Case Reports

The 2008 World Health Organization and European Organization for Treatment of Cancer joint classification has distinguished 3 categories of primary cutaneous B-cell lymphomas: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous diffuse large B-cell lymphoma, and primary cutaneous marginal zone lymphoma.^1-3 Primary cutaneous follicle center lymphoma is the most common type of cutaneous B-cell lymphoma, accounting for approximately 60% of cases worldwide.⁴ The median age at diagnosis is 60 years, and most lesions are located on the scalp, forehead, neck, and trunk.⁵ Histologically, PCFCL is characterized by dermal proliferation of centrocytes and centroblasts derived from germinal center B cells that are arranged in either a follicular, diffuse, or mixed growth pattern.¹ The cutaneous manifestations of PCFCL include solitary erythematous or violaceous plaques, nodules, or tumors of varying sizes.⁴ Grouped lesions also may be observed, but multifocal disease is rare.¹ We report a rare presentation of PCFCL mimicking folliculitis with multiple multifocal papules on the back.

Case Report

A 54-year-old woman presented with fever and leukocytosis of 4 days’ duration and was admitted to the hospital for presumed sepsis. She had a history of mastectomy for treatment of ductal carcinoma in situ of the right breast 5 years prior to the current presentation and endocrine therapy with tamoxifen. Her symptoms were thought to be a complication from a surgery for implantation of a tissue expander in the right breast 5 years prior to presentation.

During her hospital admission, she developed a papular and cystic eruption on the back that was clinically suggestive of folliculitis, transient acantholytic dermatosis (Grover disease), or miliaria rubra (Figure 1). This papular and cystic eruption initially was managed conservatively with observation as she recovered from an occult infection. Due to the persistent nature of the eruption on the back, an excisional biopsy of the cystic component was performed 2 months after her discharge from the hospital. Histologic studies showed a dense infiltrate of lymphocytes, which expanded into the deep dermis in a nodular and diffuse growth pattern that was accentuated in the periadnexal areas. The B lymphocytes were small and hyperchromatic with few scattered centroblasts (Figure 2). Further immunohistochemical studies demonstrated that the neoplastic cells were positive for CD20, CD79a, BCL-2, and BCL-6; CD3, CD5, and cyclin D1 were negative. Staining for antigen Ki-67 revealed a proliferation index of 15% to 20% among the neoplastic cells (Figure 3). These findings were consistent with either PCFCL or secondary cutaneous follicle center lymphoma.

Further evaluation for systemic disease was unremarkable. Positron emission tomography–computed tomography revealed no evidence of nodal lymphoma, and a bone marrow biopsy was negative. Other laboratory studies including lactate dehydrogenase were within reference range, which conferred a diagnosis of PCFCL. The patient was treated with localized electron beam radiation therapy to the skin of the mid back for a total dose of 24 Gy in 12 fractions at 2 Gy per fraction once daily over a 12-day period. She tolerated the treatment well and has remained clinically and radiographically without evidence of disease for more than 3 years.

Comment

Because the incidence of cutaneous B-cell lymphomas has been increasing, especially among males, non-Hispanic whites, and adults older than 50 years,¹ it is important for clinicians to have a high index of suspicion for this entity. In our patient, the clinical findings of a papular, largely asymptomatic eruption on the back with acute onset were initially thought to be consistent with folliculitis; the differential diagnosis included transient acantholytic dermatosis and miliaria rubra. Lymphoma was not in the initial clinical differential, and we only arrived at this diagnosis based on histopathologic evaluation.

The neoplastic cells typically are positive for CD20, CD79a, and BCL-6, and negative for BCL-2.⁴ Most cases of PCFCL do not express the t(14;18) translocation involving the BCL-2 locus, in contrast to systemic follicular lymphoma.¹ Systemic imaging and evaluation is needed to definitively differentiate PCFCL from systemic lymphoma with cutaneous involvement. Our patient was unusual in that BCL-2 was strongly staining in the setting of a negative systemic workup.

With regard to treatment of PCFCL, electron beam radiation therapy is highly effective and safe in patients with solitary lesions, as the remission rate is close to 100%.¹ For patients with multiple lesions confined to one area, electron beam radiation therapy also can be helpful, as in our patient. In patients with more extensive skin involvement, rituximab therapy may be preferable. Relapse following treatment with either radiation or rituximab occurs in approximately one-third of patients, but these relapses generally are limited to the skin.¹ The International Extranodal Lymphoma Study Group has noted that elevated lactate dehydrogenase, presence of more than 2 skin lesions, and presence of nodular lesions are negative prognostic factors in patients with PCFCL⁶; however, PCFCL has an excellent prognosis overall with a 5-year survival rate of 95%.¹

