Case Reports

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.

Angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) is present in from 0.1% to 0.7% of treated patients and more often involves the head, neck, face, lips, tongue, and larynx.¹ ACEI-induced angioedema results from inhibition of angiotensin-converting enzyme (ACE), which results in reduced degradation and resultant accumulation of bradykinin, a potent inflammatory mediator.²

The treatment of choice is discontinuing all ACEIs; however, the patient may be at increased risk of a subsequent angioedema attack for many weeks.³ Antihistamines (H₁ and H₂ receptor blockade), epinephrine, and glucocorticoids are effective in allergic/histaminergic angioedema but are usually ineffective for hereditary angioedema or ACEI angioedema and are not recommended for acute therapy.⁴ Kallikrein-bradykinin pathway targeted therapies are now approved by the Food and Drug Administration (FDA) for hereditary angioedema attacks and have been studied for ACEI-induced angioedema. Ecallantide and icatibant inhibit conversion of precursors to bradykinin. Multiple randomized trials of ecallantide have not shown any advantage over traditional therapies.⁵ On the other hand, icatibant has shown resolution of angioedema in several case reports and in a randomized trial.⁶ Icatibant for ACEI-induced angioedema continues to be off-label because the data are conflicting.

Case Presentation

A 67-year-old man presented with a medical history of arterial hypertension (diagnosed 17 years previously), hypercholesterolemia, type 2 diabetes mellitus, alcohol dependence, and obesity. His outpatient medications included simvastatin, aripiprazole, losartan/hydrochlorothiazide, and amlodipine. He was voluntarily admitted for inpatient detoxification. After evaluation by the internist, medication reconciliation was done, and the therapy was adjusted according to medication availability. He reported having no drug allergies, and the losartan was changed for lisinopril. About 24 hours after the first dose of lisinopril, the patient developed swelling of the lips. Antihistamine and IV steroids were administered, and the ACEI was discontinued. His baseline vital signs were temperature 98° F, heart rate 83 beats per minute, respiratory rate 19 breaths per minute, blood pressure 150/94, and oxygen saturation 98% by pulse oximeter.

During the night shift the patient’s symptoms worsened, developing difficulty swallowing and shortness of breath. He was transferred to the medicine intensive care unit (MICU), intubated, and placed on mechanical ventilation to protect his airway. Laryngoscopic examination was notable for edematous tongue, uvula, and larynx. Also, the patient had mild stridor. His laboratory test results showed normal levels of complement, tryptase, and C1 esterase. On the fourth day after admission to MICU (Figure 1), the patient extubated himself. At that time, he did not present stridor or respiratory distress and remained at the MICU for 24 hours for close monitoring.

Thirty-six hours after self-extubation the patient developed stridor and shortness of breath at the general medicine ward. In view of his clinical presentation of recurrent ACEI-induced angioedema, the Anesthesiology Service was consulted. Direct visualization of the airways showed edema of the epiglottis and vocal cords, requiring nasotracheal intubation. Two units of fresh frozen plasma (FFP) were administered. Complete resolution of angioedema took at least 72 hours even after the administration of FFP. As part of the ventilator-associated pneumonia prevention bundle, the patient continued with daily spontaneous breathing trials. On the fourth day, he was he was extubated after a cuff-leak test was positive and his rapid shallow breathing index was adequate.

The cuff-leak test is usually done to predict postextubation stridor. It consists of deflating the endotracheal tube cuff to verify if gas can pass around the tube. Absence of cuff leak is suggestive of airway edema, a risk factor for postextubation stridor and failure of extubation. For example, if the patient has an endotracheal tube that is too large in relation to the patient’s airway, the leak test can result in a false negative. In this case, fiber optic visualization of the airway can confirm the endotracheal tube occluding all the airway even with the cuff deflated and without evidence of swelling of the vocal cords. The rapid shallow breathing index is a ratio of respiratory rate over tidal volume in liters and is used to predict successful extubation. Values < 105 have a high sensitivity for successful extubation.

The patient remained under observation for 24 hours in the MICU and then was transferred to the general medicine ward. Unfortunately, 36 hours after, the patient had a new episode of angioedema requiring endotracheal intubation and placement on mechanical ventilation. This was his third episode of angioedema; he had a difficult airway classified as a Cormack-Lehane grade 3, requiring intubation with fiber-optic laryngoscope. In view of the recurrent events, a tracheostomy was done several days later. Figure 2 shows posttracheostomy X-ray with adequate position of the tracheostomy tube.

The patient was transferred to the Respiratory Care Unit and weaned off mechanical ventilation. He completed an intensive physical rehabilitation program and was discharged home. On discharge, he was followed by the Otorhinolaryngology Service and was decannulated about 5 months after. After tracheostomy decannulation, he developed asymptomatic stridor. A neck computer tomography scan revealed soft tissue thickening at the anterior and lateral aspects of the proximal tracheal likely representing granulation tissue/scarring. The findings were consistent with proximal tracheal stenosis sequelae of tracheostomy and intubation. In Figure 3, the upper portion of the curve represents the expiratory limb of the forced vital capacity and the lower portion represents inspiration. The flow-volume loop graph showed flattening of the inspiratory limb. There was a plateau in the inspiratory limb, suggestive of limitation of inspiratory flow as seen in variable extrathoracic lesions, such as glotticstricture, tumors, and vocal cord paralysis.⁷ The findings on the flow-volume loop were consistent with the subglottic stenosis identified by laryngoscopic examination. The patient was reluctant to undergo further interventions.

Discussion

The standard therapy for ACEI-inducedangioedema continues to be airway management and discontinuation of medication. However, life-threatening progression of symptoms have led to the use of off-label therapies, including FFP and bradykinin receptor antagonists, such as icatibant, which has been approved by the FDA for the treatment of hereditary angioedema. Icatibant is expensive and most hospitals do not have access to it. When considering the bradykinin pathway for therapy, FFP is commonly used. The cases described in the literature that have reported success with the use of FFP have used up to 2 units. There is no reported benefit of its use beyond 2 units. The initial randomized trials of icatibant for ACEI angioedema showed decreased time of resolution of angioedema.⁶ However, repeated trials showed conflicting results. At Veterans Affairs Caribbean Healthcare System, this medication was not available, and we decided to use FFP to improve the patient’s symptoms.

The administration of 2 units of FFP has been documented on case reports as a method to decrease the time of resolution of angioedema and the risk of recurrence. The mechanism of action thought to be involved includes the degradation of bradykinin by the enzyme ACE into inactive peptides and by supplying C1 inhibitor.⁸ No randomized clinical trial has investigated the use of FFP for the treatment of ACEI-induced angioedema. However, a retrospective cohort study report compared patients who presented with acute (nonhereditary) angioedema and airway compromise and received FFP with patients who were not treated with FFP.⁹ The study suggested a shorter ICU stay in the group treated with FFP, but the findings did not present statistical outcomes.

