Case Reports

A 46-year-old man with a remote history of general tonic-clonic seizures, for which he was taking phenytoin, presented to the ED 30 minutes after sustaining a witnessed mechanical fall. The patient had fallen onto his nondominant left hand, which resulted in an injury to his elbow. He reported neither losing consciousness nor experiencing any seizures following the incident. He denied dislocating the joint or sustaining any other injuries from the fall. He also denied a history of past left elbow injury.

The patient was alert, oriented, and provided a full history of the incident. Regarding medical history, he stated that his last seizure had occurred 10 years prior. Except for the left elbow pain, a review of his systems was negative. The patient appeared in no acute distress, and supported his left upper extremity with a bandana and his right hand.

The patient’s vital signs were normal. The physical examination was negative except for the left elbow, which had significant swelling and limited range of motion without skin break, leading to suspicion for a prehospital dislocation with self-reduction. The joints above, below, and at the injury site were assessed for neurovascular injury.

Discussion

There is a paucity of information on vascular injury from elbow dislocation in the emergency medicine literature. A recent literature search referenced orthopedic pitfalls in the ED,¹ but most data appear in the orthopedic and vascular literature. A case report from the orthopedic literature in Brazil cites a vascular injury after ED relocation of a dislocated elbow following an assault.²

The elbow is the second most commonly dislocated joint (not including the patella) after the shoulder.³ Posterior dislocations make up the majority of these injuries. Simple versus complex injuries can be differentiated by the presence or absence of fracture.⁴ Simple complications include stiffness; loss of mobility, especially with full extension; neurovascular injuries; and compartment syndrome. Complex injuries involve fractures and potential neurovascular injuries, stiffness, pain, and loss of mobility.

Soft tissue injuries, fractures, and neurovascular complaints represent the majority of ED encounters, and are commonly related to falls. The elbow is the articulation of the humerus, ulna, and radius bones. Range of motion includes, but is not limited to, flexion, extension, supination, and pronation. Tears in the lateral ulnar ligament, joint capsule, and medial collateral ligament lead to instability of the joint and increase risk of dislocation.

Fractures make up to 20% of injuries to the elbow. These include fractures of the radial head and neck (most common), olecranon, and distal humerus.⁵ Open elbow fractures are rare, as are vascular injuries (5%-13% of cases).⁶ When present, vascular elbow injuries usually involve the brachial artery, and display abnormal palpable and Doppler assessment of the brachial and radial arteries.⁶

Nerve injuries may include injury to the radial nerve. Manifestations of radial nerve injury include abnormal sensation to the dorsum of the hand, trouble straightening the arm, and wrist-drop. Ulnar nerve injury typically presents with abnormal sensation to the fourth and fifth digits and decreased grip strength.

Conclusion

Vascular abnormalities are rare complications following elbow injuries. Our patient sustained a lacerated brachial artery, which was repaired via saphenous graft; brachial and basilic vein lacerations, which were ligated; and an avulsion fracture with an unstable joint, which was stabilized with external fixation and stabilization. He was discharged the following day with full neurovascular function.

A methodical approach to assessing patients presenting with elbow injury is essential to making the correct diagnosis. This should include a careful evaluation of the joints above and below the area of injury, as well as attention to the neurovascular examination, with a heightened suspicion for a vascular abnormality in complex injuries. Doppler and ultrasound evaluation with multiple rechecks can assist with the diagnosis. Our patient was rapidly assessed with a concern for a vascular injury, and was emergently referred to vascular surgery for repair of the brachial artery and stabilization of the joint.

A 46-year-old man with a remote history of general tonic-clonic seizures, for which he was taking phenytoin, presented to the ED 30 minutes after sustaining a witnessed mechanical fall. The patient had fallen onto his nondominant left hand, which resulted in an injury to his elbow. He reported neither losing consciousness nor experiencing any seizures following the incident. He denied dislocating the joint or sustaining any other injuries from the fall. He also denied a history of past left elbow injury.

The patient was alert, oriented, and provided a full history of the incident. Regarding medical history, he stated that his last seizure had occurred 10 years prior. Except for the left elbow pain, a review of his systems was negative. The patient appeared in no acute distress, and supported his left upper extremity with a bandana and his right hand.

The patient’s vital signs were normal. The physical examination was negative except for the left elbow, which had significant swelling and limited range of motion without skin break, leading to suspicion for a prehospital dislocation with self-reduction. The joints above, below, and at the injury site were assessed for neurovascular injury.

Discussion

There is a paucity of information on vascular injury from elbow dislocation in the emergency medicine literature. A recent literature search referenced orthopedic pitfalls in the ED,¹ but most data appear in the orthopedic and vascular literature. A case report from the orthopedic literature in Brazil cites a vascular injury after ED relocation of a dislocated elbow following an assault.²

The elbow is the second most commonly dislocated joint (not including the patella) after the shoulder.³ Posterior dislocations make up the majority of these injuries. Simple versus complex injuries can be differentiated by the presence or absence of fracture.⁴ Simple complications include stiffness; loss of mobility, especially with full extension; neurovascular injuries; and compartment syndrome. Complex injuries involve fractures and potential neurovascular injuries, stiffness, pain, and loss of mobility.

Soft tissue injuries, fractures, and neurovascular complaints represent the majority of ED encounters, and are commonly related to falls. The elbow is the articulation of the humerus, ulna, and radius bones. Range of motion includes, but is not limited to, flexion, extension, supination, and pronation. Tears in the lateral ulnar ligament, joint capsule, and medial collateral ligament lead to instability of the joint and increase risk of dislocation.

Fractures make up to 20% of injuries to the elbow. These include fractures of the radial head and neck (most common), olecranon, and distal humerus.⁵ Open elbow fractures are rare, as are vascular injuries (5%-13% of cases).⁶ When present, vascular elbow injuries usually involve the brachial artery, and display abnormal palpable and Doppler assessment of the brachial and radial arteries.⁶

Nerve injuries may include injury to the radial nerve. Manifestations of radial nerve injury include abnormal sensation to the dorsum of the hand, trouble straightening the arm, and wrist-drop. Ulnar nerve injury typically presents with abnormal sensation to the fourth and fifth digits and decreased grip strength.

Conclusion

Vascular abnormalities are rare complications following elbow injuries. Our patient sustained a lacerated brachial artery, which was repaired via saphenous graft; brachial and basilic vein lacerations, which were ligated; and an avulsion fracture with an unstable joint, which was stabilized with external fixation and stabilization. He was discharged the following day with full neurovascular function.

A methodical approach to assessing patients presenting with elbow injury is essential to making the correct diagnosis. This should include a careful evaluation of the joints above and below the area of injury, as well as attention to the neurovascular examination, with a heightened suspicion for a vascular abnormality in complex injuries. Doppler and ultrasound evaluation with multiple rechecks can assist with the diagnosis. Our patient was rapidly assessed with a concern for a vascular injury, and was emergently referred to vascular surgery for repair of the brachial artery and stabilization of the joint.

A 46-year-old man with a remote history of general tonic-clonic seizures, for which he was taking phenytoin, presented to the ED 30 minutes after sustaining a witnessed mechanical fall. The patient had fallen onto his nondominant left hand, which resulted in an injury to his elbow. He reported neither losing consciousness nor experiencing any seizures following the incident. He denied dislocating the joint or sustaining any other injuries from the fall. He also denied a history of past left elbow injury.

The patient was alert, oriented, and provided a full history of the incident. Regarding medical history, he stated that his last seizure had occurred 10 years prior. Except for the left elbow pain, a review of his systems was negative. The patient appeared in no acute distress, and supported his left upper extremity with a bandana and his right hand.

The patient’s vital signs were normal. The physical examination was negative except for the left elbow, which had significant swelling and limited range of motion without skin break, leading to suspicion for a prehospital dislocation with self-reduction. The joints above, below, and at the injury site were assessed for neurovascular injury.

Discussion

There is a paucity of information on vascular injury from elbow dislocation in the emergency medicine literature. A recent literature search referenced orthopedic pitfalls in the ED,¹ but most data appear in the orthopedic and vascular literature. A case report from the orthopedic literature in Brazil cites a vascular injury after ED relocation of a dislocated elbow following an assault.²

The elbow is the second most commonly dislocated joint (not including the patella) after the shoulder.³ Posterior dislocations make up the majority of these injuries. Simple versus complex injuries can be differentiated by the presence or absence of fracture.⁴ Simple complications include stiffness; loss of mobility, especially with full extension; neurovascular injuries; and compartment syndrome. Complex injuries involve fractures and potential neurovascular injuries, stiffness, pain, and loss of mobility.

Soft tissue injuries, fractures, and neurovascular complaints represent the majority of ED encounters, and are commonly related to falls. The elbow is the articulation of the humerus, ulna, and radius bones. Range of motion includes, but is not limited to, flexion, extension, supination, and pronation. Tears in the lateral ulnar ligament, joint capsule, and medial collateral ligament lead to instability of the joint and increase risk of dislocation.

Fractures make up to 20% of injuries to the elbow. These include fractures of the radial head and neck (most common), olecranon, and distal humerus.⁵ Open elbow fractures are rare, as are vascular injuries (5%-13% of cases).⁶ When present, vascular elbow injuries usually involve the brachial artery, and display abnormal palpable and Doppler assessment of the brachial and radial arteries.⁶

Nerve injuries may include injury to the radial nerve. Manifestations of radial nerve injury include abnormal sensation to the dorsum of the hand, trouble straightening the arm, and wrist-drop. Ulnar nerve injury typically presents with abnormal sensation to the fourth and fifth digits and decreased grip strength.

Conclusion

Vascular abnormalities are rare complications following elbow injuries. Our patient sustained a lacerated brachial artery, which was repaired via saphenous graft; brachial and basilic vein lacerations, which were ligated; and an avulsion fracture with an unstable joint, which was stabilized with external fixation and stabilization. He was discharged the following day with full neurovascular function.

A methodical approach to assessing patients presenting with elbow injury is essential to making the correct diagnosis. This should include a careful evaluation of the joints above and below the area of injury, as well as attention to the neurovascular examination, with a heightened suspicion for a vascular abnormality in complex injuries. Doppler and ultrasound evaluation with multiple rechecks can assist with the diagnosis. Our patient was rapidly assessed with a concern for a vascular injury, and was emergently referred to vascular surgery for repair of the brachial artery and stabilization of the joint.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Hypoglycemia, a frequently encountered medical emergency, is usually seen in patients with diabetes, most commonly as a result of iatrogenesis. However, it can also be encountered in nondiabetic patients. Various causes, such as pancreatic islet cell tumors producing insulin, primary or secondary adrenal insufficiency, advanced liver disease, pheochromocytoma and hypothyroidism, have been found to contribute to the condition in the nondiabetic population.¹ In rare cases, an excessive production of insulin-like growth factor (IGF-2) – a condition known as nonislet cell tumor-induced hypoglycemia (NICTH) – has also been found to cause hypoglycemia. Hypoinsulinemic hypoglycemia, with low IGF-1 levels and an IGF-2-IgF1 ratio of greater than 10, is found to be suggestive of NICTH.

