be ruled out. Given the features presented in this report and others, diagnostic criteria should allow for SM and thyroid dysfunction to be concurrent diagnoses. Most importantly, we believe it is essential to identify and diagnose SM in a timely manner to facilitate SM-directed therapy, namely IVIg, to potentially minimize the disease’s notable morbidity and mortality.

Scleromyxedema (SM) is a generalized papular and sclerodermoid form of lichen myxedematosus (LM), commonly referred to as papular mucinosis. It is a rare progressive disease of unknown etiology with systemic manifestations that cause serious morbidity and mortality. Diagnostic criteria were initially created by Montgomery and Underwood¹ in 1953 and revised by Rongioletti and Rebora² in 2001 as follows: (1) generalized papular and sclerodermoid eruption; (2) histologic triad of mucin deposition, fibroblast proliferation, and fibrosis; (3) monoclonal gammopathy; and (4) absence of thyroid disease. There are several reports of LM in association with hypothyroidism, most of which can be characterized as atypical.^3-8 We present a case of SM in a patient with Hashimoto thyroiditis and propose that the presence of thyroid disease should not preclude the diagnosis of SM.

Case Report

A 44-year-old woman presented with a progressive eruption of thickened skin and papules spanning many months. The papules ranged from flesh colored to erythematous and covered more than 80% of the body surface area, most notably involving the face, neck, ears, arms, chest, abdomen, and thighs (Figures 1A and 2A). Review of systems was notable for pruritus, muscle pain but no weakness, dysphagia, and constipation. Her medical history included childhood atopic dermatitis and Hashimoto thyroiditis. Hypothyroidism was diagnosed with support of a thyroid ultrasound and thyroid peroxidase antibodies. It was treated with oral levothyroxine for 2 years prior to the skin eruption. Thyroid biopsy was not performed. Her thyroid-stimulating hormone levels notably fluctuated in the year prior to presentation despite close clinical and laboratory monitoring by an endocrinologist. Laboratory results are summarized in Table 1. Both skin and muscle⁹ biopsies were consistent with SM (Figure 3) and are summarized in Table 1.

Shortly after presentation to our clinic the patient developed acute concerns of confusion and muscle weakness. She was admitted for further inpatient management due to concern for dermato-neuro syndrome, a rare but potentially fatal decline in neurological status that can progress to coma and death, rather than myxedema coma. On admission, a thyroid function test showed subclinical hypothyroidism with a thyroid-stimulating hormone level of 6.35 uU/mL (reference range, 0.3–4.35 uU/mL) and free thyroxine (FT₄) level of 1.5 ng/dL (reference range, 0.8–2.8 ng/dL). While hospitalized she was started on intravenous levothyroxine, systemic steroids, and a course of intravenous immunoglobulin (IVIg) treatment consisting of 2 g/kg divided over 5 days. On this regimen, her mental status quickly returned to baseline and other symptoms improved, including the skin eruption (Figures 1B and 2B). She has been maintained on lenalidomide 25 mg/d for the first 3 weeks of each month as well as monthly IVIg infusions. Her thyroid levels have persistently fluctuated despite intramuscular levothyroxine dosing, but her skin has remained clear with continued SM-directed therapy.

Comment

Classification
Lichen myxedematosus is differentiated into localized and generalized forms. The former is limited to the skin and lacks monoclonal gammopathy. The latter, also known as SM, is associated with monoclonal gammopathy and systemic symptoms. Atypical LM is an umbrella term for intermediate cases.

Clinical Presentation
Skin manifestations of SM are described as 1- to 3-mm, firm, waxy, dome-shaped papules that commonly affect the hands, forearms, face, neck, trunk, and thighs. The surrounding skin may be reddish brown and edematous with evidence of skin thickening. Extracutaneous manifestations in SM are numerous and unpredictable. Any organ system can be involved, but gastrointestinal, rheumatologic, pulmonary, and cardiovascular complications are most common.¹⁰ A comprehensive multidisciplinary evaluation is necessary based on clinical symptoms and laboratory findings.

Management
Many treatments have been proposed for SM in case reports and case series. Prior treatments have had little success. Most recently, in one of the largest case series on SM, Rongioletti et al¹⁰ demonstrated IVIg to be a safe and effective treatment modality.

Differential Diagnosis
An important differential diagnosis is generalized myxedema, which is seen in long-standing hypothyroidism and may present with cutaneous mucinosis and systemic symptoms that resemble SM. Hypothyroid myxedema is associated with a widespread slowing of the body’s metabolic processes and deposition of mucin in various organs, including the skin, creating a generalized nonpitting edema. Classic clinical signs include macroglossia, periorbital puffiness, thick lips, and acral swelling. The skin tends to be cold, dry, and pale. Hair is characterized as being coarse, dry, and brittle with diffuse partial alopecia. Histologically, there is hyperkeratosis with follicular plugging and diffuse mucin and edema splaying between collagen fibers spanning the entire dermis.¹¹ In contradistinction with SM, there is no fibroblast proliferation. The treatment is thyroid replacement therapy. Hyperthyroidism has distinct clinical and histologic changes. Clinically, there is moist and smooth skin with soft, fine, and sometimes alopecic hair. Graves disease, the most common cause of hyperthyroidism, is further characterized by Graves ophthalmopathy and pretibial myxedema, or pink to brown, raised, firm, indurated, asymmetric plaques most commonly affecting the shins. Histologically there is increased mucin in the lower to mid dermis without fibroblast proliferation. The epidermis can be hyperkeratotic, which will clinically correlate with verrucous lesions.¹²

Hypothyroid encephalopathy is a rare disorder that can cause a change in mental status. It is a steroid-responsive autoimmune process characterized by encephalopathy that is associated with cognitive impairment and psychiatric features. It is a diagnosis of exclusion and should be suspected in women with a history of autoimmune disease, especially antithyroid peroxidase antibodies, a negative infectious workup, and encephalitis with behavioral changes. Although typically highly responsive to systemic steroids, IVIg also has shown efficacy.¹³

Presence of Thyroid Disease
According to a PubMed search of articles indexed for MEDLINE using the terms scleromyxedema and lichen myxedematosus, there are 7 cases in the literature that potentially describe LM associated with hypothyroidism (Table 2).^3-8 The majority of these cases lack monoclonal gammopathy; improved with thyroid replacement therapy; or had severely atypical clinical presentations, rendering them cases of atypical LM or atypical thyroid dermopathy.^3-6 Macnab and Kenny⁷ presented a case of subclinical hypothyroidism with a generalized papular eruption, monoclonal gammopathy, and consistent histologic changes that responded to IVIg therapy. These findings are suggestive of SM, but limited to the current diagnostic criteria, the patient was diagnosed with atypical LM.⁷ Shenoy et al⁸ described 2 cases of LM with hypothyroidism. One patient had biopsy-proven SM that was responsive to IVIg as well as Hashimoto thyroiditis with delayed onset of monoclonal gammopathy. The second patient had a medical history of hypothyroidism and Hodgkin lymphoma with active rheumatoid arthritis and biopsy-proven LM that was responsive to systemic steroids.⁸

Current literature states that thyroid disorder precludes the diagnosis of SM. However, historic literature would suggest otherwise. Because of inconsistent reports and theories regarding the pathogenesis of various sclerodermoid and mucin deposition diseases, in 1953 Montgomery and Underwood¹ sought to differentiate LM from scleroderma and generalized myxedema. They stressed clinical appearance and proposed diagnostic criteria for LM as generalized papular mucinosis in which “[n]o relation to disturbance of the thyroid or other endocrine glands is apparent,” whereas generalized myxedema was defined as a “[t]rue cutaneous myxedema, with diffuse edema and the usual commonly recognized changes” in patients with endocrine abnormalities.¹ With this classification, the authors made a clear distinction between mucinosis caused by thyroid abnormalities and LM, which is not caused by a thyroid disorder. Since this original description was published, associations with monoclonal gammopathy and fibroblast proliferation have been made, ultimately culminating into the current 2001 criteria that incorporate the absence of thyroid disease.²

Conclusion

We believe our case is consistent with the classification initially proposed by Montgomery and Underwood¹ and is strengthened with the more recent associations with monoclonal gammopathy and specific histopathologic findings. Although there is no definitive way to rule out myxedema coma or Hashimoto encephalopathy to describe our patient’s transient neurologic decline, her clinical symptoms, laboratory findings, and biopsy results all supported the diagnosis of SM. Furthermore, her response to SM-directed therapy, despite fluctuating thyroid function test results, also supported the diagnosis. In the setting of cutaneous mucinosis with conflicting findings for hypothyroid myxedema, LM should be ruled out. Given the features presented in this report and others, diagnostic criteria should allow for SM and thyroid dysfunction to be concurrent diagnoses. Most importantly, we believe it is essential to identify and diagnose SM in a timely manner to facilitate SM-directed therapy, namely IVIg, to potentially minimize the disease’s notable morbidity and mortality.

Patients with seizures are placed at an increased risk for sustaining burn injuries, which may occur during common daily activities such as cooking, showering, and using heaters.¹ Although patients are warned of the risks of injury at the time of their epilepsy diagnosis, patients still experience injuries that commonly occur during the seizure or the postictal phase. In a study of 134 patients with epilepsy, only 38% recalled being burned during a seizure, with approximately 9% being burned multiple times.² Another study investigated the circumstances resulting in burns in this patient population and found that cooking on a stove was the most common cause, followed by hot water while showering and exposed room heaters.¹ Another study found that the majority of burns in seizure patients were from spilled hot drinks.³

We report 2 patients who presented to the dermatology clinic with second-degree burns following nocturnal seizures. In both cases, the patients were sleeping next to exposed heaters, which led to burn injuries from seizures that occurred in the night.

Case Reports

Patient 1
A 30-year-old woman with a history of a seizure disorder presented with painful second-degree blistering burns along the left arm and flank (Figure 1). One day prior to presentation, she had woken up to find these lesions and visited the emergency department where she was prescribed silver sulfadiazine cream to prevent infection of the wound site and was referred to our dermatology clinic. Initially, the patient had difficulty pinpointing the source of the burn lesions and thought that it may have been due to sleeping with her cell phone, but she later realized that they were due to the space heater placed next to her bed. Because of the unclear etiology at the initial presentation, a skin biopsy of a lesion was taken while she was at the clinic.

Biopsy of the lesions exhibited separation of the epidermal and dermal layers (Figure 2). Thermal damage was seen extending into the dermal layers with notable edema present. A few inflammatory cells, neutrophils, and monocytes were noted in the biopsy. The initial pathology results showed the epidermis was necrotic with edema, spongiform vesicles, and few neutrophils. The histologic findings aligned with the timeline of the injury occurring 2 days prior to the biopsy. She was treated supportively using mupirocin ointment to prevent secondary infection.

Comment

Classification of Burns and Damage
According to the World Health Organization, nonfatal burn injuries are a leading cause of morbidity and occur mainly in the home and workplace.⁴ There are many types of burns: radiation, electrical, chemical, friction, and thermal. The most common type of burns are thermal burns,⁴ which can be further subdivided into wet and dry. Both of our patients experienced dry thermal burns.

Based on the skin tissue layers involved in the thermal damage, burn wounds are further divided into first-degree burns, superficial second-degree burns, deep second-degree burns, and third-degree burns.⁵ These classifications each have characteristic gross features. Based on these criteria, our patients both presented with blistering and ruptured bullae and no eschar formation, which is classified as second-degree superficial burns.

Following thermal insult to the skin, 3 zones are formed. The central zone consists of irreparable damage referred to as the zone of coagulation. The zone of stasis lies between the completely damaged central region and the outermost regions of the burn lesion, and it receives slightly less blood flow. This area can fully recover after complete perfusion is returned early in the healing process. The outermost zone of hyperemia can fully recover and is an area marked by intense vasodilation from inflammatory reactions.⁵

Wound Healing
During the healing process, metabolic activity is remarkably increased, which leads to formation of reactive oxygen species.⁶ The production of reactive oxygen species is both beneficial and harmful. It is protective against invasion of microorganisms, but it delays the re-epithelialization process. The burn injury itself generates multiple cytokines and lipid mediators.⁷ After the initial keratinocyte migration and proliferation, angiogenesis and fibrogenesis lead to the formation of the basement membrane at the dermoepidermal junction,⁵ which is followed by structural strengthening of the skin with collagen and elastin deposition. The final results of healing are dependent on the depth of the wound. With deeper burns there will be contractures and hypertrophic scarring and a possibility for hypopigmentation from melanocyte death.⁵ With more superficial injuries, the burned area appears hyperpigmented from overactivity of melanocytes during the healing process. In less severe cases of superficial burns, it can take 5 to 7 days for granulation tissue to cover the wound and to heal with little to no scarring.⁵

Burns in Patients With Seizure Disorders
Burns pose a serious risk to patients with seizure disorders that often is underappreciated by patients and health care providers. Although many burns are first-degree burns, up to 10% of burns require medical attention.¹ In the initial phase following a thermal insult, the skin’s microflora is killed off, but within a week the sterile skin can become infected.⁵ The most common microbial invasions seen in blistering wounds are due to Pseudomonas aeruginosa and Staphylococcus aureus.⁸ With larger burns associated with immunocompromising factors such as diabetes mellitus or older age, patients are at an increased risk for becoming septic. Prior to the period of infection, the damage caused by the heat leads to vasodilation of the microvasculature surrounding the injured area. In addition, release of cytokines leads to migration of inflammatory cells. With the vasodilation of vasculature, proteinaceous fluids from the intravascular space can collect between the dead epidermal and dermal layers to form blisters.⁵ In larger burns, the fluid shifts will lead to severe oncotic pressure decreases intravascularly and can lead to hypotensive shock.⁶ When burns have a more severe global effect, aggressive resuscitation and vasopressors are required to maintain perfusion of vital organs.

Both of our patients experienced painful lesions, but they were fortunate to have factors of youth, superficial damage, and low total body surface area burns for a smaller risk for infection, fluid loss, and severely disfiguring scars.⁸ Because the duration of the postictal phase can vary, there is potential for more severe burns that can leave a lifelong reminder of the event. Depending on the skin type and the depth of the thermal insult, evidence of injury may last many years in the form of hypertrophic scars, contractures, and changes in skin pigmentation.⁵ At distances 30 cm or less from the standard blow-dryer, it takes 2 minutes to cause cell death.⁹ In comparison to a heat source that is meant to provide warmth to a room, there is a notable difference in potential for severe burns with the standard heater vs the standard blow-dryer.

Along with the physical pain, the visual reminders of the injurious event can have notable psychological effects. Scars can decrease self-esteem and lead to depression, anxiety, body image problems, and sexuality issues.¹⁰

Given the immense risks associated with burn injuries and the many unfortunate outcomes, emphasis should be placed on patient education regarding safety precautions with seizure disorders. In one study, it was found that only 5% of patients recall receiving a warning about the risk for burn injuries with seizures.² It is important for patients and physicians to develop a written comprehensive safety plan that addresses the risks for daily activities during the day and night. Although patients may not remember being told about the risks, a written safety plan likely will increase patient awareness and reduce avoidable injuries. In addition to written safety plans, prior recommendations for reducing burn injuries in seizure patients include the use of fire and heater guards as well as flame-retardant clothing and blankets.¹¹

Patients with seizures are placed at an increased risk for sustaining burn injuries, which may occur during common daily activities such as cooking, showering, and using heaters.¹ Although patients are warned of the risks of injury at the time of their epilepsy diagnosis, patients still experience injuries that commonly occur during the seizure or the postictal phase. In a study of 134 patients with epilepsy, only 38% recalled being burned during a seizure, with approximately 9% being burned multiple times.² Another study investigated the circumstances resulting in burns in this patient population and found that cooking on a stove was the most common cause, followed by hot water while showering and exposed room heaters.¹ Another study found that the majority of burns in seizure patients were from spilled hot drinks.³

We report 2 patients who presented to the dermatology clinic with second-degree burns following nocturnal seizures. In both cases, the patients were sleeping next to exposed heaters, which led to burn injuries from seizures that occurred in the night.

Case Reports

Patient 1
A 30-year-old woman with a history of a seizure disorder presented with painful second-degree blistering burns along the left arm and flank (Figure 1). One day prior to presentation, she had woken up to find these lesions and visited the emergency department where she was prescribed silver sulfadiazine cream to prevent infection of the wound site and was referred to our dermatology clinic. Initially, the patient had difficulty pinpointing the source of the burn lesions and thought that it may have been due to sleeping with her cell phone, but she later realized that they were due to the space heater placed next to her bed. Because of the unclear etiology at the initial presentation, a skin biopsy of a lesion was taken while she was at the clinic.