Nevertheless, our patient had recurrent ACEI-induced angioedema refractory to FFP. In addition to ACE or kininase II, FFP contains high-molecular weight-kininogen and kallikrein, the substrates that form bradykinin, which explained the mechanism of worsening angioedema.¹⁰ No randomized trials have investigated the use of FFP for the treatment of bradykinin-induced angioedema nor the appropriate dose.

Conclusion

In view of the emerging case reports of the effectiveness of FFP, this case of refractory angioedema raises concern for its true effectiveness and other possible factors involved in the mechanism of recurrence. Probably it would be unwise to conduct randomized studies in clinical situations such as the ones outlined. A collection of case series where FFP administration was done may be a more reasonable source of conclusions to be analyzed by a panel of experts.

Angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) is present in from 0.1% to 0.7% of treated patients and more often involves the head, neck, face, lips, tongue, and larynx.¹ ACEI-induced angioedema results from inhibition of angiotensin-converting enzyme (ACE), which results in reduced degradation and resultant accumulation of bradykinin, a potent inflammatory mediator.²

The treatment of choice is discontinuing all ACEIs; however, the patient may be at increased risk of a subsequent angioedema attack for many weeks.³ Antihistamines (H₁ and H₂ receptor blockade), epinephrine, and glucocorticoids are effective in allergic/histaminergic angioedema but are usually ineffective for hereditary angioedema or ACEI angioedema and are not recommended for acute therapy.⁴ Kallikrein-bradykinin pathway targeted therapies are now approved by the Food and Drug Administration (FDA) for hereditary angioedema attacks and have been studied for ACEI-induced angioedema. Ecallantide and icatibant inhibit conversion of precursors to bradykinin. Multiple randomized trials of ecallantide have not shown any advantage over traditional therapies.⁵ On the other hand, icatibant has shown resolution of angioedema in several case reports and in a randomized trial.⁶ Icatibant for ACEI-induced angioedema continues to be off-label because the data are conflicting.

Case Presentation

A 67-year-old man presented with a medical history of arterial hypertension (diagnosed 17 years previously), hypercholesterolemia, type 2 diabetes mellitus, alcohol dependence, and obesity. His outpatient medications included simvastatin, aripiprazole, losartan/hydrochlorothiazide, and amlodipine. He was voluntarily admitted for inpatient detoxification. After evaluation by the internist, medication reconciliation was done, and the therapy was adjusted according to medication availability. He reported having no drug allergies, and the losartan was changed for lisinopril. About 24 hours after the first dose of lisinopril, the patient developed swelling of the lips. Antihistamine and IV steroids were administered, and the ACEI was discontinued. His baseline vital signs were temperature 98° F, heart rate 83 beats per minute, respiratory rate 19 breaths per minute, blood pressure 150/94, and oxygen saturation 98% by pulse oximeter.

During the night shift the patient’s symptoms worsened, developing difficulty swallowing and shortness of breath. He was transferred to the medicine intensive care unit (MICU), intubated, and placed on mechanical ventilation to protect his airway. Laryngoscopic examination was notable for edematous tongue, uvula, and larynx. Also, the patient had mild stridor. His laboratory test results showed normal levels of complement, tryptase, and C1 esterase. On the fourth day after admission to MICU (Figure 1), the patient extubated himself. At that time, he did not present stridor or respiratory distress and remained at the MICU for 24 hours for close monitoring.

Thirty-six hours after self-extubation the patient developed stridor and shortness of breath at the general medicine ward. In view of his clinical presentation of recurrent ACEI-induced angioedema, the Anesthesiology Service was consulted. Direct visualization of the airways showed edema of the epiglottis and vocal cords, requiring nasotracheal intubation. Two units of fresh frozen plasma (FFP) were administered. Complete resolution of angioedema took at least 72 hours even after the administration of FFP. As part of the ventilator-associated pneumonia prevention bundle, the patient continued with daily spontaneous breathing trials. On the fourth day, he was he was extubated after a cuff-leak test was positive and his rapid shallow breathing index was adequate.

The cuff-leak test is usually done to predict postextubation stridor. It consists of deflating the endotracheal tube cuff to verify if gas can pass around the tube. Absence of cuff leak is suggestive of airway edema, a risk factor for postextubation stridor and failure of extubation. For example, if the patient has an endotracheal tube that is too large in relation to the patient’s airway, the leak test can result in a false negative. In this case, fiber optic visualization of the airway can confirm the endotracheal tube occluding all the airway even with the cuff deflated and without evidence of swelling of the vocal cords. The rapid shallow breathing index is a ratio of respiratory rate over tidal volume in liters and is used to predict successful extubation. Values < 105 have a high sensitivity for successful extubation.

The patient remained under observation for 24 hours in the MICU and then was transferred to the general medicine ward. Unfortunately, 36 hours after, the patient had a new episode of angioedema requiring endotracheal intubation and placement on mechanical ventilation. This was his third episode of angioedema; he had a difficult airway classified as a Cormack-Lehane grade 3, requiring intubation with fiber-optic laryngoscope. In view of the recurrent events, a tracheostomy was done several days later. Figure 2 shows posttracheostomy X-ray with adequate position of the tracheostomy tube.

The patient was transferred to the Respiratory Care Unit and weaned off mechanical ventilation. He completed an intensive physical rehabilitation program and was discharged home. On discharge, he was followed by the Otorhinolaryngology Service and was decannulated about 5 months after. After tracheostomy decannulation, he developed asymptomatic stridor. A neck computer tomography scan revealed soft tissue thickening at the anterior and lateral aspects of the proximal tracheal likely representing granulation tissue/scarring. The findings were consistent with proximal tracheal stenosis sequelae of tracheostomy and intubation. In Figure 3, the upper portion of the curve represents the expiratory limb of the forced vital capacity and the lower portion represents inspiration. The flow-volume loop graph showed flattening of the inspiratory limb. There was a plateau in the inspiratory limb, suggestive of limitation of inspiratory flow as seen in variable extrathoracic lesions, such as glotticstricture, tumors, and vocal cord paralysis.⁷ The findings on the flow-volume loop were consistent with the subglottic stenosis identified by laryngoscopic examination. The patient was reluctant to undergo further interventions.

Discussion

The standard therapy for ACEI-inducedangioedema continues to be airway management and discontinuation of medication. However, life-threatening progression of symptoms have led to the use of off-label therapies, including FFP and bradykinin receptor antagonists, such as icatibant, which has been approved by the FDA for the treatment of hereditary angioedema. Icatibant is expensive and most hospitals do not have access to it. When considering the bradykinin pathway for therapy, FFP is commonly used. The cases described in the literature that have reported success with the use of FFP have used up to 2 units. There is no reported benefit of its use beyond 2 units. The initial randomized trials of icatibant for ACEI angioedema showed decreased time of resolution of angioedema.⁶ However, repeated trials showed conflicting results. At Veterans Affairs Caribbean Healthcare System, this medication was not available, and we decided to use FFP to improve the patient’s symptoms.