Case presentation and summary

An 81-year-old man with a history of diabetes mellitus, systolic heart failure, chronic kidney disease, and metastatic classical gastrointestinal spindle cell sarcoma presented to the emergency department with an acute change in mental status resulting from a new onset hypoglycemia. He was admitted, and during his hospital stay, he experienced severe hypoglycemic episodes with symptomatic presentations of diaphoresis on multiple occasions. A detailed history revealed that for diabetes, the patient had been on insulin for the first 12 years after his diagnosis, after which he was switched to metformin 500 mg twice daily for about 2 years, and as a satisfactory glycemic control was attained, eventually metformin had also been stopped 3 years prior to the current presentation.

The patient’s past medical records were obtained from the hospital at which he had been diagnosed gastrointestinal spindle cell sarcoma. Patient had not received treatment for the cancer as the disease was too widespread to be treated. The gastrointestinal spindle cell sarcoma, which had initially been surgically resected 7 years before the current presentation, had a recurrence 3 years later with abdominal and pulmonary metastasis, but no liver metastasis. No further intervention was carried out because the widely metastasized disease would not have benefited from any more surgical intervention and chemotherapy was not initiated because of the patient’s comorbid illnesses.

A blood sample drawn from the patient at the time of one hypoglycemic event, revealed low serum insulin <0.1 U/ml (normal, 2-19.6 U/ml); low C-peptide level, 0.59 ng/ml (0.8-3.85 ng/ml); low IGF-1, 16 ng/ml (5-4 ng/ml); and IGF-3, 0.9 ng/ml (2.2-4.5 ng/ml). IGF-2 levels were found to be markedly elevated at 945 ng/ml (47-350 ng/ml). The calculated IGF-2-IGF-1 ratio was 59.06 (normal, <10), suggesting NICTH as the etiology for the patient’s hypoglycemia.

The hypoglycemic episodes were initially treated with a continuous dextrose infusion followed by diazoxide treatment. However, diazoxide did not prevent his hypoglycemic episodes, so dexamethasone was considered as an alternative for his condition. The dexamethasone treatment resulted in the normalization of the patient’s serum glucose levels and resolution of his symptoms. The patient was discharged in a satisfactory state few days later and followed up thereafter. No recurrence of hypoglycemic episodes was found, and he was continued on dexamethasone therapy.

Discussion

Hypoglycemia due to NICTH is rare, with a prevalence of four times less than that of insulinoma.³ In most cases, NICTH occurs in patients with solid tumors of mesenchymal and epithelial origins such as hepatocellular carcinoma, gastric carcinoma or mesothelioma.⁴ In NICTH, the serum levels of insulin, C-peptide, and IGF-1 are usually decreased or undetectable. However, the circulating levels of total IGF2 may be increased, decreased, or normal. Concurrent normal to high morning cortisol and normal response to cosyntropin stimulation can rule out adrenal insufficiency and suggest NICTH. An IGF-2: IGF-1 ratio of >10 is considered to be clinically significant and highly suggestive of NICTH.⁵ Hypoglycemia in NICTH can be managed by administration of oral glucose, intravenous dextrose or glucagon. In some cases, diazoxide, a potent inhibitor of insulin secretion, has been found to be useful.⁶ Diazoxide directly inhibits the release of insulin through stimulation of adrenergic receptors and also has an extra pancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis.

Glucocorticoid therapy has been shown to suppress IGF-2 in a dose dependent manner and also by increasing gluconeogenesis.⁷ Surgical resection of the tumor whenever possible is the treatment of choice followed by radiotherapy and chemotherapy for inoperable disease and if successful, usually results in resolution of hypoglycemia. Imatinib, is the chemotherapeutic drug of choice for metastatic GIST, but many case reports have suggested worsening of hypoglycemia in advanced GIST with the use of the drug.⁸ The patient described in our report was not on any chemotherapy, hence hypoglycemia could not be attributed to it. On the basis of findings among 24 patients with GIST, Rikhof and colleagues have recommended monitoring plasma levels of pro-IGF-IIE to identify patients at high risk for developing hypoglycemia, especially those with progressive disease.⁹ Furthermore, over expression of IGF-2 as a predictor of potential relapse may be an area for potential research and further study.¹⁰

Hypoglycemia, a frequently encountered medical emergency, is usually seen in patients with diabetes, most commonly as a result of iatrogenesis. However, it can also be encountered in nondiabetic patients. Various causes, such as pancreatic islet cell tumors producing insulin, primary or secondary adrenal insufficiency, advanced liver disease, pheochromocytoma and hypothyroidism, have been found to contribute to the condition in the nondiabetic population.¹ In rare cases, an excessive production of insulin-like growth factor (IGF-2) – a condition known as nonislet cell tumor-induced hypoglycemia (NICTH) – has also been found to cause hypoglycemia. Hypoinsulinemic hypoglycemia, with low IGF-1 levels and an IGF-2-IgF1 ratio of greater than 10, is found to be suggestive of NICTH.

Case presentation and summary

An 81-year-old man with a history of diabetes mellitus, systolic heart failure, chronic kidney disease, and metastatic classical gastrointestinal spindle cell sarcoma presented to the emergency department with an acute change in mental status resulting from a new onset hypoglycemia. He was admitted, and during his hospital stay, he experienced severe hypoglycemic episodes with symptomatic presentations of diaphoresis on multiple occasions. A detailed history revealed that for diabetes, the patient had been on insulin for the first 12 years after his diagnosis, after which he was switched to metformin 500 mg twice daily for about 2 years, and as a satisfactory glycemic control was attained, eventually metformin had also been stopped 3 years prior to the current presentation.

The patient’s past medical records were obtained from the hospital at which he had been diagnosed gastrointestinal spindle cell sarcoma. Patient had not received treatment for the cancer as the disease was too widespread to be treated. The gastrointestinal spindle cell sarcoma, which had initially been surgically resected 7 years before the current presentation, had a recurrence 3 years later with abdominal and pulmonary metastasis, but no liver metastasis. No further intervention was carried out because the widely metastasized disease would not have benefited from any more surgical intervention and chemotherapy was not initiated because of the patient’s comorbid illnesses.

A blood sample drawn from the patient at the time of one hypoglycemic event, revealed low serum insulin <0.1 U/ml (normal, 2-19.6 U/ml); low C-peptide level, 0.59 ng/ml (0.8-3.85 ng/ml); low IGF-1, 16 ng/ml (5-4 ng/ml); and IGF-3, 0.9 ng/ml (2.2-4.5 ng/ml). IGF-2 levels were found to be markedly elevated at 945 ng/ml (47-350 ng/ml). The calculated IGF-2-IGF-1 ratio was 59.06 (normal, <10), suggesting NICTH as the etiology for the patient’s hypoglycemia.

The hypoglycemic episodes were initially treated with a continuous dextrose infusion followed by diazoxide treatment. However, diazoxide did not prevent his hypoglycemic episodes, so dexamethasone was considered as an alternative for his condition. The dexamethasone treatment resulted in the normalization of the patient’s serum glucose levels and resolution of his symptoms. The patient was discharged in a satisfactory state few days later and followed up thereafter. No recurrence of hypoglycemic episodes was found, and he was continued on dexamethasone therapy.

Discussion

Hypoglycemia due to NICTH is rare, with a prevalence of four times less than that of insulinoma.³ In most cases, NICTH occurs in patients with solid tumors of mesenchymal and epithelial origins such as hepatocellular carcinoma, gastric carcinoma or mesothelioma.⁴ In NICTH, the serum levels of insulin, C-peptide, and IGF-1 are usually decreased or undetectable. However, the circulating levels of total IGF2 may be increased, decreased, or normal. Concurrent normal to high morning cortisol and normal response to cosyntropin stimulation can rule out adrenal insufficiency and suggest NICTH. An IGF-2: IGF-1 ratio of >10 is considered to be clinically significant and highly suggestive of NICTH.⁵ Hypoglycemia in NICTH can be managed by administration of oral glucose, intravenous dextrose or glucagon. In some cases, diazoxide, a potent inhibitor of insulin secretion, has been found to be useful.⁶ Diazoxide directly inhibits the release of insulin through stimulation of adrenergic receptors and also has an extra pancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis.

Glucocorticoid therapy has been shown to suppress IGF-2 in a dose dependent manner and also by increasing gluconeogenesis.⁷ Surgical resection of the tumor whenever possible is the treatment of choice followed by radiotherapy and chemotherapy for inoperable disease and if successful, usually results in resolution of hypoglycemia. Imatinib, is the chemotherapeutic drug of choice for metastatic GIST, but many case reports have suggested worsening of hypoglycemia in advanced GIST with the use of the drug.⁸ The patient described in our report was not on any chemotherapy, hence hypoglycemia could not be attributed to it. On the basis of findings among 24 patients with GIST, Rikhof and colleagues have recommended monitoring plasma levels of pro-IGF-IIE to identify patients at high risk for developing hypoglycemia, especially those with progressive disease.⁹ Furthermore, over expression of IGF-2 as a predictor of potential relapse may be an area for potential research and further study.¹⁰

Hypoglycemia, a frequently encountered medical emergency, is usually seen in patients with diabetes, most commonly as a result of iatrogenesis. However, it can also be encountered in nondiabetic patients. Various causes, such as pancreatic islet cell tumors producing insulin, primary or secondary adrenal insufficiency, advanced liver disease, pheochromocytoma and hypothyroidism, have been found to contribute to the condition in the nondiabetic population.¹ In rare cases, an excessive production of insulin-like growth factor (IGF-2) – a condition known as nonislet cell tumor-induced hypoglycemia (NICTH) – has also been found to cause hypoglycemia. Hypoinsulinemic hypoglycemia, with low IGF-1 levels and an IGF-2-IgF1 ratio of greater than 10, is found to be suggestive of NICTH.

Case presentation and summary

An 81-year-old man with a history of diabetes mellitus, systolic heart failure, chronic kidney disease, and metastatic classical gastrointestinal spindle cell sarcoma presented to the emergency department with an acute change in mental status resulting from a new onset hypoglycemia. He was admitted, and during his hospital stay, he experienced severe hypoglycemic episodes with symptomatic presentations of diaphoresis on multiple occasions. A detailed history revealed that for diabetes, the patient had been on insulin for the first 12 years after his diagnosis, after which he was switched to metformin 500 mg twice daily for about 2 years, and as a satisfactory glycemic control was attained, eventually metformin had also been stopped 3 years prior to the current presentation.

The patient’s past medical records were obtained from the hospital at which he had been diagnosed gastrointestinal spindle cell sarcoma. Patient had not received treatment for the cancer as the disease was too widespread to be treated. The gastrointestinal spindle cell sarcoma, which had initially been surgically resected 7 years before the current presentation, had a recurrence 3 years later with abdominal and pulmonary metastasis, but no liver metastasis. No further intervention was carried out because the widely metastasized disease would not have benefited from any more surgical intervention and chemotherapy was not initiated because of the patient’s comorbid illnesses.

A blood sample drawn from the patient at the time of one hypoglycemic event, revealed low serum insulin <0.1 U/ml (normal, 2-19.6 U/ml); low C-peptide level, 0.59 ng/ml (0.8-3.85 ng/ml); low IGF-1, 16 ng/ml (5-4 ng/ml); and IGF-3, 0.9 ng/ml (2.2-4.5 ng/ml). IGF-2 levels were found to be markedly elevated at 945 ng/ml (47-350 ng/ml). The calculated IGF-2-IGF-1 ratio was 59.06 (normal, <10), suggesting NICTH as the etiology for the patient’s hypoglycemia.