Biopsy of the lesions exhibited separation of the epidermal and dermal layers (Figure 2). Thermal damage was seen extending into the dermal layers with notable edema present. A few inflammatory cells, neutrophils, and monocytes were noted in the biopsy. The initial pathology results showed the epidermis was necrotic with edema, spongiform vesicles, and few neutrophils. The histologic findings aligned with the timeline of the injury occurring 2 days prior to the biopsy. She was treated supportively using mupirocin ointment to prevent secondary infection.

Comment

Classification of Burns and Damage
According to the World Health Organization, nonfatal burn injuries are a leading cause of morbidity and occur mainly in the home and workplace.⁴ There are many types of burns: radiation, electrical, chemical, friction, and thermal. The most common type of burns are thermal burns,⁴ which can be further subdivided into wet and dry. Both of our patients experienced dry thermal burns.

Based on the skin tissue layers involved in the thermal damage, burn wounds are further divided into first-degree burns, superficial second-degree burns, deep second-degree burns, and third-degree burns.⁵ These classifications each have characteristic gross features. Based on these criteria, our patients both presented with blistering and ruptured bullae and no eschar formation, which is classified as second-degree superficial burns.

Following thermal insult to the skin, 3 zones are formed. The central zone consists of irreparable damage referred to as the zone of coagulation. The zone of stasis lies between the completely damaged central region and the outermost regions of the burn lesion, and it receives slightly less blood flow. This area can fully recover after complete perfusion is returned early in the healing process. The outermost zone of hyperemia can fully recover and is an area marked by intense vasodilation from inflammatory reactions.⁵

Wound Healing
During the healing process, metabolic activity is remarkably increased, which leads to formation of reactive oxygen species.⁶ The production of reactive oxygen species is both beneficial and harmful. It is protective against invasion of microorganisms, but it delays the re-epithelialization process. The burn injury itself generates multiple cytokines and lipid mediators.⁷ After the initial keratinocyte migration and proliferation, angiogenesis and fibrogenesis lead to the formation of the basement membrane at the dermoepidermal junction,⁵ which is followed by structural strengthening of the skin with collagen and elastin deposition. The final results of healing are dependent on the depth of the wound. With deeper burns there will be contractures and hypertrophic scarring and a possibility for hypopigmentation from melanocyte death.⁵ With more superficial injuries, the burned area appears hyperpigmented from overactivity of melanocytes during the healing process. In less severe cases of superficial burns, it can take 5 to 7 days for granulation tissue to cover the wound and to heal with little to no scarring.⁵

Burns in Patients With Seizure Disorders
Burns pose a serious risk to patients with seizure disorders that often is underappreciated by patients and health care providers. Although many burns are first-degree burns, up to 10% of burns require medical attention.¹ In the initial phase following a thermal insult, the skin’s microflora is killed off, but within a week the sterile skin can become infected.⁵ The most common microbial invasions seen in blistering wounds are due to Pseudomonas aeruginosa and Staphylococcus aureus.⁸ With larger burns associated with immunocompromising factors such as diabetes mellitus or older age, patients are at an increased risk for becoming septic. Prior to the period of infection, the damage caused by the heat leads to vasodilation of the microvasculature surrounding the injured area. In addition, release of cytokines leads to migration of inflammatory cells. With the vasodilation of vasculature, proteinaceous fluids from the intravascular space can collect between the dead epidermal and dermal layers to form blisters.⁵ In larger burns, the fluid shifts will lead to severe oncotic pressure decreases intravascularly and can lead to hypotensive shock.⁶ When burns have a more severe global effect, aggressive resuscitation and vasopressors are required to maintain perfusion of vital organs.

Both of our patients experienced painful lesions, but they were fortunate to have factors of youth, superficial damage, and low total body surface area burns for a smaller risk for infection, fluid loss, and severely disfiguring scars.⁸ Because the duration of the postictal phase can vary, there is potential for more severe burns that can leave a lifelong reminder of the event. Depending on the skin type and the depth of the thermal insult, evidence of injury may last many years in the form of hypertrophic scars, contractures, and changes in skin pigmentation.⁵ At distances 30 cm or less from the standard blow-dryer, it takes 2 minutes to cause cell death.⁹ In comparison to a heat source that is meant to provide warmth to a room, there is a notable difference in potential for severe burns with the standard heater vs the standard blow-dryer.

Along with the physical pain, the visual reminders of the injurious event can have notable psychological effects. Scars can decrease self-esteem and lead to depression, anxiety, body image problems, and sexuality issues.¹⁰

Given the immense risks associated with burn injuries and the many unfortunate outcomes, emphasis should be placed on patient education regarding safety precautions with seizure disorders. In one study, it was found that only 5% of patients recall receiving a warning about the risk for burn injuries with seizures.² It is important for patients and physicians to develop a written comprehensive safety plan that addresses the risks for daily activities during the day and night. Although patients may not remember being told about the risks, a written safety plan likely will increase patient awareness and reduce avoidable injuries. In addition to written safety plans, prior recommendations for reducing burn injuries in seizure patients include the use of fire and heater guards as well as flame-retardant clothing and blankets.¹¹

Patients with seizures are placed at an increased risk for sustaining burn injuries, which may occur during common daily activities such as cooking, showering, and using heaters.¹ Although patients are warned of the risks of injury at the time of their epilepsy diagnosis, patients still experience injuries that commonly occur during the seizure or the postictal phase. In a study of 134 patients with epilepsy, only 38% recalled being burned during a seizure, with approximately 9% being burned multiple times.² Another study investigated the circumstances resulting in burns in this patient population and found that cooking on a stove was the most common cause, followed by hot water while showering and exposed room heaters.¹ Another study found that the majority of burns in seizure patients were from spilled hot drinks.³

We report 2 patients who presented to the dermatology clinic with second-degree burns following nocturnal seizures. In both cases, the patients were sleeping next to exposed heaters, which led to burn injuries from seizures that occurred in the night.

Case Reports

Patient 1
A 30-year-old woman with a history of a seizure disorder presented with painful second-degree blistering burns along the left arm and flank (Figure 1). One day prior to presentation, she had woken up to find these lesions and visited the emergency department where she was prescribed silver sulfadiazine cream to prevent infection of the wound site and was referred to our dermatology clinic. Initially, the patient had difficulty pinpointing the source of the burn lesions and thought that it may have been due to sleeping with her cell phone, but she later realized that they were due to the space heater placed next to her bed. Because of the unclear etiology at the initial presentation, a skin biopsy of a lesion was taken while she was at the clinic.

Biopsy of the lesions exhibited separation of the epidermal and dermal layers (Figure 2). Thermal damage was seen extending into the dermal layers with notable edema present. A few inflammatory cells, neutrophils, and monocytes were noted in the biopsy. The initial pathology results showed the epidermis was necrotic with edema, spongiform vesicles, and few neutrophils. The histologic findings aligned with the timeline of the injury occurring 2 days prior to the biopsy. She was treated supportively using mupirocin ointment to prevent secondary infection.

Comment

Classification of Burns and Damage
According to the World Health Organization, nonfatal burn injuries are a leading cause of morbidity and occur mainly in the home and workplace.⁴ There are many types of burns: radiation, electrical, chemical, friction, and thermal. The most common type of burns are thermal burns,⁴ which can be further subdivided into wet and dry. Both of our patients experienced dry thermal burns.

Based on the skin tissue layers involved in the thermal damage, burn wounds are further divided into first-degree burns, superficial second-degree burns, deep second-degree burns, and third-degree burns.⁵ These classifications each have characteristic gross features. Based on these criteria, our patients both presented with blistering and ruptured bullae and no eschar formation, which is classified as second-degree superficial burns.

Following thermal insult to the skin, 3 zones are formed. The central zone consists of irreparable damage referred to as the zone of coagulation. The zone of stasis lies between the completely damaged central region and the outermost regions of the burn lesion, and it receives slightly less blood flow. This area can fully recover after complete perfusion is returned early in the healing process. The outermost zone of hyperemia can fully recover and is an area marked by intense vasodilation from inflammatory reactions.⁵

Wound Healing
During the healing process, metabolic activity is remarkably increased, which leads to formation of reactive oxygen species.⁶ The production of reactive oxygen species is both beneficial and harmful. It is protective against invasion of microorganisms, but it delays the re-epithelialization process. The burn injury itself generates multiple cytokines and lipid mediators.⁷ After the initial keratinocyte migration and proliferation, angiogenesis and fibrogenesis lead to the formation of the basement membrane at the dermoepidermal junction,⁵ which is followed by structural strengthening of the skin with collagen and elastin deposition. The final results of healing are dependent on the depth of the wound. With deeper burns there will be contractures and hypertrophic scarring and a possibility for hypopigmentation from melanocyte death.⁵ With more superficial injuries, the burned area appears hyperpigmented from overactivity of melanocytes during the healing process. In less severe cases of superficial burns, it can take 5 to 7 days for granulation tissue to cover the wound and to heal with little to no scarring.⁵

Burns in Patients With Seizure Disorders
Burns pose a serious risk to patients with seizure disorders that often is underappreciated by patients and health care providers. Although many burns are first-degree burns, up to 10% of burns require medical attention.¹ In the initial phase following a thermal insult, the skin’s microflora is killed off, but within a week the sterile skin can become infected.⁵ The most common microbial invasions seen in blistering wounds are due to Pseudomonas aeruginosa and Staphylococcus aureus.⁸ With larger burns associated with immunocompromising factors such as diabetes mellitus or older age, patients are at an increased risk for becoming septic. Prior to the period of infection, the damage caused by the heat leads to vasodilation of the microvasculature surrounding the injured area. In addition, release of cytokines leads to migration of inflammatory cells. With the vasodilation of vasculature, proteinaceous fluids from the intravascular space can collect between the dead epidermal and dermal layers to form blisters.⁵ In larger burns, the fluid shifts will lead to severe oncotic pressure decreases intravascularly and can lead to hypotensive shock.⁶ When burns have a more severe global effect, aggressive resuscitation and vasopressors are required to maintain perfusion of vital organs.

Both of our patients experienced painful lesions, but they were fortunate to have factors of youth, superficial damage, and low total body surface area burns for a smaller risk for infection, fluid loss, and severely disfiguring scars.⁸ Because the duration of the postictal phase can vary, there is potential for more severe burns that can leave a lifelong reminder of the event. Depending on the skin type and the depth of the thermal insult, evidence of injury may last many years in the form of hypertrophic scars, contractures, and changes in skin pigmentation.⁵ At distances 30 cm or less from the standard blow-dryer, it takes 2 minutes to cause cell death.⁹ In comparison to a heat source that is meant to provide warmth to a room, there is a notable difference in potential for severe burns with the standard heater vs the standard blow-dryer.

Along with the physical pain, the visual reminders of the injurious event can have notable psychological effects. Scars can decrease self-esteem and lead to depression, anxiety, body image problems, and sexuality issues.¹⁰

Given the immense risks associated with burn injuries and the many unfortunate outcomes, emphasis should be placed on patient education regarding safety precautions with seizure disorders. In one study, it was found that only 5% of patients recall receiving a warning about the risk for burn injuries with seizures.² It is important for patients and physicians to develop a written comprehensive safety plan that addresses the risks for daily activities during the day and night. Although patients may not remember being told about the risks, a written safety plan likely will increase patient awareness and reduce avoidable injuries. In addition to written safety plans, prior recommendations for reducing burn injuries in seizure patients include the use of fire and heater guards as well as flame-retardant clothing and blankets.¹¹

Alkaptonuria is a rare autosomal recessive disorder uniquely known for causing black, or darkened, urine when left standing due to the renal excretion of excess homogentisic acid (HGA). When this disorder goes undiagnosed, as demonstrated in this case, patients experience its many complications without a unifying explanation. The disorder has 3 clinical stages that occur in a predictable order: clinical silence, clinical ochronosis, and ochronotic arthropathy. These stages lead to multiple musculoskeletal, cardiovascular (CV), and renal complications that can be mitigated with management focused on decreasing homogentisic acid buildup, alleviating symptoms, and close monitoring for these complications.

Case Presentation

A 61-year-old African American male with a medical history of multiple traumatic fractures, right Achilles tendon injury, early-onset multijoint osteoarthritis, chronic low back pain, and recurrent nephrolithiasis presented to the emergency department with sudden onset of sharp left ankle pain while moving furniture. His physical exam revealed a positive Thompson test—lack of foot plantar flexion with calf squeeze—and a subsequent magnetic resonance image (MRI) showed evidence of an acute Achilles tendon rupture.

Given these findings the patient was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and rest to allow for resolution of swelling and inflammation, followed by elective surgery a month later to repair the ruptured tendon. An operative report following his surgery described “black ends to the area where the Achilles was ruptured…and tendinopathy of the flexor hallucis longus with blackening of the flexor.”

A more in-depth patient history revealed that he underwent multiple invasive and noninvasive interventions for his chronic low back and joint pain with medical management of a prior right Achilles tendon injury. His medical history also included multiple nonspecific diagnoses, such as premature atherosclerosis (diagnosed in his third decade), severe lumbar degenerative disc disease, several tendonopathies and cartilage injuries (Figure 1), pseudogout (following calcium pyrophosphate dehydrate crystals found from a left knee aspirate), and chronic pain syndrome. Along this diagnostic journey, he had several health care providers (HCPs) in rheumatology, orthopedic surgery, pain management, and podiatry who offered a range of symptom management options, including physical therapy, NSAIDs, opioid agonists, tricyclic antidepressants, gabapentin, colchicine, and epidural steroid injections, all of which provided little or no relief of his pain. The patient reported that he told a HCP, “I’ll just live with [the pain].”

At the postsurgery follow-up, the patient reported that he had noticed dark urine and dark spots on his ears in the past. He also recounted that chronic joint pain was common in his family, with both his mother and brother receiving bilateral total knee replacements. Taking into consideration the surgical report and this new history, a urine assessment for HGA was ordered and yielded a diagnosis of alkaptonuria. 

He later suffered an acute myocardial infarction leading to an incidental discovery of severe aortic stenosis on echocardiography, requiring coronary stent placements and transcatheter aortic valve replacement, respectively. He reported that with CV interventions and joint replacement surgeries, including bilateral knees and hips, his symptoms and quality of life began to significantly improve. However, he continued to have diffuse chronic joint pain unimproved with any single agent or intervention.

Discussion

Alkaptonuria is a rare autosomal recessive disorder, with a prevalence of about 1 in 100,000 to 250,000, which results from an enzyme error in an essential amino acid metabolism pathway (Figure 2).¹ This inheritable gene mutation leads to ineffective homogentisate 1,2-dioxygenase (HGD), an enzyme required to break down HGA—which is a product of phenylalanine and tyrosine metabolism.² As these patients engage in normal dietary protein intake, which includes essential amino acid phenylalanine, they develop clinically evident manifestations of the buildup and deposition of HGA.

The rarity of alkaptonuria combined with the gradual buildup of HGA makes it difficult to diagnose. A common diagnostic technique is the visualization of discolored cartilage during surgical procedures, especially when discoloration in urine or skin is not immediately evident. A few case reports have noted surgical diagnosis of black or darkening tissue, known as ochronosis, following tendon rupture—a common complication of this disorder.^3-5 Additional intervention-related case reports linked to the discovery of ochronosis include aortic valve replacement, lumbar discectomy, and bronchoscopy.^6-9 Cases like these illustrate the complex, disabling, and unclear nature of this disorder when not diagnosed early in life.

The patient in this case communicated via e-mail about his tendon repair surgery. “Something very interesting was found during the surgery,” the patient explained. “I was diagnosed with the disease called ochronosis. I don’t know much about this disease but I am beginning to know why some of the things are happening to me and why I am always in constant pain.” This was the first recognized clue toward a diagnosis of alkaptonuria.

Pathophysiology

The pathophysiology of alkaptonuria is based on the extensive deposition of HGA throughout the body. Its progression is based on 3 clinical stages: clinical silence, clinical ochronosis, and ochronotic arthropathy.¹ In the first stage the disorder is asymptomatic but includes its most notable feature—the gradual darkening of urine when exposed to air through oxidation of the renally excreted HGA. A similar process occurs in the blood through formed HGA-melanin compounds, which cause discoloration in cartilage.¹ This internal metabolic disruption accounts for the disorder’s eventual second stage, clinical ochronosis, usually with an onset in the second or third decade. Prominent features noted on physical examination primarily include discoloration of ear pinnae and eye sclera but can involve the nose, gums, teeth, and hands. The third, final, and symptomatic stage, ochronotic arthropathy, occurs by the patient’s fourth to fifth decade and presents as joint pain, usually starting with the vertebrae and larger joints like hips, knees, and shoulders, that can appear as advanced early osteoarthritis on imaging.