The administration of 2 units of FFP has been documented on case reports as a method to decrease the time of resolution of angioedema and the risk of recurrence. The mechanism of action thought to be involved includes the degradation of bradykinin by the enzyme ACE into inactive peptides and by supplying C1 inhibitor.⁸ No randomized clinical trial has investigated the use of FFP for the treatment of ACEI-induced angioedema. However, a retrospective cohort study report compared patients who presented with acute (nonhereditary) angioedema and airway compromise and received FFP with patients who were not treated with FFP.⁹ The study suggested a shorter ICU stay in the group treated with FFP, but the findings did not present statistical outcomes.

Nevertheless, our patient had recurrent ACEI-induced angioedema refractory to FFP. In addition to ACE or kininase II, FFP contains high-molecular weight-kininogen and kallikrein, the substrates that form bradykinin, which explained the mechanism of worsening angioedema.¹⁰ No randomized trials have investigated the use of FFP for the treatment of bradykinin-induced angioedema nor the appropriate dose.

Conclusion

In view of the emerging case reports of the effectiveness of FFP, this case of refractory angioedema raises concern for its true effectiveness and other possible factors involved in the mechanism of recurrence. Probably it would be unwise to conduct randomized studies in clinical situations such as the ones outlined. A collection of case series where FFP administration was done may be a more reasonable source of conclusions to be analyzed by a panel of experts.

Angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) is present in from 0.1% to 0.7% of treated patients and more often involves the head, neck, face, lips, tongue, and larynx.¹ ACEI-induced angioedema results from inhibition of angiotensin-converting enzyme (ACE), which results in reduced degradation and resultant accumulation of bradykinin, a potent inflammatory mediator.²

The treatment of choice is discontinuing all ACEIs; however, the patient may be at increased risk of a subsequent angioedema attack for many weeks.³ Antihistamines (H₁ and H₂ receptor blockade), epinephrine, and glucocorticoids are effective in allergic/histaminergic angioedema but are usually ineffective for hereditary angioedema or ACEI angioedema and are not recommended for acute therapy.⁴ Kallikrein-bradykinin pathway targeted therapies are now approved by the Food and Drug Administration (FDA) for hereditary angioedema attacks and have been studied for ACEI-induced angioedema. Ecallantide and icatibant inhibit conversion of precursors to bradykinin. Multiple randomized trials of ecallantide have not shown any advantage over traditional therapies.⁵ On the other hand, icatibant has shown resolution of angioedema in several case reports and in a randomized trial.⁶ Icatibant for ACEI-induced angioedema continues to be off-label because the data are conflicting.

Case Presentation

A 67-year-old man presented with a medical history of arterial hypertension (diagnosed 17 years previously), hypercholesterolemia, type 2 diabetes mellitus, alcohol dependence, and obesity. His outpatient medications included simvastatin, aripiprazole, losartan/hydrochlorothiazide, and amlodipine. He was voluntarily admitted for inpatient detoxification. After evaluation by the internist, medication reconciliation was done, and the therapy was adjusted according to medication availability. He reported having no drug allergies, and the losartan was changed for lisinopril. About 24 hours after the first dose of lisinopril, the patient developed swelling of the lips. Antihistamine and IV steroids were administered, and the ACEI was discontinued. His baseline vital signs were temperature 98° F, heart rate 83 beats per minute, respiratory rate 19 breaths per minute, blood pressure 150/94, and oxygen saturation 98% by pulse oximeter.

During the night shift the patient’s symptoms worsened, developing difficulty swallowing and shortness of breath. He was transferred to the medicine intensive care unit (MICU), intubated, and placed on mechanical ventilation to protect his airway. Laryngoscopic examination was notable for edematous tongue, uvula, and larynx. Also, the patient had mild stridor. His laboratory test results showed normal levels of complement, tryptase, and C1 esterase. On the fourth day after admission to MICU (Figure 1), the patient extubated himself. At that time, he did not present stridor or respiratory distress and remained at the MICU for 24 hours for close monitoring.

Thirty-six hours after self-extubation the patient developed stridor and shortness of breath at the general medicine ward. In view of his clinical presentation of recurrent ACEI-induced angioedema, the Anesthesiology Service was consulted. Direct visualization of the airways showed edema of the epiglottis and vocal cords, requiring nasotracheal intubation. Two units of fresh frozen plasma (FFP) were administered. Complete resolution of angioedema took at least 72 hours even after the administration of FFP. As part of the ventilator-associated pneumonia prevention bundle, the patient continued with daily spontaneous breathing trials. On the fourth day, he was he was extubated after a cuff-leak test was positive and his rapid shallow breathing index was adequate.

The cuff-leak test is usually done to predict postextubation stridor. It consists of deflating the endotracheal tube cuff to verify if gas can pass around the tube. Absence of cuff leak is suggestive of airway edema, a risk factor for postextubation stridor and failure of extubation. For example, if the patient has an endotracheal tube that is too large in relation to the patient’s airway, the leak test can result in a false negative. In this case, fiber optic visualization of the airway can confirm the endotracheal tube occluding all the airway even with the cuff deflated and without evidence of swelling of the vocal cords. The rapid shallow breathing index is a ratio of respiratory rate over tidal volume in liters and is used to predict successful extubation. Values < 105 have a high sensitivity for successful extubation.

The patient remained under observation for 24 hours in the MICU and then was transferred to the general medicine ward. Unfortunately, 36 hours after, the patient had a new episode of angioedema requiring endotracheal intubation and placement on mechanical ventilation. This was his third episode of angioedema; he had a difficult airway classified as a Cormack-Lehane grade 3, requiring intubation with fiber-optic laryngoscope. In view of the recurrent events, a tracheostomy was done several days later. Figure 2 shows posttracheostomy X-ray with adequate position of the tracheostomy tube.

The patient was transferred to the Respiratory Care Unit and weaned off mechanical ventilation. He completed an intensive physical rehabilitation program and was discharged home. On discharge, he was followed by the Otorhinolaryngology Service and was decannulated about 5 months after. After tracheostomy decannulation, he developed asymptomatic stridor. A neck computer tomography scan revealed soft tissue thickening at the anterior and lateral aspects of the proximal tracheal likely representing granulation tissue/scarring. The findings were consistent with proximal tracheal stenosis sequelae of tracheostomy and intubation. In Figure 3, the upper portion of the curve represents the expiratory limb of the forced vital capacity and the lower portion represents inspiration. The flow-volume loop graph showed flattening of the inspiratory limb. There was a plateau in the inspiratory limb, suggestive of limitation of inspiratory flow as seen in variable extrathoracic lesions, such as glotticstricture, tumors, and vocal cord paralysis.⁷ The findings on the flow-volume loop were consistent with the subglottic stenosis identified by laryngoscopic examination. The patient was reluctant to undergo further interventions.

