Case Reports

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.

Take-Home Points

• Rare and histologically indistinguishable from osteosarcoma of bone.
• Most common presentation is an enlarging mass in the thigh or buttock.
• Secondary extraosseous osteosarcoma usually arises in the field of prior external beam radiation or brachytherapy.
• Radiographic pattern of mineralization is central amorphous or cloudlike.
• On cross sectional imaging, the soft-tissue mass is separate from the underlying bone and periosteum.

Aside from multiple myeloma, osteosarcoma is the most common primary malignancy of bone, but extraosseous osteosarcoma is rare and accounts for only 1% of soft-tissue sarcomas and only 4% of all osteosarcomas.^1-3 Benign mesenchymal tumors, such as lipomas, are common, and they are estimated to outnumber their malignant counterparts by more than a factor of 100. However, the true ratio is unknown, as many clinically benign lipomas are not biopsied.⁴ Conventional lipoma is the most common lipoma and is biologically indolent. Conventional lipoma generally does not transform biologically into a more aggressive type of neoplasm—unlike atypical lipomatous tumors, which may demonstrate this type of evolution with multiple local recurrences.

This article is the first report of a case of radiation-associated extraosseous osteosarcoma that developed within a benign conventional lipoma. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In March 2013, a 72-year-old woman presented to a general surgeon with a right thigh mass of several weeks’ duration. The patient, who had a remote history of thyroid carcinoma, underwent thyroidectomy in 1991, excision of melanoma of the chest in 1998, and resection and adjuvant external beam radiotherapy (30 fractions) for Merkel cell carcinoma of the right proximal lateral leg (malignancy images unavailable) at an outside institution in 2003. Regional lymph node dissection at the time was negative. The patient remained disease-free the next 10 years. On presentation, magnetic resonance imaging (MRI) showed a 2.2-cm mass encircled by a tumor of lipomatous tissue within the vastus intermedius muscle, adjacent to but separate from the right distal femur (Figures 1A-1C).

Physical examination revealed marked ecchymosis of the left groin at the access site for embolization as well as massive ecchymosis and swelling along the right distal thigh, medial knee, and medial lower leg. The neurovascular structures were intact with full motor function and sensation distally, as well as normal distal pulses. No inguinal adenopathy was identified. The proximal portion of the prior radiation tattoo was at the inferior extent of the lesion on MRI.

The patient was treated with doxorubicin and ifosfamide (2 cycles) while waiting for the hematoma to shrink. Contrast-enhanced MRI showed a 2.2-cm enhancing mass with isointense T1 signal and heterogeneously hyperintense STIR (short tau inversion recovery) signal surrounded by a circumscribed nonenhancing lipomatous tumor within the vastus intermedius muscle, adjacent to the distal femoral cortex. There was no invasion of the bone, and a fat plane between the enhancing mass and the femoral cortex was identified (Figures 2A-2E).

Discussion

Extraosseous osteosarcoma, typically a high-grade malignant neoplasm of the soft tissues that produces osteoid or cartilaginous matrix, is histologically indistinguishable from osteosarcoma of bone.

Conventional lipoma, the most common subtype of lipoma, is a benign mesenchymal tumor. Other subtypes are hibernoma, fibrolipoma, angiolipoma, myelolipoma, spindle-cell lipoma, pleomorphic lipoma, and atypical lipomatous tumor.⁷ Atypical lipomatous tumor and well-differentiated liposarcoma are distinguished from each other by location: The World Health Organization recommends the term atypical lipomatous tumor for tumors that arise in the extremities and trunk lesions and well-differentiated liposarcoma for neoplasms that develop in the retroperitoneum, peritoneum, mediastinum, spermatic cord, and thoracic cavity.⁸ On PET, hypermetabolic activity is nonspecific and can be seen in malignant tumors and some benign reactive processes, such as evolving heterotopic ossification. However, simple lipomas, including those with mature ossification or dystrophic calcification, do not manifest increased FDG avidity.⁹

We are not aware of any published cases of extraosseous osteosarcoma arising within a conventional lipoma. A limited number of cases of coexisting conventional lipoma and spindle-cell lipoma or liposarcoma have been reported.^10-13 Retroperitoneal liposarcoma with areas of dedifferentiation into osteosarcoma has also been described.¹⁴ Development of malignant fibrous histiocytoma and liposarcoma have also been reported within intraosseous lipomas.¹⁵ One theory is based on premalignancy as a biological concept as opposed to a morphologic one. In other words, lesions that may be considered morphologically benign may already have the biological phenotype for malignancy that is not yet reflected morphologically.¹⁶ However, it has been suggested that such findings may instead result from initial sampling error or histologic misdiagnosis.^17,18There is a spectrum of findings on imaging studies of extraosseous osteosarcoma. Plain radiographs show a soft-tissue density with variable degrees of central calcification that reflects mineralization of deposited neoplastic bone. The pattern of calcification is characteristically amorphous or cloudlike, as opposed to the ring-and-arc observed in cartilage matrix. On CT, the soft-tissue mass of extraosseous osteosarcoma is separate from the underlying bone and periosteum—a defining characteristic that distinguishes it from conventional intramedullary and juxtacortical osteosarcoma.⁶ The central pattern of amorphous calcification helps to differentiate extraosseous osteosarcoma from heterotopic ossification, which characteristically demonstrates zonation, with trabecular architecture and mature cortical bone peripherally.¹ Enhancement of extraskeletal osteosarcoma tends to be heterogeneous and depends on the quantity of necrosis. Extraskeletal osteosarcoma tends to be isointense on T1-weighted MRI and mildly hyperintense on T2-weighted MRI.^1,6 Areas of very low signal intensity on both T1- and T2-weighted MRI may reflect mineralization.¹⁹ If intratumoral hemorrhage has occurred, there may be signal intensity of blood products of various ages.^1,3 Tumors with abundant hemorrhage can be mistaken for hematoma. FDG-PET radiotracer accumulation tends to be intense peripherally with variable central activity depending on quantity of necrosis and hemorrhage.¹The radiologic differential diagnosis includes myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component, and malignant mesenchymoma. Other common soft-tissue sarcomas, such as fibrosarcoma, leiomyosarcoma, and pleomorphic undifferentiated sarcoma, are excluded by the presence of fat within the tumor. The radiographic pattern of osteoid matrix produced by the tumor in our patient may be seen in heterotopic ossification, but the absence of mature ossification with zonation was evidence against heterotopic ossification, and microscopically it was neoplastic rather than reactive osteoid. In addition, it is possible that, because of the small size of the soft-tissue component, it was difficult to appreciate the less mature osteoid matrix peripherally. The lack of characteristic rings and arcs helps exclude benign and malignant cartilage containing neoplasms. Malignant mesenchymoma is a diagnosis of exclusion, and such tumors are usually better classified as sarcomas that have undergone heterologous differentiation.

The histologic diagnosis of extraosseous osteosarcoma requires identification of malignant mesenchymal cells that secrete neoplastic osteoid that may or may not mineralize. It is important to exclude the possibility that the malignant bone-forming tumor is part of a different type of sarcoma, the most common being dedifferentiated liposarcoma. Immunohistochemistry can be helpful in this situation, as dedifferentiated liposarcomas demonstrate nuclear expression of MDM2, CDK4, and p16, a constellation of findings rare in conventional and extraosseous osteosarcoma.^20-23 Osteosarcoma has not previously been reported as arising in a lipoma; in our patient’s case, we excluded the possibility that the fatty component represented an underlying atypical lipomatous tumor/well-differentiated or dedifferentiated liposarcoma on the basis of morphology and lack of expression of MDM2, CDK4, and p16.

Although histologically identical to osteosarcoma of bone, extraosseous osteosarcoma is treated differently because of its relatively decreased chemosensitivity and radiosensitivity. Treatment tends to be focused on limb-sparing wide local excision, and local recurrence complicates about 50% of cases.¹ Neoadjuvant or adjuvant treatment with radiation or chemotherapy is often provided.⁶ Platinum and doxorubicin chemotherapeutic agents, which are first-line treatments for osteosarcoma of bone, tend to be less effective in extraosseous osteosarcoma, and ifosfamide is more often used instead.⁵

Primary extraosseous osteosarcoma classically has a poor prognosis, with 2- to 3-year mortality of 50%, and prognosis tends to be worse for secondary radiation-induced sarcomas than for primary sarcomas.^2,6 However, with there being improved treatment protocols involving surgery and chemoradiation, more recent 5-year survival rates without metastatic disease are between 60% and 80%, though there is no definite consensus regarding the optimal systemic therapy regimen.^1,24 In a 2014 review of 53 patients who presented with localized disease, Choi and colleagues²⁵ identified a 3-year cumulative 39% incidence of death caused by disease, and in 2016 Sio and colleagues²⁶ reported that 55% of patients, most of whom had stage 3 disease, were alive at median follow-up of 45 months. Similar to osteosarcoma of bone, metastases may develop up to 10 years after primary treatment and are most commonly to the lung (80%-88%). Because extraosseous osteosarcoma is rare, no definite prognostic factors have been determined, but metastases at presentation and large tumor size (>5 cm) likely portend a worse prognosis.^2,3,27 Fibroblastic and chondroblastic subtypes may have a slightly better prognosis.^6,28

Conclusion

Extraosseous osteosarcoma is a rare malignancy that should be considered in the appropriate clinical and imaging scenario. This article is the first report of a case of a radiation-associated extraosseous osteosarcoma that developed within a lipoma with preoperative and postoperative multimodality imaging.