Treatment

This clinical manifestation of alkaptonuria requires that HCPs manage patients with 3 strategies: decrease HGA buildup, alleviate symptoms, and monitor for disorder complications. Decreasing HGA buildup is a difficult aspect of management given the natural physiology of protein intake and metabolism. Three approaches to limit HGA buildup incorporate decreasing protein intake, inhibiting enzyme production of HGA, and increasing HGA excretion. Phenylalanine is an essential amino acid—meaning its levels are dependent on dietary protein intake. Patients should be advised to adhere to a low protein diet, especially phenylalanine and tyrosine, to lessen HGA concentrations.

Manipulating the metabolic pathway of phenylalanine with medication is a second option. An example of this is nitisinone, a US Food and Drug Administration-approved medication for treatment of tyrosinemia. It acts by inhibiting hydroxyphenylpyruvic acid dioxygenase, one of the enzymes that converts tyrosine into HGA, to prevent the buildup of damaging tyrosine byproducts. At low doses it has been effective in decreasing HGA concentrations in alkaptonuria and tyrosinemia.^10,11 Due to this mechanism of action, nitisinone directly causes increased tyrosine levels. Therefore, tyrosine toxicity, usually not predicted by tyrosine levels, has been associated with eye-related adverse effects (AEs), including keratopathy, diminished visual acuity, and corneal tissue damage.^1,2,10 Incidence of these AEs have not been clearly documented, but routine monitoring should include patient education on ocular symptoms and slit-lamp examinations.¹²

In addition, case reports have shown that high-dose ascorbic acid (vitamin C) promotes HGA, tyrosine, and phenylalanine excretion in urine, which may slow the progression of alkaptonuria, but clinical effect has not been proven.¹³ Additionally, high vitamin C intake is considered a risk factor for nephrolithiasis, which must be balanced with the increased risk of stone formation from HGA excretion.¹⁴ These dietary and medical options can be considered, especially in the setting of severe symptoms or complications, but the risks must be discussed with patients.

A second and commonly utilized strategy for caring for these patients is symptom management. As demonstrated through this case report, there is no clear medication that adequately addresses the pain caused by HGA deposition. Patients should be referred to a pain specialist to allow for single provider prescribing of pain medications. This patient found most relief and least AEs with tramadol but eventually self-discontinued due to diminishing pain relief. Given the eventual involvement of large joints, these patients will often require further symptom management with joint replacement surgery, usually much earlier than patients who undergo these surgeries for age-related osteoarthritis. The imperative aspect of symptom management is to engage patients in shared decision making with clear expectation setting.

Given the progressive nature of alkaptonuria, providers must monitor and address complications that are a result of this disorder. HGA becomes pathologic by binding to and weakening collagen fibers.⁵ This gradual buildup leads to degenerative changes in weight-bearing lower vertebrae and large joints that can become severe. Due to HGA’s interaction with collagen fibers, tendon involvement leading to inflammation, calcification, and rupture can result as patients enter the third stage, ochronotic arthropathy, of the disorder (Figure 3).¹⁵ Many of these arthropathies will require medical and surgical management and can be urgent in situations like tendon ruptures and meniscal tears. Understanding the pathophysiology of tendinopathies in patients with alkaptonuria also can aid orthopedic surgeons during the postoperative period where patients may be at risk for poor healing.⁵

A second area of complications includes CV involvement. This patient was diagnosed with premature atherosclerosis and underwent cardiac interventions, including coronary stent placement and valve replacements at age 63 years. This early cardiac involvement was likely due in part to the deposition of HGA and collagen injury in CV tissue leading to damage of the endocardium, aortic intima, heart valves, and coronary arteries.¹ HCPs should monitor for these manifestations with regular visits, chest computed tomography, and echocardiographic studies.²

The most classic aspect of this rare disorder is urine darkening due to the renal excretion of HGA and comprises the third area of complications. This process leads to chronically acidic urine—every urinalysis in this patient’s chart displayed the lowest pH measurable—and an increased risk for calcification and precipitation of solutes within the kidney and urinary tract (Figure 4). Both X-ray and ultrasound imaging should be used to identify kidney and prostate stones in the setting of abdominal or genitourinary pain or infection. Patients with diminished renal function may manifest a more severe and rapidly progressing form of alkaptonuria that exacerbates symptoms and complications, but direct damage to the kidneys by HGA is not evident.

Conclusion

Alkaptonuria is a rare autosomal recessive metabolic disorder that has a progressively debilitating pathophysiologic course spanning decades of a patient’s life. Its low prevalence and gradually progressive nature make it a difficult diagnosis to make without clinical suspicion. In patients with early-onset degenerative joint disease, tendinopathy, and cartilage or skin discoloration, congenital metabolic disorders like alkaptonuria should be considered.

As this case shows, suspicion and diagnosis can occur during surgical intervention in which tendon discoloration is directly visualized, especially in patients without prominent skin or cartilage discoloration. Once the diagnosis is made through elevated levels of urine HGA, there are 3 management strategies, including decreasing homogentisic acid buildup, providing symptom management, and monitoring for arthropathic, CV, and genitourinary complications.

Alkaptonuria is a rare autosomal recessive disorder uniquely known for causing black, or darkened, urine when left standing due to the renal excretion of excess homogentisic acid (HGA). When this disorder goes undiagnosed, as demonstrated in this case, patients experience its many complications without a unifying explanation. The disorder has 3 clinical stages that occur in a predictable order: clinical silence, clinical ochronosis, and ochronotic arthropathy. These stages lead to multiple musculoskeletal, cardiovascular (CV), and renal complications that can be mitigated with management focused on decreasing homogentisic acid buildup, alleviating symptoms, and close monitoring for these complications.

Case Presentation

A 61-year-old African American male with a medical history of multiple traumatic fractures, right Achilles tendon injury, early-onset multijoint osteoarthritis, chronic low back pain, and recurrent nephrolithiasis presented to the emergency department with sudden onset of sharp left ankle pain while moving furniture. His physical exam revealed a positive Thompson test—lack of foot plantar flexion with calf squeeze—and a subsequent magnetic resonance image (MRI) showed evidence of an acute Achilles tendon rupture.

Given these findings the patient was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and rest to allow for resolution of swelling and inflammation, followed by elective surgery a month later to repair the ruptured tendon. An operative report following his surgery described “black ends to the area where the Achilles was ruptured…and tendinopathy of the flexor hallucis longus with blackening of the flexor.”

A more in-depth patient history revealed that he underwent multiple invasive and noninvasive interventions for his chronic low back and joint pain with medical management of a prior right Achilles tendon injury. His medical history also included multiple nonspecific diagnoses, such as premature atherosclerosis (diagnosed in his third decade), severe lumbar degenerative disc disease, several tendonopathies and cartilage injuries (Figure 1), pseudogout (following calcium pyrophosphate dehydrate crystals found from a left knee aspirate), and chronic pain syndrome. Along this diagnostic journey, he had several health care providers (HCPs) in rheumatology, orthopedic surgery, pain management, and podiatry who offered a range of symptom management options, including physical therapy, NSAIDs, opioid agonists, tricyclic antidepressants, gabapentin, colchicine, and epidural steroid injections, all of which provided little or no relief of his pain. The patient reported that he told a HCP, “I’ll just live with [the pain].”

At the postsurgery follow-up, the patient reported that he had noticed dark urine and dark spots on his ears in the past. He also recounted that chronic joint pain was common in his family, with both his mother and brother receiving bilateral total knee replacements. Taking into consideration the surgical report and this new history, a urine assessment for HGA was ordered and yielded a diagnosis of alkaptonuria. 

He later suffered an acute myocardial infarction leading to an incidental discovery of severe aortic stenosis on echocardiography, requiring coronary stent placements and transcatheter aortic valve replacement, respectively. He reported that with CV interventions and joint replacement surgeries, including bilateral knees and hips, his symptoms and quality of life began to significantly improve. However, he continued to have diffuse chronic joint pain unimproved with any single agent or intervention.

Discussion

Alkaptonuria is a rare autosomal recessive disorder, with a prevalence of about 1 in 100,000 to 250,000, which results from an enzyme error in an essential amino acid metabolism pathway (Figure 2).¹ This inheritable gene mutation leads to ineffective homogentisate 1,2-dioxygenase (HGD), an enzyme required to break down HGA—which is a product of phenylalanine and tyrosine metabolism.² As these patients engage in normal dietary protein intake, which includes essential amino acid phenylalanine, they develop clinically evident manifestations of the buildup and deposition of HGA.

The rarity of alkaptonuria combined with the gradual buildup of HGA makes it difficult to diagnose. A common diagnostic technique is the visualization of discolored cartilage during surgical procedures, especially when discoloration in urine or skin is not immediately evident. A few case reports have noted surgical diagnosis of black or darkening tissue, known as ochronosis, following tendon rupture—a common complication of this disorder.^3-5 Additional intervention-related case reports linked to the discovery of ochronosis include aortic valve replacement, lumbar discectomy, and bronchoscopy.^6-9 Cases like these illustrate the complex, disabling, and unclear nature of this disorder when not diagnosed early in life.

The patient in this case communicated via e-mail about his tendon repair surgery. “Something very interesting was found during the surgery,” the patient explained. “I was diagnosed with the disease called ochronosis. I don’t know much about this disease but I am beginning to know why some of the things are happening to me and why I am always in constant pain.” This was the first recognized clue toward a diagnosis of alkaptonuria.

Pathophysiology

The pathophysiology of alkaptonuria is based on the extensive deposition of HGA throughout the body. Its progression is based on 3 clinical stages: clinical silence, clinical ochronosis, and ochronotic arthropathy.¹ In the first stage the disorder is asymptomatic but includes its most notable feature—the gradual darkening of urine when exposed to air through oxidation of the renally excreted HGA. A similar process occurs in the blood through formed HGA-melanin compounds, which cause discoloration in cartilage.¹ This internal metabolic disruption accounts for the disorder’s eventual second stage, clinical ochronosis, usually with an onset in the second or third decade. Prominent features noted on physical examination primarily include discoloration of ear pinnae and eye sclera but can involve the nose, gums, teeth, and hands. The third, final, and symptomatic stage, ochronotic arthropathy, occurs by the patient’s fourth to fifth decade and presents as joint pain, usually starting with the vertebrae and larger joints like hips, knees, and shoulders, that can appear as advanced early osteoarthritis on imaging.

Treatment

This clinical manifestation of alkaptonuria requires that HCPs manage patients with 3 strategies: decrease HGA buildup, alleviate symptoms, and monitor for disorder complications. Decreasing HGA buildup is a difficult aspect of management given the natural physiology of protein intake and metabolism. Three approaches to limit HGA buildup incorporate decreasing protein intake, inhibiting enzyme production of HGA, and increasing HGA excretion. Phenylalanine is an essential amino acid—meaning its levels are dependent on dietary protein intake. Patients should be advised to adhere to a low protein diet, especially phenylalanine and tyrosine, to lessen HGA concentrations.

Manipulating the metabolic pathway of phenylalanine with medication is a second option. An example of this is nitisinone, a US Food and Drug Administration-approved medication for treatment of tyrosinemia. It acts by inhibiting hydroxyphenylpyruvic acid dioxygenase, one of the enzymes that converts tyrosine into HGA, to prevent the buildup of damaging tyrosine byproducts. At low doses it has been effective in decreasing HGA concentrations in alkaptonuria and tyrosinemia.^10,11 Due to this mechanism of action, nitisinone directly causes increased tyrosine levels. Therefore, tyrosine toxicity, usually not predicted by tyrosine levels, has been associated with eye-related adverse effects (AEs), including keratopathy, diminished visual acuity, and corneal tissue damage.^1,2,10 Incidence of these AEs have not been clearly documented, but routine monitoring should include patient education on ocular symptoms and slit-lamp examinations.¹²

In addition, case reports have shown that high-dose ascorbic acid (vitamin C) promotes HGA, tyrosine, and phenylalanine excretion in urine, which may slow the progression of alkaptonuria, but clinical effect has not been proven.¹³ Additionally, high vitamin C intake is considered a risk factor for nephrolithiasis, which must be balanced with the increased risk of stone formation from HGA excretion.¹⁴ These dietary and medical options can be considered, especially in the setting of severe symptoms or complications, but the risks must be discussed with patients.

A second and commonly utilized strategy for caring for these patients is symptom management. As demonstrated through this case report, there is no clear medication that adequately addresses the pain caused by HGA deposition. Patients should be referred to a pain specialist to allow for single provider prescribing of pain medications. This patient found most relief and least AEs with tramadol but eventually self-discontinued due to diminishing pain relief. Given the eventual involvement of large joints, these patients will often require further symptom management with joint replacement surgery, usually much earlier than patients who undergo these surgeries for age-related osteoarthritis. The imperative aspect of symptom management is to engage patients in shared decision making with clear expectation setting.

Given the progressive nature of alkaptonuria, providers must monitor and address complications that are a result of this disorder. HGA becomes pathologic by binding to and weakening collagen fibers.⁵ This gradual buildup leads to degenerative changes in weight-bearing lower vertebrae and large joints that can become severe. Due to HGA’s interaction with collagen fibers, tendon involvement leading to inflammation, calcification, and rupture can result as patients enter the third stage, ochronotic arthropathy, of the disorder (Figure 3).¹⁵ Many of these arthropathies will require medical and surgical management and can be urgent in situations like tendon ruptures and meniscal tears. Understanding the pathophysiology of tendinopathies in patients with alkaptonuria also can aid orthopedic surgeons during the postoperative period where patients may be at risk for poor healing.⁵

A second area of complications includes CV involvement. This patient was diagnosed with premature atherosclerosis and underwent cardiac interventions, including coronary stent placement and valve replacements at age 63 years. This early cardiac involvement was likely due in part to the deposition of HGA and collagen injury in CV tissue leading to damage of the endocardium, aortic intima, heart valves, and coronary arteries.¹ HCPs should monitor for these manifestations with regular visits, chest computed tomography, and echocardiographic studies.²

The most classic aspect of this rare disorder is urine darkening due to the renal excretion of HGA and comprises the third area of complications. This process leads to chronically acidic urine—every urinalysis in this patient’s chart displayed the lowest pH measurable—and an increased risk for calcification and precipitation of solutes within the kidney and urinary tract (Figure 4). Both X-ray and ultrasound imaging should be used to identify kidney and prostate stones in the setting of abdominal or genitourinary pain or infection. Patients with diminished renal function may manifest a more severe and rapidly progressing form of alkaptonuria that exacerbates symptoms and complications, but direct damage to the kidneys by HGA is not evident.

Conclusion

Alkaptonuria is a rare autosomal recessive metabolic disorder that has a progressively debilitating pathophysiologic course spanning decades of a patient’s life. Its low prevalence and gradually progressive nature make it a difficult diagnosis to make without clinical suspicion. In patients with early-onset degenerative joint disease, tendinopathy, and cartilage or skin discoloration, congenital metabolic disorders like alkaptonuria should be considered.

As this case shows, suspicion and diagnosis can occur during surgical intervention in which tendon discoloration is directly visualized, especially in patients without prominent skin or cartilage discoloration. Once the diagnosis is made through elevated levels of urine HGA, there are 3 management strategies, including decreasing homogentisic acid buildup, providing symptom management, and monitoring for arthropathic, CV, and genitourinary complications.

Alkaptonuria is a rare autosomal recessive disorder uniquely known for causing black, or darkened, urine when left standing due to the renal excretion of excess homogentisic acid (HGA). When this disorder goes undiagnosed, as demonstrated in this case, patients experience its many complications without a unifying explanation. The disorder has 3 clinical stages that occur in a predictable order: clinical silence, clinical ochronosis, and ochronotic arthropathy. These stages lead to multiple musculoskeletal, cardiovascular (CV), and renal complications that can be mitigated with management focused on decreasing homogentisic acid buildup, alleviating symptoms, and close monitoring for these complications.

Case Presentation

A 61-year-old African American male with a medical history of multiple traumatic fractures, right Achilles tendon injury, early-onset multijoint osteoarthritis, chronic low back pain, and recurrent nephrolithiasis presented to the emergency department with sudden onset of sharp left ankle pain while moving furniture. His physical exam revealed a positive Thompson test—lack of foot plantar flexion with calf squeeze—and a subsequent magnetic resonance image (MRI) showed evidence of an acute Achilles tendon rupture.

Given these findings the patient was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and rest to allow for resolution of swelling and inflammation, followed by elective surgery a month later to repair the ruptured tendon. An operative report following his surgery described “black ends to the area where the Achilles was ruptured…and tendinopathy of the flexor hallucis longus with blackening of the flexor.”