Discussion

The standard therapy for ACEI-inducedangioedema continues to be airway management and discontinuation of medication. However, life-threatening progression of symptoms have led to the use of off-label therapies, including FFP and bradykinin receptor antagonists, such as icatibant, which has been approved by the FDA for the treatment of hereditary angioedema. Icatibant is expensive and most hospitals do not have access to it. When considering the bradykinin pathway for therapy, FFP is commonly used. The cases described in the literature that have reported success with the use of FFP have used up to 2 units. There is no reported benefit of its use beyond 2 units. The initial randomized trials of icatibant for ACEI angioedema showed decreased time of resolution of angioedema.⁶ However, repeated trials showed conflicting results. At Veterans Affairs Caribbean Healthcare System, this medication was not available, and we decided to use FFP to improve the patient’s symptoms.

The administration of 2 units of FFP has been documented on case reports as a method to decrease the time of resolution of angioedema and the risk of recurrence. The mechanism of action thought to be involved includes the degradation of bradykinin by the enzyme ACE into inactive peptides and by supplying C1 inhibitor.⁸ No randomized clinical trial has investigated the use of FFP for the treatment of ACEI-induced angioedema. However, a retrospective cohort study report compared patients who presented with acute (nonhereditary) angioedema and airway compromise and received FFP with patients who were not treated with FFP.⁹ The study suggested a shorter ICU stay in the group treated with FFP, but the findings did not present statistical outcomes.

Nevertheless, our patient had recurrent ACEI-induced angioedema refractory to FFP. In addition to ACE or kininase II, FFP contains high-molecular weight-kininogen and kallikrein, the substrates that form bradykinin, which explained the mechanism of worsening angioedema.¹⁰ No randomized trials have investigated the use of FFP for the treatment of bradykinin-induced angioedema nor the appropriate dose.

Conclusion

In view of the emerging case reports of the effectiveness of FFP, this case of refractory angioedema raises concern for its true effectiveness and other possible factors involved in the mechanism of recurrence. Probably it would be unwise to conduct randomized studies in clinical situations such as the ones outlined. A collection of case series where FFP administration was done may be a more reasonable source of conclusions to be analyzed by a panel of experts.

Plastic and orthopedic surgeons worked closely with therapists in military hospitals to rehabilitate soldiers afflicted with upper extremity trauma during World War II. Together, they developed treatment protocols. In 1975, the American Society for Hand Therapists (ASHT) was created during the American Society for Surgery of the Hand meeting. The ASHT application process required case studies, patient logs, and clinical hours, so membership was equivalent to competency. In May 1991, the first hand certification examination took place and designated the first group of certified hand therapists (CHT).¹

In the US Department of Veterans Affairs collaboration takes place between different services and communication is facilitated using the electronic heath record. The case presented here is an example of several services (emergency medicine, plastic/hand surgery, and occupational therapy) working together to develop a treatment plan for a condition that often goes undiagnosed or untreated. This article describes an innovative application of hand extensor tendon therapy clinical decision making to rehabilitate foot extensor tendons when the plastic surgery service was called on to work outside its usual comfort zone of the hand and upper extremity. The hand therapist applied hand extensor tendon rehabilitation principles to recover toe extensor lacerations.

Certified hand therapists (CHTs) are key to a successful hand surgery practice. The Plastic Surgery Service at the Malcom Randall VA Medical Center in Gainesville, Florida, relies heavily on the CHTs to optimize patient outcomes. The hand surgery clinic and hand therapy clinics are in the same hospital building, allowing for easy face-to-face communication. Hand therapy students are able to observe cases in the operating room. Immediately after surgery, follow-up consults are scheduled to coordinate postoperative care between the services.

Case Presentation

A 66-year-old man with a history of chronic obstructive pulmonary disease and spinal stenosis presented to the emergency department (ED) with a right dorsal foot wound and an exposed lacerated tendon after dropping a mirror on his foot (Figure 1). He was unable to extend his third toe. The ED physician called the in-house plastic surgery service, which can expedite upper extremity tendon injuries to clinic and surgery if indicated.²

The next day, the patient was examined in the plastic surgery clinic and found to have a completely lacerated extensor digitorum brevis to the second toe and a completely lacerated extensor digitorum longus to the third toe. These were located proximal to the metatarsal phalangeal joints. Surgery was scheduled for the following week.

In surgery, the tendons were sharply debrided and repaired using a 3.0 Ethibond suture placed in a modified Kessler technique followed by a horizontal mattress for a total of a 4-core repair. This was reinforced with a No. 6 Prolene to the paratendon. The surgery was performed under IV sedation and an ankle block, using 17 minutes of tourniquet time.

On postoperative day 1, the patient was seen in plastic surgery and occupational therapy clinic. The hand therapist modified the hand extensor tendon repair protocol since there was no known protocol for repairs of the foot and toe extensor tendon. The patient was placed in an ankle foot orthosis with a toe extension device created by heating and molding a low-temperature thermoplastic sheet (Figure 2). The toes were boosted into slight hyper extension. This was done to reduce tension across the extensor tendon repair site. All of the toes were held in about 20°of extension, as the extensor digitorum longus (EDL) has a common origin, to aide in adherence of wearing and for comfort. No standing or weight bearing was permitted for 3 weeks.

A wheelchair was issued in lieu of crutches to inhibit the work of toe extension with gait swing-through. Otherwise, the patient would generate tension on the extensor tendon in order for the toes to clear the ground. It was postulated that it would be difficult to turn off the toe extensors while using crutches. Maximal laxity was desired because edema and early scar formation could increase tension on the repair, resulting in rupture if the patient tried to fire the muscle belly even while in passive extension.

The patient kept his appointments and progressed steadily. He started passive toe extension and relaxation once per day for 30 repetitions at 1 week to aide in tendon glide. He started place and hold techniques in toe extension at 3 weeks. This progressed to active extension 50% effort plus active flexion at 4 weeks after surgery, then 75% extension effort plus toe towel crunches at 5 weeks. Toe crunches are toe flexion exercises with a washcloth on the floor with active bending of the toes with light resistance similar to picking up a marble with the toes. He was found to have a third toe extensor lag at that time that was correctible. The patient was actively able to flex and extend the toe independently. The early extension lag was felt to be secondary to edema and scar formation, which, over time are anticipated to resolve and contract and effectively shorten the tendon. Tendon gliding, and scar massage were reviewed. The patient’s last therapy session occurred 7 weeks after surgery, and he was cleared for full activity at 12 weeks. There was no further follow-up as he was planning on back surgery 2 weeks later.

Discussion

The North Florida/South Georgia Veterans Health System is fortunate to have 4 CHTs on staff. CHTs take a 200 question 4 hour certifying exam after being licensed for a minimum of 3 years as a physical or occupational therapist and completing 4,000 hours of direct upper extremity patient experience. Pass rates from 2008 to 2018 ranged from 52% to 68%.³ These clinicians are key to the success of our hand surgery service, utilizing their education and skills on our elective and trauma cases. The hand therapy service applied their knowledge of hand extensor rehabilitation protocols to rehabilitate the patient’s toe extensor in the absence of clear guidelines.