Am J Orthop. 2017;46(3):E200-E206. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Rare and histologically indistinguishable from osteosarcoma of bone.
• Most common presentation is an enlarging mass in the thigh or buttock.
• Secondary extraosseous osteosarcoma usually arises in the field of prior external beam radiation or brachytherapy.
• Radiographic pattern of mineralization is central amorphous or cloudlike.
• On cross sectional imaging, the soft-tissue mass is separate from the underlying bone and periosteum.

Aside from multiple myeloma, osteosarcoma is the most common primary malignancy of bone, but extraosseous osteosarcoma is rare and accounts for only 1% of soft-tissue sarcomas and only 4% of all osteosarcomas.^1-3 Benign mesenchymal tumors, such as lipomas, are common, and they are estimated to outnumber their malignant counterparts by more than a factor of 100. However, the true ratio is unknown, as many clinically benign lipomas are not biopsied.⁴ Conventional lipoma is the most common lipoma and is biologically indolent. Conventional lipoma generally does not transform biologically into a more aggressive type of neoplasm—unlike atypical lipomatous tumors, which may demonstrate this type of evolution with multiple local recurrences.

This article is the first report of a case of radiation-associated extraosseous osteosarcoma that developed within a benign conventional lipoma. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In March 2013, a 72-year-old woman presented to a general surgeon with a right thigh mass of several weeks’ duration. The patient, who had a remote history of thyroid carcinoma, underwent thyroidectomy in 1991, excision of melanoma of the chest in 1998, and resection and adjuvant external beam radiotherapy (30 fractions) for Merkel cell carcinoma of the right proximal lateral leg (malignancy images unavailable) at an outside institution in 2003. Regional lymph node dissection at the time was negative. The patient remained disease-free the next 10 years. On presentation, magnetic resonance imaging (MRI) showed a 2.2-cm mass encircled by a tumor of lipomatous tissue within the vastus intermedius muscle, adjacent to but separate from the right distal femur (Figures 1A-1C).

Physical examination revealed marked ecchymosis of the left groin at the access site for embolization as well as massive ecchymosis and swelling along the right distal thigh, medial knee, and medial lower leg. The neurovascular structures were intact with full motor function and sensation distally, as well as normal distal pulses. No inguinal adenopathy was identified. The proximal portion of the prior radiation tattoo was at the inferior extent of the lesion on MRI.

The patient was treated with doxorubicin and ifosfamide (2 cycles) while waiting for the hematoma to shrink. Contrast-enhanced MRI showed a 2.2-cm enhancing mass with isointense T1 signal and heterogeneously hyperintense STIR (short tau inversion recovery) signal surrounded by a circumscribed nonenhancing lipomatous tumor within the vastus intermedius muscle, adjacent to the distal femoral cortex. There was no invasion of the bone, and a fat plane between the enhancing mass and the femoral cortex was identified (Figures 2A-2E).

Discussion

Extraosseous osteosarcoma, typically a high-grade malignant neoplasm of the soft tissues that produces osteoid or cartilaginous matrix, is histologically indistinguishable from osteosarcoma of bone.

Conventional lipoma, the most common subtype of lipoma, is a benign mesenchymal tumor. Other subtypes are hibernoma, fibrolipoma, angiolipoma, myelolipoma, spindle-cell lipoma, pleomorphic lipoma, and atypical lipomatous tumor.⁷ Atypical lipomatous tumor and well-differentiated liposarcoma are distinguished from each other by location: The World Health Organization recommends the term atypical lipomatous tumor for tumors that arise in the extremities and trunk lesions and well-differentiated liposarcoma for neoplasms that develop in the retroperitoneum, peritoneum, mediastinum, spermatic cord, and thoracic cavity.⁸ On PET, hypermetabolic activity is nonspecific and can be seen in malignant tumors and some benign reactive processes, such as evolving heterotopic ossification. However, simple lipomas, including those with mature ossification or dystrophic calcification, do not manifest increased FDG avidity.⁹

We are not aware of any published cases of extraosseous osteosarcoma arising within a conventional lipoma. A limited number of cases of coexisting conventional lipoma and spindle-cell lipoma or liposarcoma have been reported.^10-13 Retroperitoneal liposarcoma with areas of dedifferentiation into osteosarcoma has also been described.¹⁴ Development of malignant fibrous histiocytoma and liposarcoma have also been reported within intraosseous lipomas.¹⁵ One theory is based on premalignancy as a biological concept as opposed to a morphologic one. In other words, lesions that may be considered morphologically benign may already have the biological phenotype for malignancy that is not yet reflected morphologically.¹⁶ However, it has been suggested that such findings may instead result from initial sampling error or histologic misdiagnosis.^17,18There is a spectrum of findings on imaging studies of extraosseous osteosarcoma. Plain radiographs show a soft-tissue density with variable degrees of central calcification that reflects mineralization of deposited neoplastic bone. The pattern of calcification is characteristically amorphous or cloudlike, as opposed to the ring-and-arc observed in cartilage matrix. On CT, the soft-tissue mass of extraosseous osteosarcoma is separate from the underlying bone and periosteum—a defining characteristic that distinguishes it from conventional intramedullary and juxtacortical osteosarcoma.⁶ The central pattern of amorphous calcification helps to differentiate extraosseous osteosarcoma from heterotopic ossification, which characteristically demonstrates zonation, with trabecular architecture and mature cortical bone peripherally.¹ Enhancement of extraskeletal osteosarcoma tends to be heterogeneous and depends on the quantity of necrosis. Extraskeletal osteosarcoma tends to be isointense on T1-weighted MRI and mildly hyperintense on T2-weighted MRI.^1,6 Areas of very low signal intensity on both T1- and T2-weighted MRI may reflect mineralization.¹⁹ If intratumoral hemorrhage has occurred, there may be signal intensity of blood products of various ages.^1,3 Tumors with abundant hemorrhage can be mistaken for hematoma. FDG-PET radiotracer accumulation tends to be intense peripherally with variable central activity depending on quantity of necrosis and hemorrhage.¹The radiologic differential diagnosis includes myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component, and malignant mesenchymoma. Other common soft-tissue sarcomas, such as fibrosarcoma, leiomyosarcoma, and pleomorphic undifferentiated sarcoma, are excluded by the presence of fat within the tumor. The radiographic pattern of osteoid matrix produced by the tumor in our patient may be seen in heterotopic ossification, but the absence of mature ossification with zonation was evidence against heterotopic ossification, and microscopically it was neoplastic rather than reactive osteoid. In addition, it is possible that, because of the small size of the soft-tissue component, it was difficult to appreciate the less mature osteoid matrix peripherally. The lack of characteristic rings and arcs helps exclude benign and malignant cartilage containing neoplasms. Malignant mesenchymoma is a diagnosis of exclusion, and such tumors are usually better classified as sarcomas that have undergone heterologous differentiation.

The histologic diagnosis of extraosseous osteosarcoma requires identification of malignant mesenchymal cells that secrete neoplastic osteoid that may or may not mineralize. It is important to exclude the possibility that the malignant bone-forming tumor is part of a different type of sarcoma, the most common being dedifferentiated liposarcoma. Immunohistochemistry can be helpful in this situation, as dedifferentiated liposarcomas demonstrate nuclear expression of MDM2, CDK4, and p16, a constellation of findings rare in conventional and extraosseous osteosarcoma.^20-23 Osteosarcoma has not previously been reported as arising in a lipoma; in our patient’s case, we excluded the possibility that the fatty component represented an underlying atypical lipomatous tumor/well-differentiated or dedifferentiated liposarcoma on the basis of morphology and lack of expression of MDM2, CDK4, and p16.

Although histologically identical to osteosarcoma of bone, extraosseous osteosarcoma is treated differently because of its relatively decreased chemosensitivity and radiosensitivity. Treatment tends to be focused on limb-sparing wide local excision, and local recurrence complicates about 50% of cases.¹ Neoadjuvant or adjuvant treatment with radiation or chemotherapy is often provided.⁶ Platinum and doxorubicin chemotherapeutic agents, which are first-line treatments for osteosarcoma of bone, tend to be less effective in extraosseous osteosarcoma, and ifosfamide is more often used instead.⁵

Primary extraosseous osteosarcoma classically has a poor prognosis, with 2- to 3-year mortality of 50%, and prognosis tends to be worse for secondary radiation-induced sarcomas than for primary sarcomas.^2,6 However, with there being improved treatment protocols involving surgery and chemoradiation, more recent 5-year survival rates without metastatic disease are between 60% and 80%, though there is no definite consensus regarding the optimal systemic therapy regimen.^1,24 In a 2014 review of 53 patients who presented with localized disease, Choi and colleagues²⁵ identified a 3-year cumulative 39% incidence of death caused by disease, and in 2016 Sio and colleagues²⁶ reported that 55% of patients, most of whom had stage 3 disease, were alive at median follow-up of 45 months. Similar to osteosarcoma of bone, metastases may develop up to 10 years after primary treatment and are most commonly to the lung (80%-88%). Because extraosseous osteosarcoma is rare, no definite prognostic factors have been determined, but metastases at presentation and large tumor size (>5 cm) likely portend a worse prognosis.^2,3,27 Fibroblastic and chondroblastic subtypes may have a slightly better prognosis.^6,28

Conclusion

Extraosseous osteosarcoma is a rare malignancy that should be considered in the appropriate clinical and imaging scenario. This article is the first report of a case of a radiation-associated extraosseous osteosarcoma that developed within a lipoma with preoperative and postoperative multimodality imaging.