A more in-depth patient history revealed that he underwent multiple invasive and noninvasive interventions for his chronic low back and joint pain with medical management of a prior right Achilles tendon injury. His medical history also included multiple nonspecific diagnoses, such as premature atherosclerosis (diagnosed in his third decade), severe lumbar degenerative disc disease, several tendonopathies and cartilage injuries (Figure 1), pseudogout (following calcium pyrophosphate dehydrate crystals found from a left knee aspirate), and chronic pain syndrome. Along this diagnostic journey, he had several health care providers (HCPs) in rheumatology, orthopedic surgery, pain management, and podiatry who offered a range of symptom management options, including physical therapy, NSAIDs, opioid agonists, tricyclic antidepressants, gabapentin, colchicine, and epidural steroid injections, all of which provided little or no relief of his pain. The patient reported that he told a HCP, “I’ll just live with [the pain].”

At the postsurgery follow-up, the patient reported that he had noticed dark urine and dark spots on his ears in the past. He also recounted that chronic joint pain was common in his family, with both his mother and brother receiving bilateral total knee replacements. Taking into consideration the surgical report and this new history, a urine assessment for HGA was ordered and yielded a diagnosis of alkaptonuria. 

He later suffered an acute myocardial infarction leading to an incidental discovery of severe aortic stenosis on echocardiography, requiring coronary stent placements and transcatheter aortic valve replacement, respectively. He reported that with CV interventions and joint replacement surgeries, including bilateral knees and hips, his symptoms and quality of life began to significantly improve. However, he continued to have diffuse chronic joint pain unimproved with any single agent or intervention.

Discussion

Alkaptonuria is a rare autosomal recessive disorder, with a prevalence of about 1 in 100,000 to 250,000, which results from an enzyme error in an essential amino acid metabolism pathway (Figure 2).¹ This inheritable gene mutation leads to ineffective homogentisate 1,2-dioxygenase (HGD), an enzyme required to break down HGA—which is a product of phenylalanine and tyrosine metabolism.² As these patients engage in normal dietary protein intake, which includes essential amino acid phenylalanine, they develop clinically evident manifestations of the buildup and deposition of HGA.

The rarity of alkaptonuria combined with the gradual buildup of HGA makes it difficult to diagnose. A common diagnostic technique is the visualization of discolored cartilage during surgical procedures, especially when discoloration in urine or skin is not immediately evident. A few case reports have noted surgical diagnosis of black or darkening tissue, known as ochronosis, following tendon rupture—a common complication of this disorder.^3-5 Additional intervention-related case reports linked to the discovery of ochronosis include aortic valve replacement, lumbar discectomy, and bronchoscopy.^6-9 Cases like these illustrate the complex, disabling, and unclear nature of this disorder when not diagnosed early in life.

The patient in this case communicated via e-mail about his tendon repair surgery. “Something very interesting was found during the surgery,” the patient explained. “I was diagnosed with the disease called ochronosis. I don’t know much about this disease but I am beginning to know why some of the things are happening to me and why I am always in constant pain.” This was the first recognized clue toward a diagnosis of alkaptonuria.

Pathophysiology

The pathophysiology of alkaptonuria is based on the extensive deposition of HGA throughout the body. Its progression is based on 3 clinical stages: clinical silence, clinical ochronosis, and ochronotic arthropathy.¹ In the first stage the disorder is asymptomatic but includes its most notable feature—the gradual darkening of urine when exposed to air through oxidation of the renally excreted HGA. A similar process occurs in the blood through formed HGA-melanin compounds, which cause discoloration in cartilage.¹ This internal metabolic disruption accounts for the disorder’s eventual second stage, clinical ochronosis, usually with an onset in the second or third decade. Prominent features noted on physical examination primarily include discoloration of ear pinnae and eye sclera but can involve the nose, gums, teeth, and hands. The third, final, and symptomatic stage, ochronotic arthropathy, occurs by the patient’s fourth to fifth decade and presents as joint pain, usually starting with the vertebrae and larger joints like hips, knees, and shoulders, that can appear as advanced early osteoarthritis on imaging.

Treatment

This clinical manifestation of alkaptonuria requires that HCPs manage patients with 3 strategies: decrease HGA buildup, alleviate symptoms, and monitor for disorder complications. Decreasing HGA buildup is a difficult aspect of management given the natural physiology of protein intake and metabolism. Three approaches to limit HGA buildup incorporate decreasing protein intake, inhibiting enzyme production of HGA, and increasing HGA excretion. Phenylalanine is an essential amino acid—meaning its levels are dependent on dietary protein intake. Patients should be advised to adhere to a low protein diet, especially phenylalanine and tyrosine, to lessen HGA concentrations.

Manipulating the metabolic pathway of phenylalanine with medication is a second option. An example of this is nitisinone, a US Food and Drug Administration-approved medication for treatment of tyrosinemia. It acts by inhibiting hydroxyphenylpyruvic acid dioxygenase, one of the enzymes that converts tyrosine into HGA, to prevent the buildup of damaging tyrosine byproducts. At low doses it has been effective in decreasing HGA concentrations in alkaptonuria and tyrosinemia.^10,11 Due to this mechanism of action, nitisinone directly causes increased tyrosine levels. Therefore, tyrosine toxicity, usually not predicted by tyrosine levels, has been associated with eye-related adverse effects (AEs), including keratopathy, diminished visual acuity, and corneal tissue damage.^1,2,10 Incidence of these AEs have not been clearly documented, but routine monitoring should include patient education on ocular symptoms and slit-lamp examinations.¹²

In addition, case reports have shown that high-dose ascorbic acid (vitamin C) promotes HGA, tyrosine, and phenylalanine excretion in urine, which may slow the progression of alkaptonuria, but clinical effect has not been proven.¹³ Additionally, high vitamin C intake is considered a risk factor for nephrolithiasis, which must be balanced with the increased risk of stone formation from HGA excretion.¹⁴ These dietary and medical options can be considered, especially in the setting of severe symptoms or complications, but the risks must be discussed with patients.

A second and commonly utilized strategy for caring for these patients is symptom management. As demonstrated through this case report, there is no clear medication that adequately addresses the pain caused by HGA deposition. Patients should be referred to a pain specialist to allow for single provider prescribing of pain medications. This patient found most relief and least AEs with tramadol but eventually self-discontinued due to diminishing pain relief. Given the eventual involvement of large joints, these patients will often require further symptom management with joint replacement surgery, usually much earlier than patients who undergo these surgeries for age-related osteoarthritis. The imperative aspect of symptom management is to engage patients in shared decision making with clear expectation setting.

Given the progressive nature of alkaptonuria, providers must monitor and address complications that are a result of this disorder. HGA becomes pathologic by binding to and weakening collagen fibers.⁵ This gradual buildup leads to degenerative changes in weight-bearing lower vertebrae and large joints that can become severe. Due to HGA’s interaction with collagen fibers, tendon involvement leading to inflammation, calcification, and rupture can result as patients enter the third stage, ochronotic arthropathy, of the disorder (Figure 3).¹⁵ Many of these arthropathies will require medical and surgical management and can be urgent in situations like tendon ruptures and meniscal tears. Understanding the pathophysiology of tendinopathies in patients with alkaptonuria also can aid orthopedic surgeons during the postoperative period where patients may be at risk for poor healing.⁵

A second area of complications includes CV involvement. This patient was diagnosed with premature atherosclerosis and underwent cardiac interventions, including coronary stent placement and valve replacements at age 63 years. This early cardiac involvement was likely due in part to the deposition of HGA and collagen injury in CV tissue leading to damage of the endocardium, aortic intima, heart valves, and coronary arteries.¹ HCPs should monitor for these manifestations with regular visits, chest computed tomography, and echocardiographic studies.²

The most classic aspect of this rare disorder is urine darkening due to the renal excretion of HGA and comprises the third area of complications. This process leads to chronically acidic urine—every urinalysis in this patient’s chart displayed the lowest pH measurable—and an increased risk for calcification and precipitation of solutes within the kidney and urinary tract (Figure 4). Both X-ray and ultrasound imaging should be used to identify kidney and prostate stones in the setting of abdominal or genitourinary pain or infection. Patients with diminished renal function may manifest a more severe and rapidly progressing form of alkaptonuria that exacerbates symptoms and complications, but direct damage to the kidneys by HGA is not evident.

Conclusion

Alkaptonuria is a rare autosomal recessive metabolic disorder that has a progressively debilitating pathophysiologic course spanning decades of a patient’s life. Its low prevalence and gradually progressive nature make it a difficult diagnosis to make without clinical suspicion. In patients with early-onset degenerative joint disease, tendinopathy, and cartilage or skin discoloration, congenital metabolic disorders like alkaptonuria should be considered.

As this case shows, suspicion and diagnosis can occur during surgical intervention in which tendon discoloration is directly visualized, especially in patients without prominent skin or cartilage discoloration. Once the diagnosis is made through elevated levels of urine HGA, there are 3 management strategies, including decreasing homogentisic acid buildup, providing symptom management, and monitoring for arthropathic, CV, and genitourinary complications.

Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.

►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.¹ Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis. 

To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.¹ And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.

►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient? 

►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.

It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.¹ The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.¹

►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?

►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.

►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?

►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).

Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.²

This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.

►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?

►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.³

^►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?

►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.⁴

►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.

Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.

►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.¹ Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis. 

To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.¹ And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.

►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient? 

►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.

It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.¹ The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.¹

►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?

►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.

►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?

►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).

Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.²

This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.

►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?

►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.³

^►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?

►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.⁴

►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.

Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.

►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.¹ Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis. 

To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.¹ And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.

►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient? 

►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.

It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.¹ The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.¹

►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?

►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.

►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?

►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).

Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.²

This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.

►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?

►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.³

^►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?

►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.⁴

►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a key co-stimulatory receptor expressed on activated T cells that negatively regulates T-cell activation.^1-3 It exerts its effects in part by the prevention of IL-2 transcription and inhibition of cell-cycle progression.⁴ Cytotoxic T-lymphocyte–associated antigen 4 also is expressed by a subset of CD25⁺CD4⁺ regulatory T cells (Tregs), where it plays a role in immune tolerance.⁵ Blockade has demonstrated antitumor activity as well as immune activation, and CTLA-4 dysregulation has been implicated in autoimmune diseases such as alopecia areata (AA).⁶

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4 and one of a growing class of immune checkpoint inhibitor therapies for metastatic melanoma. Phase 2 and 3 clinical trials have shown an improved survival effect of ipilimumab in patients with advanced melanoma,^7-10 with 3-year survival rates ranging from 20.8% to 46.5%.^10,11 The US Food and Drug Administration approved ipilimumab in 2011 for treatment of unresectable or metastatic melanoma.¹² The most common toxicities of ipilimumab are immune-related adverse effects (irAEs), which represent loss of tolerance to self-antigens.¹³ Immune-related adverse effects occur in 64.2% of patients,¹⁴ with severe or life-threatening irAEs in 17.8% of patients.¹⁴ Rates of irAEs appear dose dependent but consistent across increased doses.¹⁵ Cutaneous irAEs occur in more than 47% of patients¹⁶ and commonly manifest as pruritus with or without a diffuse morbilliform rash,^10,17 though less common skin reactions, including vitiligo, vasculitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis, have been documented.^9,18

Generalized AA and its more widespread variant, alopecia universalis, have been reported as adverse effects of ipilimumab monotherapy in 2 prior cases in the English-language literature (Table).^17,19 Alopecia areata also has been attributed to combination immune checkpoint inhibitor therapy.^20,21 We report a case of AA attributable to ipilimumab monotherapy that was localized exclusively to the scalp and remote in onset following treatment.

Case Report

An 88-year-old man with pT3bpN3 nodular melanoma of the back demonstrated multiple lung metastases by positron emission tomography–computed tomography. Lactate dehydrogenase was within reference range, and his Eastern Cooperative Oncology Group performance status was 0 (fully active). One month later, he was started on ipilimumab 3 mg/kg intravenous infusion every 3 weeks for a total of 4 doses. At approximately week 6, his course was complicated by mild fatigue, a faintly erythematous morbilliform rash, and mild pruritus, with laboratory evidence of subclinical hyperthyroidism. Follow-up positron emission tomography–computed tomography at the conclusion of treatment demonstrated complete regression of previously noted hypermetabolic foci. His symptoms and subclinical hyperthyroidism resolved several months later.

Seventeen months after completion of ipilimumab therapy (at age 90 years), the patient’s barber noted new-onset hair loss on the right occipital scalp. Physical examination demonstrated a well-circumscribed patch of nonscarring alopecia (approximately 6 cm) that was clinically consistent with AA (Figure). There were no associated symptoms or other involved areas of hair loss. He denied any personal or family history of AA. The patient’s melanoma has remained in remission to date.

Comment

This case is unique in that AA was localized to a single circumscribed patch on the scalp and occurred nearly 1.5 years after treatment with ipilimumab, which may indicate a robust blockade of CTLA-4 given the remote development of autoimmunity in the setting of persistent remission of melanoma. Although the appearance of AA may be coincidental, onset at 90 years of age would be unusual. The mean age of onset of AA has been reported between 25.2 and 36.3 years,^22,23 and its incidence in men older than 60 years is only 6.4 per 100,000 person-years.²⁴

Although AA is a rare irAE of CTLA-4 blockade, the disease has been increasingly linked to CTLA-4 dysregulation in both animal models and humans.^6,25,26 A genome-wide association study of 1054 patients with AA and 3278 controls implicated several genes controlling activation and proliferation of Tregs, including CTLA-4.²⁷ More specifically, single-nucleotide polymorphisms of the CTLA-4 gene were found to be associated with AA in a study of 1196 unrelated patients and 1280 controls,²⁸ and Megiorni et al²⁹ identified a single-nucleotide polymorphism of CTLA-4, CT60, as a contributory genetic determinant of AA in Italian patients.

Given the role of CTLA-4 dysregulation in the pathogenesis of AA, the very low rates of AA in ipilimumab are somewhat surprising, which may represent a reporting bias. Alternatively, there may be sufficient Treg activity to prevent high rates of AA at a lower ipilimumab dose of 3 mg/kg but insufficient activity to prevent development of other irAEs. With US Food and Drug Administration approval of ipilimumab at a higher dose of 10 mg/kg for use as adjuvant therapy for stage III melanomas,¹² less common cutaneous irAEs such as AA may be seen with increased frequency. Clinicians planning ipilimumab therapy should discuss this side effect and other potential irAEs with their patients before initiation of treatment.

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a key co-stimulatory receptor expressed on activated T cells that negatively regulates T-cell activation.^1-3 It exerts its effects in part by the prevention of IL-2 transcription and inhibition of cell-cycle progression.⁴ Cytotoxic T-lymphocyte–associated antigen 4 also is expressed by a subset of CD25⁺CD4⁺ regulatory T cells (Tregs), where it plays a role in immune tolerance.⁵ Blockade has demonstrated antitumor activity as well as immune activation, and CTLA-4 dysregulation has been implicated in autoimmune diseases such as alopecia areata (AA).⁶

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4 and one of a growing class of immune checkpoint inhibitor therapies for metastatic melanoma. Phase 2 and 3 clinical trials have shown an improved survival effect of ipilimumab in patients with advanced melanoma,^7-10 with 3-year survival rates ranging from 20.8% to 46.5%.^10,11 The US Food and Drug Administration approved ipilimumab in 2011 for treatment of unresectable or metastatic melanoma.¹² The most common toxicities of ipilimumab are immune-related adverse effects (irAEs), which represent loss of tolerance to self-antigens.¹³ Immune-related adverse effects occur in 64.2% of patients,¹⁴ with severe or life-threatening irAEs in 17.8% of patients.¹⁴ Rates of irAEs appear dose dependent but consistent across increased doses.¹⁵ Cutaneous irAEs occur in more than 47% of patients¹⁶ and commonly manifest as pruritus with or without a diffuse morbilliform rash,^10,17 though less common skin reactions, including vitiligo, vasculitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis, have been documented.^9,18

Generalized AA and its more widespread variant, alopecia universalis, have been reported as adverse effects of ipilimumab monotherapy in 2 prior cases in the English-language literature (Table).^17,19 Alopecia areata also has been attributed to combination immune checkpoint inhibitor therapy.^20,21 We report a case of AA attributable to ipilimumab monotherapy that was localized exclusively to the scalp and remote in onset following treatment.