Hand extensor tendon rehabilitation protocols are based on the location of the repair on the hand or forearm. Nine extensor zones are named, distal to proximal, from the distal interphalangeal joints to the proximal forearm (Figure 3). In his review of extensor hallucis longus (EHL) repairs, Al-Qattan described 6 foot-extensor tendon zones, distal to proximal, from the first toe at the insertion of the big toe extensor to the distal leg proximal to the extensor retinaculum (Figure 4).⁴ Zone 3 is over the metatarsophalangeal joint; zone 5 is under the extensor retinaculum. The extensor tendon repairs described in this report were in dorsal foot zone 4 (proximal to the metatarsophalangeal joint and over the metatarsals), which would be most comparable to hand extensor zone 6 (proximal to the metacarpal phalangeal joint and over the metacarpals).

The EDL originates on the lateral condyle of the tibia and anterior surface of the fibula and the interosseous membrane, passes under the extensor retinaculum, and divides into 4 separate tendons. The 4 tendons split into 3 slips; the central one inserts on the middle phalanx, and the lateral ones insert onto the distal phalanx of the 4 lateral toes, which allows for toe extension.⁵ The EDL common origin for the muscle belly that serves 4 tendon slips has clinical significance because rehabilitation for one digit will affect the others. Knowledge of the anatomical structures guides the clinical decision making whether it is in the hand or foot. The EDL works synergistically with the extensor digitorum brevis (EDBr) to dorsiflex (extend) the toe phalanges. The EDB originates at the supralateral surface of the calcaneus, lateral talocalcaneal ligament and cruciate crural ligament and inserts at the lateral side of the EDL of second, third, and fourth toes at the level of the metatarsophalangeal joint.⁶

Repair of lacerated extensor tendons in the foot is the recommended treatment. Chronic extensor lag of the phalanges can result in a claw toe deformity, difficulty controlling the toes when putting on shoes or socks, and catching of the toe on fabric or insoles.⁷ The extensor tendons are close to the deep and superficial peroneal nerves and to the dorsalis pedis artery, none of which were involved in this case report.

There are case reports and series of EHL repairs that all involves at least 3 weeks of immobilization.^4,8,9 The EHL dorsiflexes the big toe. Al-Qattan’s series involved placing K wires across the interphalangeal joint of the big toe and across the metatarsophalangeal joint, which were removed at 6 weeks, in addition to 3.0 polypropylene tendon mattress sutures. All patients in this series healed without tendon rupture or infection. Our PubMed search did not reveal any specific protocol for the EDL or EDB tendons, which are anatomically most comparable to the extensor digitorum communis (EDC) tendons in the hand. The EDC originates at the lateral epicondyle of the humerus, also divides into 4 separate tendons and is responsible for extending the 4 ulnar sided fingers at the metacarpophalangeal joint.¹⁰

Tendon repair protocols are a balance between preventing tendon rupture by too aggressive therapy and with preventing tendon adhesions from prolonged immobilization. Orthotic fabrication plays a key early role with blocking possible forces creating unacceptable strain or tension across the surgical repair site. Traditionally, extensor tendon repairs in the hand were immobilized for at least 3 weeks to prevent rupture. This is still the preferred protocol for the patient unwilling or unable to follow instructions. The downside to this method is extension lags, extrinsic tightness, and adhesions that prevent flexion, which can require prolonged therapy or tenolysis surgery to correct.^11-13

Early passive motion (EPM) was promoted in the 1980s when studies found better functional outcomes and fewer adhesions. This involved either a dynamic extension splint that relied on elastic bands (Louisville protocol) to keep tension off the repair or the Duran protocol that relied on a static splint and the patient doing the passive exercises with his other uninjured hand. Critics of the EPM protocol point to the costs of the splints and demands of postoperative hand therapy.¹¹

Early active motion (EAM) is the most recent development in hand tendon rehabilitation and starts within days of surgery. Studies have found an earlier regain of total active motion in patients who are mobilized earlier.¹² EAM protocols can be divided into controlled active motion (CAM) and relative motion extension splinting (RMES). CAM splints are forearm based and cross more joints. Relative motion splinting is the least restrictive, which makes it less likely that the patient will remove it. Patient friendly splints are ideal because tendon ruptures are often secondary to nonadherence.¹³ The yoke splint is an example of a RMES, which places the repaired digit in slightly greater extension at the metacarpal phalangeal joint than the other digits (Figure 5), allowing use of the uninjured digits.

The toe extensors do not have the juncturae tendinum connecting the individual EDL tendons to each other, as found between the EDC tendons in the hand. These connective bands can mask a single extensor tendon laceration in the hand when the patient is still able to extend the digit to neutral in the event of a more proximal dorsal hand laceration. A case can be made for closing the skin only in lesser toe extensor injuries in poor surgical candidates because the extensor lag would not be appreciated functionally when wearing shoes. There would be less functional impact when letting a toe extensor go untreated compared with that of a hand extensor. Routine activities such as typing or getting the fingers into a tight pocket could be challenging if hand extensors were untreated. The rehabilitation for toe extensors is more inconvenient when a patient is nonweight bearing, compared with wearing a hand yoke splint.

Conclusion

The case described used an early passive motion protocol without the dynamic splint to rehabilitate the third toe EDL and second toe EDB. This was felt to be the most patient and therapist friendly option, given the previously unchartered territory. The foot orthosis was in stock at the adjacent physical therapy clinic, and the toe booster was created in the hand therapy clinic with readily available supplies. Ideally, one would like to return structures to their anatomic site and control the healing process in the event of a traumatic injury to prevent nonanatomic healing between structures and painful scar adhesions in an area with little subcutaneous tissue. This patient’s tendon repair was still intact at 7 weeks and on his way to recovery, demonstrating good scar management techniques. The risks and benefits to lesser toe tendon repair and recovery would have to be weighed on an individual basis.

Acknowledgments
This project is the result of work supported with resources and use of facilities at the Malcom Randall VA Medical Center in Gainesville, Florida.

Plastic and orthopedic surgeons worked closely with therapists in military hospitals to rehabilitate soldiers afflicted with upper extremity trauma during World War II. Together, they developed treatment protocols. In 1975, the American Society for Hand Therapists (ASHT) was created during the American Society for Surgery of the Hand meeting. The ASHT application process required case studies, patient logs, and clinical hours, so membership was equivalent to competency. In May 1991, the first hand certification examination took place and designated the first group of certified hand therapists (CHT).¹

In the US Department of Veterans Affairs collaboration takes place between different services and communication is facilitated using the electronic heath record. The case presented here is an example of several services (emergency medicine, plastic/hand surgery, and occupational therapy) working together to develop a treatment plan for a condition that often goes undiagnosed or untreated. This article describes an innovative application of hand extensor tendon therapy clinical decision making to rehabilitate foot extensor tendons when the plastic surgery service was called on to work outside its usual comfort zone of the hand and upper extremity. The hand therapist applied hand extensor tendon rehabilitation principles to recover toe extensor lacerations.