The hypoglycemic episodes were initially treated with a continuous dextrose infusion followed by diazoxide treatment. However, diazoxide did not prevent his hypoglycemic episodes, so dexamethasone was considered as an alternative for his condition. The dexamethasone treatment resulted in the normalization of the patient’s serum glucose levels and resolution of his symptoms. The patient was discharged in a satisfactory state few days later and followed up thereafter. No recurrence of hypoglycemic episodes was found, and he was continued on dexamethasone therapy.

Discussion

Hypoglycemia due to NICTH is rare, with a prevalence of four times less than that of insulinoma.³ In most cases, NICTH occurs in patients with solid tumors of mesenchymal and epithelial origins such as hepatocellular carcinoma, gastric carcinoma or mesothelioma.⁴ In NICTH, the serum levels of insulin, C-peptide, and IGF-1 are usually decreased or undetectable. However, the circulating levels of total IGF2 may be increased, decreased, or normal. Concurrent normal to high morning cortisol and normal response to cosyntropin stimulation can rule out adrenal insufficiency and suggest NICTH. An IGF-2: IGF-1 ratio of >10 is considered to be clinically significant and highly suggestive of NICTH.⁵ Hypoglycemia in NICTH can be managed by administration of oral glucose, intravenous dextrose or glucagon. In some cases, diazoxide, a potent inhibitor of insulin secretion, has been found to be useful.⁶ Diazoxide directly inhibits the release of insulin through stimulation of adrenergic receptors and also has an extra pancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis.

Glucocorticoid therapy has been shown to suppress IGF-2 in a dose dependent manner and also by increasing gluconeogenesis.⁷ Surgical resection of the tumor whenever possible is the treatment of choice followed by radiotherapy and chemotherapy for inoperable disease and if successful, usually results in resolution of hypoglycemia. Imatinib, is the chemotherapeutic drug of choice for metastatic GIST, but many case reports have suggested worsening of hypoglycemia in advanced GIST with the use of the drug.⁸ The patient described in our report was not on any chemotherapy, hence hypoglycemia could not be attributed to it. On the basis of findings among 24 patients with GIST, Rikhof and colleagues have recommended monitoring plasma levels of pro-IGF-IIE to identify patients at high risk for developing hypoglycemia, especially those with progressive disease.⁹ Furthermore, over expression of IGF-2 as a predictor of potential relapse may be an area for potential research and further study.¹⁰

Pregnancy is generally found to offer a respite from multiple sclerosis (MS). Pregnant women rarely develop MS or to have relapses. But in a unique and challenging case, a woman in her 14th week of her second pregnancy developed signs and symptoms of tumefactive multiple sclerosis (TMS), a rare subtype of MS. The TMS was only one of several unexpected clinical puzzles, according to the clinicians reporting on the case.

The patient, who had been healthy, was admitted with acute onset of paresthesias and word-finding difficulty. She had just had a long drive from Florida, and the the clinicians first assumed that she was fatigued from the trip and from the pregnancy. A magnetic resonance imaging (MRI) scan of the brain, however, suggested an ischemic event.

While hospitalized, the patient’s condition rapidly worsened. More scan and test findings proved consistent with TMS. A repeat MRI scan showed interval progression with a growing tumefactive demyelinating lesion (TDL) with diffuse surrounding edema and new periventricular signal changes. Although rare, TDLs often represent fulminant forms of MS, the clinicians note. Because the lesions mimic strokes, tumors, and abscesses, diagnosis is difficult. Moreover, the gadolinium (which was avoided because it can cause birth defects) might have helped them visualize lesions sooner.

The patient was started on high-dose IV methylprednisolone and plasma exchange, but the response was mild. The poor response to both treatment modalities is infrequent in TMS, the clinicians say—yet another unforeseen obstacle.

In addition to counseling the patient about the usual protective effects of pregnancy, her clinicians counseled her “extensively” about natalizumab and the possible beneficial effects of disease-modifying therapies. But the patient made the difficult decision to terminate the pregnancy, in part because she felt it was better to focus on her existing child rather than on caring for 2 young children while having a chronic progressive disease with uncertain recovery.

Another surprise was in store. Within 12 hours after an uncomplicated dilatation and curettage, the patient was able to move her right arm. That “drastic improvement” was followed by moderate improvement in her right leg. Her “paradoxical” improvement after the termination might indicate a “different from expected” hormonal influence in the pathogenesis of TMS, the clinicians say, but more likely represents a delayed corroborating effect of steroids and plasma exchange.

In the following weeks, the patient’s recovery was “satisfying” with gradual improvement and partial return of expressive language.  Eighteen months later, the patient was clinically stable on natalizumab.

Source:
Pakneshan S, Bernitsas E. BMJ Case Rep. 2017. pii: bcr-2017-219534.
 doi: 10.1136/bcr-2017-219534.

Pregnancy is generally found to offer a respite from multiple sclerosis (MS). Pregnant women rarely develop MS or to have relapses. But in a unique and challenging case, a woman in her 14th week of her second pregnancy developed signs and symptoms of tumefactive multiple sclerosis (TMS), a rare subtype of MS. The TMS was only one of several unexpected clinical puzzles, according to the clinicians reporting on the case.

The patient, who had been healthy, was admitted with acute onset of paresthesias and word-finding difficulty. She had just had a long drive from Florida, and the the clinicians first assumed that she was fatigued from the trip and from the pregnancy. A magnetic resonance imaging (MRI) scan of the brain, however, suggested an ischemic event.

While hospitalized, the patient’s condition rapidly worsened. More scan and test findings proved consistent with TMS. A repeat MRI scan showed interval progression with a growing tumefactive demyelinating lesion (TDL) with diffuse surrounding edema and new periventricular signal changes. Although rare, TDLs often represent fulminant forms of MS, the clinicians note. Because the lesions mimic strokes, tumors, and abscesses, diagnosis is difficult. Moreover, the gadolinium (which was avoided because it can cause birth defects) might have helped them visualize lesions sooner.

The patient was started on high-dose IV methylprednisolone and plasma exchange, but the response was mild. The poor response to both treatment modalities is infrequent in TMS, the clinicians say—yet another unforeseen obstacle.

In addition to counseling the patient about the usual protective effects of pregnancy, her clinicians counseled her “extensively” about natalizumab and the possible beneficial effects of disease-modifying therapies. But the patient made the difficult decision to terminate the pregnancy, in part because she felt it was better to focus on her existing child rather than on caring for 2 young children while having a chronic progressive disease with uncertain recovery.

Another surprise was in store. Within 12 hours after an uncomplicated dilatation and curettage, the patient was able to move her right arm. That “drastic improvement” was followed by moderate improvement in her right leg. Her “paradoxical” improvement after the termination might indicate a “different from expected” hormonal influence in the pathogenesis of TMS, the clinicians say, but more likely represents a delayed corroborating effect of steroids and plasma exchange.

In the following weeks, the patient’s recovery was “satisfying” with gradual improvement and partial return of expressive language.  Eighteen months later, the patient was clinically stable on natalizumab.

Source:
Pakneshan S, Bernitsas E. BMJ Case Rep. 2017. pii: bcr-2017-219534.
 doi: 10.1136/bcr-2017-219534.

Pregnancy is generally found to offer a respite from multiple sclerosis (MS). Pregnant women rarely develop MS or to have relapses. But in a unique and challenging case, a woman in her 14th week of her second pregnancy developed signs and symptoms of tumefactive multiple sclerosis (TMS), a rare subtype of MS. The TMS was only one of several unexpected clinical puzzles, according to the clinicians reporting on the case.

The patient, who had been healthy, was admitted with acute onset of paresthesias and word-finding difficulty. She had just had a long drive from Florida, and the the clinicians first assumed that she was fatigued from the trip and from the pregnancy. A magnetic resonance imaging (MRI) scan of the brain, however, suggested an ischemic event.

While hospitalized, the patient’s condition rapidly worsened. More scan and test findings proved consistent with TMS. A repeat MRI scan showed interval progression with a growing tumefactive demyelinating lesion (TDL) with diffuse surrounding edema and new periventricular signal changes. Although rare, TDLs often represent fulminant forms of MS, the clinicians note. Because the lesions mimic strokes, tumors, and abscesses, diagnosis is difficult. Moreover, the gadolinium (which was avoided because it can cause birth defects) might have helped them visualize lesions sooner.

The patient was started on high-dose IV methylprednisolone and plasma exchange, but the response was mild. The poor response to both treatment modalities is infrequent in TMS, the clinicians say—yet another unforeseen obstacle.

In addition to counseling the patient about the usual protective effects of pregnancy, her clinicians counseled her “extensively” about natalizumab and the possible beneficial effects of disease-modifying therapies. But the patient made the difficult decision to terminate the pregnancy, in part because she felt it was better to focus on her existing child rather than on caring for 2 young children while having a chronic progressive disease with uncertain recovery.

Another surprise was in store. Within 12 hours after an uncomplicated dilatation and curettage, the patient was able to move her right arm. That “drastic improvement” was followed by moderate improvement in her right leg. Her “paradoxical” improvement after the termination might indicate a “different from expected” hormonal influence in the pathogenesis of TMS, the clinicians say, but more likely represents a delayed corroborating effect of steroids and plasma exchange.

In the following weeks, the patient’s recovery was “satisfying” with gradual improvement and partial return of expressive language.  Eighteen months later, the patient was clinically stable on natalizumab.

Source:
Pakneshan S, Bernitsas E. BMJ Case Rep. 2017. pii: bcr-2017-219534.
 doi: 10.1136/bcr-2017-219534.

Chronic obstructive pulmonary disease (COPD) affects between 11 and 24 million people in the U.S. and is the third leading cause of death in this country.^1,2 Airflow obstruction on spirometry in addition to respiratory symptoms is required to establish a diagnosis of COPD.^3,4 As many as 40% of patients with a clinical diagnosis of COPD have not had spirometry or have spirometry results inconsistent with the diagnosis of COPD.^5,6 In addition to recommended spirometry, many patients with COPD do not receive other evidence-based therapies.^7,8

About 50% of patients in the Minneapolis VA Health Care System (MVAHCS) receive care in its rural community-based outreach clinics (CBOCs). Data regarding the quality of general medical care between rural and urban populations are sparse; however, studies suggest that the quality of care delivered in rural clinics may be lower than the care provided in an urban setting.^9-12 Care for patients with COPD in an urban setting is suboptimal with only 58% of patients receiving guideline-based care, and there are no comparative data for penetrance in the rural setting.⁸ Most published studies on patients with COPD treated in rural vs urban locations are outcomes studies that queried statewide or national registry data evaluating the frequency of emergency department (ED) visits or hospital admissions for COPD exacerbations, all-cause mortality, or COPD exacerbation-related mortality.^13-18 There are no studies examining potential differences in the quality of health care received by patients with COPD in rural vs urban locations or whether these potential differences are associated with changes in health care utilization.