Case Report

An 88-year-old man with pT3bpN3 nodular melanoma of the back demonstrated multiple lung metastases by positron emission tomography–computed tomography. Lactate dehydrogenase was within reference range, and his Eastern Cooperative Oncology Group performance status was 0 (fully active). One month later, he was started on ipilimumab 3 mg/kg intravenous infusion every 3 weeks for a total of 4 doses. At approximately week 6, his course was complicated by mild fatigue, a faintly erythematous morbilliform rash, and mild pruritus, with laboratory evidence of subclinical hyperthyroidism. Follow-up positron emission tomography–computed tomography at the conclusion of treatment demonstrated complete regression of previously noted hypermetabolic foci. His symptoms and subclinical hyperthyroidism resolved several months later.

Seventeen months after completion of ipilimumab therapy (at age 90 years), the patient’s barber noted new-onset hair loss on the right occipital scalp. Physical examination demonstrated a well-circumscribed patch of nonscarring alopecia (approximately 6 cm) that was clinically consistent with AA (Figure). There were no associated symptoms or other involved areas of hair loss. He denied any personal or family history of AA. The patient’s melanoma has remained in remission to date.

Comment

This case is unique in that AA was localized to a single circumscribed patch on the scalp and occurred nearly 1.5 years after treatment with ipilimumab, which may indicate a robust blockade of CTLA-4 given the remote development of autoimmunity in the setting of persistent remission of melanoma. Although the appearance of AA may be coincidental, onset at 90 years of age would be unusual. The mean age of onset of AA has been reported between 25.2 and 36.3 years,^22,23 and its incidence in men older than 60 years is only 6.4 per 100,000 person-years.²⁴

Although AA is a rare irAE of CTLA-4 blockade, the disease has been increasingly linked to CTLA-4 dysregulation in both animal models and humans.^6,25,26 A genome-wide association study of 1054 patients with AA and 3278 controls implicated several genes controlling activation and proliferation of Tregs, including CTLA-4.²⁷ More specifically, single-nucleotide polymorphisms of the CTLA-4 gene were found to be associated with AA in a study of 1196 unrelated patients and 1280 controls,²⁸ and Megiorni et al²⁹ identified a single-nucleotide polymorphism of CTLA-4, CT60, as a contributory genetic determinant of AA in Italian patients.

Given the role of CTLA-4 dysregulation in the pathogenesis of AA, the very low rates of AA in ipilimumab are somewhat surprising, which may represent a reporting bias. Alternatively, there may be sufficient Treg activity to prevent high rates of AA at a lower ipilimumab dose of 3 mg/kg but insufficient activity to prevent development of other irAEs. With US Food and Drug Administration approval of ipilimumab at a higher dose of 10 mg/kg for use as adjuvant therapy for stage III melanomas,¹² less common cutaneous irAEs such as AA may be seen with increased frequency. Clinicians planning ipilimumab therapy should discuss this side effect and other potential irAEs with their patients before initiation of treatment.

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) is a key co-stimulatory receptor expressed on activated T cells that negatively regulates T-cell activation.^1-3 It exerts its effects in part by the prevention of IL-2 transcription and inhibition of cell-cycle progression.⁴ Cytotoxic T-lymphocyte–associated antigen 4 also is expressed by a subset of CD25⁺CD4⁺ regulatory T cells (Tregs), where it plays a role in immune tolerance.⁵ Blockade has demonstrated antitumor activity as well as immune activation, and CTLA-4 dysregulation has been implicated in autoimmune diseases such as alopecia areata (AA).⁶

Ipilimumab is a fully humanized monoclonal antibody against CTLA-4 and one of a growing class of immune checkpoint inhibitor therapies for metastatic melanoma. Phase 2 and 3 clinical trials have shown an improved survival effect of ipilimumab in patients with advanced melanoma,^7-10 with 3-year survival rates ranging from 20.8% to 46.5%.^10,11 The US Food and Drug Administration approved ipilimumab in 2011 for treatment of unresectable or metastatic melanoma.¹² The most common toxicities of ipilimumab are immune-related adverse effects (irAEs), which represent loss of tolerance to self-antigens.¹³ Immune-related adverse effects occur in 64.2% of patients,¹⁴ with severe or life-threatening irAEs in 17.8% of patients.¹⁴ Rates of irAEs appear dose dependent but consistent across increased doses.¹⁵ Cutaneous irAEs occur in more than 47% of patients¹⁶ and commonly manifest as pruritus with or without a diffuse morbilliform rash,^10,17 though less common skin reactions, including vitiligo, vasculitis, and Stevens-Johnson syndrome/toxic epidermal necrolysis, have been documented.^9,18

Generalized AA and its more widespread variant, alopecia universalis, have been reported as adverse effects of ipilimumab monotherapy in 2 prior cases in the English-language literature (Table).^17,19 Alopecia areata also has been attributed to combination immune checkpoint inhibitor therapy.^20,21 We report a case of AA attributable to ipilimumab monotherapy that was localized exclusively to the scalp and remote in onset following treatment.

Case Report

An 88-year-old man with pT3bpN3 nodular melanoma of the back demonstrated multiple lung metastases by positron emission tomography–computed tomography. Lactate dehydrogenase was within reference range, and his Eastern Cooperative Oncology Group performance status was 0 (fully active). One month later, he was started on ipilimumab 3 mg/kg intravenous infusion every 3 weeks for a total of 4 doses. At approximately week 6, his course was complicated by mild fatigue, a faintly erythematous morbilliform rash, and mild pruritus, with laboratory evidence of subclinical hyperthyroidism. Follow-up positron emission tomography–computed tomography at the conclusion of treatment demonstrated complete regression of previously noted hypermetabolic foci. His symptoms and subclinical hyperthyroidism resolved several months later.

Seventeen months after completion of ipilimumab therapy (at age 90 years), the patient’s barber noted new-onset hair loss on the right occipital scalp. Physical examination demonstrated a well-circumscribed patch of nonscarring alopecia (approximately 6 cm) that was clinically consistent with AA (Figure). There were no associated symptoms or other involved areas of hair loss. He denied any personal or family history of AA. The patient’s melanoma has remained in remission to date.

Comment

This case is unique in that AA was localized to a single circumscribed patch on the scalp and occurred nearly 1.5 years after treatment with ipilimumab, which may indicate a robust blockade of CTLA-4 given the remote development of autoimmunity in the setting of persistent remission of melanoma. Although the appearance of AA may be coincidental, onset at 90 years of age would be unusual. The mean age of onset of AA has been reported between 25.2 and 36.3 years,^22,23 and its incidence in men older than 60 years is only 6.4 per 100,000 person-years.²⁴

Although AA is a rare irAE of CTLA-4 blockade, the disease has been increasingly linked to CTLA-4 dysregulation in both animal models and humans.^6,25,26 A genome-wide association study of 1054 patients with AA and 3278 controls implicated several genes controlling activation and proliferation of Tregs, including CTLA-4.²⁷ More specifically, single-nucleotide polymorphisms of the CTLA-4 gene were found to be associated with AA in a study of 1196 unrelated patients and 1280 controls,²⁸ and Megiorni et al²⁹ identified a single-nucleotide polymorphism of CTLA-4, CT60, as a contributory genetic determinant of AA in Italian patients.

Given the role of CTLA-4 dysregulation in the pathogenesis of AA, the very low rates of AA in ipilimumab are somewhat surprising, which may represent a reporting bias. Alternatively, there may be sufficient Treg activity to prevent high rates of AA at a lower ipilimumab dose of 3 mg/kg but insufficient activity to prevent development of other irAEs. With US Food and Drug Administration approval of ipilimumab at a higher dose of 10 mg/kg for use as adjuvant therapy for stage III melanomas,¹² less common cutaneous irAEs such as AA may be seen with increased frequency. Clinicians planning ipilimumab therapy should discuss this side effect and other potential irAEs with their patients before initiation of treatment.

Blastomycosis is a systemic fungal infection that is endemic in the South Central, Midwest, and southeastern regions of the United States, as well as in provinces of Canada bordering the Great Lakes. After inhalation of Blastomyces dermatitidis spores, which are taken up by bronchopulmonary macrophages, there is an approximate 30- to 45-day incubation period. The initial response at the infected site is suppurative, which progresses to granuloma formation. Blastomyces dermatitidis most commonly infects the lungs, followed by the skin, bones, prostate, and central nervous system (CNS). Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent.

We present the case of a 38-year-old man with a medical history of human immunodeficiency virus (HIV) infection and AIDS who reported a 3- to 4-week history of respiratory and cutaneous symptoms. Initial clinical impression favored secondary syphilis; however, after laboratory evaluation and lack of response to treatment for syphilis, further investigation revealed a diagnosis of widespread cutaneous North American blastomycosis.

Case Report

A 38-year-old man with a medical history of HIV infection and AIDS presented to the emergency department at a medical center in Minneapolis, Minnesota, with a cough; chest discomfort; and concomitant nonpainful, mildly pruritic papules and plaques of 3 to 4 weeks’ duration that initially appeared on the face and ears and spread to the trunk, arms, palms, legs, and feet. He had a nonpainful ulcer on the glans penis. Symptoms began while he was living in Atlanta, Georgia, before relocating to Minneapolis. A chest radiograph was negative.

The initial clinical impression favored secondary syphilis. Intramuscular penicillin G benzathine (2.4 million U) weekly for 3 weeks was initiated by the primary care team based on clinical suspicion alone without laboratory evidence of a positive rapid plasma reagin or VDRL test. Because laboratory evaluation and lack of response to treatment did not support syphilis, dermatology consultation was requested.

The patient had a history of crack cocaine abuse. He reported sexual activity with a single female partner while living in a halfway house in the Minneapolis–St. Paul area. Physical examination showed an age-appropriate man in no acute distress who was alert and oriented. He had well-demarcated papules and plaques on the forehead, ears, nose, cutaneous and mucosal lips, chest, back, arms, legs, palms, and soles. Many of the facial papules were pink, nonscaly, and concentrated around the nose and mouth; some were umbilicated (Figure 1). Trunk and extensor papules and plaques were well demarcated, oval, and scaly; some had erosions centrally and were excoriated. Palmar papules were round and had peripheral brown hyperpigmentation and central scale (Figure 2). A 1-cm, shallow, nontender, oval ulceration withraised borders was located on the glans penis under the foreskin (Figure 3).

A rapid plasma reagin test was nonreactive; a fluorescent treponemal antibody absorption test was negative. Chest radiograph, magnetic resonance imaging, and electroencephalogram were normal. In addition, spinal fluid drawn from a tap was negative on India ink and Gram stain preparations and was negative for cryptococcal antigen. In addition, spinal fluid was negative for fungal and bacterial growth, as were blood cultures.

Abnormal tests included a positive enzyme-linked immunosorbent assay and Western blot test for HIV, with an absolute CD4 count of 6 cells/mL and a viral load more than 100,000 copies/mL. Urine histoplasmosis antigen was markedly elevated. A potassium hydroxide preparation was performed on the skin of the right forearm, revealing broad-based budding yeast, later confirmed on skin and sputum cultures to be B dermatitidis.

Punch biopsy from the upper back revealed a mixed acute and granulomatous infiltrate with numerous yeast forms (Figure 4A) that were highlighted by Grocott-Gomori methenamine-silver (Figure 4B) and periodic acid–Schiff (Figure 4C) stains.

Comment

Diagnosis
Our patient had an interesting and dramatic presentation of widespread cutaneous North American blastomycosis that was initially considered to be secondary syphilis because of involvement of the palms and soles and the presence of the painless penile ulcer. In addition, the initial skin biopsy finding was considered morphologically consistent with Cryptococcus neoformans based on positive Grocott-Gomori methenamine-silver and periodic acid–Schiff stains and an equivocal mucicarmine stain. However, the potassium hydroxide preparation of skin and positive urine histoplasmosis antigen strongly suggested blastomycosis, which was confirmed by culture of B dermatitidis. The urine histoplasmosis antigen can cross-react with B dermatitidis and other mycoses (eg, Paracoccidioides brasiliensis and Penicillium marneffei); however, because the treatment of either of these mycoses is similar, the value of the test remains high.¹

Skin tests and serologic markers are useful epidemiologic tools but are of inadequate sensitivity and specificity to be diagnostic for B dermatitidis. Diagnosis depends on direct examination of tissue or isolation of the fungus in culture.²

Source of Infection
The probable occult source of cutaneous infection was the lungs, given the natural history of disseminated blastomycosis; the history of cough and chest discomfort; the widespread nature of skin lesions; and the ultimate growth of rare yeast forms in sputum. Cutaneous infection generally is from disseminated disease and rarely from direct inoculation.

Unlike many other systemic dimorphic mycoses, blastomycosis usually occurs in healthy hosts and is frequently associated with point-source outbreak. Immunosuppressed patients typically develop infection following exposure to the organism, but reactivation also can occur. Blastomycosis is uncommon among HIV-infected individuals and is not recognized as an AIDS-defining illness.

In a review from Canada of 133 patients with blastomycosis, nearly half had an underlying medical condition but not one typically associated with marked immunosuppression.³ Only 2 of 133 patients had HIV infection. Overall mortality was 6.3%, and the average duration of symptoms before diagnosis was less in those who died vs those who survived the disease.³ In the setting of AIDS or other marked immunosuppression, disease usually is more severe, with multiple-system involvement, including the CNS, and can progress rapidly to death.²

Treatment
Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent. There are no randomized, blinded trials comparing antifungal agents, and data on the treatment of blastomycosis in patients infected with HIV are limited. Amphotericin B 3 mg/kg every 24 hours is recommended in life-threatening systemic disease and CNS disease as well as in patients with immune suppression, including AIDS.⁴ In a retrospective study of 326 patients with blastomycosis, those receiving amphotericin B had a cure rate of 86.5% with a relapse rate of 3.9%; patients receiving ketoconazole had a cure rate of 81.7% with a relapse rate of 14%.⁴ Although data are limited, chronic suppressive therapy generally is recommended in patients with HIV who have been treated for blastomycosis. Fluconazole, itraconazole, and ketoconazole are all used as chronic suppressive therapy; however, given the higher relapse rate observed with ketoconazole, itraconazole is preferred. Because neither ketoconazole nor itraconazole penetrates the blood-brain barrier, these drugs are not recommended in cases of CNS involvement. Patients with CNS disease or intolerance to itraconazole should be treated with fluconazole for chronic suppression.³

Blastomycosis is a systemic fungal infection that is endemic in the South Central, Midwest, and southeastern regions of the United States, as well as in provinces of Canada bordering the Great Lakes. After inhalation of Blastomyces dermatitidis spores, which are taken up by bronchopulmonary macrophages, there is an approximate 30- to 45-day incubation period. The initial response at the infected site is suppurative, which progresses to granuloma formation. Blastomyces dermatitidis most commonly infects the lungs, followed by the skin, bones, prostate, and central nervous system (CNS). Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent.

We present the case of a 38-year-old man with a medical history of human immunodeficiency virus (HIV) infection and AIDS who reported a 3- to 4-week history of respiratory and cutaneous symptoms. Initial clinical impression favored secondary syphilis; however, after laboratory evaluation and lack of response to treatment for syphilis, further investigation revealed a diagnosis of widespread cutaneous North American blastomycosis.

Case Report

A 38-year-old man with a medical history of HIV infection and AIDS presented to the emergency department at a medical center in Minneapolis, Minnesota, with a cough; chest discomfort; and concomitant nonpainful, mildly pruritic papules and plaques of 3 to 4 weeks’ duration that initially appeared on the face and ears and spread to the trunk, arms, palms, legs, and feet. He had a nonpainful ulcer on the glans penis. Symptoms began while he was living in Atlanta, Georgia, before relocating to Minneapolis. A chest radiograph was negative.

The initial clinical impression favored secondary syphilis. Intramuscular penicillin G benzathine (2.4 million U) weekly for 3 weeks was initiated by the primary care team based on clinical suspicion alone without laboratory evidence of a positive rapid plasma reagin or VDRL test. Because laboratory evaluation and lack of response to treatment did not support syphilis, dermatology consultation was requested.

The patient had a history of crack cocaine abuse. He reported sexual activity with a single female partner while living in a halfway house in the Minneapolis–St. Paul area. Physical examination showed an age-appropriate man in no acute distress who was alert and oriented. He had well-demarcated papules and plaques on the forehead, ears, nose, cutaneous and mucosal lips, chest, back, arms, legs, palms, and soles. Many of the facial papules were pink, nonscaly, and concentrated around the nose and mouth; some were umbilicated (Figure 1). Trunk and extensor papules and plaques were well demarcated, oval, and scaly; some had erosions centrally and were excoriated. Palmar papules were round and had peripheral brown hyperpigmentation and central scale (Figure 2). A 1-cm, shallow, nontender, oval ulceration withraised borders was located on the glans penis under the foreskin (Figure 3).