Certified hand therapists (CHTs) are key to a successful hand surgery practice. The Plastic Surgery Service at the Malcom Randall VA Medical Center in Gainesville, Florida, relies heavily on the CHTs to optimize patient outcomes. The hand surgery clinic and hand therapy clinics are in the same hospital building, allowing for easy face-to-face communication. Hand therapy students are able to observe cases in the operating room. Immediately after surgery, follow-up consults are scheduled to coordinate postoperative care between the services.

Case Presentation

A 66-year-old man with a history of chronic obstructive pulmonary disease and spinal stenosis presented to the emergency department (ED) with a right dorsal foot wound and an exposed lacerated tendon after dropping a mirror on his foot (Figure 1). He was unable to extend his third toe. The ED physician called the in-house plastic surgery service, which can expedite upper extremity tendon injuries to clinic and surgery if indicated.²

The next day, the patient was examined in the plastic surgery clinic and found to have a completely lacerated extensor digitorum brevis to the second toe and a completely lacerated extensor digitorum longus to the third toe. These were located proximal to the metatarsal phalangeal joints. Surgery was scheduled for the following week.

In surgery, the tendons were sharply debrided and repaired using a 3.0 Ethibond suture placed in a modified Kessler technique followed by a horizontal mattress for a total of a 4-core repair. This was reinforced with a No. 6 Prolene to the paratendon. The surgery was performed under IV sedation and an ankle block, using 17 minutes of tourniquet time.

On postoperative day 1, the patient was seen in plastic surgery and occupational therapy clinic. The hand therapist modified the hand extensor tendon repair protocol since there was no known protocol for repairs of the foot and toe extensor tendon. The patient was placed in an ankle foot orthosis with a toe extension device created by heating and molding a low-temperature thermoplastic sheet (Figure 2). The toes were boosted into slight hyper extension. This was done to reduce tension across the extensor tendon repair site. All of the toes were held in about 20°of extension, as the extensor digitorum longus (EDL) has a common origin, to aide in adherence of wearing and for comfort. No standing or weight bearing was permitted for 3 weeks.

A wheelchair was issued in lieu of crutches to inhibit the work of toe extension with gait swing-through. Otherwise, the patient would generate tension on the extensor tendon in order for the toes to clear the ground. It was postulated that it would be difficult to turn off the toe extensors while using crutches. Maximal laxity was desired because edema and early scar formation could increase tension on the repair, resulting in rupture if the patient tried to fire the muscle belly even while in passive extension.

The patient kept his appointments and progressed steadily. He started passive toe extension and relaxation once per day for 30 repetitions at 1 week to aide in tendon glide. He started place and hold techniques in toe extension at 3 weeks. This progressed to active extension 50% effort plus active flexion at 4 weeks after surgery, then 75% extension effort plus toe towel crunches at 5 weeks. Toe crunches are toe flexion exercises with a washcloth on the floor with active bending of the toes with light resistance similar to picking up a marble with the toes. He was found to have a third toe extensor lag at that time that was correctible. The patient was actively able to flex and extend the toe independently. The early extension lag was felt to be secondary to edema and scar formation, which, over time are anticipated to resolve and contract and effectively shorten the tendon. Tendon gliding, and scar massage were reviewed. The patient’s last therapy session occurred 7 weeks after surgery, and he was cleared for full activity at 12 weeks. There was no further follow-up as he was planning on back surgery 2 weeks later.

Discussion

The North Florida/South Georgia Veterans Health System is fortunate to have 4 CHTs on staff. CHTs take a 200 question 4 hour certifying exam after being licensed for a minimum of 3 years as a physical or occupational therapist and completing 4,000 hours of direct upper extremity patient experience. Pass rates from 2008 to 2018 ranged from 52% to 68%.³ These clinicians are key to the success of our hand surgery service, utilizing their education and skills on our elective and trauma cases. The hand therapy service applied their knowledge of hand extensor rehabilitation protocols to rehabilitate the patient’s toe extensor in the absence of clear guidelines.

Hand extensor tendon rehabilitation protocols are based on the location of the repair on the hand or forearm. Nine extensor zones are named, distal to proximal, from the distal interphalangeal joints to the proximal forearm (Figure 3). In his review of extensor hallucis longus (EHL) repairs, Al-Qattan described 6 foot-extensor tendon zones, distal to proximal, from the first toe at the insertion of the big toe extensor to the distal leg proximal to the extensor retinaculum (Figure 4).⁴ Zone 3 is over the metatarsophalangeal joint; zone 5 is under the extensor retinaculum. The extensor tendon repairs described in this report were in dorsal foot zone 4 (proximal to the metatarsophalangeal joint and over the metatarsals), which would be most comparable to hand extensor zone 6 (proximal to the metacarpal phalangeal joint and over the metacarpals).

The EDL originates on the lateral condyle of the tibia and anterior surface of the fibula and the interosseous membrane, passes under the extensor retinaculum, and divides into 4 separate tendons. The 4 tendons split into 3 slips; the central one inserts on the middle phalanx, and the lateral ones insert onto the distal phalanx of the 4 lateral toes, which allows for toe extension.⁵ The EDL common origin for the muscle belly that serves 4 tendon slips has clinical significance because rehabilitation for one digit will affect the others. Knowledge of the anatomical structures guides the clinical decision making whether it is in the hand or foot. The EDL works synergistically with the extensor digitorum brevis (EDBr) to dorsiflex (extend) the toe phalanges. The EDB originates at the supralateral surface of the calcaneus, lateral talocalcaneal ligament and cruciate crural ligament and inserts at the lateral side of the EDL of second, third, and fourth toes at the level of the metatarsophalangeal joint.⁶

Repair of lacerated extensor tendons in the foot is the recommended treatment. Chronic extensor lag of the phalanges can result in a claw toe deformity, difficulty controlling the toes when putting on shoes or socks, and catching of the toe on fabric or insoles.⁷ The extensor tendons are close to the deep and superficial peroneal nerves and to the dorsalis pedis artery, none of which were involved in this case report.

