Every patient who is initially diagnosed with epilepsy should also be evaluated for coexisting psychiatric problems, according to Andres Kanner with the Department of Neurology, University of Miami School of Medicine. Kanner noted that psychiatric comorbidities often existed in patients before they were diagnosed with a seizure. That, coupled with the fact that drug therapy and surgery for epilepsy often cause psychiatric symptoms, is part of the justification for conducting these evaluations.

Kanner AM. Psychiatric comorbidities in new onset epilepsy: Should they be always investigated? Seizure. 2017;49:79-82.

Every patient who is initially diagnosed with epilepsy should also be evaluated for coexisting psychiatric problems, according to Andres Kanner with the Department of Neurology, University of Miami School of Medicine. Kanner noted that psychiatric comorbidities often existed in patients before they were diagnosed with a seizure. That, coupled with the fact that drug therapy and surgery for epilepsy often cause psychiatric symptoms, is part of the justification for conducting these evaluations.

Kanner AM. Psychiatric comorbidities in new onset epilepsy: Should they be always investigated? Seizure. 2017;49:79-82.

Every patient who is initially diagnosed with epilepsy should also be evaluated for coexisting psychiatric problems, according to Andres Kanner with the Department of Neurology, University of Miami School of Medicine. Kanner noted that psychiatric comorbidities often existed in patients before they were diagnosed with a seizure. That, coupled with the fact that drug therapy and surgery for epilepsy often cause psychiatric symptoms, is part of the justification for conducting these evaluations.

Kanner AM. Psychiatric comorbidities in new onset epilepsy: Should they be always investigated? Seizure. 2017;49:79-82.

Although a recent analysis of adverse effects (AEs) found differences between AEs reported for generic versions compared with brand name versions of the 3 common antiepileptic drugs (AEDs), when approved generic formulations were compared to unapproved generics, reporting odds ratios were similar for authorized generic AEDs and generic AEDs. The researchers concluded that the differences were the result of perception biases. There were differences in drug AE reports of suicide and suicide ideation between authorized generic and brand name drugs that could not be explained by bias.

Rahman MM, Alatawi Y, Cheng N, et al. Comparison of brand versus generic antiepileptic drug adverse event reporting rates in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) [published online June 3, 2017]. Epilepsy Res. doi: http://dx.doi.org/10.1016/j.eplepsyres.2017.06.007

Although a recent analysis of adverse effects (AEs) found differences between AEs reported for generic versions compared with brand name versions of the 3 common antiepileptic drugs (AEDs), when approved generic formulations were compared to unapproved generics, reporting odds ratios were similar for authorized generic AEDs and generic AEDs. The researchers concluded that the differences were the result of perception biases. There were differences in drug AE reports of suicide and suicide ideation between authorized generic and brand name drugs that could not be explained by bias.

Rahman MM, Alatawi Y, Cheng N, et al. Comparison of brand versus generic antiepileptic drug adverse event reporting rates in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) [published online June 3, 2017]. Epilepsy Res. doi: http://dx.doi.org/10.1016/j.eplepsyres.2017.06.007

Although a recent analysis of adverse effects (AEs) found differences between AEs reported for generic versions compared with brand name versions of the 3 common antiepileptic drugs (AEDs), when approved generic formulations were compared to unapproved generics, reporting odds ratios were similar for authorized generic AEDs and generic AEDs. The researchers concluded that the differences were the result of perception biases. There were differences in drug AE reports of suicide and suicide ideation between authorized generic and brand name drugs that could not be explained by bias.

Rahman MM, Alatawi Y, Cheng N, et al. Comparison of brand versus generic antiepileptic drug adverse event reporting rates in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) [published online June 3, 2017]. Epilepsy Res. doi: http://dx.doi.org/10.1016/j.eplepsyres.2017.06.007

The likelihood of experiencing a recurrent seizure is closely linked to a person’s stress level, according to a recent study that looked at 52 individuals with a single unprovoked seizure and 29 with newly diagnosed epilepsy. The researchers, who looked at adult residents in low-income areas of Northern Manhattan and Harlem, New York City, found that generalized anxiety disorder increased the risk of a recurrent seizure threefold. In a second analysis, a mood disorder more than doubled the risk of a recurrent seizure.    