The authors sought to determine whether patients with the diagnosis of COPD treated in the MVAHCS and its 13 CBOCs receive similar quality of disease-related health care in rural vs urban primary care clinic locations. The authors hypothesized that patients who receive their primary care in rural clinics would be less likely to have had spirometry or to receive respiratory immunizations and short- or long-acting inhalers and that discrepancies would be associated with increased health care utilization in rural areas as measured by prescriptions for systemic corticosteroids, antibiotics, ED visits, or hospital admissions for COPD exacerbations.

Methods

The MVAHCS has 14 primary care locations; these locations were designated as rural or urban based on the Rural-Urban Commuting Area codes.^19,20 There were 4 urban locations and 10 rural clinics; all rural clinics were farther than 40 miles from the main Minneapolis VAMC.

Patient Selection

The authors performed a retrospective chart review after receiving an institutional review board waiver for this quality assessment study. All patients who had a prior ICD-9 encounter diagnosis of COPD (codes: 491.0, 491.1, 491.2, 491.20, 491.21, 491.22, 491.8, 491.9, 492.0, 492.8, 494, 494.0, 494.1, 496) and who were seen in primary care during March 2015 were identified. Each subject’s first visit during that month was used as the start of the retrospective 1-year look-back period. All eligible subjects were sorted based on their rural or urban location and a randomly assigned number. Patients were then selected according to ascending numbers from each rural and urban clinic in proportion to the clinic’s representation among all eligible patients.

Outcomes

The primary outcomes—possible discrepancies in quality of health care for patients with COPD in rural vs urban primary care clinics—were assessed by (1) prior spirometry; (2) any prior pneumonia vaccination; (3) an influenza vaccination within the past year; (4) prescriptions within the past year for a short-acting beta agonist (SABA) metered-dose inhaler; and (5) prescriptions for a long-acting inhalers, including long-acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs), or inhaled corticosteroids (ICSs).

Secondary outcomes included (1) an active prescription for home oxygen within the past calendar year; (2) health care utilization assessed via prescriptions for intermittent courses of oral corticosteroids; (3) prescriptions for respiratory antibiotics (macrolides, tetracyclines, fluoroquinolones) within the past year for COPD exacerbations; (4) ED visits; (5) hospital admissions (and need for mechanical ventilation) for COPD exacerbations within the past year; and (6) whether patients were seen by either VA or Non-VA pulmonology providers.

Data Collection

Patients’ demographic data and comorbidities were collected via chart review. A 1-year prescription medication list was obtained by an electronic database search of the MVAHCS electronic medical record (EMR). Additional antibiotics and corticosteroid prescriptions for COPD exacerbations paid for by the VA but filled at a local pharmacy were manually searched from a separate database to supplement the electronic prescription list. Comparison of the electronic prescription list and pharmacy records in 25% of patients found 100% concordance in the prescription lists. The investigator manually reviewed and extracted the following data from the EMR, scanned-in records, and a Midwest VA COPD registry database: most recent spirometry results; immunization status for influenza in the past year; prior pneumonia vaccination; home oxygen prescription; whether the patient received respiratory antibiotic or intermittent oral corticosteroid treatment for COPD exacerbations; whether the patient had a ED visit or hospital admission for COPD exacerbation with or without need for mechanical ventilation; and whether the patient had been seen by a pulmonology provider. The investigator reviewed all primary care provider notes in the past year for documentation of non-VA ED visits or hospitalizations that were not present in the EMR, Midwest VA COPD registry database, or scanned patient records.

Data Analysis

Results are described as mean ± standard deviation, median (interquartile range) or proportion, expressed as a percentage as appropriate for the level of measurement and distribution. The proportions meeting the COPD quality of health care outcomes in the urban and rural groups were compared using a chi-square test of proportions, and 95% confidence intervals (CI) on the differences were estimated. Samples of 400 patients each from the rural and urban groups were estimated to provide a 95% 2-sided CI on the differences of about ± 0.05 (5%), assuming the proportion meeting the quality of care outcomes in the urban group would be at least 0.8 (80%).

Results

The authors identified 1,538 patients with a previous encounter diagnosis of COPD who were seen in a primary care clinic in the MVAHCS in March of 2015. The authors reviewed the medical records of 801 randomly selected patients: 400 rural clinic patients and 401 urban clinic patients. Demographic characteristics and major comorbidities of rural and urban patients were similar except more rural patients were white, and fewer had a record of obstructive sleep apnea, alcoholism, or addictive disorders (Table 1). Prescriptions for common chronic medical conditions were similar for rural and urban groups, including medications for depression (31% vs 33%) or diabetes mellitus (25% vs 28%). In patients who had spirometry, the severity of COPD, as assessed by mean forced expiratory volume (FEV₁), was similar between rural and urban patients (2.06 L vs 2.10 L).

Quality of COPD Care

Spirometry was documented in fewer rural clinic patients than in urban clinic patients (51% vs 82%; difference 31%, 95% CI: 25% to 37%) (Table 2).

COPD Outcomes

Home oxygen prescription rates were similar for rural and urban clinic patients (8% vs 9%; difference 1%, 95% CI: -2% to 5%). Rural patients received fewer prescriptions for intermittent oral corticosteroids (17% vs 31%; difference 14%, 95% CI: 9% to 20%) and antibiotics for COPD exacerbations (18% vs 32%; difference 14%, 95% CI: 8% to 20%). Rural patients had fewer ED visits for COPD exacerbations (7% vs 13%; difference 6%, 95% CI: 2% to 10%), and similar admission rates for COPD exacerbations (5% vs 6%; difference 1%, 95% CI: -2% to 4%). Of the few patients hospitalized for COPD exacerbations, none required mechanical ventilation. There was no significant difference in the number of rural vs urban patients seen by a pulmonologist in the calendar year of the study (6% vs 9%; difference 3%, 95% CI:-1% to 6%), with the majority seen by VA providers: 20/24 rural patients and 35/35 urban patients.

Discussion

Fewer rural patients had prior spirometry; otherwise, the COPD-related quality metrics were similar between rural and urban patient groups in the MVAHCS, including immunizations for pneumonia and influenza, and prescribing rates for short- and long-acting inhaler therapy. Despite the similarity in these COPD quality measures, rural clinic patients seemed to have less health care utilization related to COPD exacerbations.

Spirometry with airflow obstruction in the presence of respiratory symptoms is required for accurate diagnosis of COPD.^3,4 Spirometry has been available at the MVAHCS hospital-based clinic for years. Efforts to address this disparity led to implementation of on-site spirometry at all rural and urban clinics about 2 years prior to the patient enrollment visit date for the study. Fewer rural patients had spirometry, which is possibly from prior disparity in resources; yet rates of spirometry in all patients with a clinical diagnosis of COPD in the MVAHCS are higher (rural 51%, urban 82%) than previously reported. A nationwide study of 94,000 veterans with recent clinical diagnosis of COPD found only 37% had spirometry within 2.5 years of diagnosis,²¹ and another non-VA study (n = 553) showed only 31% of patients discharged from a hospital with a diagnosis of COPD exacerbation had spirometry performed within a 8-year period prior to hospitalization.²²

Annual influenza vaccines are recommended for everyone aged > 6 months, and the pneumonia vaccine is recommended for all patients with COPD in order to reduce the risk of COPD exacerbations and pneumonias.^23,24 The rates of vaccination at MVAHCS rural and urban clinics for both influenza (79% vs 81%) and pneumococcus (88% vs 91%) are higher than previously published studies of patients with COPD for influenza vaccination (30%-51%) and pneumonia vaccination (21%-51%) and did not differ between rural and urban clinics.^7,25-28 The observed high vaccination rates may be due to EMR prompts and requirements to document vaccination status and offer recommended vaccinations.

Long-acting inhalers have been shown to reduce rates of COPD exacerbations and improve patients’ quality of life.²⁹ The authors found no disparity in the prescription rate of short- or long-acting inhalers between rural and urban patients, and no difference in the severity of COPD, as indicated by FEV₁, that might influence prescription rates.

The authors attempted to evaluate health care resource utilization as an indicator of health care quality and outcomes. Based on previous reports, the authors expected to find lower quality of care and increased utilization in rural patients. Previous studies have shown rural patients can be more symptomatic with a higher body mass index, airflow obstruction, dyspnea, and exercise capacity index (BODE index) than are patients in urban settings.^16,30 Statewide and national registry data have shown rural patients have higher rates of primary care visits, ER visits, and hospitalizations for COPD exacerbations.

Rural patients also have been shown to have higher mortality rates and were more likely to be in a long-term care center and less likely to have home care or palliative care than were their urban counterparts.^13-18,31 If the severity of illness is similar in rural and urban areas, higher health care utilization related to COPD would suggest that patients in rural settings may be receiving inferior quality of health care. The authors could not find any previous reports of the quality of COPD care delivered in rural vs urban settings.

In this study the only difference in quality of care was the lower proportion of rural patients with a record of spirometry that is needed to confirm the diagnosis. The observed differences in the quality of care measures wouldn’t be expected to lead to large differences in the outcome measures. Contrary to the literature and the observed similarity in quality of care, rural patients had better COPD outcomes perhaps due to unmeasured differences in risk or failure to capture medical visits outside of the VA system. The severity of COPD based on FEV₁ and concurrent diagnoses, such as heart failure, did not suggest that rural patients in this comparison had a higher burden of illness or risk of poor COPD outcomes.

More than 70,000 patients spanning a large geographic region receive primary care at MVAHCS, which provides comparable care to all COPD patients, regardless of location, by using the same EMR system, providing evidence-based order sets for disease management, proactively offering on-site and remote COPD case managers for high-risk patients, and more recently, implementing on-site spirometry testing in all clinics. This approach as opposed to the traditional outreach clinic model may in part explain the similarity in quality of care in urban and rural clinics that was not reported in previous studies.

Limitations

This study was performed retrospectively, increasing the potential of missing data, especially from outside the VA health care system. Patients were not randomly assigned to rural or urban clinics, so differences in patient characteristics could exist. Alcohol and addictive disorders were more common in urban patients, which might affect adherence to prescribed medications. In addition, lower rate of obstructive sleep apnea was found in the rural population, which has been linked to increased airway inflammation and COPD exacerbations resulting in hospitalization.^32,33 Mortality was not assessed as all patients were alive and seen in clinic at time of enrollment.

The authors were not able to record a patients’ residence in a long-term care facility or institutionalization, use of home care, or palliative care services due to limitations in the EMR system. Whether patients received comanaged primary care or underwent pulmonary rehabilitation could not be obtained from the EMR. Most patients never had lung volumes or diffusion capacity and thus were not included. The authors could not report whether inhaler therapy was appropriate compared with the Global Initiative for Chronic Obstructive Lund Disease(GOLD)severity score because most of the spirometry was done at a discordant time to when inhaler therapy was assessed, and new GOLD guidelines include patient symptoms that were not reliably recorded in the EMR. Last, the authors had hoped to include smoking status and cessation practices as part of the quality measures, but due to significant variability in patients’ documented smoking status in the same period, the data were deemed unreliable.

Conclusion

No disparities were found between rural and urban clinics in the quality of health care for patients with COPD in the MVAHCS except that fewer rural patients had prior spirometry; a difference that is likely due to the fact that only recently has spirometry been implemented in the MVAHCS rural clinics. Overall the quality of COPD care was high and above the previously reported rates. Further larger studies of rural and urban quality of health care for patients with COPD are needed in other VA and non-VA systems to determine whether disparities exist and whether they are associated with clinical outcomes, including ED visits, hospitalizations, and mortality.