Am J Orthop. 2017;46(3):E200-E206. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Rare and histologically indistinguishable from osteosarcoma of bone.
• Most common presentation is an enlarging mass in the thigh or buttock.
• Secondary extraosseous osteosarcoma usually arises in the field of prior external beam radiation or brachytherapy.
• Radiographic pattern of mineralization is central amorphous or cloudlike.
• On cross sectional imaging, the soft-tissue mass is separate from the underlying bone and periosteum.

Aside from multiple myeloma, osteosarcoma is the most common primary malignancy of bone, but extraosseous osteosarcoma is rare and accounts for only 1% of soft-tissue sarcomas and only 4% of all osteosarcomas.^1-3 Benign mesenchymal tumors, such as lipomas, are common, and they are estimated to outnumber their malignant counterparts by more than a factor of 100. However, the true ratio is unknown, as many clinically benign lipomas are not biopsied.⁴ Conventional lipoma is the most common lipoma and is biologically indolent. Conventional lipoma generally does not transform biologically into a more aggressive type of neoplasm—unlike atypical lipomatous tumors, which may demonstrate this type of evolution with multiple local recurrences.

This article is the first report of a case of radiation-associated extraosseous osteosarcoma that developed within a benign conventional lipoma. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In March 2013, a 72-year-old woman presented to a general surgeon with a right thigh mass of several weeks’ duration. The patient, who had a remote history of thyroid carcinoma, underwent thyroidectomy in 1991, excision of melanoma of the chest in 1998, and resection and adjuvant external beam radiotherapy (30 fractions) for Merkel cell carcinoma of the right proximal lateral leg (malignancy images unavailable) at an outside institution in 2003. Regional lymph node dissection at the time was negative. The patient remained disease-free the next 10 years. On presentation, magnetic resonance imaging (MRI) showed a 2.2-cm mass encircled by a tumor of lipomatous tissue within the vastus intermedius muscle, adjacent to but separate from the right distal femur (Figures 1A-1C).

Physical examination revealed marked ecchymosis of the left groin at the access site for embolization as well as massive ecchymosis and swelling along the right distal thigh, medial knee, and medial lower leg. The neurovascular structures were intact with full motor function and sensation distally, as well as normal distal pulses. No inguinal adenopathy was identified. The proximal portion of the prior radiation tattoo was at the inferior extent of the lesion on MRI.

The patient was treated with doxorubicin and ifosfamide (2 cycles) while waiting for the hematoma to shrink. Contrast-enhanced MRI showed a 2.2-cm enhancing mass with isointense T1 signal and heterogeneously hyperintense STIR (short tau inversion recovery) signal surrounded by a circumscribed nonenhancing lipomatous tumor within the vastus intermedius muscle, adjacent to the distal femoral cortex. There was no invasion of the bone, and a fat plane between the enhancing mass and the femoral cortex was identified (Figures 2A-2E).

Discussion

Extraosseous osteosarcoma, typically a high-grade malignant neoplasm of the soft tissues that produces osteoid or cartilaginous matrix, is histologically indistinguishable from osteosarcoma of bone.

Conventional lipoma, the most common subtype of lipoma, is a benign mesenchymal tumor. Other subtypes are hibernoma, fibrolipoma, angiolipoma, myelolipoma, spindle-cell lipoma, pleomorphic lipoma, and atypical lipomatous tumor.⁷ Atypical lipomatous tumor and well-differentiated liposarcoma are distinguished from each other by location: The World Health Organization recommends the term atypical lipomatous tumor for tumors that arise in the extremities and trunk lesions and well-differentiated liposarcoma for neoplasms that develop in the retroperitoneum, peritoneum, mediastinum, spermatic cord, and thoracic cavity.⁸ On PET, hypermetabolic activity is nonspecific and can be seen in malignant tumors and some benign reactive processes, such as evolving heterotopic ossification. However, simple lipomas, including those with mature ossification or dystrophic calcification, do not manifest increased FDG avidity.⁹

We are not aware of any published cases of extraosseous osteosarcoma arising within a conventional lipoma. A limited number of cases of coexisting conventional lipoma and spindle-cell lipoma or liposarcoma have been reported.^10-13 Retroperitoneal liposarcoma with areas of dedifferentiation into osteosarcoma has also been described.¹⁴ Development of malignant fibrous histiocytoma and liposarcoma have also been reported within intraosseous lipomas.¹⁵ One theory is based on premalignancy as a biological concept as opposed to a morphologic one. In other words, lesions that may be considered morphologically benign may already have the biological phenotype for malignancy that is not yet reflected morphologically.¹⁶ However, it has been suggested that such findings may instead result from initial sampling error or histologic misdiagnosis.^17,18There is a spectrum of findings on imaging studies of extraosseous osteosarcoma. Plain radiographs show a soft-tissue density with variable degrees of central calcification that reflects mineralization of deposited neoplastic bone. The pattern of calcification is characteristically amorphous or cloudlike, as opposed to the ring-and-arc observed in cartilage matrix. On CT, the soft-tissue mass of extraosseous osteosarcoma is separate from the underlying bone and periosteum—a defining characteristic that distinguishes it from conventional intramedullary and juxtacortical osteosarcoma.⁶ The central pattern of amorphous calcification helps to differentiate extraosseous osteosarcoma from heterotopic ossification, which characteristically demonstrates zonation, with trabecular architecture and mature cortical bone peripherally.¹ Enhancement of extraskeletal osteosarcoma tends to be heterogeneous and depends on the quantity of necrosis. Extraskeletal osteosarcoma tends to be isointense on T1-weighted MRI and mildly hyperintense on T2-weighted MRI.^1,6 Areas of very low signal intensity on both T1- and T2-weighted MRI may reflect mineralization.¹⁹ If intratumoral hemorrhage has occurred, there may be signal intensity of blood products of various ages.^1,3 Tumors with abundant hemorrhage can be mistaken for hematoma. FDG-PET radiotracer accumulation tends to be intense peripherally with variable central activity depending on quantity of necrosis and hemorrhage.¹The radiologic differential diagnosis includes myositis ossificans, chondrosseous lipoma, parosteal lipoma (ossifying variant), liposarcoma with metaplastic bone, dedifferentiated liposarcoma with osteosarcoma or chondrosarcoma component, and malignant mesenchymoma. Other common soft-tissue sarcomas, such as fibrosarcoma, leiomyosarcoma, and pleomorphic undifferentiated sarcoma, are excluded by the presence of fat within the tumor. The radiographic pattern of osteoid matrix produced by the tumor in our patient may be seen in heterotopic ossification, but the absence of mature ossification with zonation was evidence against heterotopic ossification, and microscopically it was neoplastic rather than reactive osteoid. In addition, it is possible that, because of the small size of the soft-tissue component, it was difficult to appreciate the less mature osteoid matrix peripherally. The lack of characteristic rings and arcs helps exclude benign and malignant cartilage containing neoplasms. Malignant mesenchymoma is a diagnosis of exclusion, and such tumors are usually better classified as sarcomas that have undergone heterologous differentiation.

The histologic diagnosis of extraosseous osteosarcoma requires identification of malignant mesenchymal cells that secrete neoplastic osteoid that may or may not mineralize. It is important to exclude the possibility that the malignant bone-forming tumor is part of a different type of sarcoma, the most common being dedifferentiated liposarcoma. Immunohistochemistry can be helpful in this situation, as dedifferentiated liposarcomas demonstrate nuclear expression of MDM2, CDK4, and p16, a constellation of findings rare in conventional and extraosseous osteosarcoma.^20-23 Osteosarcoma has not previously been reported as arising in a lipoma; in our patient’s case, we excluded the possibility that the fatty component represented an underlying atypical lipomatous tumor/well-differentiated or dedifferentiated liposarcoma on the basis of morphology and lack of expression of MDM2, CDK4, and p16.

Although histologically identical to osteosarcoma of bone, extraosseous osteosarcoma is treated differently because of its relatively decreased chemosensitivity and radiosensitivity. Treatment tends to be focused on limb-sparing wide local excision, and local recurrence complicates about 50% of cases.¹ Neoadjuvant or adjuvant treatment with radiation or chemotherapy is often provided.⁶ Platinum and doxorubicin chemotherapeutic agents, which are first-line treatments for osteosarcoma of bone, tend to be less effective in extraosseous osteosarcoma, and ifosfamide is more often used instead.⁵

Primary extraosseous osteosarcoma classically has a poor prognosis, with 2- to 3-year mortality of 50%, and prognosis tends to be worse for secondary radiation-induced sarcomas than for primary sarcomas.^2,6 However, with there being improved treatment protocols involving surgery and chemoradiation, more recent 5-year survival rates without metastatic disease are between 60% and 80%, though there is no definite consensus regarding the optimal systemic therapy regimen.^1,24 In a 2014 review of 53 patients who presented with localized disease, Choi and colleagues²⁵ identified a 3-year cumulative 39% incidence of death caused by disease, and in 2016 Sio and colleagues²⁶ reported that 55% of patients, most of whom had stage 3 disease, were alive at median follow-up of 45 months. Similar to osteosarcoma of bone, metastases may develop up to 10 years after primary treatment and are most commonly to the lung (80%-88%). Because extraosseous osteosarcoma is rare, no definite prognostic factors have been determined, but metastases at presentation and large tumor size (>5 cm) likely portend a worse prognosis.^2,3,27 Fibroblastic and chondroblastic subtypes may have a slightly better prognosis.^6,28

Conclusion

Extraosseous osteosarcoma is a rare malignancy that should be considered in the appropriate clinical and imaging scenario. This article is the first report of a case of a radiation-associated extraosseous osteosarcoma that developed within a lipoma with preoperative and postoperative multimodality imaging.