Baldin E, Hauser WS, Pack A, Hesdorffer DC. Stress is associated with an increased risk of recurrent seizures in adults. Epilepsia. 2017;58:1037-1046.

The likelihood of experiencing a recurrent seizure is closely linked to a person’s stress level, according to a recent study that looked at 52 individuals with a single unprovoked seizure and 29 with newly diagnosed epilepsy. The researchers, who looked at adult residents in low-income areas of Northern Manhattan and Harlem, New York City, found that generalized anxiety disorder increased the risk of a recurrent seizure threefold. In a second analysis, a mood disorder more than doubled the risk of a recurrent seizure.    

Baldin E, Hauser WS, Pack A, Hesdorffer DC. Stress is associated with an increased risk of recurrent seizures in adults. Epilepsia. 2017;58:1037-1046.

The likelihood of experiencing a recurrent seizure is closely linked to a person’s stress level, according to a recent study that looked at 52 individuals with a single unprovoked seizure and 29 with newly diagnosed epilepsy. The researchers, who looked at adult residents in low-income areas of Northern Manhattan and Harlem, New York City, found that generalized anxiety disorder increased the risk of a recurrent seizure threefold. In a second analysis, a mood disorder more than doubled the risk of a recurrent seizure.    

Baldin E, Hauser WS, Pack A, Hesdorffer DC. Stress is associated with an increased risk of recurrent seizures in adults. Epilepsia. 2017;58:1037-1046.

SAN DIEGO – Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes, according to a post-hoc analysis of the multicenter, randomized, controlled, open-label Systolic Blood Pressure Intervention Trial (SPRINT).

Thus, prediabetes did not undercut the cardiovascular benefits of intensive systolic blood pressure (SBP) control in older, high-risk, hypertensive patients, Adam P. Bress, PharmD, MS, and his associates concluded in a late-breaking poster presented at the annual scientific sessions of the American Diabetes Association.

SAN DIEGO – Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes, according to a post-hoc analysis of the multicenter, randomized, controlled, open-label Systolic Blood Pressure Intervention Trial (SPRINT).

Thus, prediabetes did not undercut the cardiovascular benefits of intensive systolic blood pressure (SBP) control in older, high-risk, hypertensive patients, Adam P. Bress, PharmD, MS, and his associates concluded in a late-breaking poster presented at the annual scientific sessions of the American Diabetes Association.

SAN DIEGO – Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes, according to a post-hoc analysis of the multicenter, randomized, controlled, open-label Systolic Blood Pressure Intervention Trial (SPRINT).

Thus, prediabetes did not undercut the cardiovascular benefits of intensive systolic blood pressure (SBP) control in older, high-risk, hypertensive patients, Adam P. Bress, PharmD, MS, and his associates concluded in a late-breaking poster presented at the annual scientific sessions of the American Diabetes Association.

Three members of the hospital medicine community – Thiruvoipati Nanda Kumar, MD; Anthony Aghenta, MD, MS, FACP; and Angela Aboutalib, MD – recently were honored for their work by the International Association of HealthCare Professionals, earning spots in its publication, The Leading Physicians of the World.

Hospitalist and internist Dr. Nanda Kumar serves patients at Vibra Hospital in Redding, Calif., where he is also a clinical associate professor at the University of California at Davis. He is a member of both the Society of Hospital Medicine and the American Diabetes Association.

Dr. Aghenta is a 17-year veteran internist who currently serves as medical director for Coronado Healthcare Center in Phoenix. There, he also is affiliated with St. Joseph’s Hospital and Medical Center. A member of SHM, Dr. Aghenta also has the title of Fellow of the American College of Physicians.

Dr. Aboutalib, whose experience as an internist includes expertise in hospital medicine, serves as hospitalist and medical director of clinical operations at U.S. Acute Care Solutions, Canton, Ohio. Previously, this member of the American College of Physicians served South Physicians as a hospitalist at Mercy Hospital in Chicago.
 

Andrew Dunn, MD, MPH, FACP, SFHM, recently was named chair-elect of the Board of Regents of the American College of Physicians (ACP), the national organization of internists. He assumed the role at the start of the ACP’s annual scientific meeting held in San Diego, March 30–April 1.