A rapid plasma reagin test was nonreactive; a fluorescent treponemal antibody absorption test was negative. Chest radiograph, magnetic resonance imaging, and electroencephalogram were normal. In addition, spinal fluid drawn from a tap was negative on India ink and Gram stain preparations and was negative for cryptococcal antigen. In addition, spinal fluid was negative for fungal and bacterial growth, as were blood cultures.

Abnormal tests included a positive enzyme-linked immunosorbent assay and Western blot test for HIV, with an absolute CD4 count of 6 cells/mL and a viral load more than 100,000 copies/mL. Urine histoplasmosis antigen was markedly elevated. A potassium hydroxide preparation was performed on the skin of the right forearm, revealing broad-based budding yeast, later confirmed on skin and sputum cultures to be B dermatitidis.

Punch biopsy from the upper back revealed a mixed acute and granulomatous infiltrate with numerous yeast forms (Figure 4A) that were highlighted by Grocott-Gomori methenamine-silver (Figure 4B) and periodic acid–Schiff (Figure 4C) stains.

Comment

Diagnosis
Our patient had an interesting and dramatic presentation of widespread cutaneous North American blastomycosis that was initially considered to be secondary syphilis because of involvement of the palms and soles and the presence of the painless penile ulcer. In addition, the initial skin biopsy finding was considered morphologically consistent with Cryptococcus neoformans based on positive Grocott-Gomori methenamine-silver and periodic acid–Schiff stains and an equivocal mucicarmine stain. However, the potassium hydroxide preparation of skin and positive urine histoplasmosis antigen strongly suggested blastomycosis, which was confirmed by culture of B dermatitidis. The urine histoplasmosis antigen can cross-react with B dermatitidis and other mycoses (eg, Paracoccidioides brasiliensis and Penicillium marneffei); however, because the treatment of either of these mycoses is similar, the value of the test remains high.¹

Skin tests and serologic markers are useful epidemiologic tools but are of inadequate sensitivity and specificity to be diagnostic for B dermatitidis. Diagnosis depends on direct examination of tissue or isolation of the fungus in culture.²

Source of Infection
The probable occult source of cutaneous infection was the lungs, given the natural history of disseminated blastomycosis; the history of cough and chest discomfort; the widespread nature of skin lesions; and the ultimate growth of rare yeast forms in sputum. Cutaneous infection generally is from disseminated disease and rarely from direct inoculation.

Unlike many other systemic dimorphic mycoses, blastomycosis usually occurs in healthy hosts and is frequently associated with point-source outbreak. Immunosuppressed patients typically develop infection following exposure to the organism, but reactivation also can occur. Blastomycosis is uncommon among HIV-infected individuals and is not recognized as an AIDS-defining illness.

In a review from Canada of 133 patients with blastomycosis, nearly half had an underlying medical condition but not one typically associated with marked immunosuppression.³ Only 2 of 133 patients had HIV infection. Overall mortality was 6.3%, and the average duration of symptoms before diagnosis was less in those who died vs those who survived the disease.³ In the setting of AIDS or other marked immunosuppression, disease usually is more severe, with multiple-system involvement, including the CNS, and can progress rapidly to death.²

Treatment
Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent. There are no randomized, blinded trials comparing antifungal agents, and data on the treatment of blastomycosis in patients infected with HIV are limited. Amphotericin B 3 mg/kg every 24 hours is recommended in life-threatening systemic disease and CNS disease as well as in patients with immune suppression, including AIDS.⁴ In a retrospective study of 326 patients with blastomycosis, those receiving amphotericin B had a cure rate of 86.5% with a relapse rate of 3.9%; patients receiving ketoconazole had a cure rate of 81.7% with a relapse rate of 14%.⁴ Although data are limited, chronic suppressive therapy generally is recommended in patients with HIV who have been treated for blastomycosis. Fluconazole, itraconazole, and ketoconazole are all used as chronic suppressive therapy; however, given the higher relapse rate observed with ketoconazole, itraconazole is preferred. Because neither ketoconazole nor itraconazole penetrates the blood-brain barrier, these drugs are not recommended in cases of CNS involvement. Patients with CNS disease or intolerance to itraconazole should be treated with fluconazole for chronic suppression.³

Blastomycosis is a systemic fungal infection that is endemic in the South Central, Midwest, and southeastern regions of the United States, as well as in provinces of Canada bordering the Great Lakes. After inhalation of Blastomyces dermatitidis spores, which are taken up by bronchopulmonary macrophages, there is an approximate 30- to 45-day incubation period. The initial response at the infected site is suppurative, which progresses to granuloma formation. Blastomyces dermatitidis most commonly infects the lungs, followed by the skin, bones, prostate, and central nervous system (CNS). Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent.

We present the case of a 38-year-old man with a medical history of human immunodeficiency virus (HIV) infection and AIDS who reported a 3- to 4-week history of respiratory and cutaneous symptoms. Initial clinical impression favored secondary syphilis; however, after laboratory evaluation and lack of response to treatment for syphilis, further investigation revealed a diagnosis of widespread cutaneous North American blastomycosis.

Case Report

A 38-year-old man with a medical history of HIV infection and AIDS presented to the emergency department at a medical center in Minneapolis, Minnesota, with a cough; chest discomfort; and concomitant nonpainful, mildly pruritic papules and plaques of 3 to 4 weeks’ duration that initially appeared on the face and ears and spread to the trunk, arms, palms, legs, and feet. He had a nonpainful ulcer on the glans penis. Symptoms began while he was living in Atlanta, Georgia, before relocating to Minneapolis. A chest radiograph was negative.

The initial clinical impression favored secondary syphilis. Intramuscular penicillin G benzathine (2.4 million U) weekly for 3 weeks was initiated by the primary care team based on clinical suspicion alone without laboratory evidence of a positive rapid plasma reagin or VDRL test. Because laboratory evaluation and lack of response to treatment did not support syphilis, dermatology consultation was requested.

The patient had a history of crack cocaine abuse. He reported sexual activity with a single female partner while living in a halfway house in the Minneapolis–St. Paul area. Physical examination showed an age-appropriate man in no acute distress who was alert and oriented. He had well-demarcated papules and plaques on the forehead, ears, nose, cutaneous and mucosal lips, chest, back, arms, legs, palms, and soles. Many of the facial papules were pink, nonscaly, and concentrated around the nose and mouth; some were umbilicated (Figure 1). Trunk and extensor papules and plaques were well demarcated, oval, and scaly; some had erosions centrally and were excoriated. Palmar papules were round and had peripheral brown hyperpigmentation and central scale (Figure 2). A 1-cm, shallow, nontender, oval ulceration withraised borders was located on the glans penis under the foreskin (Figure 3).

A rapid plasma reagin test was nonreactive; a fluorescent treponemal antibody absorption test was negative. Chest radiograph, magnetic resonance imaging, and electroencephalogram were normal. In addition, spinal fluid drawn from a tap was negative on India ink and Gram stain preparations and was negative for cryptococcal antigen. In addition, spinal fluid was negative for fungal and bacterial growth, as were blood cultures.

Abnormal tests included a positive enzyme-linked immunosorbent assay and Western blot test for HIV, with an absolute CD4 count of 6 cells/mL and a viral load more than 100,000 copies/mL. Urine histoplasmosis antigen was markedly elevated. A potassium hydroxide preparation was performed on the skin of the right forearm, revealing broad-based budding yeast, later confirmed on skin and sputum cultures to be B dermatitidis.

Punch biopsy from the upper back revealed a mixed acute and granulomatous infiltrate with numerous yeast forms (Figure 4A) that were highlighted by Grocott-Gomori methenamine-silver (Figure 4B) and periodic acid–Schiff (Figure 4C) stains.

Comment

Diagnosis
Our patient had an interesting and dramatic presentation of widespread cutaneous North American blastomycosis that was initially considered to be secondary syphilis because of involvement of the palms and soles and the presence of the painless penile ulcer. In addition, the initial skin biopsy finding was considered morphologically consistent with Cryptococcus neoformans based on positive Grocott-Gomori methenamine-silver and periodic acid–Schiff stains and an equivocal mucicarmine stain. However, the potassium hydroxide preparation of skin and positive urine histoplasmosis antigen strongly suggested blastomycosis, which was confirmed by culture of B dermatitidis. The urine histoplasmosis antigen can cross-react with B dermatitidis and other mycoses (eg, Paracoccidioides brasiliensis and Penicillium marneffei); however, because the treatment of either of these mycoses is similar, the value of the test remains high.¹

Skin tests and serologic markers are useful epidemiologic tools but are of inadequate sensitivity and specificity to be diagnostic for B dermatitidis. Diagnosis depends on direct examination of tissue or isolation of the fungus in culture.²

Source of Infection
The probable occult source of cutaneous infection was the lungs, given the natural history of disseminated blastomycosis; the history of cough and chest discomfort; the widespread nature of skin lesions; and the ultimate growth of rare yeast forms in sputum. Cutaneous infection generally is from disseminated disease and rarely from direct inoculation.

Unlike many other systemic dimorphic mycoses, blastomycosis usually occurs in healthy hosts and is frequently associated with point-source outbreak. Immunosuppressed patients typically develop infection following exposure to the organism, but reactivation also can occur. Blastomycosis is uncommon among HIV-infected individuals and is not recognized as an AIDS-defining illness.

In a review from Canada of 133 patients with blastomycosis, nearly half had an underlying medical condition but not one typically associated with marked immunosuppression.³ Only 2 of 133 patients had HIV infection. Overall mortality was 6.3%, and the average duration of symptoms before diagnosis was less in those who died vs those who survived the disease.³ In the setting of AIDS or other marked immunosuppression, disease usually is more severe, with multiple-system involvement, including the CNS, and can progress rapidly to death.²

Treatment
Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent. There are no randomized, blinded trials comparing antifungal agents, and data on the treatment of blastomycosis in patients infected with HIV are limited. Amphotericin B 3 mg/kg every 24 hours is recommended in life-threatening systemic disease and CNS disease as well as in patients with immune suppression, including AIDS.⁴ In a retrospective study of 326 patients with blastomycosis, those receiving amphotericin B had a cure rate of 86.5% with a relapse rate of 3.9%; patients receiving ketoconazole had a cure rate of 81.7% with a relapse rate of 14%.⁴ Although data are limited, chronic suppressive therapy generally is recommended in patients with HIV who have been treated for blastomycosis. Fluconazole, itraconazole, and ketoconazole are all used as chronic suppressive therapy; however, given the higher relapse rate observed with ketoconazole, itraconazole is preferred. Because neither ketoconazole nor itraconazole penetrates the blood-brain barrier, these drugs are not recommended in cases of CNS involvement. Patients with CNS disease or intolerance to itraconazole should be treated with fluconazole for chronic suppression.³

Angiosarcomas are malignant tumors of the vascular endothelium and are typically idiopathic. These tumors comprise 2% of all soft tissue sarcomas and have an estimated incidence of 2 per million.^1,2 Known causes of angiosarcoma include genetic syndromes—such as von Hippel- Lindau, Chuvash polycythemia, Bannayan- Riley-Ruvalcaba, Cowden, and hamartomatous polyposis syndromes— chronic lymphedema, and exposure to radiation.³ Vinyl chloride, arsenicals, and thorotrast are known to increase the incidence of liver angiosarcoma.⁴

Malignant transformation of hemangioma is rare. We describe metastatic angiosarcoma in a patient with a large, longterm treatment-resistant subcutaneous hemangioma, illustrating such a possibility. We review similar cases and discuss the value of determining pathogenesis in such patients.

Case Presentation and Summary

A 55-year-old female with a long-standing childhood hemangioma of the left lower extremity was referred to Ochsner Medical Center for tissue diagnosis of new pulmonary nodules. Her medical history included a 7 pack-year smoking history; she had quit 3 years prior. Her family history included a sister who died from breast cancer. The patient initially had a progressive, intermittently bleeding tumor in the left foot at age 7. She was diagnosed with hemangioma in her twenties. At that point, her tumor began to involve the posterior calf and femur, causing deformity. She had multiple surgical resections but reportedly all pathology demonstrated benign hemangioma. She received radiation for pain, a routine treatment at the time, but developed a focus of progression in the heel. Above-knee amputation was considered but could not be performed when hemangioma was discovered in the hip area. She was lost to follow-up between 2001 and 2015. Lower extremity magnetic resonance imaging in 2015 was stable with imaging prior to 2001. A repeat biopsy in 2016 demonstrated hemangioma. The patient then received radiation to a wider field, including the femur, with minimal response. She completed a course of steroids as well. Bevacizumab was started in 2017 and improved foot deformity. She also briefly trialed pazopanib for 4 weeks in 2018 in an attempt to switch to oral medications. Despite partial response, she discontinued both agents in July 2018 because of toxicity and the burden of recurrent infusions.

Four months later, she presented with 2 months of intermittent hemoptysis and 18 months of metallic odors. Additionally, she lost 25 pounds in 3 months, which she attributed to a diet plan. At this visit, her left lower extremity exhibited multiple subcutaneous tumors and nodules.

Computed tomography (CT) with contrast demonstrated innumerable pulmonary nodules, the largest measuring 2.2 cm in the right lower lobe superior segment. Positron emission tomography (PET)/CT revealed 2 nodules with mild hypermetabolic activity; the largest nodule had a maximum standardized uptake value of 2.7. Bronchoalveolar lavage studies showed intra-alveolar hemorrhage with hemosiderin-laden macrophages. No malignancy, granuloma, or dysplasia was found in transbronchial needle aspirate of the largest nodule. The patient had no lymphadenopathy.

At this hospital, surgical resection by video-assisted thoracoscopic surgery confirmed multifocal malignant epithelioid neoplasm suspicious for angiosarcoma. Multiple areas showed proliferation of atypical epithelioid-to-spindle cells. There were prominent associated hemosiderin-laden macrophages, fresh red blood cells, and dilated blood-filled spaces. Cells demonstrated hyperchromasia with irregular nuclear contours, prominent nucleoli, and mitoses  (FIGURE 1). Additionally, there were areas of focal organizing pneumonia. For atypical cells, staining was CD31-positive and CD34-negative. Staining was strongly positive for ERG. There was increased Ki-67 with retained INI expression and patchy weak reactivity for Fli-1.

Next-generation sequencing was performed. Specimen tumor content was 15%. Genomic findings included IDH1 p.R132C mutation, with variant allele frequency <10%. Testing was inconclusive for MSI and TMB mutations. PD-L1 assessment could not be performed. Unfortunately, the patient did not qualify for any clinical trials, as there were no matching alterations. This patient was lost to follow-up.

Discussion

Angiosarcoma accounts for 2% of soft tissue sarcomas.¹ Cutaneous angiosarcomas most commonly occur in the face and scalp of the elderly, or in sites of chronic lymphedema. Angiosarcoma also develops following radiation therapy.⁵ For breast cancers and tumors of the head and neck, irradiation has <1% risk of inducing secondary malignancy, including angiosarcoma.⁶

This patient had a new diagnosis of angiosarcoma in the setting of long-standing benign hemangioma with history of radiation treatment. Thus, it is unclear whether this angiosarcoma was primary, radiation-induced, or secondary to transformation from the preexisting vascular tumor. Post-irradiation sarcoma carries a less favorable prognosis compared to de novo sarcoma; however, reports conflict on whether this holds for angiosarcoma subtypes.⁶ Determining etiology may benefit patients for prognostication and possibly inform future selection of treatment modalities.

The mutational signature in radiation- associated sarcomas differs from that of sporadic sarcomas. First, radiation- associated sarcomas demonstrate more frequent small deletions and balanced translocations. TP53 mutations are found in up to 1/3 of radiation-associated sarcomas and are more often due to small deletions than in sporadic sarcomas.⁷ High-level MYC amplification occurs in 54%-100% of secondary angiosarcomas, compared to 0-7% in sporadic angiosarcomas. Co-amplification of FLT4 occurs in 11%-25% of secondary angiosarcomas.⁸ Additionally, transcriptome analysis revealed differential expression of a 135-gene signature compared to non-radiation- induced sarcomas.⁷ Although this patient was not specifically analyzed for such alterations, such tests may differentiate post-irradiation angiosarcoma from sporadic etiologies.

In this patient, the R132C IDH1 mutation was identified and may be the first reported case in angiosarcoma. Typically, this mutation occurs in chondrosarcoma, myeloid neoplasms, gliomas, and cholangiocarcinomas. It is also found in spindle cell hemangiomas but not in other vascular tumors.⁹ The clinical significance of this mutation is uncertain at this time.