Chronic obstructive pulmonary disease (COPD) affects between 11 and 24 million people in the U.S. and is the third leading cause of death in this country.^1,2 Airflow obstruction on spirometry in addition to respiratory symptoms is required to establish a diagnosis of COPD.^3,4 As many as 40% of patients with a clinical diagnosis of COPD have not had spirometry or have spirometry results inconsistent with the diagnosis of COPD.^5,6 In addition to recommended spirometry, many patients with COPD do not receive other evidence-based therapies.^7,8

About 50% of patients in the Minneapolis VA Health Care System (MVAHCS) receive care in its rural community-based outreach clinics (CBOCs). Data regarding the quality of general medical care between rural and urban populations are sparse; however, studies suggest that the quality of care delivered in rural clinics may be lower than the care provided in an urban setting.^9-12 Care for patients with COPD in an urban setting is suboptimal with only 58% of patients receiving guideline-based care, and there are no comparative data for penetrance in the rural setting.⁸ Most published studies on patients with COPD treated in rural vs urban locations are outcomes studies that queried statewide or national registry data evaluating the frequency of emergency department (ED) visits or hospital admissions for COPD exacerbations, all-cause mortality, or COPD exacerbation-related mortality.^13-18 There are no studies examining potential differences in the quality of health care received by patients with COPD in rural vs urban locations or whether these potential differences are associated with changes in health care utilization.

The authors sought to determine whether patients with the diagnosis of COPD treated in the MVAHCS and its 13 CBOCs receive similar quality of disease-related health care in rural vs urban primary care clinic locations. The authors hypothesized that patients who receive their primary care in rural clinics would be less likely to have had spirometry or to receive respiratory immunizations and short- or long-acting inhalers and that discrepancies would be associated with increased health care utilization in rural areas as measured by prescriptions for systemic corticosteroids, antibiotics, ED visits, or hospital admissions for COPD exacerbations.

Methods

The MVAHCS has 14 primary care locations; these locations were designated as rural or urban based on the Rural-Urban Commuting Area codes.^19,20 There were 4 urban locations and 10 rural clinics; all rural clinics were farther than 40 miles from the main Minneapolis VAMC.

Patient Selection

The authors performed a retrospective chart review after receiving an institutional review board waiver for this quality assessment study. All patients who had a prior ICD-9 encounter diagnosis of COPD (codes: 491.0, 491.1, 491.2, 491.20, 491.21, 491.22, 491.8, 491.9, 492.0, 492.8, 494, 494.0, 494.1, 496) and who were seen in primary care during March 2015 were identified. Each subject’s first visit during that month was used as the start of the retrospective 1-year look-back period. All eligible subjects were sorted based on their rural or urban location and a randomly assigned number. Patients were then selected according to ascending numbers from each rural and urban clinic in proportion to the clinic’s representation among all eligible patients.

Outcomes

The primary outcomes—possible discrepancies in quality of health care for patients with COPD in rural vs urban primary care clinics—were assessed by (1) prior spirometry; (2) any prior pneumonia vaccination; (3) an influenza vaccination within the past year; (4) prescriptions within the past year for a short-acting beta agonist (SABA) metered-dose inhaler; and (5) prescriptions for a long-acting inhalers, including long-acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs), or inhaled corticosteroids (ICSs).

Secondary outcomes included (1) an active prescription for home oxygen within the past calendar year; (2) health care utilization assessed via prescriptions for intermittent courses of oral corticosteroids; (3) prescriptions for respiratory antibiotics (macrolides, tetracyclines, fluoroquinolones) within the past year for COPD exacerbations; (4) ED visits; (5) hospital admissions (and need for mechanical ventilation) for COPD exacerbations within the past year; and (6) whether patients were seen by either VA or Non-VA pulmonology providers.

Data Collection

Patients’ demographic data and comorbidities were collected via chart review. A 1-year prescription medication list was obtained by an electronic database search of the MVAHCS electronic medical record (EMR). Additional antibiotics and corticosteroid prescriptions for COPD exacerbations paid for by the VA but filled at a local pharmacy were manually searched from a separate database to supplement the electronic prescription list. Comparison of the electronic prescription list and pharmacy records in 25% of patients found 100% concordance in the prescription lists. The investigator manually reviewed and extracted the following data from the EMR, scanned-in records, and a Midwest VA COPD registry database: most recent spirometry results; immunization status for influenza in the past year; prior pneumonia vaccination; home oxygen prescription; whether the patient received respiratory antibiotic or intermittent oral corticosteroid treatment for COPD exacerbations; whether the patient had a ED visit or hospital admission for COPD exacerbation with or without need for mechanical ventilation; and whether the patient had been seen by a pulmonology provider. The investigator reviewed all primary care provider notes in the past year for documentation of non-VA ED visits or hospitalizations that were not present in the EMR, Midwest VA COPD registry database, or scanned patient records.

Data Analysis

Results are described as mean ± standard deviation, median (interquartile range) or proportion, expressed as a percentage as appropriate for the level of measurement and distribution. The proportions meeting the COPD quality of health care outcomes in the urban and rural groups were compared using a chi-square test of proportions, and 95% confidence intervals (CI) on the differences were estimated. Samples of 400 patients each from the rural and urban groups were estimated to provide a 95% 2-sided CI on the differences of about ± 0.05 (5%), assuming the proportion meeting the quality of care outcomes in the urban group would be at least 0.8 (80%).

Results

The authors identified 1,538 patients with a previous encounter diagnosis of COPD who were seen in a primary care clinic in the MVAHCS in March of 2015. The authors reviewed the medical records of 801 randomly selected patients: 400 rural clinic patients and 401 urban clinic patients. Demographic characteristics and major comorbidities of rural and urban patients were similar except more rural patients were white, and fewer had a record of obstructive sleep apnea, alcoholism, or addictive disorders (Table 1). Prescriptions for common chronic medical conditions were similar for rural and urban groups, including medications for depression (31% vs 33%) or diabetes mellitus (25% vs 28%). In patients who had spirometry, the severity of COPD, as assessed by mean forced expiratory volume (FEV₁), was similar between rural and urban patients (2.06 L vs 2.10 L).

Quality of COPD Care

Spirometry was documented in fewer rural clinic patients than in urban clinic patients (51% vs 82%; difference 31%, 95% CI: 25% to 37%) (Table 2).

COPD Outcomes

Home oxygen prescription rates were similar for rural and urban clinic patients (8% vs 9%; difference 1%, 95% CI: -2% to 5%). Rural patients received fewer prescriptions for intermittent oral corticosteroids (17% vs 31%; difference 14%, 95% CI: 9% to 20%) and antibiotics for COPD exacerbations (18% vs 32%; difference 14%, 95% CI: 8% to 20%). Rural patients had fewer ED visits for COPD exacerbations (7% vs 13%; difference 6%, 95% CI: 2% to 10%), and similar admission rates for COPD exacerbations (5% vs 6%; difference 1%, 95% CI: -2% to 4%). Of the few patients hospitalized for COPD exacerbations, none required mechanical ventilation. There was no significant difference in the number of rural vs urban patients seen by a pulmonologist in the calendar year of the study (6% vs 9%; difference 3%, 95% CI:-1% to 6%), with the majority seen by VA providers: 20/24 rural patients and 35/35 urban patients.

Discussion

Fewer rural patients had prior spirometry; otherwise, the COPD-related quality metrics were similar between rural and urban patient groups in the MVAHCS, including immunizations for pneumonia and influenza, and prescribing rates for short- and long-acting inhaler therapy. Despite the similarity in these COPD quality measures, rural clinic patients seemed to have less health care utilization related to COPD exacerbations.

Spirometry with airflow obstruction in the presence of respiratory symptoms is required for accurate diagnosis of COPD.^3,4 Spirometry has been available at the MVAHCS hospital-based clinic for years. Efforts to address this disparity led to implementation of on-site spirometry at all rural and urban clinics about 2 years prior to the patient enrollment visit date for the study. Fewer rural patients had spirometry, which is possibly from prior disparity in resources; yet rates of spirometry in all patients with a clinical diagnosis of COPD in the MVAHCS are higher (rural 51%, urban 82%) than previously reported. A nationwide study of 94,000 veterans with recent clinical diagnosis of COPD found only 37% had spirometry within 2.5 years of diagnosis,²¹ and another non-VA study (n = 553) showed only 31% of patients discharged from a hospital with a diagnosis of COPD exacerbation had spirometry performed within a 8-year period prior to hospitalization.²²

Annual influenza vaccines are recommended for everyone aged > 6 months, and the pneumonia vaccine is recommended for all patients with COPD in order to reduce the risk of COPD exacerbations and pneumonias.^23,24 The rates of vaccination at MVAHCS rural and urban clinics for both influenza (79% vs 81%) and pneumococcus (88% vs 91%) are higher than previously published studies of patients with COPD for influenza vaccination (30%-51%) and pneumonia vaccination (21%-51%) and did not differ between rural and urban clinics.^7,25-28 The observed high vaccination rates may be due to EMR prompts and requirements to document vaccination status and offer recommended vaccinations.

Long-acting inhalers have been shown to reduce rates of COPD exacerbations and improve patients’ quality of life.²⁹ The authors found no disparity in the prescription rate of short- or long-acting inhalers between rural and urban patients, and no difference in the severity of COPD, as indicated by FEV₁, that might influence prescription rates.

The authors attempted to evaluate health care resource utilization as an indicator of health care quality and outcomes. Based on previous reports, the authors expected to find lower quality of care and increased utilization in rural patients. Previous studies have shown rural patients can be more symptomatic with a higher body mass index, airflow obstruction, dyspnea, and exercise capacity index (BODE index) than are patients in urban settings.^16,30 Statewide and national registry data have shown rural patients have higher rates of primary care visits, ER visits, and hospitalizations for COPD exacerbations.

Rural patients also have been shown to have higher mortality rates and were more likely to be in a long-term care center and less likely to have home care or palliative care than were their urban counterparts.^13-18,31 If the severity of illness is similar in rural and urban areas, higher health care utilization related to COPD would suggest that patients in rural settings may be receiving inferior quality of health care. The authors could not find any previous reports of the quality of COPD care delivered in rural vs urban settings.

In this study the only difference in quality of care was the lower proportion of rural patients with a record of spirometry that is needed to confirm the diagnosis. The observed differences in the quality of care measures wouldn’t be expected to lead to large differences in the outcome measures. Contrary to the literature and the observed similarity in quality of care, rural patients had better COPD outcomes perhaps due to unmeasured differences in risk or failure to capture medical visits outside of the VA system. The severity of COPD based on FEV₁ and concurrent diagnoses, such as heart failure, did not suggest that rural patients in this comparison had a higher burden of illness or risk of poor COPD outcomes.

More than 70,000 patients spanning a large geographic region receive primary care at MVAHCS, which provides comparable care to all COPD patients, regardless of location, by using the same EMR system, providing evidence-based order sets for disease management, proactively offering on-site and remote COPD case managers for high-risk patients, and more recently, implementing on-site spirometry testing in all clinics. This approach as opposed to the traditional outreach clinic model may in part explain the similarity in quality of care in urban and rural clinics that was not reported in previous studies.