Susan Herson, MD, has been named the new chief of staff at the Bath, N.Y., Veterans Affairs Medical Center. Dr. Herson comes to Bath from the Sioux Falls (S.D.) VA, where she was a hospitalist, a hospitalist-clinician educator, and medical director of clinical documentation improvement, while also serving as clinical assistant professor for New York Medical College and medical director at Norwalk (Conn.) Hospital.

Dr. Herson served in the U.S. Navy, doing her training at Walter Reed Medical Center, Bethesda, Md. She was a general medical officer while stationed at U.S. Marine Corps Base Camp Lejeune in Jacksonville, N.C.
 

Chad Whelan, MD, has been elevated to president of the Loyola (Ill.) University Medical Center, moving up from his chair as senior vice president and chief medical officer. This longtime hospitalist also serves as a professor of medicine in the Loyola Chicago Stritch School of Medicine.

Kevin Tulipana, DO, recently was promoted to medical director of hospital medicine at Cancer Treatment Centers of America’s Southwest Regional Medical Center in Tulsa, Okla. Previously, Dr. Tulipana was a hospitalist in the special care unit at CTCA Tulsa.

Mustafa Sardini, MD, has been named Envision Physician Services’ 2017 Hospital Medicine Physician of the Year. Dr. Sardini is the site medical director as Baylor Scott & White Medical Center, Sunnyvale, Texas. EPS presents the award to a hospitalist who peers deem as a leader in the industry.
 

Business moves

Physicians’ Alliance, (PAL) recently announced plans to partner with Penn State Health. As the largest independent physician group in Lancaster County, Pa., they will bring its more than 120 physicians, hospitalists, and dieticians to central Pennsylvania giant Penn State.

The alliance will allow patients of PAL physicians access to advanced care at Milton S. Hershey Medical Center and Penn State Children’s Hospital in Hershey.
 

Envision Healthcare, Greenwood Village, Colo. has created the Envision Physical Services (EPS) as a result of a merger with AmSurg ambulatory surgical center in December 2016. EPS combines EmCare and Sheridan Healthcare’s physician services divisions.

EPS specializes in hospital medicine, anesthesia, emergency medicine, radiology, and surgical services.

Three members of the hospital medicine community – Thiruvoipati Nanda Kumar, MD; Anthony Aghenta, MD, MS, FACP; and Angela Aboutalib, MD – recently were honored for their work by the International Association of HealthCare Professionals, earning spots in its publication, The Leading Physicians of the World.

Hospitalist and internist Dr. Nanda Kumar serves patients at Vibra Hospital in Redding, Calif., where he is also a clinical associate professor at the University of California at Davis. He is a member of both the Society of Hospital Medicine and the American Diabetes Association.

Dr. Aghenta is a 17-year veteran internist who currently serves as medical director for Coronado Healthcare Center in Phoenix. There, he also is affiliated with St. Joseph’s Hospital and Medical Center. A member of SHM, Dr. Aghenta also has the title of Fellow of the American College of Physicians.

Dr. Aboutalib, whose experience as an internist includes expertise in hospital medicine, serves as hospitalist and medical director of clinical operations at U.S. Acute Care Solutions, Canton, Ohio. Previously, this member of the American College of Physicians served South Physicians as a hospitalist at Mercy Hospital in Chicago.
 

Andrew Dunn, MD, MPH, FACP, SFHM, recently was named chair-elect of the Board of Regents of the American College of Physicians (ACP), the national organization of internists. He assumed the role at the start of the ACP’s annual scientific meeting held in San Diego, March 30–April 1.

Susan Herson, MD, has been named the new chief of staff at the Bath, N.Y., Veterans Affairs Medical Center. Dr. Herson comes to Bath from the Sioux Falls (S.D.) VA, where she was a hospitalist, a hospitalist-clinician educator, and medical director of clinical documentation improvement, while also serving as clinical assistant professor for New York Medical College and medical director at Norwalk (Conn.) Hospital.

Dr. Herson served in the U.S. Navy, doing her training at Walter Reed Medical Center, Bethesda, Md. She was a general medical officer while stationed at U.S. Marine Corps Base Camp Lejeune in Jacksonville, N.C.
 

Chad Whelan, MD, has been elevated to president of the Loyola (Ill.) University Medical Center, moving up from his chair as senior vice president and chief medical officer. This longtime hospitalist also serves as a professor of medicine in the Loyola Chicago Stritch School of Medicine.