Am J Orthop. 2017;46(3):E200-E206. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.¹ Numerous etiologies have been described, but the disease commonly remains idiopathic.^2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.^4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.

Case Report

A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).

Comment

Established therapies for LCV carry serious side-effect profiles, which can preclude their use.⁵ Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.⁵ Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.^5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.^5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.⁷ It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.^8,9 A case of methemoglobinemia due to topical dapsone has been reported.¹⁰ Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.

Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.

Conclusion

Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.

Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.¹ Numerous etiologies have been described, but the disease commonly remains idiopathic.^2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.^4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.

Case Report

A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).

Comment

Established therapies for LCV carry serious side-effect profiles, which can preclude their use.⁵ Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.⁵ Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.^5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.^5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.⁷ It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.^8,9 A case of methemoglobinemia due to topical dapsone has been reported.¹⁰ Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.

Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.

Conclusion

Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.

Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.¹ Numerous etiologies have been described, but the disease commonly remains idiopathic.^2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.^4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.

Case Report

A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).

Comment

Established therapies for LCV carry serious side-effect profiles, which can preclude their use.⁵ Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.⁵ Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.^5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.^5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.⁷ It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.^8,9 A case of methemoglobinemia due to topical dapsone has been reported.¹⁰ Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.

Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.

Conclusion

Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.

Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.

Case Report

A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.

The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.

The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.

Comment

Classification and Clinical Presentation
The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.^1,2

Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.³ IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.^3,4

Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.^5-8

Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.^5,8

Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.⁶ Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.^4,6,8

Histopathology
Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.^4,6

Differential
The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.

Management
The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.⁴ The blockade of IL-1β results in complete resolution of symptoms.

In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.^2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.^2,7

The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.⁴ In one study, most patients did not report injection-site reactions.⁷ Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.^2,7

MWS and BCNS
Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.⁹

Conclusion

Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.

Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.

Case Report

A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.

The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.

The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.

Comment

Classification and Clinical Presentation
The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.^1,2

Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.³ IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.^3,4

Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.^5-8

Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.^5,8

Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.⁶ Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.^4,6,8

Histopathology
Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.^4,6

Differential
The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.

Management
The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.⁴ The blockade of IL-1β results in complete resolution of symptoms.

In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.^2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.^2,7

The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.⁴ In one study, most patients did not report injection-site reactions.⁷ Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.^2,7

MWS and BCNS
Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.⁹

Conclusion

Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.

Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.

Case Report

A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.

The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.

The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.

Comment

Classification and Clinical Presentation
The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.^1,2

Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.³ IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.^3,4

Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.^5-8

Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.^5,8

Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.⁶ Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.^4,6,8

Histopathology
Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.^4,6

Differential
The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.

Management
The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.⁴ The blockade of IL-1β results in complete resolution of symptoms.

In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.^2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.^2,7

The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.⁴ In one study, most patients did not report injection-site reactions.⁷ Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.^2,7

MWS and BCNS
Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.⁹

Conclusion

Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.

Case

A 29-year-old man presented to the ED with a 3-day history of constant left-sided low back pain that radiated to his left buttock and groin. The patient stated the pain worsened with movement, making it difficult for him to walk. He reported lifting heavy boxes at work, but denied any trauma. The patient also denied recent fevers, chills, chest pain, dyspnea, abdominal pain, urinary or fecal incontinence, weakness, numbness, or saddle anesthesia. Regarding his medical history, he had an appendectomy as a child, but reported no other surgeries or medical issues. His social history was significant for narcotic and inhalant use and daily tobacco use. The patient also reported taking heroin intravenously (IV) 6 months prior.

Vital signs at presentation were: heart rate (HR), 92 beats/min; respiratory rate, 15 breaths/min; blood pressure, 118/80 mm Hg; and temperature, 98.2°F. Oxygen saturation was 98% on room air.

The patient was a well-developed young man in no apparent distress. Dermatological examination showed bilateral track marks in the antecubital fossa. The musculoskeletal (MSK) examination demonstrated left gluteal tenderness to palpation and decreased active and passive range of motion of the left hip, especially with internal rotation and flexion. He had no midline tenderness, and the lower extremities had normal pulses and no motor or sensory deficits.

The patient’s pain improved with IV fluids, diazepam, and ketorolac, and he was able to ambulate with assistance. He was clinically diagnosed with sciatica, and discharged home with prescriptions for diazepam and ibuprofen. He was also instructed to follow-up with an orthopedist within 7 days from discharge.

The patient returned to the ED the following day with similar complaints of unabating left-sided pain and difficulty ambulating. His vital signs were notable for an elevated HR of 106 beats/min. Physical examination findings were unchanged from his presentation the previous day, and an X-ray of the lumbar spine showed no abnormalities.

After receiving IV analgesics, the patient’s pain improved and his tachycardia resolved. He was discharged home with instructions to continue taking diazepam, and was also given prescriptions for prednisone and oxycodone/acetaminophen. He was instructed to follow-up with an orthopedist within 24 hours.

Over the next 9 days, the patient was seen twice by an orthopedist, who ordered imaging of the lumbar spine, including a repeat X-ray and contrast-enhanced magnetic resonance imaging (MRI), both of which were unremarkable. The patient completed the prescribed course of diclofenac, oxycodone/acetaminophen, and prednisone, but experienced only minimal pain relief. The orthopedist prescribed the diclofenac to supplement the medication regimen that he was already on.

At the second follow-up visit, the orthopedist ordered an MRI of the patient’s left hip, which demonstrated inflammation of the left sacroiliac joint (SIJ) with effusion, and a 1-cm by 1-cm collection adjacent to the left psoas muscle; these findings were concerning for septic arthritis (Figure). Based on the MRI study, a computed tomography (CT)-guided arthrocentesis of the left SIJ was performed by an interventional radiologist.

Discussion

Infectious sacroiliitis (ISI) is a rare form of infectious arthritis affecting the SIJ, with an incidence of 1 to 2 reported cases per year.¹ The literature on ISI currently consists only of case reports and case series. This infection is often diagnosed after the disease has progressed, with a mean time to diagnosis of 43.3 days.²

Infectious arthritis of any joint has a prevalence of 2 to 10 per 100,000 people. In 50% of cases, the knee is the joint most commonly affected, followed by the hip, shoulder, and elbow.³ Regardless of location, infectious arthritis is associated with significant morbidity and mortality due to sepsis and irreversible loss of joint function.⁴

Risk factors for ISI include IV drug use, pregnancy, trauma, endocarditis, and immunosuppression.¹ The decision to initiate the workup for ISI can be difficult to make because the condition may present without signs of an infectious etiology, such as toxic appearance, inflammatory changes surrounding the joint, or even fever—only 41% of affected patients in one case series were febrile.² The workup is often time-consuming, invasive, and expensive.

Although delayed diagnosis and treatment of septic arthritis is associated with significant adverse effects, there is unfortunately no consensus to guide the workup for ISI. As opposed to Kocher’s criteria for the differentiation of septic hip arthritis from transient synovitis in pediatric patients or well-known red-flags for further evaluation of low back pain, physicians are left without much guidance when considering laboratory workup or imaging decisions to evaluate for ISI.

Sacroiliac Joint

As previously noted, the SIJ is not commonly affected by infection. It is a diarthrodial, L-shaped joint comprised of the posterior ilium and sacrum, and is a near-rigid structure with very limited movement that provides stability to the axial skeleton.⁵ The SIJ is often overlooked as a secondary cause of low back pain in younger patients with rheumatologic conditions (eg, ankylosing spondylitis, Reiter syndrome), pregnancy-associated ligamentous laxity, and osteoarthritis in elderly patients. In one study, 88.2% of sacroiliitis cases were inflammatory, 8.8% infectious, and 2.9% degenerative.⁶

Signs and Symptoms

As our case illustrates, ISI often presents with nonspecific symptoms and physical findings.⁷ Patients typically present with fever, painful manipulation of the SIJ, and unilateral lumbo-gluteal pain.² The components of the history and physical examination suspicious for an infectious etiology include the subacute presentation; unresolved pain despite treatment; tenderness to palpation; decreased range of motion; and recent IV drug use, which increases the risk of infectious disease due to unsterile practices and direct inoculation of pathogens into the bloodstream⁸ and a further predilection into the axial skeleton. ⁹ It is important to obtain an accurate social history; however, patients may not be forthright about disclosing sensitive information such as sexual history and illicit drug use.

Physical Assessment

The SIJ is best appreciated in the seated patient by palpating one fingerbreadth medial to the posterior superior iliac spine as he or she slowly bends forward.¹⁰ Tenderness elicited while in this position is suggestive of SIJ inflammation. The area of tenderness may be lower than anticipated and lateral to the gluteal cleft, as synovial fluid is typically relegated to the lower half of the joint.

Several adjunctive physical examination maneuvers, such as the Gaenslen test and Flexion Abduction External Rotation test (FABER test or Patrick’s test) can isolate SIJ pathology or dysfunction. The Gaenslen test is performed by asking the patient to lie supine and flex the affected hip and knee, with the lumbar spine flat against the examination table. Hyperextending the contralateral thigh downward will reproduce pain in the affected SIJ.

The FABER test is a simple but less specific examination technique to assess joint pain in the hip, lumbar, and sacroiliac joints.¹¹ In this assessment, the clinician flexes the patient’s affected knee to 90°, externally rotates the hip, and applies downward pressure on the knee. Pain reproduced in the affected SI region is sensitive for joint inflammation.