There are approximately 36 reported cases of malignant disease arising in patients with less aggressive vascular tumors (TABLE 1). Of these, 25 of 36 involve angiosarcoma arising in patients with hemangioma. Four cases of angiosarcoma were reported in patients with hemangioendothelioma, 1 case of hemangioendothelioma in a patient with hemangioma, 1 case of Dabska tumor in a patient with hemangioma, and 1 case of angiosarcoma in a patient with Dabska tumor. Fifteen cases involved initial disease with adult onset and 21 involved initial disease with pediatric onset, suggesting even distribution. Malignant disease mostly occurred in adulthood, in 26 out of 33 cases. Latency to malignancy ranged from concurrent discovery to 54 years. Mean latency, excluding cases with concurrent discovery, was shorter with adult-onset initial disease, at 4.2 years, compared to 16 years among patients with onset of initial disease in childhood. Longer latency in the pediatric-onset population correlated with longer latent periods for radiation-induced angiosarcoma following benign disease, which is reported to average 23 years.¹⁰ Thirteen of 19 cases with pediatric onset disease had a history of radiotherapy, while 2 of 13 cases with adult onset disease did. Sixteen cases involved tumor in the bone and soft tissue, as in this patient. Notably, 4 of these cases involved long-standing hemangioma for 10 years or more, as in this patient, suggesting a possible correlation between long-standing vascular tumors and malignant transformation. Angiosarcoma arising in non-irradiated patients suggests that malignant transformation and de novo transformation may compete with radiation-induced mutation in tumorigenesis. Further, 8 cases involved angiosarcoma growing within another vascular tumor, demonstrating the possibility of malignant transformation. Dehner and Ishak described a histological model for quantifying such a risk; a validated model may be particularly useful in patients with long-standing hemangioma.¹¹

Etiology of tumorigenesis in cases of angiosarcoma arising in patients with a history of benign hemangioma may benefit prognostication and inform treatment selection in the future. Owing to long latent periods, radiation-associated angiosarcoma incidence may rise, as radiation therapy for benign hemangioma was recently routine. Future research may provide insight into disease progression and possibly predict the risk of angiosarcoma in patients with long-standing benign disease. TSJ

Angiosarcomas are malignant tumors of the vascular endothelium and are typically idiopathic. These tumors comprise 2% of all soft tissue sarcomas and have an estimated incidence of 2 per million.^1,2 Known causes of angiosarcoma include genetic syndromes—such as von Hippel- Lindau, Chuvash polycythemia, Bannayan- Riley-Ruvalcaba, Cowden, and hamartomatous polyposis syndromes— chronic lymphedema, and exposure to radiation.³ Vinyl chloride, arsenicals, and thorotrast are known to increase the incidence of liver angiosarcoma.⁴

Malignant transformation of hemangioma is rare. We describe metastatic angiosarcoma in a patient with a large, longterm treatment-resistant subcutaneous hemangioma, illustrating such a possibility. We review similar cases and discuss the value of determining pathogenesis in such patients.

Case Presentation and Summary

A 55-year-old female with a long-standing childhood hemangioma of the left lower extremity was referred to Ochsner Medical Center for tissue diagnosis of new pulmonary nodules. Her medical history included a 7 pack-year smoking history; she had quit 3 years prior. Her family history included a sister who died from breast cancer. The patient initially had a progressive, intermittently bleeding tumor in the left foot at age 7. She was diagnosed with hemangioma in her twenties. At that point, her tumor began to involve the posterior calf and femur, causing deformity. She had multiple surgical resections but reportedly all pathology demonstrated benign hemangioma. She received radiation for pain, a routine treatment at the time, but developed a focus of progression in the heel. Above-knee amputation was considered but could not be performed when hemangioma was discovered in the hip area. She was lost to follow-up between 2001 and 2015. Lower extremity magnetic resonance imaging in 2015 was stable with imaging prior to 2001. A repeat biopsy in 2016 demonstrated hemangioma. The patient then received radiation to a wider field, including the femur, with minimal response. She completed a course of steroids as well. Bevacizumab was started in 2017 and improved foot deformity. She also briefly trialed pazopanib for 4 weeks in 2018 in an attempt to switch to oral medications. Despite partial response, she discontinued both agents in July 2018 because of toxicity and the burden of recurrent infusions.

Four months later, she presented with 2 months of intermittent hemoptysis and 18 months of metallic odors. Additionally, she lost 25 pounds in 3 months, which she attributed to a diet plan. At this visit, her left lower extremity exhibited multiple subcutaneous tumors and nodules.

Computed tomography (CT) with contrast demonstrated innumerable pulmonary nodules, the largest measuring 2.2 cm in the right lower lobe superior segment. Positron emission tomography (PET)/CT revealed 2 nodules with mild hypermetabolic activity; the largest nodule had a maximum standardized uptake value of 2.7. Bronchoalveolar lavage studies showed intra-alveolar hemorrhage with hemosiderin-laden macrophages. No malignancy, granuloma, or dysplasia was found in transbronchial needle aspirate of the largest nodule. The patient had no lymphadenopathy.

At this hospital, surgical resection by video-assisted thoracoscopic surgery confirmed multifocal malignant epithelioid neoplasm suspicious for angiosarcoma. Multiple areas showed proliferation of atypical epithelioid-to-spindle cells. There were prominent associated hemosiderin-laden macrophages, fresh red blood cells, and dilated blood-filled spaces. Cells demonstrated hyperchromasia with irregular nuclear contours, prominent nucleoli, and mitoses  (FIGURE 1). Additionally, there were areas of focal organizing pneumonia. For atypical cells, staining was CD31-positive and CD34-negative. Staining was strongly positive for ERG. There was increased Ki-67 with retained INI expression and patchy weak reactivity for Fli-1.

Next-generation sequencing was performed. Specimen tumor content was 15%. Genomic findings included IDH1 p.R132C mutation, with variant allele frequency <10%. Testing was inconclusive for MSI and TMB mutations. PD-L1 assessment could not be performed. Unfortunately, the patient did not qualify for any clinical trials, as there were no matching alterations. This patient was lost to follow-up.

Discussion

Angiosarcoma accounts for 2% of soft tissue sarcomas.¹ Cutaneous angiosarcomas most commonly occur in the face and scalp of the elderly, or in sites of chronic lymphedema. Angiosarcoma also develops following radiation therapy.⁵ For breast cancers and tumors of the head and neck, irradiation has <1% risk of inducing secondary malignancy, including angiosarcoma.⁶

This patient had a new diagnosis of angiosarcoma in the setting of long-standing benign hemangioma with history of radiation treatment. Thus, it is unclear whether this angiosarcoma was primary, radiation-induced, or secondary to transformation from the preexisting vascular tumor. Post-irradiation sarcoma carries a less favorable prognosis compared to de novo sarcoma; however, reports conflict on whether this holds for angiosarcoma subtypes.⁶ Determining etiology may benefit patients for prognostication and possibly inform future selection of treatment modalities.

The mutational signature in radiation- associated sarcomas differs from that of sporadic sarcomas. First, radiation- associated sarcomas demonstrate more frequent small deletions and balanced translocations. TP53 mutations are found in up to 1/3 of radiation-associated sarcomas and are more often due to small deletions than in sporadic sarcomas.⁷ High-level MYC amplification occurs in 54%-100% of secondary angiosarcomas, compared to 0-7% in sporadic angiosarcomas. Co-amplification of FLT4 occurs in 11%-25% of secondary angiosarcomas.⁸ Additionally, transcriptome analysis revealed differential expression of a 135-gene signature compared to non-radiation- induced sarcomas.⁷ Although this patient was not specifically analyzed for such alterations, such tests may differentiate post-irradiation angiosarcoma from sporadic etiologies.

In this patient, the R132C IDH1 mutation was identified and may be the first reported case in angiosarcoma. Typically, this mutation occurs in chondrosarcoma, myeloid neoplasms, gliomas, and cholangiocarcinomas. It is also found in spindle cell hemangiomas but not in other vascular tumors.⁹ The clinical significance of this mutation is uncertain at this time.

There are approximately 36 reported cases of malignant disease arising in patients with less aggressive vascular tumors (TABLE 1). Of these, 25 of 36 involve angiosarcoma arising in patients with hemangioma. Four cases of angiosarcoma were reported in patients with hemangioendothelioma, 1 case of hemangioendothelioma in a patient with hemangioma, 1 case of Dabska tumor in a patient with hemangioma, and 1 case of angiosarcoma in a patient with Dabska tumor. Fifteen cases involved initial disease with adult onset and 21 involved initial disease with pediatric onset, suggesting even distribution. Malignant disease mostly occurred in adulthood, in 26 out of 33 cases. Latency to malignancy ranged from concurrent discovery to 54 years. Mean latency, excluding cases with concurrent discovery, was shorter with adult-onset initial disease, at 4.2 years, compared to 16 years among patients with onset of initial disease in childhood. Longer latency in the pediatric-onset population correlated with longer latent periods for radiation-induced angiosarcoma following benign disease, which is reported to average 23 years.¹⁰ Thirteen of 19 cases with pediatric onset disease had a history of radiotherapy, while 2 of 13 cases with adult onset disease did. Sixteen cases involved tumor in the bone and soft tissue, as in this patient. Notably, 4 of these cases involved long-standing hemangioma for 10 years or more, as in this patient, suggesting a possible correlation between long-standing vascular tumors and malignant transformation. Angiosarcoma arising in non-irradiated patients suggests that malignant transformation and de novo transformation may compete with radiation-induced mutation in tumorigenesis. Further, 8 cases involved angiosarcoma growing within another vascular tumor, demonstrating the possibility of malignant transformation. Dehner and Ishak described a histological model for quantifying such a risk; a validated model may be particularly useful in patients with long-standing hemangioma.¹¹

Etiology of tumorigenesis in cases of angiosarcoma arising in patients with a history of benign hemangioma may benefit prognostication and inform treatment selection in the future. Owing to long latent periods, radiation-associated angiosarcoma incidence may rise, as radiation therapy for benign hemangioma was recently routine. Future research may provide insight into disease progression and possibly predict the risk of angiosarcoma in patients with long-standing benign disease. TSJ

Angiosarcomas are malignant tumors of the vascular endothelium and are typically idiopathic. These tumors comprise 2% of all soft tissue sarcomas and have an estimated incidence of 2 per million.^1,2 Known causes of angiosarcoma include genetic syndromes—such as von Hippel- Lindau, Chuvash polycythemia, Bannayan- Riley-Ruvalcaba, Cowden, and hamartomatous polyposis syndromes— chronic lymphedema, and exposure to radiation.³ Vinyl chloride, arsenicals, and thorotrast are known to increase the incidence of liver angiosarcoma.⁴

Malignant transformation of hemangioma is rare. We describe metastatic angiosarcoma in a patient with a large, longterm treatment-resistant subcutaneous hemangioma, illustrating such a possibility. We review similar cases and discuss the value of determining pathogenesis in such patients.

Case Presentation and Summary

A 55-year-old female with a long-standing childhood hemangioma of the left lower extremity was referred to Ochsner Medical Center for tissue diagnosis of new pulmonary nodules. Her medical history included a 7 pack-year smoking history; she had quit 3 years prior. Her family history included a sister who died from breast cancer. The patient initially had a progressive, intermittently bleeding tumor in the left foot at age 7. She was diagnosed with hemangioma in her twenties. At that point, her tumor began to involve the posterior calf and femur, causing deformity. She had multiple surgical resections but reportedly all pathology demonstrated benign hemangioma. She received radiation for pain, a routine treatment at the time, but developed a focus of progression in the heel. Above-knee amputation was considered but could not be performed when hemangioma was discovered in the hip area. She was lost to follow-up between 2001 and 2015. Lower extremity magnetic resonance imaging in 2015 was stable with imaging prior to 2001. A repeat biopsy in 2016 demonstrated hemangioma. The patient then received radiation to a wider field, including the femur, with minimal response. She completed a course of steroids as well. Bevacizumab was started in 2017 and improved foot deformity. She also briefly trialed pazopanib for 4 weeks in 2018 in an attempt to switch to oral medications. Despite partial response, she discontinued both agents in July 2018 because of toxicity and the burden of recurrent infusions.

Four months later, she presented with 2 months of intermittent hemoptysis and 18 months of metallic odors. Additionally, she lost 25 pounds in 3 months, which she attributed to a diet plan. At this visit, her left lower extremity exhibited multiple subcutaneous tumors and nodules.

Computed tomography (CT) with contrast demonstrated innumerable pulmonary nodules, the largest measuring 2.2 cm in the right lower lobe superior segment. Positron emission tomography (PET)/CT revealed 2 nodules with mild hypermetabolic activity; the largest nodule had a maximum standardized uptake value of 2.7. Bronchoalveolar lavage studies showed intra-alveolar hemorrhage with hemosiderin-laden macrophages. No malignancy, granuloma, or dysplasia was found in transbronchial needle aspirate of the largest nodule. The patient had no lymphadenopathy.

At this hospital, surgical resection by video-assisted thoracoscopic surgery confirmed multifocal malignant epithelioid neoplasm suspicious for angiosarcoma. Multiple areas showed proliferation of atypical epithelioid-to-spindle cells. There were prominent associated hemosiderin-laden macrophages, fresh red blood cells, and dilated blood-filled spaces. Cells demonstrated hyperchromasia with irregular nuclear contours, prominent nucleoli, and mitoses  (FIGURE 1). Additionally, there were areas of focal organizing pneumonia. For atypical cells, staining was CD31-positive and CD34-negative. Staining was strongly positive for ERG. There was increased Ki-67 with retained INI expression and patchy weak reactivity for Fli-1.

Next-generation sequencing was performed. Specimen tumor content was 15%. Genomic findings included IDH1 p.R132C mutation, with variant allele frequency <10%. Testing was inconclusive for MSI and TMB mutations. PD-L1 assessment could not be performed. Unfortunately, the patient did not qualify for any clinical trials, as there were no matching alterations. This patient was lost to follow-up.

Discussion

Angiosarcoma accounts for 2% of soft tissue sarcomas.¹ Cutaneous angiosarcomas most commonly occur in the face and scalp of the elderly, or in sites of chronic lymphedema. Angiosarcoma also develops following radiation therapy.⁵ For breast cancers and tumors of the head and neck, irradiation has <1% risk of inducing secondary malignancy, including angiosarcoma.⁶

This patient had a new diagnosis of angiosarcoma in the setting of long-standing benign hemangioma with history of radiation treatment. Thus, it is unclear whether this angiosarcoma was primary, radiation-induced, or secondary to transformation from the preexisting vascular tumor. Post-irradiation sarcoma carries a less favorable prognosis compared to de novo sarcoma; however, reports conflict on whether this holds for angiosarcoma subtypes.⁶ Determining etiology may benefit patients for prognostication and possibly inform future selection of treatment modalities.

The mutational signature in radiation- associated sarcomas differs from that of sporadic sarcomas. First, radiation- associated sarcomas demonstrate more frequent small deletions and balanced translocations. TP53 mutations are found in up to 1/3 of radiation-associated sarcomas and are more often due to small deletions than in sporadic sarcomas.⁷ High-level MYC amplification occurs in 54%-100% of secondary angiosarcomas, compared to 0-7% in sporadic angiosarcomas. Co-amplification of FLT4 occurs in 11%-25% of secondary angiosarcomas.⁸ Additionally, transcriptome analysis revealed differential expression of a 135-gene signature compared to non-radiation- induced sarcomas.⁷ Although this patient was not specifically analyzed for such alterations, such tests may differentiate post-irradiation angiosarcoma from sporadic etiologies.

In this patient, the R132C IDH1 mutation was identified and may be the first reported case in angiosarcoma. Typically, this mutation occurs in chondrosarcoma, myeloid neoplasms, gliomas, and cholangiocarcinomas. It is also found in spindle cell hemangiomas but not in other vascular tumors.⁹ The clinical significance of this mutation is uncertain at this time.