Kevin Tulipana, DO, recently was promoted to medical director of hospital medicine at Cancer Treatment Centers of America’s Southwest Regional Medical Center in Tulsa, Okla. Previously, Dr. Tulipana was a hospitalist in the special care unit at CTCA Tulsa.

Mustafa Sardini, MD, has been named Envision Physician Services’ 2017 Hospital Medicine Physician of the Year. Dr. Sardini is the site medical director as Baylor Scott & White Medical Center, Sunnyvale, Texas. EPS presents the award to a hospitalist who peers deem as a leader in the industry.
 

Business moves

Physicians’ Alliance, (PAL) recently announced plans to partner with Penn State Health. As the largest independent physician group in Lancaster County, Pa., they will bring its more than 120 physicians, hospitalists, and dieticians to central Pennsylvania giant Penn State.

The alliance will allow patients of PAL physicians access to advanced care at Milton S. Hershey Medical Center and Penn State Children’s Hospital in Hershey.
 

Envision Healthcare, Greenwood Village, Colo. has created the Envision Physical Services (EPS) as a result of a merger with AmSurg ambulatory surgical center in December 2016. EPS combines EmCare and Sheridan Healthcare’s physician services divisions.

EPS specializes in hospital medicine, anesthesia, emergency medicine, radiology, and surgical services.

Three members of the hospital medicine community – Thiruvoipati Nanda Kumar, MD; Anthony Aghenta, MD, MS, FACP; and Angela Aboutalib, MD – recently were honored for their work by the International Association of HealthCare Professionals, earning spots in its publication, The Leading Physicians of the World.

Hospitalist and internist Dr. Nanda Kumar serves patients at Vibra Hospital in Redding, Calif., where he is also a clinical associate professor at the University of California at Davis. He is a member of both the Society of Hospital Medicine and the American Diabetes Association.

Dr. Aghenta is a 17-year veteran internist who currently serves as medical director for Coronado Healthcare Center in Phoenix. There, he also is affiliated with St. Joseph’s Hospital and Medical Center. A member of SHM, Dr. Aghenta also has the title of Fellow of the American College of Physicians.

Dr. Aboutalib, whose experience as an internist includes expertise in hospital medicine, serves as hospitalist and medical director of clinical operations at U.S. Acute Care Solutions, Canton, Ohio. Previously, this member of the American College of Physicians served South Physicians as a hospitalist at Mercy Hospital in Chicago.
 

Andrew Dunn, MD, MPH, FACP, SFHM, recently was named chair-elect of the Board of Regents of the American College of Physicians (ACP), the national organization of internists. He assumed the role at the start of the ACP’s annual scientific meeting held in San Diego, March 30–April 1.

Susan Herson, MD, has been named the new chief of staff at the Bath, N.Y., Veterans Affairs Medical Center. Dr. Herson comes to Bath from the Sioux Falls (S.D.) VA, where she was a hospitalist, a hospitalist-clinician educator, and medical director of clinical documentation improvement, while also serving as clinical assistant professor for New York Medical College and medical director at Norwalk (Conn.) Hospital.

Dr. Herson served in the U.S. Navy, doing her training at Walter Reed Medical Center, Bethesda, Md. She was a general medical officer while stationed at U.S. Marine Corps Base Camp Lejeune in Jacksonville, N.C.
 

Chad Whelan, MD, has been elevated to president of the Loyola (Ill.) University Medical Center, moving up from his chair as senior vice president and chief medical officer. This longtime hospitalist also serves as a professor of medicine in the Loyola Chicago Stritch School of Medicine.

Kevin Tulipana, DO, recently was promoted to medical director of hospital medicine at Cancer Treatment Centers of America’s Southwest Regional Medical Center in Tulsa, Okla. Previously, Dr. Tulipana was a hospitalist in the special care unit at CTCA Tulsa.

Mustafa Sardini, MD, has been named Envision Physician Services’ 2017 Hospital Medicine Physician of the Year. Dr. Sardini is the site medical director as Baylor Scott & White Medical Center, Sunnyvale, Texas. EPS presents the award to a hospitalist who peers deem as a leader in the industry.
 

Business moves

Physicians’ Alliance, (PAL) recently announced plans to partner with Penn State Health. As the largest independent physician group in Lancaster County, Pa., they will bring its more than 120 physicians, hospitalists, and dieticians to central Pennsylvania giant Penn State.