Laboratory and Imaging Studies

Laboratory studies typically show inconsistent and nonspecific findings, such as the elevated ESR and CRP levels seen in our patient.^2,12 Imaging studies to assess the SIJ for signs of infection are therefore essential for confirming infection.

Magnetic resonance imaging is the preferred imaging modality to assess for ISI, since it has the highest sensitivity in visualizing joint effusion and bone marrow edema compared to other modalities. Computed tomography, however, can be helpful in visualizing associated abscesses and guiding arthrocentesis.¹² Plain X-ray may not demonstrate early changes in bone.¹³ The confirmatory study for ISI is synovial fluid analysis and culture.⁷

Treatment

Infectious sacroiliitis secondary to P aeruginosa, a gram-negative bacillus, is difficult to treat because of the glycocalyx and slime production that protects the pathogen from antibiotics, the development of multiple-antimicrobial resistance, and poor drug penetration into bones and abscesses.¹⁴ Antibiotic treatment should cover Staphylococcus aureus and may be broadened to cover gram-negative bacilli. The recommended duration of treatment is at least a 2-week course of IV antibiotics, followed by a 6-week course of oral antibiotics.² Therapy also includes pain control and surgical intervention for abscesses, osteomyelitis, and refractory cases.⁷

Complications

Complications and long-term sequelae are common in ISI, often due to late diagnosis of the condition. Our case illustrates the delayed diagnosis of Pseudomonas ISI with candidemia in a young man with a history of IV drug use presenting with atraumatic low back pain. His clinical course was complicated by a thromboembolic event, likely secondary to immobility and a hypercoagulable state from infection and inflammation.¹⁵ Infectious sacroiliitis secondary to P aeruginosa is most commonly seen in patients with immunosuppression, hospitalization, and IV drug use.²

Summary

Infectious sacroiliitis remains a diagnostic challenge for physicians due to its rare incidence and nonspecific clinical manifestations. Our case illustrates the importance of maintaining a high level of clinical suspicion for infectious arthritis in young patients presenting with common MSK complaints in the presence of infectious risk factors. Emergency physicians should consider red flags, abnormal vital signs, and patient recidivism when deciding on the most appropriate workup.

Case

A 29-year-old man presented to the ED with a 3-day history of constant left-sided low back pain that radiated to his left buttock and groin. The patient stated the pain worsened with movement, making it difficult for him to walk. He reported lifting heavy boxes at work, but denied any trauma. The patient also denied recent fevers, chills, chest pain, dyspnea, abdominal pain, urinary or fecal incontinence, weakness, numbness, or saddle anesthesia. Regarding his medical history, he had an appendectomy as a child, but reported no other surgeries or medical issues. His social history was significant for narcotic and inhalant use and daily tobacco use. The patient also reported taking heroin intravenously (IV) 6 months prior.

Vital signs at presentation were: heart rate (HR), 92 beats/min; respiratory rate, 15 breaths/min; blood pressure, 118/80 mm Hg; and temperature, 98.2°F. Oxygen saturation was 98% on room air.

The patient was a well-developed young man in no apparent distress. Dermatological examination showed bilateral track marks in the antecubital fossa. The musculoskeletal (MSK) examination demonstrated left gluteal tenderness to palpation and decreased active and passive range of motion of the left hip, especially with internal rotation and flexion. He had no midline tenderness, and the lower extremities had normal pulses and no motor or sensory deficits.

The patient’s pain improved with IV fluids, diazepam, and ketorolac, and he was able to ambulate with assistance. He was clinically diagnosed with sciatica, and discharged home with prescriptions for diazepam and ibuprofen. He was also instructed to follow-up with an orthopedist within 7 days from discharge.

The patient returned to the ED the following day with similar complaints of unabating left-sided pain and difficulty ambulating. His vital signs were notable for an elevated HR of 106 beats/min. Physical examination findings were unchanged from his presentation the previous day, and an X-ray of the lumbar spine showed no abnormalities.

After receiving IV analgesics, the patient’s pain improved and his tachycardia resolved. He was discharged home with instructions to continue taking diazepam, and was also given prescriptions for prednisone and oxycodone/acetaminophen. He was instructed to follow-up with an orthopedist within 24 hours.

Over the next 9 days, the patient was seen twice by an orthopedist, who ordered imaging of the lumbar spine, including a repeat X-ray and contrast-enhanced magnetic resonance imaging (MRI), both of which were unremarkable. The patient completed the prescribed course of diclofenac, oxycodone/acetaminophen, and prednisone, but experienced only minimal pain relief. The orthopedist prescribed the diclofenac to supplement the medication regimen that he was already on.

At the second follow-up visit, the orthopedist ordered an MRI of the patient’s left hip, which demonstrated inflammation of the left sacroiliac joint (SIJ) with effusion, and a 1-cm by 1-cm collection adjacent to the left psoas muscle; these findings were concerning for septic arthritis (Figure). Based on the MRI study, a computed tomography (CT)-guided arthrocentesis of the left SIJ was performed by an interventional radiologist.

Discussion

Infectious sacroiliitis (ISI) is a rare form of infectious arthritis affecting the SIJ, with an incidence of 1 to 2 reported cases per year.¹ The literature on ISI currently consists only of case reports and case series. This infection is often diagnosed after the disease has progressed, with a mean time to diagnosis of 43.3 days.²

Infectious arthritis of any joint has a prevalence of 2 to 10 per 100,000 people. In 50% of cases, the knee is the joint most commonly affected, followed by the hip, shoulder, and elbow.³ Regardless of location, infectious arthritis is associated with significant morbidity and mortality due to sepsis and irreversible loss of joint function.⁴

Risk factors for ISI include IV drug use, pregnancy, trauma, endocarditis, and immunosuppression.¹ The decision to initiate the workup for ISI can be difficult to make because the condition may present without signs of an infectious etiology, such as toxic appearance, inflammatory changes surrounding the joint, or even fever—only 41% of affected patients in one case series were febrile.² The workup is often time-consuming, invasive, and expensive.

Although delayed diagnosis and treatment of septic arthritis is associated with significant adverse effects, there is unfortunately no consensus to guide the workup for ISI. As opposed to Kocher’s criteria for the differentiation of septic hip arthritis from transient synovitis in pediatric patients or well-known red-flags for further evaluation of low back pain, physicians are left without much guidance when considering laboratory workup or imaging decisions to evaluate for ISI.

Sacroiliac Joint

As previously noted, the SIJ is not commonly affected by infection. It is a diarthrodial, L-shaped joint comprised of the posterior ilium and sacrum, and is a near-rigid structure with very limited movement that provides stability to the axial skeleton.⁵ The SIJ is often overlooked as a secondary cause of low back pain in younger patients with rheumatologic conditions (eg, ankylosing spondylitis, Reiter syndrome), pregnancy-associated ligamentous laxity, and osteoarthritis in elderly patients. In one study, 88.2% of sacroiliitis cases were inflammatory, 8.8% infectious, and 2.9% degenerative.⁶

Signs and Symptoms

As our case illustrates, ISI often presents with nonspecific symptoms and physical findings.⁷ Patients typically present with fever, painful manipulation of the SIJ, and unilateral lumbo-gluteal pain.² The components of the history and physical examination suspicious for an infectious etiology include the subacute presentation; unresolved pain despite treatment; tenderness to palpation; decreased range of motion; and recent IV drug use, which increases the risk of infectious disease due to unsterile practices and direct inoculation of pathogens into the bloodstream⁸ and a further predilection into the axial skeleton. ⁹ It is important to obtain an accurate social history; however, patients may not be forthright about disclosing sensitive information such as sexual history and illicit drug use.

Physical Assessment

The SIJ is best appreciated in the seated patient by palpating one fingerbreadth medial to the posterior superior iliac spine as he or she slowly bends forward.¹⁰ Tenderness elicited while in this position is suggestive of SIJ inflammation. The area of tenderness may be lower than anticipated and lateral to the gluteal cleft, as synovial fluid is typically relegated to the lower half of the joint.

Several adjunctive physical examination maneuvers, such as the Gaenslen test and Flexion Abduction External Rotation test (FABER test or Patrick’s test) can isolate SIJ pathology or dysfunction. The Gaenslen test is performed by asking the patient to lie supine and flex the affected hip and knee, with the lumbar spine flat against the examination table. Hyperextending the contralateral thigh downward will reproduce pain in the affected SIJ.

The FABER test is a simple but less specific examination technique to assess joint pain in the hip, lumbar, and sacroiliac joints.¹¹ In this assessment, the clinician flexes the patient’s affected knee to 90°, externally rotates the hip, and applies downward pressure on the knee. Pain reproduced in the affected SI region is sensitive for joint inflammation.

Laboratory and Imaging Studies

Laboratory studies typically show inconsistent and nonspecific findings, such as the elevated ESR and CRP levels seen in our patient.^2,12 Imaging studies to assess the SIJ for signs of infection are therefore essential for confirming infection.