Limitations

This study was performed retrospectively, increasing the potential of missing data, especially from outside the VA health care system. Patients were not randomly assigned to rural or urban clinics, so differences in patient characteristics could exist. Alcohol and addictive disorders were more common in urban patients, which might affect adherence to prescribed medications. In addition, lower rate of obstructive sleep apnea was found in the rural population, which has been linked to increased airway inflammation and COPD exacerbations resulting in hospitalization.^32,33 Mortality was not assessed as all patients were alive and seen in clinic at time of enrollment.

The authors were not able to record a patients’ residence in a long-term care facility or institutionalization, use of home care, or palliative care services due to limitations in the EMR system. Whether patients received comanaged primary care or underwent pulmonary rehabilitation could not be obtained from the EMR. Most patients never had lung volumes or diffusion capacity and thus were not included. The authors could not report whether inhaler therapy was appropriate compared with the Global Initiative for Chronic Obstructive Lund Disease(GOLD)severity score because most of the spirometry was done at a discordant time to when inhaler therapy was assessed, and new GOLD guidelines include patient symptoms that were not reliably recorded in the EMR. Last, the authors had hoped to include smoking status and cessation practices as part of the quality measures, but due to significant variability in patients’ documented smoking status in the same period, the data were deemed unreliable.

Conclusion

No disparities were found between rural and urban clinics in the quality of health care for patients with COPD in the MVAHCS except that fewer rural patients had prior spirometry; a difference that is likely due to the fact that only recently has spirometry been implemented in the MVAHCS rural clinics. Overall the quality of COPD care was high and above the previously reported rates. Further larger studies of rural and urban quality of health care for patients with COPD are needed in other VA and non-VA systems to determine whether disparities exist and whether they are associated with clinical outcomes, including ED visits, hospitalizations, and mortality.

Chronic obstructive pulmonary disease (COPD) affects between 11 and 24 million people in the U.S. and is the third leading cause of death in this country.^1,2 Airflow obstruction on spirometry in addition to respiratory symptoms is required to establish a diagnosis of COPD.^3,4 As many as 40% of patients with a clinical diagnosis of COPD have not had spirometry or have spirometry results inconsistent with the diagnosis of COPD.^5,6 In addition to recommended spirometry, many patients with COPD do not receive other evidence-based therapies.^7,8

About 50% of patients in the Minneapolis VA Health Care System (MVAHCS) receive care in its rural community-based outreach clinics (CBOCs). Data regarding the quality of general medical care between rural and urban populations are sparse; however, studies suggest that the quality of care delivered in rural clinics may be lower than the care provided in an urban setting.^9-12 Care for patients with COPD in an urban setting is suboptimal with only 58% of patients receiving guideline-based care, and there are no comparative data for penetrance in the rural setting.⁸ Most published studies on patients with COPD treated in rural vs urban locations are outcomes studies that queried statewide or national registry data evaluating the frequency of emergency department (ED) visits or hospital admissions for COPD exacerbations, all-cause mortality, or COPD exacerbation-related mortality.^13-18 There are no studies examining potential differences in the quality of health care received by patients with COPD in rural vs urban locations or whether these potential differences are associated with changes in health care utilization.

The authors sought to determine whether patients with the diagnosis of COPD treated in the MVAHCS and its 13 CBOCs receive similar quality of disease-related health care in rural vs urban primary care clinic locations. The authors hypothesized that patients who receive their primary care in rural clinics would be less likely to have had spirometry or to receive respiratory immunizations and short- or long-acting inhalers and that discrepancies would be associated with increased health care utilization in rural areas as measured by prescriptions for systemic corticosteroids, antibiotics, ED visits, or hospital admissions for COPD exacerbations.

Methods

The MVAHCS has 14 primary care locations; these locations were designated as rural or urban based on the Rural-Urban Commuting Area codes.^19,20 There were 4 urban locations and 10 rural clinics; all rural clinics were farther than 40 miles from the main Minneapolis VAMC.

Patient Selection

The authors performed a retrospective chart review after receiving an institutional review board waiver for this quality assessment study. All patients who had a prior ICD-9 encounter diagnosis of COPD (codes: 491.0, 491.1, 491.2, 491.20, 491.21, 491.22, 491.8, 491.9, 492.0, 492.8, 494, 494.0, 494.1, 496) and who were seen in primary care during March 2015 were identified. Each subject’s first visit during that month was used as the start of the retrospective 1-year look-back period. All eligible subjects were sorted based on their rural or urban location and a randomly assigned number. Patients were then selected according to ascending numbers from each rural and urban clinic in proportion to the clinic’s representation among all eligible patients.

Outcomes

The primary outcomes—possible discrepancies in quality of health care for patients with COPD in rural vs urban primary care clinics—were assessed by (1) prior spirometry; (2) any prior pneumonia vaccination; (3) an influenza vaccination within the past year; (4) prescriptions within the past year for a short-acting beta agonist (SABA) metered-dose inhaler; and (5) prescriptions for a long-acting inhalers, including long-acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs), or inhaled corticosteroids (ICSs).

Secondary outcomes included (1) an active prescription for home oxygen within the past calendar year; (2) health care utilization assessed via prescriptions for intermittent courses of oral corticosteroids; (3) prescriptions for respiratory antibiotics (macrolides, tetracyclines, fluoroquinolones) within the past year for COPD exacerbations; (4) ED visits; (5) hospital admissions (and need for mechanical ventilation) for COPD exacerbations within the past year; and (6) whether patients were seen by either VA or Non-VA pulmonology providers.

Data Collection

Patients’ demographic data and comorbidities were collected via chart review. A 1-year prescription medication list was obtained by an electronic database search of the MVAHCS electronic medical record (EMR). Additional antibiotics and corticosteroid prescriptions for COPD exacerbations paid for by the VA but filled at a local pharmacy were manually searched from a separate database to supplement the electronic prescription list. Comparison of the electronic prescription list and pharmacy records in 25% of patients found 100% concordance in the prescription lists. The investigator manually reviewed and extracted the following data from the EMR, scanned-in records, and a Midwest VA COPD registry database: most recent spirometry results; immunization status for influenza in the past year; prior pneumonia vaccination; home oxygen prescription; whether the patient received respiratory antibiotic or intermittent oral corticosteroid treatment for COPD exacerbations; whether the patient had a ED visit or hospital admission for COPD exacerbation with or without need for mechanical ventilation; and whether the patient had been seen by a pulmonology provider. The investigator reviewed all primary care provider notes in the past year for documentation of non-VA ED visits or hospitalizations that were not present in the EMR, Midwest VA COPD registry database, or scanned patient records.

Data Analysis

Results are described as mean ± standard deviation, median (interquartile range) or proportion, expressed as a percentage as appropriate for the level of measurement and distribution. The proportions meeting the COPD quality of health care outcomes in the urban and rural groups were compared using a chi-square test of proportions, and 95% confidence intervals (CI) on the differences were estimated. Samples of 400 patients each from the rural and urban groups were estimated to provide a 95% 2-sided CI on the differences of about ± 0.05 (5%), assuming the proportion meeting the quality of care outcomes in the urban group would be at least 0.8 (80%).

Results

The authors identified 1,538 patients with a previous encounter diagnosis of COPD who were seen in a primary care clinic in the MVAHCS in March of 2015. The authors reviewed the medical records of 801 randomly selected patients: 400 rural clinic patients and 401 urban clinic patients. Demographic characteristics and major comorbidities of rural and urban patients were similar except more rural patients were white, and fewer had a record of obstructive sleep apnea, alcoholism, or addictive disorders (Table 1). Prescriptions for common chronic medical conditions were similar for rural and urban groups, including medications for depression (31% vs 33%) or diabetes mellitus (25% vs 28%). In patients who had spirometry, the severity of COPD, as assessed by mean forced expiratory volume (FEV₁), was similar between rural and urban patients (2.06 L vs 2.10 L).

Quality of COPD Care

Spirometry was documented in fewer rural clinic patients than in urban clinic patients (51% vs 82%; difference 31%, 95% CI: 25% to 37%) (Table 2).

COPD Outcomes

Home oxygen prescription rates were similar for rural and urban clinic patients (8% vs 9%; difference 1%, 95% CI: -2% to 5%). Rural patients received fewer prescriptions for intermittent oral corticosteroids (17% vs 31%; difference 14%, 95% CI: 9% to 20%) and antibiotics for COPD exacerbations (18% vs 32%; difference 14%, 95% CI: 8% to 20%). Rural patients had fewer ED visits for COPD exacerbations (7% vs 13%; difference 6%, 95% CI: 2% to 10%), and similar admission rates for COPD exacerbations (5% vs 6%; difference 1%, 95% CI: -2% to 4%). Of the few patients hospitalized for COPD exacerbations, none required mechanical ventilation. There was no significant difference in the number of rural vs urban patients seen by a pulmonologist in the calendar year of the study (6% vs 9%; difference 3%, 95% CI:-1% to 6%), with the majority seen by VA providers: 20/24 rural patients and 35/35 urban patients.

Discussion

Fewer rural patients had prior spirometry; otherwise, the COPD-related quality metrics were similar between rural and urban patient groups in the MVAHCS, including immunizations for pneumonia and influenza, and prescribing rates for short- and long-acting inhaler therapy. Despite the similarity in these COPD quality measures, rural clinic patients seemed to have less health care utilization related to COPD exacerbations.

Spirometry with airflow obstruction in the presence of respiratory symptoms is required for accurate diagnosis of COPD.^3,4 Spirometry has been available at the MVAHCS hospital-based clinic for years. Efforts to address this disparity led to implementation of on-site spirometry at all rural and urban clinics about 2 years prior to the patient enrollment visit date for the study. Fewer rural patients had spirometry, which is possibly from prior disparity in resources; yet rates of spirometry in all patients with a clinical diagnosis of COPD in the MVAHCS are higher (rural 51%, urban 82%) than previously reported. A nationwide study of 94,000 veterans with recent clinical diagnosis of COPD found only 37% had spirometry within 2.5 years of diagnosis,²¹ and another non-VA study (n = 553) showed only 31% of patients discharged from a hospital with a diagnosis of COPD exacerbation had spirometry performed within a 8-year period prior to hospitalization.²²

Annual influenza vaccines are recommended for everyone aged > 6 months, and the pneumonia vaccine is recommended for all patients with COPD in order to reduce the risk of COPD exacerbations and pneumonias.^23,24 The rates of vaccination at MVAHCS rural and urban clinics for both influenza (79% vs 81%) and pneumococcus (88% vs 91%) are higher than previously published studies of patients with COPD for influenza vaccination (30%-51%) and pneumonia vaccination (21%-51%) and did not differ between rural and urban clinics.^7,25-28 The observed high vaccination rates may be due to EMR prompts and requirements to document vaccination status and offer recommended vaccinations.

Long-acting inhalers have been shown to reduce rates of COPD exacerbations and improve patients’ quality of life.²⁹ The authors found no disparity in the prescription rate of short- or long-acting inhalers between rural and urban patients, and no difference in the severity of COPD, as indicated by FEV₁, that might influence prescription rates.