The alliance will allow patients of PAL physicians access to advanced care at Milton S. Hershey Medical Center and Penn State Children’s Hospital in Hershey.
 

Envision Healthcare, Greenwood Village, Colo. has created the Envision Physical Services (EPS) as a result of a merger with AmSurg ambulatory surgical center in December 2016. EPS combines EmCare and Sheridan Healthcare’s physician services divisions.

EPS specializes in hospital medicine, anesthesia, emergency medicine, radiology, and surgical services.

CHICAGO – A total annual surgeon volume of fewer than 25 operations was associated with increased 1-year mortality and reoperation rates, according to a study presented at the 2017 American Association for Thoracic Surgery Centennial.

Improvements in repair rates, survival, and freedom from reoperation increased with increasing surgeon case volumes, Joanna Chikwe, MD, and her colleagues at the Icahn School of Medicine at Mount Sinai, New York, stated.

mlesney@frontlinemedcom.com

CHICAGO – A total annual surgeon volume of fewer than 25 operations was associated with increased 1-year mortality and reoperation rates, according to a study presented at the 2017 American Association for Thoracic Surgery Centennial.

Improvements in repair rates, survival, and freedom from reoperation increased with increasing surgeon case volumes, Joanna Chikwe, MD, and her colleagues at the Icahn School of Medicine at Mount Sinai, New York, stated.

mlesney@frontlinemedcom.com

CHICAGO – A total annual surgeon volume of fewer than 25 operations was associated with increased 1-year mortality and reoperation rates, according to a study presented at the 2017 American Association for Thoracic Surgery Centennial.

Improvements in repair rates, survival, and freedom from reoperation increased with increasing surgeon case volumes, Joanna Chikwe, MD, and her colleagues at the Icahn School of Medicine at Mount Sinai, New York, stated.

mlesney@frontlinemedcom.com

This month, our “Flashback” article highlights Congress’s long-term attempt to repeal the Sustainable Growth Rate formula for physician reimbursement and base our payments on patient health outcomes. Although the Medicare Access and Quality Improvement Act of 2013 (highlighted in our 2013 article) sponsored by Rep. Michael Burgess and passed unanimously in the House of Representatives did not become law, it did set the stage for the passage of H.R.2 – the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA). Also sponsored by Rep. Burgess and passed with bipartisan support, MACRA has now become the foundation for our transition from fee-for-service reimbursement to value-based care.

In just 2 short years, we have all become familiar with terms like MIPS (Merit-based Incentive Payment System) and APMs (Alternative Payment Models). These two methods of reimbursement will become the backbone of a growing percentage of our revenue going forward. Gastroenterologists should embrace these programs and work to find our unique position in the health care value chain.

Larry R. Kosinski, MD, MBA, AGAF, FACG, is a managing partner of Illinois Gastroenterology Group, the Clinical Private Practice Councillor for the AGA, and serves on its Governing Board. He is president and chief medical officer of Project Sonar and an Associate Editor of GI & Hepatology News.

This month, our “Flashback” article highlights Congress’s long-term attempt to repeal the Sustainable Growth Rate formula for physician reimbursement and base our payments on patient health outcomes. Although the Medicare Access and Quality Improvement Act of 2013 (highlighted in our 2013 article) sponsored by Rep. Michael Burgess and passed unanimously in the House of Representatives did not become law, it did set the stage for the passage of H.R.2 – the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA). Also sponsored by Rep. Burgess and passed with bipartisan support, MACRA has now become the foundation for our transition from fee-for-service reimbursement to value-based care.

In just 2 short years, we have all become familiar with terms like MIPS (Merit-based Incentive Payment System) and APMs (Alternative Payment Models). These two methods of reimbursement will become the backbone of a growing percentage of our revenue going forward. Gastroenterologists should embrace these programs and work to find our unique position in the health care value chain.

Larry R. Kosinski, MD, MBA, AGAF, FACG, is a managing partner of Illinois Gastroenterology Group, the Clinical Private Practice Councillor for the AGA, and serves on its Governing Board. He is president and chief medical officer of Project Sonar and an Associate Editor of GI & Hepatology News.