Magnetic resonance imaging is the preferred imaging modality to assess for ISI, since it has the highest sensitivity in visualizing joint effusion and bone marrow edema compared to other modalities. Computed tomography, however, can be helpful in visualizing associated abscesses and guiding arthrocentesis.¹² Plain X-ray may not demonstrate early changes in bone.¹³ The confirmatory study for ISI is synovial fluid analysis and culture.⁷

Treatment

Infectious sacroiliitis secondary to P aeruginosa, a gram-negative bacillus, is difficult to treat because of the glycocalyx and slime production that protects the pathogen from antibiotics, the development of multiple-antimicrobial resistance, and poor drug penetration into bones and abscesses.¹⁴ Antibiotic treatment should cover Staphylococcus aureus and may be broadened to cover gram-negative bacilli. The recommended duration of treatment is at least a 2-week course of IV antibiotics, followed by a 6-week course of oral antibiotics.² Therapy also includes pain control and surgical intervention for abscesses, osteomyelitis, and refractory cases.⁷

Complications

Complications and long-term sequelae are common in ISI, often due to late diagnosis of the condition. Our case illustrates the delayed diagnosis of Pseudomonas ISI with candidemia in a young man with a history of IV drug use presenting with atraumatic low back pain. His clinical course was complicated by a thromboembolic event, likely secondary to immobility and a hypercoagulable state from infection and inflammation.¹⁵ Infectious sacroiliitis secondary to P aeruginosa is most commonly seen in patients with immunosuppression, hospitalization, and IV drug use.²

Summary

Infectious sacroiliitis remains a diagnostic challenge for physicians due to its rare incidence and nonspecific clinical manifestations. Our case illustrates the importance of maintaining a high level of clinical suspicion for infectious arthritis in young patients presenting with common MSK complaints in the presence of infectious risk factors. Emergency physicians should consider red flags, abnormal vital signs, and patient recidivism when deciding on the most appropriate workup.

Case

A 29-year-old man presented to the ED with a 3-day history of constant left-sided low back pain that radiated to his left buttock and groin. The patient stated the pain worsened with movement, making it difficult for him to walk. He reported lifting heavy boxes at work, but denied any trauma. The patient also denied recent fevers, chills, chest pain, dyspnea, abdominal pain, urinary or fecal incontinence, weakness, numbness, or saddle anesthesia. Regarding his medical history, he had an appendectomy as a child, but reported no other surgeries or medical issues. His social history was significant for narcotic and inhalant use and daily tobacco use. The patient also reported taking heroin intravenously (IV) 6 months prior.

Vital signs at presentation were: heart rate (HR), 92 beats/min; respiratory rate, 15 breaths/min; blood pressure, 118/80 mm Hg; and temperature, 98.2°F. Oxygen saturation was 98% on room air.

The patient was a well-developed young man in no apparent distress. Dermatological examination showed bilateral track marks in the antecubital fossa. The musculoskeletal (MSK) examination demonstrated left gluteal tenderness to palpation and decreased active and passive range of motion of the left hip, especially with internal rotation and flexion. He had no midline tenderness, and the lower extremities had normal pulses and no motor or sensory deficits.

The patient’s pain improved with IV fluids, diazepam, and ketorolac, and he was able to ambulate with assistance. He was clinically diagnosed with sciatica, and discharged home with prescriptions for diazepam and ibuprofen. He was also instructed to follow-up with an orthopedist within 7 days from discharge.

The patient returned to the ED the following day with similar complaints of unabating left-sided pain and difficulty ambulating. His vital signs were notable for an elevated HR of 106 beats/min. Physical examination findings were unchanged from his presentation the previous day, and an X-ray of the lumbar spine showed no abnormalities.

After receiving IV analgesics, the patient’s pain improved and his tachycardia resolved. He was discharged home with instructions to continue taking diazepam, and was also given prescriptions for prednisone and oxycodone/acetaminophen. He was instructed to follow-up with an orthopedist within 24 hours.

Over the next 9 days, the patient was seen twice by an orthopedist, who ordered imaging of the lumbar spine, including a repeat X-ray and contrast-enhanced magnetic resonance imaging (MRI), both of which were unremarkable. The patient completed the prescribed course of diclofenac, oxycodone/acetaminophen, and prednisone, but experienced only minimal pain relief. The orthopedist prescribed the diclofenac to supplement the medication regimen that he was already on.

At the second follow-up visit, the orthopedist ordered an MRI of the patient’s left hip, which demonstrated inflammation of the left sacroiliac joint (SIJ) with effusion, and a 1-cm by 1-cm collection adjacent to the left psoas muscle; these findings were concerning for septic arthritis (Figure). Based on the MRI study, a computed tomography (CT)-guided arthrocentesis of the left SIJ was performed by an interventional radiologist.

Discussion

Infectious sacroiliitis (ISI) is a rare form of infectious arthritis affecting the SIJ, with an incidence of 1 to 2 reported cases per year.¹ The literature on ISI currently consists only of case reports and case series. This infection is often diagnosed after the disease has progressed, with a mean time to diagnosis of 43.3 days.²

Infectious arthritis of any joint has a prevalence of 2 to 10 per 100,000 people. In 50% of cases, the knee is the joint most commonly affected, followed by the hip, shoulder, and elbow.³ Regardless of location, infectious arthritis is associated with significant morbidity and mortality due to sepsis and irreversible loss of joint function.⁴

Risk factors for ISI include IV drug use, pregnancy, trauma, endocarditis, and immunosuppression.¹ The decision to initiate the workup for ISI can be difficult to make because the condition may present without signs of an infectious etiology, such as toxic appearance, inflammatory changes surrounding the joint, or even fever—only 41% of affected patients in one case series were febrile.² The workup is often time-consuming, invasive, and expensive.

Although delayed diagnosis and treatment of septic arthritis is associated with significant adverse effects, there is unfortunately no consensus to guide the workup for ISI. As opposed to Kocher’s criteria for the differentiation of septic hip arthritis from transient synovitis in pediatric patients or well-known red-flags for further evaluation of low back pain, physicians are left without much guidance when considering laboratory workup or imaging decisions to evaluate for ISI.

Sacroiliac Joint

As previously noted, the SIJ is not commonly affected by infection. It is a diarthrodial, L-shaped joint comprised of the posterior ilium and sacrum, and is a near-rigid structure with very limited movement that provides stability to the axial skeleton.⁵ The SIJ is often overlooked as a secondary cause of low back pain in younger patients with rheumatologic conditions (eg, ankylosing spondylitis, Reiter syndrome), pregnancy-associated ligamentous laxity, and osteoarthritis in elderly patients. In one study, 88.2% of sacroiliitis cases were inflammatory, 8.8% infectious, and 2.9% degenerative.⁶

Signs and Symptoms

As our case illustrates, ISI often presents with nonspecific symptoms and physical findings.⁷ Patients typically present with fever, painful manipulation of the SIJ, and unilateral lumbo-gluteal pain.² The components of the history and physical examination suspicious for an infectious etiology include the subacute presentation; unresolved pain despite treatment; tenderness to palpation; decreased range of motion; and recent IV drug use, which increases the risk of infectious disease due to unsterile practices and direct inoculation of pathogens into the bloodstream⁸ and a further predilection into the axial skeleton. ⁹ It is important to obtain an accurate social history; however, patients may not be forthright about disclosing sensitive information such as sexual history and illicit drug use.

Physical Assessment

The SIJ is best appreciated in the seated patient by palpating one fingerbreadth medial to the posterior superior iliac spine as he or she slowly bends forward.¹⁰ Tenderness elicited while in this position is suggestive of SIJ inflammation. The area of tenderness may be lower than anticipated and lateral to the gluteal cleft, as synovial fluid is typically relegated to the lower half of the joint.

Several adjunctive physical examination maneuvers, such as the Gaenslen test and Flexion Abduction External Rotation test (FABER test or Patrick’s test) can isolate SIJ pathology or dysfunction. The Gaenslen test is performed by asking the patient to lie supine and flex the affected hip and knee, with the lumbar spine flat against the examination table. Hyperextending the contralateral thigh downward will reproduce pain in the affected SIJ.

The FABER test is a simple but less specific examination technique to assess joint pain in the hip, lumbar, and sacroiliac joints.¹¹ In this assessment, the clinician flexes the patient’s affected knee to 90°, externally rotates the hip, and applies downward pressure on the knee. Pain reproduced in the affected SI region is sensitive for joint inflammation.

Laboratory and Imaging Studies

Laboratory studies typically show inconsistent and nonspecific findings, such as the elevated ESR and CRP levels seen in our patient.^2,12 Imaging studies to assess the SIJ for signs of infection are therefore essential for confirming infection.

Magnetic resonance imaging is the preferred imaging modality to assess for ISI, since it has the highest sensitivity in visualizing joint effusion and bone marrow edema compared to other modalities. Computed tomography, however, can be helpful in visualizing associated abscesses and guiding arthrocentesis.¹² Plain X-ray may not demonstrate early changes in bone.¹³ The confirmatory study for ISI is synovial fluid analysis and culture.⁷

Treatment

Infectious sacroiliitis secondary to P aeruginosa, a gram-negative bacillus, is difficult to treat because of the glycocalyx and slime production that protects the pathogen from antibiotics, the development of multiple-antimicrobial resistance, and poor drug penetration into bones and abscesses.¹⁴ Antibiotic treatment should cover Staphylococcus aureus and may be broadened to cover gram-negative bacilli. The recommended duration of treatment is at least a 2-week course of IV antibiotics, followed by a 6-week course of oral antibiotics.² Therapy also includes pain control and surgical intervention for abscesses, osteomyelitis, and refractory cases.⁷

Complications

Complications and long-term sequelae are common in ISI, often due to late diagnosis of the condition. Our case illustrates the delayed diagnosis of Pseudomonas ISI with candidemia in a young man with a history of IV drug use presenting with atraumatic low back pain. His clinical course was complicated by a thromboembolic event, likely secondary to immobility and a hypercoagulable state from infection and inflammation.¹⁵ Infectious sacroiliitis secondary to P aeruginosa is most commonly seen in patients with immunosuppression, hospitalization, and IV drug use.²

Summary

Infectious sacroiliitis remains a diagnostic challenge for physicians due to its rare incidence and nonspecific clinical manifestations. Our case illustrates the importance of maintaining a high level of clinical suspicion for infectious arthritis in young patients presenting with common MSK complaints in the presence of infectious risk factors. Emergency physicians should consider red flags, abnormal vital signs, and patient recidivism when deciding on the most appropriate workup.