The authors attempted to evaluate health care resource utilization as an indicator of health care quality and outcomes. Based on previous reports, the authors expected to find lower quality of care and increased utilization in rural patients. Previous studies have shown rural patients can be more symptomatic with a higher body mass index, airflow obstruction, dyspnea, and exercise capacity index (BODE index) than are patients in urban settings.^16,30 Statewide and national registry data have shown rural patients have higher rates of primary care visits, ER visits, and hospitalizations for COPD exacerbations.

Rural patients also have been shown to have higher mortality rates and were more likely to be in a long-term care center and less likely to have home care or palliative care than were their urban counterparts.^13-18,31 If the severity of illness is similar in rural and urban areas, higher health care utilization related to COPD would suggest that patients in rural settings may be receiving inferior quality of health care. The authors could not find any previous reports of the quality of COPD care delivered in rural vs urban settings.

In this study the only difference in quality of care was the lower proportion of rural patients with a record of spirometry that is needed to confirm the diagnosis. The observed differences in the quality of care measures wouldn’t be expected to lead to large differences in the outcome measures. Contrary to the literature and the observed similarity in quality of care, rural patients had better COPD outcomes perhaps due to unmeasured differences in risk or failure to capture medical visits outside of the VA system. The severity of COPD based on FEV₁ and concurrent diagnoses, such as heart failure, did not suggest that rural patients in this comparison had a higher burden of illness or risk of poor COPD outcomes.

More than 70,000 patients spanning a large geographic region receive primary care at MVAHCS, which provides comparable care to all COPD patients, regardless of location, by using the same EMR system, providing evidence-based order sets for disease management, proactively offering on-site and remote COPD case managers for high-risk patients, and more recently, implementing on-site spirometry testing in all clinics. This approach as opposed to the traditional outreach clinic model may in part explain the similarity in quality of care in urban and rural clinics that was not reported in previous studies.

Limitations

This study was performed retrospectively, increasing the potential of missing data, especially from outside the VA health care system. Patients were not randomly assigned to rural or urban clinics, so differences in patient characteristics could exist. Alcohol and addictive disorders were more common in urban patients, which might affect adherence to prescribed medications. In addition, lower rate of obstructive sleep apnea was found in the rural population, which has been linked to increased airway inflammation and COPD exacerbations resulting in hospitalization.^32,33 Mortality was not assessed as all patients were alive and seen in clinic at time of enrollment.

The authors were not able to record a patients’ residence in a long-term care facility or institutionalization, use of home care, or palliative care services due to limitations in the EMR system. Whether patients received comanaged primary care or underwent pulmonary rehabilitation could not be obtained from the EMR. Most patients never had lung volumes or diffusion capacity and thus were not included. The authors could not report whether inhaler therapy was appropriate compared with the Global Initiative for Chronic Obstructive Lund Disease(GOLD)severity score because most of the spirometry was done at a discordant time to when inhaler therapy was assessed, and new GOLD guidelines include patient symptoms that were not reliably recorded in the EMR. Last, the authors had hoped to include smoking status and cessation practices as part of the quality measures, but due to significant variability in patients’ documented smoking status in the same period, the data were deemed unreliable.

Conclusion

No disparities were found between rural and urban clinics in the quality of health care for patients with COPD in the MVAHCS except that fewer rural patients had prior spirometry; a difference that is likely due to the fact that only recently has spirometry been implemented in the MVAHCS rural clinics. Overall the quality of COPD care was high and above the previously reported rates. Further larger studies of rural and urban quality of health care for patients with COPD are needed in other VA and non-VA systems to determine whether disparities exist and whether they are associated with clinical outcomes, including ED visits, hospitalizations, and mortality.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Take-Home Points

• Stability of the foot is dependent on both the medial and lateral longitudinal columns; injuries to a single column alone are extremely rare.
• Midfoot fractures that are recognized and treated early have generally favorable outcomes compared to those identified in a delayed fashion.
• The most frequent complication of navicular dislocation is AVN, which is said to occur in as many as 25% of cases.
• Many specialists agree that navicular dislocations are best treated with open reduction.
• Ultimately, the goals of surgical intervention are to minimize pain and to establish stability of the plantigrade foot.

Traumatic dislocation of the tarsal navicular (especially without a navicular body fracture) is uncommon.¹ The regional anatomy and ligamentous architecture confer stability to the midfoot.^2-6 Navicular dislocation is part of a complex disruption involving structures in the adjacent column.⁶

Navicular dislocation has been associated with several bony and soft-tissue injury patterns, including comminuted intra-articular fracture of the calcaneus and associated calcaneocuboid joint subluxation; fracture and subluxation of the calcaneocuboid joint; fracture-dislocation of the calcaneocuboid joint with fractures of the third and fourth metatarsals; and a combination of fractures of the intermediate cuneiform, the second through fourth metatarsals, and the cuboid.^4–11 In this article, we report a case of open complete navicular dislocation with talar head fracture and associated subtalar and calcaneocuboid subluxations in a 45-year-old man. The injury was managed with open reduction and stabilization with Kirschner wires (K-wires), which later required naviculocuneiform and intercuneiform fusion for posttraumatic avascular necrosis (AVN). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 45-year-old man sustained blunt trauma to the right foot in a high-speed head-on collision. He was hemodynamically stable with isolated complaints of pain in the foot. Physical examination revealed a grossly open 10-cm wound extending from the heel pad medially to the dorsal surface of the navicular. The navicular was clearly visible through the wound.

Plain radiographs of the foot showed complete medial dislocation of the navicular with complete disruption of all 3 naviculocuneiform joints (Figures 1A-1C).

Discussion

The naviculocuneiform joints are important for the dissipation of loading stresses on the midfoot but provide little motion. The plantar and dorsal ligaments are thick structures that stabilize these joints, predisposing the navicular to fracture rather than isolated dislocation. The stability of the foot is dependent on both the medial and lateral longitudinal columns, and it is thought impossible to injure one column without disrupting the other.⁶ Several patterns of associated lateral column disruptions have been documented, including 3 cases similar to our patient’s, involving navicular dislocation with associated calcaneocuboid joint injuries.^5,6,10

Authors have proposed several mechanisms accounting for navicular dislocations. In the setting of acute trauma, the navicular displaces dorsally as the result of forefoot plantar flexion and axial loading.⁴ A severe abduction/pronation injury leading to a midtarsal dislocation followed by a spontaneous reduction can force the navicular to dislocate medially.⁶ This disruption of the naviculocuneiform joint and concurrent “nutcracker” injury to the lateral column can produce an associated disruption of the calcaneocuboid joint.⁶ Depending on the direction of the deforming force, the forefoot can dislocate superolaterally if the force is plantar or inferolaterally if the force is dorsal. The remaining soft-tissue attachments help determine the position of the navicular. A third postulated mechanism involves a complex wringing injury to the forefoot.¹⁰Most specialists agree that navicular dislocations are best treated with open reduction.^4,6 The goal of surgical intervention is to establish a stable plantigrade foot and to minimize pain. The current literature supports using either wires or screws to maintain reduction of midfoot injuries. Wires can be used for both talonavicular and naviculocuneiform fixation. Screws can be placed across the naviculocuneiform joints, as there is little normal physiologic motion through these joints.⁴ The talonavicular joint and the cuboid-metatarsal joints provide most of the motion in the midfoot and should not be readily fused.⁵ Stabilization of both columns is considered necessary to avoid complications such as subluxation and midfoot deformity.Given the postreduction stability of the lateral column in the present case, bicolumnar stabilization was not considered necessary. It is possible that subsequent collapse of the midfoot may have been attenuated in the presence of lateral fixation, but this would not necessarily have prevented complications of AVN.

Midfoot fractures that are recognized and treated early have generally favorable outcomes,^5-11 though chronic pain and subsequent deformity are not uncommon. Perhaps the most frequently reported complication of navicular dislocation is AVN, which is thought to occur in approximately 25% of cases.¹² AVN is a well-recognized complication of hindfoot and midfoot trauma. In the tarsal navicular, blood supply to the central-third watershed region is marginal. Small branches of the posterior tibial and dorsalis pedis arteries that supply the medial and lateral areas are readily injured. Not surprisingly, the risk for AVN is high when the dislocated bone is severely displaced.⁶ In some circumstances, the shared blood supply of the posterior tibialis may be the only remaining osseous supply. The tendon and its soft-tissue attachments should therefore be carefully monitored during dissection and reduction.⁶ In most cases, AVN of the foot manifests clinically within the first 10 months after injury, as was the case with our patient.¹³ AVN can result in the Charcot-like collapse of the medial column, leading to progressive midfoot plantar deformities.⁴ Variations of midfoot fusion are often required.^4,6AVN may be difficult to differentiate from posttraumatic arthritis. These conditions can have similar clinical presentations and appearances on plain radiographs. In such situations, magnetic resonance imaging or bone scintigraphy may determine the diagnosis. Damage to the articular surface at time of injury and residual articular displacement, instability, and joint subluxation after injury are considered risk factors for the development of posttraumatic arthritis in the foot and ankle.¹⁴ Reports suggest that the severity of the damage to the articular surface is directly proportional to the degree of arthritis.¹⁴ Such damage may not be initially visible, especially in axial impaction injuries, but latent deterioration of the articular surface can occur.¹⁵ For patients with significant dislocations of the naviculocuneiform joints, some authors advocate primary and early fusion¹⁵ instead of the more conservative approach used here. Primary fusions are argued to have minimal deleterious effects on function, secondary to the absence of normal physiologic motion through the affected joints.¹⁵ However, there is relatively little published evidence on long-term outcomes in primary versus secondary naviculocuneiform fusions.

Successful treatment of midfoot fractures and dislocations requires intimate knowledge of foot and ankle anatomy and mechanics. Surgeons must be able to anticipate, identify, and counsel patients about acute and delayed complications in these already challenging injuries.

Am J Orthop. 2017;46(3):E186-E189. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Stability of the foot is dependent on both the medial and lateral longitudinal columns; injuries to a single column alone are extremely rare.
• Midfoot fractures that are recognized and treated early have generally favorable outcomes compared to those identified in a delayed fashion.
• The most frequent complication of navicular dislocation is AVN, which is said to occur in as many as 25% of cases.
• Many specialists agree that navicular dislocations are best treated with open reduction.
• Ultimately, the goals of surgical intervention are to minimize pain and to establish stability of the plantigrade foot.

Traumatic dislocation of the tarsal navicular (especially without a navicular body fracture) is uncommon.¹ The regional anatomy and ligamentous architecture confer stability to the midfoot.^2-6 Navicular dislocation is part of a complex disruption involving structures in the adjacent column.⁶

Navicular dislocation has been associated with several bony and soft-tissue injury patterns, including comminuted intra-articular fracture of the calcaneus and associated calcaneocuboid joint subluxation; fracture and subluxation of the calcaneocuboid joint; fracture-dislocation of the calcaneocuboid joint with fractures of the third and fourth metatarsals; and a combination of fractures of the intermediate cuneiform, the second through fourth metatarsals, and the cuboid.^4–11 In this article, we report a case of open complete navicular dislocation with talar head fracture and associated subtalar and calcaneocuboid subluxations in a 45-year-old man. The injury was managed with open reduction and stabilization with Kirschner wires (K-wires), which later required naviculocuneiform and intercuneiform fusion for posttraumatic avascular necrosis (AVN). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 45-year-old man sustained blunt trauma to the right foot in a high-speed head-on collision. He was hemodynamically stable with isolated complaints of pain in the foot. Physical examination revealed a grossly open 10-cm wound extending from the heel pad medially to the dorsal surface of the navicular. The navicular was clearly visible through the wound.