There are case reports and series of EHL repairs that all involves at least 3 weeks of immobilization.^4,8,9 The EHL dorsiflexes the big toe. Al-Qattan’s series involved placing K wires across the interphalangeal joint of the big toe and across the metatarsophalangeal joint, which were removed at 6 weeks, in addition to 3.0 polypropylene tendon mattress sutures. All patients in this series healed without tendon rupture or infection. Our PubMed search did not reveal any specific protocol for the EDL or EDB tendons, which are anatomically most comparable to the extensor digitorum communis (EDC) tendons in the hand. The EDC originates at the lateral epicondyle of the humerus, also divides into 4 separate tendons and is responsible for extending the 4 ulnar sided fingers at the metacarpophalangeal joint.¹⁰

Tendon repair protocols are a balance between preventing tendon rupture by too aggressive therapy and with preventing tendon adhesions from prolonged immobilization. Orthotic fabrication plays a key early role with blocking possible forces creating unacceptable strain or tension across the surgical repair site. Traditionally, extensor tendon repairs in the hand were immobilized for at least 3 weeks to prevent rupture. This is still the preferred protocol for the patient unwilling or unable to follow instructions. The downside to this method is extension lags, extrinsic tightness, and adhesions that prevent flexion, which can require prolonged therapy or tenolysis surgery to correct.^11-13

Early passive motion (EPM) was promoted in the 1980s when studies found better functional outcomes and fewer adhesions. This involved either a dynamic extension splint that relied on elastic bands (Louisville protocol) to keep tension off the repair or the Duran protocol that relied on a static splint and the patient doing the passive exercises with his other uninjured hand. Critics of the EPM protocol point to the costs of the splints and demands of postoperative hand therapy.¹¹

Early active motion (EAM) is the most recent development in hand tendon rehabilitation and starts within days of surgery. Studies have found an earlier regain of total active motion in patients who are mobilized earlier.¹² EAM protocols can be divided into controlled active motion (CAM) and relative motion extension splinting (RMES). CAM splints are forearm based and cross more joints. Relative motion splinting is the least restrictive, which makes it less likely that the patient will remove it. Patient friendly splints are ideal because tendon ruptures are often secondary to nonadherence.¹³ The yoke splint is an example of a RMES, which places the repaired digit in slightly greater extension at the metacarpal phalangeal joint than the other digits (Figure 5), allowing use of the uninjured digits.

The toe extensors do not have the juncturae tendinum connecting the individual EDL tendons to each other, as found between the EDC tendons in the hand. These connective bands can mask a single extensor tendon laceration in the hand when the patient is still able to extend the digit to neutral in the event of a more proximal dorsal hand laceration. A case can be made for closing the skin only in lesser toe extensor injuries in poor surgical candidates because the extensor lag would not be appreciated functionally when wearing shoes. There would be less functional impact when letting a toe extensor go untreated compared with that of a hand extensor. Routine activities such as typing or getting the fingers into a tight pocket could be challenging if hand extensors were untreated. The rehabilitation for toe extensors is more inconvenient when a patient is nonweight bearing, compared with wearing a hand yoke splint.

Conclusion

The case described used an early passive motion protocol without the dynamic splint to rehabilitate the third toe EDL and second toe EDB. This was felt to be the most patient and therapist friendly option, given the previously unchartered territory. The foot orthosis was in stock at the adjacent physical therapy clinic, and the toe booster was created in the hand therapy clinic with readily available supplies. Ideally, one would like to return structures to their anatomic site and control the healing process in the event of a traumatic injury to prevent nonanatomic healing between structures and painful scar adhesions in an area with little subcutaneous tissue. This patient’s tendon repair was still intact at 7 weeks and on his way to recovery, demonstrating good scar management techniques. The risks and benefits to lesser toe tendon repair and recovery would have to be weighed on an individual basis.

Acknowledgments
This project is the result of work supported with resources and use of facilities at the Malcom Randall VA Medical Center in Gainesville, Florida.

Plastic and orthopedic surgeons worked closely with therapists in military hospitals to rehabilitate soldiers afflicted with upper extremity trauma during World War II. Together, they developed treatment protocols. In 1975, the American Society for Hand Therapists (ASHT) was created during the American Society for Surgery of the Hand meeting. The ASHT application process required case studies, patient logs, and clinical hours, so membership was equivalent to competency. In May 1991, the first hand certification examination took place and designated the first group of certified hand therapists (CHT).¹

In the US Department of Veterans Affairs collaboration takes place between different services and communication is facilitated using the electronic heath record. The case presented here is an example of several services (emergency medicine, plastic/hand surgery, and occupational therapy) working together to develop a treatment plan for a condition that often goes undiagnosed or untreated. This article describes an innovative application of hand extensor tendon therapy clinical decision making to rehabilitate foot extensor tendons when the plastic surgery service was called on to work outside its usual comfort zone of the hand and upper extremity. The hand therapist applied hand extensor tendon rehabilitation principles to recover toe extensor lacerations.

Certified hand therapists (CHTs) are key to a successful hand surgery practice. The Plastic Surgery Service at the Malcom Randall VA Medical Center in Gainesville, Florida, relies heavily on the CHTs to optimize patient outcomes. The hand surgery clinic and hand therapy clinics are in the same hospital building, allowing for easy face-to-face communication. Hand therapy students are able to observe cases in the operating room. Immediately after surgery, follow-up consults are scheduled to coordinate postoperative care between the services.

Case Presentation

A 66-year-old man with a history of chronic obstructive pulmonary disease and spinal stenosis presented to the emergency department (ED) with a right dorsal foot wound and an exposed lacerated tendon after dropping a mirror on his foot (Figure 1). He was unable to extend his third toe. The ED physician called the in-house plastic surgery service, which can expedite upper extremity tendon injuries to clinic and surgery if indicated.²

The next day, the patient was examined in the plastic surgery clinic and found to have a completely lacerated extensor digitorum brevis to the second toe and a completely lacerated extensor digitorum longus to the third toe. These were located proximal to the metatarsal phalangeal joints. Surgery was scheduled for the following week.

In surgery, the tendons were sharply debrided and repaired using a 3.0 Ethibond suture placed in a modified Kessler technique followed by a horizontal mattress for a total of a 4-core repair. This was reinforced with a No. 6 Prolene to the paratendon. The surgery was performed under IV sedation and an ankle block, using 17 minutes of tourniquet time.

On postoperative day 1, the patient was seen in plastic surgery and occupational therapy clinic. The hand therapist modified the hand extensor tendon repair protocol since there was no known protocol for repairs of the foot and toe extensor tendon. The patient was placed in an ankle foot orthosis with a toe extension device created by heating and molding a low-temperature thermoplastic sheet (Figure 2). The toes were boosted into slight hyper extension. This was done to reduce tension across the extensor tendon repair site. All of the toes were held in about 20°of extension, as the extensor digitorum longus (EDL) has a common origin, to aide in adherence of wearing and for comfort. No standing or weight bearing was permitted for 3 weeks.

A wheelchair was issued in lieu of crutches to inhibit the work of toe extension with gait swing-through. Otherwise, the patient would generate tension on the extensor tendon in order for the toes to clear the ground. It was postulated that it would be difficult to turn off the toe extensors while using crutches. Maximal laxity was desired because edema and early scar formation could increase tension on the repair, resulting in rupture if the patient tried to fire the muscle belly even while in passive extension.

The patient kept his appointments and progressed steadily. He started passive toe extension and relaxation once per day for 30 repetitions at 1 week to aide in tendon glide. He started place and hold techniques in toe extension at 3 weeks. This progressed to active extension 50% effort plus active flexion at 4 weeks after surgery, then 75% extension effort plus toe towel crunches at 5 weeks. Toe crunches are toe flexion exercises with a washcloth on the floor with active bending of the toes with light resistance similar to picking up a marble with the toes. He was found to have a third toe extensor lag at that time that was correctible. The patient was actively able to flex and extend the toe independently. The early extension lag was felt to be secondary to edema and scar formation, which, over time are anticipated to resolve and contract and effectively shorten the tendon. Tendon gliding, and scar massage were reviewed. The patient’s last therapy session occurred 7 weeks after surgery, and he was cleared for full activity at 12 weeks. There was no further follow-up as he was planning on back surgery 2 weeks later.