A 20-year-old woman with no significant medical history presented to the ED with a several-month history of worsening abdominal pain. She reported that although she previously had been evaluated at multiple EDs, no cause of her abdominal pain had been identified. The patient further noted that the pain had significantly increased the day of this presentation.

Physical examination revealed guarding and rebound tenderness in the midabdomen. Computed tomography (CT) studies of the abdomen and pelvis were performed; representative scout and axial images of the upper abdomen are shown above (Figures 1 and 2).

What is the suspected diagnosis?

Answer

The scout image of the abdomen revealed a distended stomach (white arrows, Figure 3), which displaced multiple loops of small bowel into the lower abdomen. The axial image through the upper abdomen showed air and solid material within the distended stomach (white arrows, Figure 4). Multiple foci of extraluminal (free) air were seen anteriorly (white asterisks, Figure 4). A coronal reformat of the CT better demonstrated the distended stomach filled with debris (white arrows, Figure 5), extraluminal air (white asterisk, Figure 5), and pneumatosis (air within the walls of multiple small bowel loops; red arrows, Figure 5).

These findings indicated a bowel obstruction and perforation due to the presence of a gastric bezoar. Upon further questioning, the patient admitted to a stress-related habit of eating her own hair (trichophagia) over the past 3 to 4 months.

Bezoars

Gastric bezoars are aggregates of nondigestible material that collect within the gastrointestinal system, usually fruit/vegetable matter (phytobezoars) or hair (trichobezoars). Phytobezoars are most common in patients with a history of reduced gastric motility and/or prior gastric surgery. Trichobezoars, similar to the one seen in this case, typically occur in young women and/or patients with psychiatric illness.¹

Gastric bezoars are typically located in the gastric body but may extend into the small bowel and cause bowel obstruction. Trichobezoars that extend into the small bowel are referred to as “Rapunzel syndrome” (based on the fairy tale of the princess with long hair).

Clinical Presentation

Patients with gastric bezoars often present to the ED with nonspecific complaints of abdominal pain, including early satiety, weight loss, signs of anemia, abdominal pain, bloating, and symptoms of small bowel obstruction (SBO).² Obtaining a thorough history is important to identify trichophagia, as only a small percentage of patients have evidence of alopecia on examination.

Workup

The workup for patients with gastric bezoars typically involves multiple imaging modalities. While abdominal radiography may demonstrate distention of the stomach, these findings are often nonspecific, and the characteristic feature of a mass with a diffusely mottled appearance is visualized in less than 20% of cases.

Computed tomography is the test of choice for detecting a bezoar, with a reported sensitivity of 97%.³ This modality is also useful for assessing the size of a bezoar and evaluating for complications such as SBO, perforation (free-air), or pneumatosis—all of which were revealed on this patient’s CT studies.

Treatment

The treatment for patients with large or obstructing gastric bezoars is surgical resection; both open and laparoscopic techniques have been described in the literature.^2,4 The patient in this case was admitted to the hospital, where she underwent surgical removal of the bezoar. She was discharged home on hospital day 6 with outpatient psychiatric follow-up.

A 20-year-old woman with no significant medical history presented to the ED with a several-month history of worsening abdominal pain. She reported that although she previously had been evaluated at multiple EDs, no cause of her abdominal pain had been identified. The patient further noted that the pain had significantly increased the day of this presentation.

Physical examination revealed guarding and rebound tenderness in the midabdomen. Computed tomography (CT) studies of the abdomen and pelvis were performed; representative scout and axial images of the upper abdomen are shown above (Figures 1 and 2).

What is the suspected diagnosis?

Answer

The scout image of the abdomen revealed a distended stomach (white arrows, Figure 3), which displaced multiple loops of small bowel into the lower abdomen. The axial image through the upper abdomen showed air and solid material within the distended stomach (white arrows, Figure 4). Multiple foci of extraluminal (free) air were seen anteriorly (white asterisks, Figure 4). A coronal reformat of the CT better demonstrated the distended stomach filled with debris (white arrows, Figure 5), extraluminal air (white asterisk, Figure 5), and pneumatosis (air within the walls of multiple small bowel loops; red arrows, Figure 5).

These findings indicated a bowel obstruction and perforation due to the presence of a gastric bezoar. Upon further questioning, the patient admitted to a stress-related habit of eating her own hair (trichophagia) over the past 3 to 4 months.

Bezoars

Gastric bezoars are aggregates of nondigestible material that collect within the gastrointestinal system, usually fruit/vegetable matter (phytobezoars) or hair (trichobezoars). Phytobezoars are most common in patients with a history of reduced gastric motility and/or prior gastric surgery. Trichobezoars, similar to the one seen in this case, typically occur in young women and/or patients with psychiatric illness.¹

Gastric bezoars are typically located in the gastric body but may extend into the small bowel and cause bowel obstruction. Trichobezoars that extend into the small bowel are referred to as “Rapunzel syndrome” (based on the fairy tale of the princess with long hair).

Clinical Presentation

Patients with gastric bezoars often present to the ED with nonspecific complaints of abdominal pain, including early satiety, weight loss, signs of anemia, abdominal pain, bloating, and symptoms of small bowel obstruction (SBO).² Obtaining a thorough history is important to identify trichophagia, as only a small percentage of patients have evidence of alopecia on examination.

Workup

The workup for patients with gastric bezoars typically involves multiple imaging modalities. While abdominal radiography may demonstrate distention of the stomach, these findings are often nonspecific, and the characteristic feature of a mass with a diffusely mottled appearance is visualized in less than 20% of cases.

Computed tomography is the test of choice for detecting a bezoar, with a reported sensitivity of 97%.³ This modality is also useful for assessing the size of a bezoar and evaluating for complications such as SBO, perforation (free-air), or pneumatosis—all of which were revealed on this patient’s CT studies.

Treatment

The treatment for patients with large or obstructing gastric bezoars is surgical resection; both open and laparoscopic techniques have been described in the literature.^2,4 The patient in this case was admitted to the hospital, where she underwent surgical removal of the bezoar. She was discharged home on hospital day 6 with outpatient psychiatric follow-up.

A 20-year-old woman with no significant medical history presented to the ED with a several-month history of worsening abdominal pain. She reported that although she previously had been evaluated at multiple EDs, no cause of her abdominal pain had been identified. The patient further noted that the pain had significantly increased the day of this presentation.

Physical examination revealed guarding and rebound tenderness in the midabdomen. Computed tomography (CT) studies of the abdomen and pelvis were performed; representative scout and axial images of the upper abdomen are shown above (Figures 1 and 2).

What is the suspected diagnosis?

Answer

The scout image of the abdomen revealed a distended stomach (white arrows, Figure 3), which displaced multiple loops of small bowel into the lower abdomen. The axial image through the upper abdomen showed air and solid material within the distended stomach (white arrows, Figure 4). Multiple foci of extraluminal (free) air were seen anteriorly (white asterisks, Figure 4). A coronal reformat of the CT better demonstrated the distended stomach filled with debris (white arrows, Figure 5), extraluminal air (white asterisk, Figure 5), and pneumatosis (air within the walls of multiple small bowel loops; red arrows, Figure 5).

These findings indicated a bowel obstruction and perforation due to the presence of a gastric bezoar. Upon further questioning, the patient admitted to a stress-related habit of eating her own hair (trichophagia) over the past 3 to 4 months.

Bezoars

Gastric bezoars are aggregates of nondigestible material that collect within the gastrointestinal system, usually fruit/vegetable matter (phytobezoars) or hair (trichobezoars). Phytobezoars are most common in patients with a history of reduced gastric motility and/or prior gastric surgery. Trichobezoars, similar to the one seen in this case, typically occur in young women and/or patients with psychiatric illness.¹

Gastric bezoars are typically located in the gastric body but may extend into the small bowel and cause bowel obstruction. Trichobezoars that extend into the small bowel are referred to as “Rapunzel syndrome” (based on the fairy tale of the princess with long hair).

Clinical Presentation

Patients with gastric bezoars often present to the ED with nonspecific complaints of abdominal pain, including early satiety, weight loss, signs of anemia, abdominal pain, bloating, and symptoms of small bowel obstruction (SBO).² Obtaining a thorough history is important to identify trichophagia, as only a small percentage of patients have evidence of alopecia on examination.

Workup

The workup for patients with gastric bezoars typically involves multiple imaging modalities. While abdominal radiography may demonstrate distention of the stomach, these findings are often nonspecific, and the characteristic feature of a mass with a diffusely mottled appearance is visualized in less than 20% of cases.

Computed tomography is the test of choice for detecting a bezoar, with a reported sensitivity of 97%.³ This modality is also useful for assessing the size of a bezoar and evaluating for complications such as SBO, perforation (free-air), or pneumatosis—all of which were revealed on this patient’s CT studies.

Treatment

The treatment for patients with large or obstructing gastric bezoars is surgical resection; both open and laparoscopic techniques have been described in the literature.^2,4 The patient in this case was admitted to the hospital, where she underwent surgical removal of the bezoar. She was discharged home on hospital day 6 with outpatient psychiatric follow-up.