Plain radiographs of the foot showed complete medial dislocation of the navicular with complete disruption of all 3 naviculocuneiform joints (Figures 1A-1C).

Discussion

The naviculocuneiform joints are important for the dissipation of loading stresses on the midfoot but provide little motion. The plantar and dorsal ligaments are thick structures that stabilize these joints, predisposing the navicular to fracture rather than isolated dislocation. The stability of the foot is dependent on both the medial and lateral longitudinal columns, and it is thought impossible to injure one column without disrupting the other.⁶ Several patterns of associated lateral column disruptions have been documented, including 3 cases similar to our patient’s, involving navicular dislocation with associated calcaneocuboid joint injuries.^5,6,10

Authors have proposed several mechanisms accounting for navicular dislocations. In the setting of acute trauma, the navicular displaces dorsally as the result of forefoot plantar flexion and axial loading.⁴ A severe abduction/pronation injury leading to a midtarsal dislocation followed by a spontaneous reduction can force the navicular to dislocate medially.⁶ This disruption of the naviculocuneiform joint and concurrent “nutcracker” injury to the lateral column can produce an associated disruption of the calcaneocuboid joint.⁶ Depending on the direction of the deforming force, the forefoot can dislocate superolaterally if the force is plantar or inferolaterally if the force is dorsal. The remaining soft-tissue attachments help determine the position of the navicular. A third postulated mechanism involves a complex wringing injury to the forefoot.¹⁰Most specialists agree that navicular dislocations are best treated with open reduction.^4,6 The goal of surgical intervention is to establish a stable plantigrade foot and to minimize pain. The current literature supports using either wires or screws to maintain reduction of midfoot injuries. Wires can be used for both talonavicular and naviculocuneiform fixation. Screws can be placed across the naviculocuneiform joints, as there is little normal physiologic motion through these joints.⁴ The talonavicular joint and the cuboid-metatarsal joints provide most of the motion in the midfoot and should not be readily fused.⁵ Stabilization of both columns is considered necessary to avoid complications such as subluxation and midfoot deformity.Given the postreduction stability of the lateral column in the present case, bicolumnar stabilization was not considered necessary. It is possible that subsequent collapse of the midfoot may have been attenuated in the presence of lateral fixation, but this would not necessarily have prevented complications of AVN.

Midfoot fractures that are recognized and treated early have generally favorable outcomes,^5-11 though chronic pain and subsequent deformity are not uncommon. Perhaps the most frequently reported complication of navicular dislocation is AVN, which is thought to occur in approximately 25% of cases.¹² AVN is a well-recognized complication of hindfoot and midfoot trauma. In the tarsal navicular, blood supply to the central-third watershed region is marginal. Small branches of the posterior tibial and dorsalis pedis arteries that supply the medial and lateral areas are readily injured. Not surprisingly, the risk for AVN is high when the dislocated bone is severely displaced.⁶ In some circumstances, the shared blood supply of the posterior tibialis may be the only remaining osseous supply. The tendon and its soft-tissue attachments should therefore be carefully monitored during dissection and reduction.⁶ In most cases, AVN of the foot manifests clinically within the first 10 months after injury, as was the case with our patient.¹³ AVN can result in the Charcot-like collapse of the medial column, leading to progressive midfoot plantar deformities.⁴ Variations of midfoot fusion are often required.^4,6AVN may be difficult to differentiate from posttraumatic arthritis. These conditions can have similar clinical presentations and appearances on plain radiographs. In such situations, magnetic resonance imaging or bone scintigraphy may determine the diagnosis. Damage to the articular surface at time of injury and residual articular displacement, instability, and joint subluxation after injury are considered risk factors for the development of posttraumatic arthritis in the foot and ankle.¹⁴ Reports suggest that the severity of the damage to the articular surface is directly proportional to the degree of arthritis.¹⁴ Such damage may not be initially visible, especially in axial impaction injuries, but latent deterioration of the articular surface can occur.¹⁵ For patients with significant dislocations of the naviculocuneiform joints, some authors advocate primary and early fusion¹⁵ instead of the more conservative approach used here. Primary fusions are argued to have minimal deleterious effects on function, secondary to the absence of normal physiologic motion through the affected joints.¹⁵ However, there is relatively little published evidence on long-term outcomes in primary versus secondary naviculocuneiform fusions.

Successful treatment of midfoot fractures and dislocations requires intimate knowledge of foot and ankle anatomy and mechanics. Surgeons must be able to anticipate, identify, and counsel patients about acute and delayed complications in these already challenging injuries.

Am J Orthop. 2017;46(3):E186-E189. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Stability of the foot is dependent on both the medial and lateral longitudinal columns; injuries to a single column alone are extremely rare.
• Midfoot fractures that are recognized and treated early have generally favorable outcomes compared to those identified in a delayed fashion.
• The most frequent complication of navicular dislocation is AVN, which is said to occur in as many as 25% of cases.
• Many specialists agree that navicular dislocations are best treated with open reduction.
• Ultimately, the goals of surgical intervention are to minimize pain and to establish stability of the plantigrade foot.

Traumatic dislocation of the tarsal navicular (especially without a navicular body fracture) is uncommon.¹ The regional anatomy and ligamentous architecture confer stability to the midfoot.^2-6 Navicular dislocation is part of a complex disruption involving structures in the adjacent column.⁶

Navicular dislocation has been associated with several bony and soft-tissue injury patterns, including comminuted intra-articular fracture of the calcaneus and associated calcaneocuboid joint subluxation; fracture and subluxation of the calcaneocuboid joint; fracture-dislocation of the calcaneocuboid joint with fractures of the third and fourth metatarsals; and a combination of fractures of the intermediate cuneiform, the second through fourth metatarsals, and the cuboid.^4–11 In this article, we report a case of open complete navicular dislocation with talar head fracture and associated subtalar and calcaneocuboid subluxations in a 45-year-old man. The injury was managed with open reduction and stabilization with Kirschner wires (K-wires), which later required naviculocuneiform and intercuneiform fusion for posttraumatic avascular necrosis (AVN). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 45-year-old man sustained blunt trauma to the right foot in a high-speed head-on collision. He was hemodynamically stable with isolated complaints of pain in the foot. Physical examination revealed a grossly open 10-cm wound extending from the heel pad medially to the dorsal surface of the navicular. The navicular was clearly visible through the wound.

Plain radiographs of the foot showed complete medial dislocation of the navicular with complete disruption of all 3 naviculocuneiform joints (Figures 1A-1C).

Discussion

The naviculocuneiform joints are important for the dissipation of loading stresses on the midfoot but provide little motion. The plantar and dorsal ligaments are thick structures that stabilize these joints, predisposing the navicular to fracture rather than isolated dislocation. The stability of the foot is dependent on both the medial and lateral longitudinal columns, and it is thought impossible to injure one column without disrupting the other.⁶ Several patterns of associated lateral column disruptions have been documented, including 3 cases similar to our patient’s, involving navicular dislocation with associated calcaneocuboid joint injuries.^5,6,10

Authors have proposed several mechanisms accounting for navicular dislocations. In the setting of acute trauma, the navicular displaces dorsally as the result of forefoot plantar flexion and axial loading.⁴ A severe abduction/pronation injury leading to a midtarsal dislocation followed by a spontaneous reduction can force the navicular to dislocate medially.⁶ This disruption of the naviculocuneiform joint and concurrent “nutcracker” injury to the lateral column can produce an associated disruption of the calcaneocuboid joint.⁶ Depending on the direction of the deforming force, the forefoot can dislocate superolaterally if the force is plantar or inferolaterally if the force is dorsal. The remaining soft-tissue attachments help determine the position of the navicular. A third postulated mechanism involves a complex wringing injury to the forefoot.¹⁰Most specialists agree that navicular dislocations are best treated with open reduction.^4,6 The goal of surgical intervention is to establish a stable plantigrade foot and to minimize pain. The current literature supports using either wires or screws to maintain reduction of midfoot injuries. Wires can be used for both talonavicular and naviculocuneiform fixation. Screws can be placed across the naviculocuneiform joints, as there is little normal physiologic motion through these joints.⁴ The talonavicular joint and the cuboid-metatarsal joints provide most of the motion in the midfoot and should not be readily fused.⁵ Stabilization of both columns is considered necessary to avoid complications such as subluxation and midfoot deformity.Given the postreduction stability of the lateral column in the present case, bicolumnar stabilization was not considered necessary. It is possible that subsequent collapse of the midfoot may have been attenuated in the presence of lateral fixation, but this would not necessarily have prevented complications of AVN.

Midfoot fractures that are recognized and treated early have generally favorable outcomes,^5-11 though chronic pain and subsequent deformity are not uncommon. Perhaps the most frequently reported complication of navicular dislocation is AVN, which is thought to occur in approximately 25% of cases.¹² AVN is a well-recognized complication of hindfoot and midfoot trauma. In the tarsal navicular, blood supply to the central-third watershed region is marginal. Small branches of the posterior tibial and dorsalis pedis arteries that supply the medial and lateral areas are readily injured. Not surprisingly, the risk for AVN is high when the dislocated bone is severely displaced.⁶ In some circumstances, the shared blood supply of the posterior tibialis may be the only remaining osseous supply. The tendon and its soft-tissue attachments should therefore be carefully monitored during dissection and reduction.⁶ In most cases, AVN of the foot manifests clinically within the first 10 months after injury, as was the case with our patient.¹³ AVN can result in the Charcot-like collapse of the medial column, leading to progressive midfoot plantar deformities.⁴ Variations of midfoot fusion are often required.^4,6AVN may be difficult to differentiate from posttraumatic arthritis. These conditions can have similar clinical presentations and appearances on plain radiographs. In such situations, magnetic resonance imaging or bone scintigraphy may determine the diagnosis. Damage to the articular surface at time of injury and residual articular displacement, instability, and joint subluxation after injury are considered risk factors for the development of posttraumatic arthritis in the foot and ankle.¹⁴ Reports suggest that the severity of the damage to the articular surface is directly proportional to the degree of arthritis.¹⁴ Such damage may not be initially visible, especially in axial impaction injuries, but latent deterioration of the articular surface can occur.¹⁵ For patients with significant dislocations of the naviculocuneiform joints, some authors advocate primary and early fusion¹⁵ instead of the more conservative approach used here. Primary fusions are argued to have minimal deleterious effects on function, secondary to the absence of normal physiologic motion through the affected joints.¹⁵ However, there is relatively little published evidence on long-term outcomes in primary versus secondary naviculocuneiform fusions.

Successful treatment of midfoot fractures and dislocations requires intimate knowledge of foot and ankle anatomy and mechanics. Surgeons must be able to anticipate, identify, and counsel patients about acute and delayed complications in these already challenging injuries.

Am J Orthop. 2017;46(3):E186-E189. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.