This month, our “Flashback” article highlights Congress’s long-term attempt to repeal the Sustainable Growth Rate formula for physician reimbursement and base our payments on patient health outcomes. Although the Medicare Access and Quality Improvement Act of 2013 (highlighted in our 2013 article) sponsored by Rep. Michael Burgess and passed unanimously in the House of Representatives did not become law, it did set the stage for the passage of H.R.2 – the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA). Also sponsored by Rep. Burgess and passed with bipartisan support, MACRA has now become the foundation for our transition from fee-for-service reimbursement to value-based care.

In just 2 short years, we have all become familiar with terms like MIPS (Merit-based Incentive Payment System) and APMs (Alternative Payment Models). These two methods of reimbursement will become the backbone of a growing percentage of our revenue going forward. Gastroenterologists should embrace these programs and work to find our unique position in the health care value chain.

Larry R. Kosinski, MD, MBA, AGAF, FACG, is a managing partner of Illinois Gastroenterology Group, the Clinical Private Practice Councillor for the AGA, and serves on its Governing Board. He is president and chief medical officer of Project Sonar and an Associate Editor of GI & Hepatology News.

SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.

At week 52, hemoglobin A_1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.

Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA_1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA_1c level exceeded 8%.

A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA_1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.

Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.

Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m² after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m² with exenatide/placebo, and by 0.8 mL/min per 1.73 m² with dapagliflozin/placebo.

Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m², and systolic blood pressure averaged 130 mm Hg.

AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.

SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.

At week 52, hemoglobin A_1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.

Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA_1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA_1c level exceeded 8%.

A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA_1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.

Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.

Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m² after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m² with exenatide/placebo, and by 0.8 mL/min per 1.73 m² with dapagliflozin/placebo.

Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m², and systolic blood pressure averaged 130 mm Hg.

AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.

SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.

At week 52, hemoglobin A_1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.

Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA_1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA_1c level exceeded 8%.

A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA_1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.

Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.

Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m² after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m² with exenatide/placebo, and by 0.8 mL/min per 1.73 m² with dapagliflozin/placebo.

Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m², and systolic blood pressure averaged 130 mm Hg.

AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.

An investigational dengue vaccine against all four serotypes appears to be safe and immunogenic in children aged 2-17 years, whether or not they previously have been exposed to the virus, said Xavier Sáez-Llorens, MD, of Hospital del Niño Dr José Renán Esquivel, Panama City, Republic of Panama, and his associates.

Studies show dengue to be the most common mosquito-borne viral disease affecting humans, occurring in 125 countries and causing approximately 100 million symptomatic infections annually. Vector control has not halted the global spread of dengue, necessitating development of vaccines. A vaccine for people aged 9 years and older has been licensed, but there remains the need for a safe and effective vaccine against all four dengue virus serotypes for all ages, said Dr. Sáez-Llorens and his associates.

World Health Organization

cnellist@frontlinemedcom.com

An investigational dengue vaccine against all four serotypes appears to be safe and immunogenic in children aged 2-17 years, whether or not they previously have been exposed to the virus, said Xavier Sáez-Llorens, MD, of Hospital del Niño Dr José Renán Esquivel, Panama City, Republic of Panama, and his associates.

Studies show dengue to be the most common mosquito-borne viral disease affecting humans, occurring in 125 countries and causing approximately 100 million symptomatic infections annually. Vector control has not halted the global spread of dengue, necessitating development of vaccines. A vaccine for people aged 9 years and older has been licensed, but there remains the need for a safe and effective vaccine against all four dengue virus serotypes for all ages, said Dr. Sáez-Llorens and his associates.

World Health Organization

cnellist@frontlinemedcom.com

An investigational dengue vaccine against all four serotypes appears to be safe and immunogenic in children aged 2-17 years, whether or not they previously have been exposed to the virus, said Xavier Sáez-Llorens, MD, of Hospital del Niño Dr José Renán Esquivel, Panama City, Republic of Panama, and his associates.

Studies show dengue to be the most common mosquito-borne viral disease affecting humans, occurring in 125 countries and causing approximately 100 million symptomatic infections annually. Vector control has not halted the global spread of dengue, necessitating development of vaccines. A vaccine for people aged 9 years and older has been licensed, but there remains the need for a safe and effective vaccine against all four dengue virus serotypes for all ages, said Dr. Sáez-Llorens and his associates.

World Health Organization

cnellist@frontlinemedcom.com

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.