Discussion

The North Florida/South Georgia Veterans Health System is fortunate to have 4 CHTs on staff. CHTs take a 200 question 4 hour certifying exam after being licensed for a minimum of 3 years as a physical or occupational therapist and completing 4,000 hours of direct upper extremity patient experience. Pass rates from 2008 to 2018 ranged from 52% to 68%.³ These clinicians are key to the success of our hand surgery service, utilizing their education and skills on our elective and trauma cases. The hand therapy service applied their knowledge of hand extensor rehabilitation protocols to rehabilitate the patient’s toe extensor in the absence of clear guidelines.

Hand extensor tendon rehabilitation protocols are based on the location of the repair on the hand or forearm. Nine extensor zones are named, distal to proximal, from the distal interphalangeal joints to the proximal forearm (Figure 3). In his review of extensor hallucis longus (EHL) repairs, Al-Qattan described 6 foot-extensor tendon zones, distal to proximal, from the first toe at the insertion of the big toe extensor to the distal leg proximal to the extensor retinaculum (Figure 4).⁴ Zone 3 is over the metatarsophalangeal joint; zone 5 is under the extensor retinaculum. The extensor tendon repairs described in this report were in dorsal foot zone 4 (proximal to the metatarsophalangeal joint and over the metatarsals), which would be most comparable to hand extensor zone 6 (proximal to the metacarpal phalangeal joint and over the metacarpals).

The EDL originates on the lateral condyle of the tibia and anterior surface of the fibula and the interosseous membrane, passes under the extensor retinaculum, and divides into 4 separate tendons. The 4 tendons split into 3 slips; the central one inserts on the middle phalanx, and the lateral ones insert onto the distal phalanx of the 4 lateral toes, which allows for toe extension.⁵ The EDL common origin for the muscle belly that serves 4 tendon slips has clinical significance because rehabilitation for one digit will affect the others. Knowledge of the anatomical structures guides the clinical decision making whether it is in the hand or foot. The EDL works synergistically with the extensor digitorum brevis (EDBr) to dorsiflex (extend) the toe phalanges. The EDB originates at the supralateral surface of the calcaneus, lateral talocalcaneal ligament and cruciate crural ligament and inserts at the lateral side of the EDL of second, third, and fourth toes at the level of the metatarsophalangeal joint.⁶

Repair of lacerated extensor tendons in the foot is the recommended treatment. Chronic extensor lag of the phalanges can result in a claw toe deformity, difficulty controlling the toes when putting on shoes or socks, and catching of the toe on fabric or insoles.⁷ The extensor tendons are close to the deep and superficial peroneal nerves and to the dorsalis pedis artery, none of which were involved in this case report.

There are case reports and series of EHL repairs that all involves at least 3 weeks of immobilization.^4,8,9 The EHL dorsiflexes the big toe. Al-Qattan’s series involved placing K wires across the interphalangeal joint of the big toe and across the metatarsophalangeal joint, which were removed at 6 weeks, in addition to 3.0 polypropylene tendon mattress sutures. All patients in this series healed without tendon rupture or infection. Our PubMed search did not reveal any specific protocol for the EDL or EDB tendons, which are anatomically most comparable to the extensor digitorum communis (EDC) tendons in the hand. The EDC originates at the lateral epicondyle of the humerus, also divides into 4 separate tendons and is responsible for extending the 4 ulnar sided fingers at the metacarpophalangeal joint.¹⁰

Tendon repair protocols are a balance between preventing tendon rupture by too aggressive therapy and with preventing tendon adhesions from prolonged immobilization. Orthotic fabrication plays a key early role with blocking possible forces creating unacceptable strain or tension across the surgical repair site. Traditionally, extensor tendon repairs in the hand were immobilized for at least 3 weeks to prevent rupture. This is still the preferred protocol for the patient unwilling or unable to follow instructions. The downside to this method is extension lags, extrinsic tightness, and adhesions that prevent flexion, which can require prolonged therapy or tenolysis surgery to correct.^11-13

Early passive motion (EPM) was promoted in the 1980s when studies found better functional outcomes and fewer adhesions. This involved either a dynamic extension splint that relied on elastic bands (Louisville protocol) to keep tension off the repair or the Duran protocol that relied on a static splint and the patient doing the passive exercises with his other uninjured hand. Critics of the EPM protocol point to the costs of the splints and demands of postoperative hand therapy.¹¹

Early active motion (EAM) is the most recent development in hand tendon rehabilitation and starts within days of surgery. Studies have found an earlier regain of total active motion in patients who are mobilized earlier.¹² EAM protocols can be divided into controlled active motion (CAM) and relative motion extension splinting (RMES). CAM splints are forearm based and cross more joints. Relative motion splinting is the least restrictive, which makes it less likely that the patient will remove it. Patient friendly splints are ideal because tendon ruptures are often secondary to nonadherence.¹³ The yoke splint is an example of a RMES, which places the repaired digit in slightly greater extension at the metacarpal phalangeal joint than the other digits (Figure 5), allowing use of the uninjured digits.

The toe extensors do not have the juncturae tendinum connecting the individual EDL tendons to each other, as found between the EDC tendons in the hand. These connective bands can mask a single extensor tendon laceration in the hand when the patient is still able to extend the digit to neutral in the event of a more proximal dorsal hand laceration. A case can be made for closing the skin only in lesser toe extensor injuries in poor surgical candidates because the extensor lag would not be appreciated functionally when wearing shoes. There would be less functional impact when letting a toe extensor go untreated compared with that of a hand extensor. Routine activities such as typing or getting the fingers into a tight pocket could be challenging if hand extensors were untreated. The rehabilitation for toe extensors is more inconvenient when a patient is nonweight bearing, compared with wearing a hand yoke splint.

Conclusion

The case described used an early passive motion protocol without the dynamic splint to rehabilitate the third toe EDL and second toe EDB. This was felt to be the most patient and therapist friendly option, given the previously unchartered territory. The foot orthosis was in stock at the adjacent physical therapy clinic, and the toe booster was created in the hand therapy clinic with readily available supplies. Ideally, one would like to return structures to their anatomic site and control the healing process in the event of a traumatic injury to prevent nonanatomic healing between structures and painful scar adhesions in an area with little subcutaneous tissue. This patient’s tendon repair was still intact at 7 weeks and on his way to recovery, demonstrating good scar management techniques. The risks and benefits to lesser toe tendon repair and recovery would have to be weighed on an individual basis.

Acknowledgments
This project is the result of work supported with resources and use of facilities at the Malcom Randall VA Medical Center in Gainesville, Florida.