THE CASE

A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.

A urine culture initially grew Klebsiella pneumoniae, which we successfully treated with ciprofloxacin. A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.

We started the patient on oral duloxetine 30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.

At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.

DISCUSSION

UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.^1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.⁴ And those costs are expected to increase 25% by 2020, mainly because of the aging population.

Risk factors for UI other than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.^5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.^7,8

Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.

Risk factors for women include hysterectomy,⁷ increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.⁶ Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.⁵

Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.⁹

Types and treatment of UI

There are 5 types of UI: urge, stress, overflow, functional, and mixed.¹⁰

• Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
• Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
• Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
• Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
• Mixed incontinence is when symptoms of stress and urgency incontinence are present.

There are 3 broad categories of treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).¹¹ Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.¹² Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.¹³

A novel treatment for neurogenic UI?

Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.

The role of duloxetine. Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment, is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.

As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.¹⁴ Thus, the concentrations of 5-HT and norepinephrine increase in the synaptic cleft.

Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.

Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI¹⁵ and mixed UI.¹⁶ Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome¹⁷ and in women with multiple sclerosis and depression.¹⁸ However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.

THE TAKEAWAY

Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.

Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.

Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.

ACKNOWLEDGEMENTS
The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.

THE CASE

A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.

A urine culture initially grew Klebsiella pneumoniae, which we successfully treated with ciprofloxacin. A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.

We started the patient on oral duloxetine 30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.

At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.

DISCUSSION

UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.^1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.⁴ And those costs are expected to increase 25% by 2020, mainly because of the aging population.

Risk factors for UI other than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.^5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.^7,8

Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.

Risk factors for women include hysterectomy,⁷ increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.⁶ Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.⁵

Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.⁹

Types and treatment of UI

There are 5 types of UI: urge, stress, overflow, functional, and mixed.¹⁰

• Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
• Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
• Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
• Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
• Mixed incontinence is when symptoms of stress and urgency incontinence are present.

There are 3 broad categories of treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).¹¹ Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.¹² Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.¹³

A novel treatment for neurogenic UI?

Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.

The role of duloxetine. Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment, is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.

As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.¹⁴ Thus, the concentrations of 5-HT and norepinephrine increase in the synaptic cleft.

Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.

Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI¹⁵ and mixed UI.¹⁶ Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome¹⁷ and in women with multiple sclerosis and depression.¹⁸ However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.

THE TAKEAWAY

Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.

Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.

Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.

ACKNOWLEDGEMENTS
The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.

THE CASE

A 57-year-old African American woman was being treated at our clinic for neurogenic urinary incontinence (UI). The UI, which occurred day and night, began 2 years earlier following a laminectomy of vertebrae C3 to C6 with spinal fusion of C3 to C7 for cervical spinal stenosis. The UI persisted despite physical therapy and trials of oxybutynin and imipramine. Since the surgery, the patient had also been experiencing chronic (debilitating) neuropathic pain in both legs, and the sensation of incomplete bladder emptying. She denied bowel incontinence or saddle anesthesia. Her prescription medications included hydrocodone-acetaminophen 7.5/325 mg every 6 hours as needed for pain and lisinopril 20 mg/d for essential hypertension. The patient’s body mass index (BMI) was 23.3.

A urine culture initially grew Klebsiella pneumoniae, which we successfully treated with ciprofloxacin. A urinalysis was unremarkable, and blood urea nitrogen and creatinine levels were within normal limits.

We started the patient on oral duloxetine 30 mg/d for her neuropathic pain. The patient hadn’t undergone a urologic evaluation before starting duloxetine, so no urodynamic studies or measurements had been conducted. At that point, we sent the patient to a urologist for an evaluation.

At a follow-up visit with one of our clinic providers <3 months later, the patient reported that the duloxetine was providing her with some pain relief and that she was “waking up dry” in the mornings and having fewer UI symptoms throughout the day, as well as at night. The patient denied any adverse effects such as nausea, gastrointestinal upset, weight changes, xerostomia, fatigue, insomnia, headaches, or dizziness. Duloxetine was titrated up to 60 mg/d for better control of her neuropathic pain. At the next follow-up visit at our clinic 3 months later, her UI was 80% to 90% improved and she was able to stop her opioid pain medications.

DISCUSSION

UI is a significant problem in the United States and around the world. For women, the prevalence of UI ranges from 15% to 69%; among men, the prevalence is 5% to 24%.^1-3 The economic burden of UI includes both medical and nonmedical (eg, pads, diapers, laundry, and dry cleaning) care. The total national cost was estimated at $66 billion in 2007: $49 billion for direct medical costs, $2 billion for direct nonmedical costs, and $15 billion for indirect costs.⁴ And those costs are expected to increase 25% by 2020, mainly because of the aging population.

Risk factors for UI other than gender include advancing age, obesity, non-Hispanic white race, depression, hypertension, type 2 diabetes mellitus, neurologic disease, and functional limitations/general poor health.^5-7 Comorbid depression and BMI >30, as well as the presence and duration of diabetes, increase the odds for developing UI.^7,8

Duloxetine has been shown to be effective for the treatment of stress and mixed urinary incontinence. This case suggests it may be useful for neurogenic urinary incontinence, as well.

Risk factors for women include hysterectomy,⁷ increasing parity, and delivery of at least one infant >9.5 pounds; the risk is the same for both vaginal and cesarean-section delivery.⁶ Specific risk factors for men include prostate cancer, prostate surgery, and prostate radiation.⁵

Significant, chronic comorbidities of UI include depression and chronic pain. While quality of life is negatively affected by UI alone, the coexistence of depression and UI produces an additive negative effect on quality of life.⁹

Types and treatment of UI

There are 5 types of UI: urge, stress, overflow, functional, and mixed.¹⁰

• Urge incontinence is the leakage of urine following a sensation of sudden urgency to void.
• Stress incontinence is urine leakage associated with increased intra-abdominal pressure such as with coughing or sneezing and is typically associated with weakened pelvic floor musculature.
• Overflow incontinence is more common in men, and is typically caused by prostatic disease. The urethral outlet is obstructed leading to increased pressure within the bladder and subsequent leakage of urine.
• Functional incontinence is caused by physical or cognitive impairment leading to a decreased ability to get to a bathroom quickly enough to void.
• Mixed incontinence is when symptoms of stress and urgency incontinence are present.

There are 3 broad categories of treatment methods for urinary incontinence: behavioral, pharmacologic, and surgical. Behavioral interventions are subdivided into caregiver-dependent (prompted voiding, habit retraining, and timed voiding) and patient-directed (bladder training, pelvic floor muscle training, strategies for bladder control, education, and self-monitoring) techniques. Pharmacologic treatment typically consists of antimuscarinics (eg, oxybutynin, tolterodine, solifenacin) and tricyclic antidepressants (eg, imipramine).¹¹ Injections of onabotulinumtoxinA into the detrusor muscle have also been shown to reduce the symptoms of urinary incontinence.¹² Surgical options for treatment of UI include retro-pubic suspension, slings, and, in some instances, artificial urethral sphincters.¹³

A novel treatment for neurogenic UI?

Despite the many treatments available for UI, none comprehensively addresses UI and its common comorbidities.

The role of duloxetine. Normal micturition is regulated by the somatic nervous system and an autonomic reflex arc; the neurotransmitters serotonin and norepinephrine play an important role in the neural regulation of micturition and urinary continence. Duloxetine, alone or as an adjunctive treatment, is a potential novel therapy that treats 2 common comorbidities of UI—chronic pain and depression.

As a selective serotonin norepinephrine reuptake inhibitor (SNRI), duloxetine acts at the molecular level to block the reuptake of serotonin and norepinephrine from synaptic clefts. Specifically, the medication blocks the 5-hydroxytryptamine (5-HT) reuptake transporters, as well as the norepinephrine transporters, of pre-synaptic neurons.¹⁴ Thus, the concentrations of 5-HT and norepinephrine increase in the synaptic cleft.

Functionally, the accumulation of norepinephrine inhibits micturition by relaxing the detrusor muscle and constricting the urethral smooth muscle. In addition, a higher concentration of 5-HT at the neuromuscular junction leads to constriction of the external urethral sphincter.

Duloxetine has been shown to be effective in the treatment of other types of UI, such as stress UI¹⁵ and mixed UI.¹⁶ Additionally, it was found to be effective when compared with placebo in women with overactive bladder syndrome¹⁷ and in women with multiple sclerosis and depression.¹⁸ However, we are not aware of any cases using duloxetine for the treatment of neurogenic UI.

THE TAKEAWAY

Duloxetine is a potential novel drug choice for the treatment of neurogenic UI. Its effects on serotonin and norepinephrine at the synaptic cleft and neuromuscular junction could provide relief for those who have not found relief from other therapies. Further research—particularly a prospective, randomized controlled trial—is needed to determine if duloxetine is, in fact, more than just a theoretical candidate to treat UI and, if so, the most effective dosing.

Offering duloxetine for the treatment of neurogenic urinary incontinence would potentially address coexisting conditions, such as pain or depression.

Offering duloxetine for the treatment of neurogenic UI would potentially address coexisting conditions—such as pain or depression—thus improving patient compliance and reducing health care spending. Before beginning therapy, urodynamic studies to identify the type of UI should be completed, or, at a minimum, post-void residual volume should be measured.

ACKNOWLEDGEMENTS
The authors would like to thank Julie Hughbanks, MLS, Library Manager, Parkview Health Resource Library, for her assistance with the library searches used for this case report.