There are approximately 36 reported cases of malignant disease arising in patients with less aggressive vascular tumors (TABLE 1). Of these, 25 of 36 involve angiosarcoma arising in patients with hemangioma. Four cases of angiosarcoma were reported in patients with hemangioendothelioma, 1 case of hemangioendothelioma in a patient with hemangioma, 1 case of Dabska tumor in a patient with hemangioma, and 1 case of angiosarcoma in a patient with Dabska tumor. Fifteen cases involved initial disease with adult onset and 21 involved initial disease with pediatric onset, suggesting even distribution. Malignant disease mostly occurred in adulthood, in 26 out of 33 cases. Latency to malignancy ranged from concurrent discovery to 54 years. Mean latency, excluding cases with concurrent discovery, was shorter with adult-onset initial disease, at 4.2 years, compared to 16 years among patients with onset of initial disease in childhood. Longer latency in the pediatric-onset population correlated with longer latent periods for radiation-induced angiosarcoma following benign disease, which is reported to average 23 years.¹⁰ Thirteen of 19 cases with pediatric onset disease had a history of radiotherapy, while 2 of 13 cases with adult onset disease did. Sixteen cases involved tumor in the bone and soft tissue, as in this patient. Notably, 4 of these cases involved long-standing hemangioma for 10 years or more, as in this patient, suggesting a possible correlation between long-standing vascular tumors and malignant transformation. Angiosarcoma arising in non-irradiated patients suggests that malignant transformation and de novo transformation may compete with radiation-induced mutation in tumorigenesis. Further, 8 cases involved angiosarcoma growing within another vascular tumor, demonstrating the possibility of malignant transformation. Dehner and Ishak described a histological model for quantifying such a risk; a validated model may be particularly useful in patients with long-standing hemangioma.¹¹

Etiology of tumorigenesis in cases of angiosarcoma arising in patients with a history of benign hemangioma may benefit prognostication and inform treatment selection in the future. Owing to long latent periods, radiation-associated angiosarcoma incidence may rise, as radiation therapy for benign hemangioma was recently routine. Future research may provide insight into disease progression and possibly predict the risk of angiosarcoma in patients with long-standing benign disease. TSJ

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

Diagnosis of a neutrophilic dermatosis, such as pyoderma gangrenosum (PG), often is challenging at onset because it can be impossible to distinguish clinically and histopathologically from acute infection in an immunosuppressed patient, necessitating a detailed history as well as correlation pathology with microbial tissue cultures. The dermatologist’s ability to distinguish a neutrophilic dermatosis from active infection is of paramount importance because the decision to treat with surgical debridement, in addition to an antibiotic regimen, can have grave consequences in the misdiagnosed patient.

Pyoderma gangrenosum is a neutrophilic dermatosis histologically characterized by a pandermal neutrophilic infiltrate without evidence of an infectious cause or true vasculitis. It is classically associated with inflammatory bowel disease or an underlying hematologic malignancy. Pyoderma gangrenosum in the setting of chronic lymphocytic leukemia (CLL) is rare, with as few as 4 cases having been described in the literature and only 1 case of PG developing after a surgical procedure.^1-4 We present a case of PG occurring at a chest tube site in a patient with CLL. We highlight the challenges and therapeutic importance of arriving at the correct diagnosis.

Case Report

An 87-year-old man with a history of refractory CLL was admitted to the hospital with pneumonia and pleural effusion requiring chest tube placement (left). His most recent therapeutic regimen for CLL was rituximab and bendamustine, which was administered 9 days prior to admission. After removal of the chest tube, an erythematous plaque with central necrosis surrounding the chest tube site developed (Figure 1A). During this time period, the patient had documented intermittent fevers, leukopenia, and neutropenia. Serial blood cultures yielded no growth. Because the patient was on broad-spectrum antibiotic coverage, dermatology was consulted for possible angioinvasive fungal infection.

Physical examination revealed an indurated, erythematous-violaceous, targetoid, well-defined, ulcerated plaque with central necrosis on the left side of the chest. Notably, we observed an isolated bulla with an erythematous base within the right antecubital fossa at the site of intravenous placement, suggesting pathergy.

Multiple punch biopsies revealed an ulcer with an underlying dense neutrophilic infiltrate within the dermis and subcutaneous tissues (Figure 2). Grocott-Gomori methenamine-silver, periodic acid–Schiff, and acid-fast bacillus stains were all negative for organisms. Tissue cultures for bacterial, fungal, and acid-fast bacilli revealed no growth. Due to the rapidly expanding nature of the plaque and the possibility of infection despite negative microbial stains and cultures, the patient was scheduled for surgical debridement by the surgical team.

Comment

Pathogenesis of PG
Pyoderma gangrenosum lies in the spectrum of neutrophilic dermatoses, which are characterized histologically by a pandermal neutrophilic infiltrate without evidence of an infectious cause or true vasculitis. Clinically, PG typically presents as a steadily expanding ulceration with an undermined or slightly raised border, and often is associated with the pathergy phenomenon. Historically, PG is classically linked to inflammatory bowel disease; however, association with underlying malignancy, including acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, and myeloid metaplasia, also has been described.⁵

Pathogenesis of CLL
Chronic lymphocytic leukemia represents the most prevalent form of leukemia in US adults, with the second highest annual incidence.⁶ Cutaneous findings are seen in 25% of patients with CLL, varying from leukemia cutis to secondary findings such as vasculitis, purpura, generalized pruritus, exfoliative erythroderma, paraneoplastic pemphigus, infections, and rarely neutrophilic dermatoses.⁷ According to a PubMed search of articles indexed for MEDLINE using the term pyoderma gangrenosum in CLL, only 4 cases of PG occurring in the setting of CLL exist in the literature, with 1 case demonstrating development after a surgical procedure, making ours the second such case (Table).^1-4

Sweet syndrome is classically the most challenging entity within the spectrum to differentiate from PG. However, our case outlines several key distinguishing features:

• The lesion in classic PG is a rapidly expanding ulceration with undermined borders, whereas SS is less commonly associated with ulceration and instead classically presents with multiple edematous papules that progress to juicy plaques.⁸

• The pathergy phenomenon has been reported in SS, though it is more commonly associated with PG.⁹

• In reported cases of SS that were related to cutaneous trauma, lesions developed outside the area of trauma and there was documented leukocytosis and neutrophilia.^10-14

• Although leukocytosis is part of the minor diagnostic criteria for SS, it is not required for the diagnosis of PG. Considering that our patient had ulcerated lesions, lesions only at the site of trauma, and leukopenia with intermittent neutropenia, the diagnosis was consistent with PG.

The primary value of early recognition and diagnosis of PG lies in the physician’s ability to distinguish PG from an infectious process, which can be challenging in an immunosuppressed patient with an underlying hematologic malignancy.

Conclusion

This case report represents our experience in arriving at the correct diagnosis of PG in a febrile neutrophilic patient with CLL. In the case of PG in a complicated patient, it is critical to initiate appropriate treatment and avoid inappropriate therapies. Aggressive surgical debridement could have resulted in a fatal outcome for our patient, highlighting the need for dermatologists to raise physician awareness of this challenging disease.

Acknowledgments
The authors acknowledge the contributions of Sarah Shalin, MD, PhD; Nikhil Meena, MD; and Aditya Chada, MD (all from Little Rock, Arkansas), for excellent patient care.

Diagnosis of a neutrophilic dermatosis, such as pyoderma gangrenosum (PG), often is challenging at onset because it can be impossible to distinguish clinically and histopathologically from acute infection in an immunosuppressed patient, necessitating a detailed history as well as correlation pathology with microbial tissue cultures. The dermatologist’s ability to distinguish a neutrophilic dermatosis from active infection is of paramount importance because the decision to treat with surgical debridement, in addition to an antibiotic regimen, can have grave consequences in the misdiagnosed patient.

Pyoderma gangrenosum is a neutrophilic dermatosis histologically characterized by a pandermal neutrophilic infiltrate without evidence of an infectious cause or true vasculitis. It is classically associated with inflammatory bowel disease or an underlying hematologic malignancy. Pyoderma gangrenosum in the setting of chronic lymphocytic leukemia (CLL) is rare, with as few as 4 cases having been described in the literature and only 1 case of PG developing after a surgical procedure.^1-4 We present a case of PG occurring at a chest tube site in a patient with CLL. We highlight the challenges and therapeutic importance of arriving at the correct diagnosis.

Case Report

An 87-year-old man with a history of refractory CLL was admitted to the hospital with pneumonia and pleural effusion requiring chest tube placement (left). His most recent therapeutic regimen for CLL was rituximab and bendamustine, which was administered 9 days prior to admission. After removal of the chest tube, an erythematous plaque with central necrosis surrounding the chest tube site developed (Figure 1A). During this time period, the patient had documented intermittent fevers, leukopenia, and neutropenia. Serial blood cultures yielded no growth. Because the patient was on broad-spectrum antibiotic coverage, dermatology was consulted for possible angioinvasive fungal infection.

Physical examination revealed an indurated, erythematous-violaceous, targetoid, well-defined, ulcerated plaque with central necrosis on the left side of the chest. Notably, we observed an isolated bulla with an erythematous base within the right antecubital fossa at the site of intravenous placement, suggesting pathergy.

Multiple punch biopsies revealed an ulcer with an underlying dense neutrophilic infiltrate within the dermis and subcutaneous tissues (Figure 2). Grocott-Gomori methenamine-silver, periodic acid–Schiff, and acid-fast bacillus stains were all negative for organisms. Tissue cultures for bacterial, fungal, and acid-fast bacilli revealed no growth. Due to the rapidly expanding nature of the plaque and the possibility of infection despite negative microbial stains and cultures, the patient was scheduled for surgical debridement by the surgical team.

Comment

Pathogenesis of PG
Pyoderma gangrenosum lies in the spectrum of neutrophilic dermatoses, which are characterized histologically by a pandermal neutrophilic infiltrate without evidence of an infectious cause or true vasculitis. Clinically, PG typically presents as a steadily expanding ulceration with an undermined or slightly raised border, and often is associated with the pathergy phenomenon. Historically, PG is classically linked to inflammatory bowel disease; however, association with underlying malignancy, including acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, and myeloid metaplasia, also has been described.⁵

Pathogenesis of CLL
Chronic lymphocytic leukemia represents the most prevalent form of leukemia in US adults, with the second highest annual incidence.⁶ Cutaneous findings are seen in 25% of patients with CLL, varying from leukemia cutis to secondary findings such as vasculitis, purpura, generalized pruritus, exfoliative erythroderma, paraneoplastic pemphigus, infections, and rarely neutrophilic dermatoses.⁷ According to a PubMed search of articles indexed for MEDLINE using the term pyoderma gangrenosum in CLL, only 4 cases of PG occurring in the setting of CLL exist in the literature, with 1 case demonstrating development after a surgical procedure, making ours the second such case (Table).^1-4

Sweet syndrome is classically the most challenging entity within the spectrum to differentiate from PG. However, our case outlines several key distinguishing features:

• The lesion in classic PG is a rapidly expanding ulceration with undermined borders, whereas SS is less commonly associated with ulceration and instead classically presents with multiple edematous papules that progress to juicy plaques.⁸

• The pathergy phenomenon has been reported in SS, though it is more commonly associated with PG.⁹

• In reported cases of SS that were related to cutaneous trauma, lesions developed outside the area of trauma and there was documented leukocytosis and neutrophilia.^10-14

• Although leukocytosis is part of the minor diagnostic criteria for SS, it is not required for the diagnosis of PG. Considering that our patient had ulcerated lesions, lesions only at the site of trauma, and leukopenia with intermittent neutropenia, the diagnosis was consistent with PG.

The primary value of early recognition and diagnosis of PG lies in the physician’s ability to distinguish PG from an infectious process, which can be challenging in an immunosuppressed patient with an underlying hematologic malignancy.

Conclusion

This case report represents our experience in arriving at the correct diagnosis of PG in a febrile neutrophilic patient with CLL. In the case of PG in a complicated patient, it is critical to initiate appropriate treatment and avoid inappropriate therapies. Aggressive surgical debridement could have resulted in a fatal outcome for our patient, highlighting the need for dermatologists to raise physician awareness of this challenging disease.

Acknowledgments
The authors acknowledge the contributions of Sarah Shalin, MD, PhD; Nikhil Meena, MD; and Aditya Chada, MD (all from Little Rock, Arkansas), for excellent patient care.

Diagnosis of a neutrophilic dermatosis, such as pyoderma gangrenosum (PG), often is challenging at onset because it can be impossible to distinguish clinically and histopathologically from acute infection in an immunosuppressed patient, necessitating a detailed history as well as correlation pathology with microbial tissue cultures. The dermatologist’s ability to distinguish a neutrophilic dermatosis from active infection is of paramount importance because the decision to treat with surgical debridement, in addition to an antibiotic regimen, can have grave consequences in the misdiagnosed patient.

Pyoderma gangrenosum is a neutrophilic dermatosis histologically characterized by a pandermal neutrophilic infiltrate without evidence of an infectious cause or true vasculitis. It is classically associated with inflammatory bowel disease or an underlying hematologic malignancy. Pyoderma gangrenosum in the setting of chronic lymphocytic leukemia (CLL) is rare, with as few as 4 cases having been described in the literature and only 1 case of PG developing after a surgical procedure.^1-4 We present a case of PG occurring at a chest tube site in a patient with CLL. We highlight the challenges and therapeutic importance of arriving at the correct diagnosis.

Case Report

An 87-year-old man with a history of refractory CLL was admitted to the hospital with pneumonia and pleural effusion requiring chest tube placement (left). His most recent therapeutic regimen for CLL was rituximab and bendamustine, which was administered 9 days prior to admission. After removal of the chest tube, an erythematous plaque with central necrosis surrounding the chest tube site developed (Figure 1A). During this time period, the patient had documented intermittent fevers, leukopenia, and neutropenia. Serial blood cultures yielded no growth. Because the patient was on broad-spectrum antibiotic coverage, dermatology was consulted for possible angioinvasive fungal infection.

Physical examination revealed an indurated, erythematous-violaceous, targetoid, well-defined, ulcerated plaque with central necrosis on the left side of the chest. Notably, we observed an isolated bulla with an erythematous base within the right antecubital fossa at the site of intravenous placement, suggesting pathergy.

Multiple punch biopsies revealed an ulcer with an underlying dense neutrophilic infiltrate within the dermis and subcutaneous tissues (Figure 2). Grocott-Gomori methenamine-silver, periodic acid–Schiff, and acid-fast bacillus stains were all negative for organisms. Tissue cultures for bacterial, fungal, and acid-fast bacilli revealed no growth. Due to the rapidly expanding nature of the plaque and the possibility of infection despite negative microbial stains and cultures, the patient was scheduled for surgical debridement by the surgical team.

Comment

Pathogenesis of PG
Pyoderma gangrenosum lies in the spectrum of neutrophilic dermatoses, which are characterized histologically by a pandermal neutrophilic infiltrate without evidence of an infectious cause or true vasculitis. Clinically, PG typically presents as a steadily expanding ulceration with an undermined or slightly raised border, and often is associated with the pathergy phenomenon. Historically, PG is classically linked to inflammatory bowel disease; however, association with underlying malignancy, including acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, and myeloid metaplasia, also has been described.⁵

Pathogenesis of CLL
Chronic lymphocytic leukemia represents the most prevalent form of leukemia in US adults, with the second highest annual incidence.⁶ Cutaneous findings are seen in 25% of patients with CLL, varying from leukemia cutis to secondary findings such as vasculitis, purpura, generalized pruritus, exfoliative erythroderma, paraneoplastic pemphigus, infections, and rarely neutrophilic dermatoses.⁷ According to a PubMed search of articles indexed for MEDLINE using the term pyoderma gangrenosum in CLL, only 4 cases of PG occurring in the setting of CLL exist in the literature, with 1 case demonstrating development after a surgical procedure, making ours the second such case (Table).^1-4

Sweet syndrome is classically the most challenging entity within the spectrum to differentiate from PG. However, our case outlines several key distinguishing features:

• The lesion in classic PG is a rapidly expanding ulceration with undermined borders, whereas SS is less commonly associated with ulceration and instead classically presents with multiple edematous papules that progress to juicy plaques.⁸

• The pathergy phenomenon has been reported in SS, though it is more commonly associated with PG.⁹

• In reported cases of SS that were related to cutaneous trauma, lesions developed outside the area of trauma and there was documented leukocytosis and neutrophilia.^10-14

• Although leukocytosis is part of the minor diagnostic criteria for SS, it is not required for the diagnosis of PG. Considering that our patient had ulcerated lesions, lesions only at the site of trauma, and leukopenia with intermittent neutropenia, the diagnosis was consistent with PG.

The primary value of early recognition and diagnosis of PG lies in the physician’s ability to distinguish PG from an infectious process, which can be challenging in an immunosuppressed patient with an underlying hematologic malignancy.

Conclusion

This case report represents our experience in arriving at the correct diagnosis of PG in a febrile neutrophilic patient with CLL. In the case of PG in a complicated patient, it is critical to initiate appropriate treatment and avoid inappropriate therapies. Aggressive surgical debridement could have resulted in a fatal outcome for our patient, highlighting the need for dermatologists to raise physician awareness of this challenging disease.

Acknowledgments
The authors acknowledge the contributions of Sarah Shalin, MD, PhD; Nikhil Meena, MD; and Aditya Chada, MD (all from Little Rock, Arkansas), for excellent patient care.