Other rare heterogeneous presentations of PCFCL have been reported in the literature. A large multinodular mass on the scalp with multifocal facial lesions has been described in a patient with essential thrombocytopenia.⁷ Another report identified a variant of PCFCL characterized by multiple erythematous firm papules that were distributed in a miliary pattern, predominantly on the forehead and cheeks.⁸ Barzilai et al⁹ described 4 patients with PCFCL who developed lesions that were clinically similar to rosacea or rhinophyma, including papulonodular eruptions on the cheeks; infiltrated erythematous nasal plaques; and small flesh-colored to erythematous papules on the cheeks, nose, helices, and upper back. Hodak et al¹⁰ identified 2 cases of PCFCL that manifested as anetoderma, a condition characterized by the focal loss of elastic tissue. In the setting of chronic lymphocytic leukemia, PCFCL has been observed as a red or violaceous nodule with a centrally depressed scar on the legs.¹¹ In one case, PCFCL manifested as recurrent episodes of extraorbital swelling and a multifocal red-blue macular lesion that extended from the inferior orbital rim to the nasojugal fold.¹² An interesting presentation of PCFCL was noted as a small, recurring, blood-filled blister on the cheek with perineural spread of the tumor along cranial nerves V2, V3, VII, and VIII.¹³ In the pediatric literature, PCFCL has been reported to present as an erythematous nodule with a smooth surface and a hard elastic consistency that appeared on the nose and nasolabial fold and spread to the ipsilateral cheek, maxillary sinus, and soft palate.¹⁴ In many of these unusual cases, the diagnosis of PCFCL was made after treatment with topical or systemic anti-inflammatory therapies failed.

Increased recognition of anomalous presentations of PCFCL among dermatologists can lead to more timely diagnoses and treatment. Based on our experience with this patient, we recommend considering biopsy for histopathologic evaluation when treating patients with presumed folliculitis or transient acantholytic dermatosis that does not improve with routine treatment or is accompanied by systemic symptoms.

The 2008 World Health Organization and European Organization for Treatment of Cancer joint classification has distinguished 3 categories of primary cutaneous B-cell lymphomas: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous diffuse large B-cell lymphoma, and primary cutaneous marginal zone lymphoma.^1-3 Primary cutaneous follicle center lymphoma is the most common type of cutaneous B-cell lymphoma, accounting for approximately 60% of cases worldwide.⁴ The median age at diagnosis is 60 years, and most lesions are located on the scalp, forehead, neck, and trunk.⁵ Histologically, PCFCL is characterized by dermal proliferation of centrocytes and centroblasts derived from germinal center B cells that are arranged in either a follicular, diffuse, or mixed growth pattern.¹ The cutaneous manifestations of PCFCL include solitary erythematous or violaceous plaques, nodules, or tumors of varying sizes.⁴ Grouped lesions also may be observed, but multifocal disease is rare.¹ We report a rare presentation of PCFCL mimicking folliculitis with multiple multifocal papules on the back.

Case Report

A 54-year-old woman presented with fever and leukocytosis of 4 days’ duration and was admitted to the hospital for presumed sepsis. She had a history of mastectomy for treatment of ductal carcinoma in situ of the right breast 5 years prior to the current presentation and endocrine therapy with tamoxifen. Her symptoms were thought to be a complication from a surgery for implantation of a tissue expander in the right breast 5 years prior to presentation.

During her hospital admission, she developed a papular and cystic eruption on the back that was clinically suggestive of folliculitis, transient acantholytic dermatosis (Grover disease), or miliaria rubra (Figure 1). This papular and cystic eruption initially was managed conservatively with observation as she recovered from an occult infection. Due to the persistent nature of the eruption on the back, an excisional biopsy of the cystic component was performed 2 months after her discharge from the hospital. Histologic studies showed a dense infiltrate of lymphocytes, which expanded into the deep dermis in a nodular and diffuse growth pattern that was accentuated in the periadnexal areas. The B lymphocytes were small and hyperchromatic with few scattered centroblasts (Figure 2). Further immunohistochemical studies demonstrated that the neoplastic cells were positive for CD20, CD79a, BCL-2, and BCL-6; CD3, CD5, and cyclin D1 were negative. Staining for antigen Ki-67 revealed a proliferation index of 15% to 20% among the neoplastic cells (Figure 3). These findings were consistent with either PCFCL or secondary cutaneous follicle center lymphoma.

Further evaluation for systemic disease was unremarkable. Positron emission tomography–computed tomography revealed no evidence of nodal lymphoma, and a bone marrow biopsy was negative. Other laboratory studies including lactate dehydrogenase were within reference range, which conferred a diagnosis of PCFCL. The patient was treated with localized electron beam radiation therapy to the skin of the mid back for a total dose of 24 Gy in 12 fractions at 2 Gy per fraction once daily over a 12-day period. She tolerated the treatment well and has remained clinically and radiographically without evidence of disease for more than 3 years.

Comment

Because the incidence of cutaneous B-cell lymphomas has been increasing, especially among males, non-Hispanic whites, and adults older than 50 years,¹ it is important for clinicians to have a high index of suspicion for this entity. In our patient, the clinical findings of a papular, largely asymptomatic eruption on the back with acute onset were initially thought to be consistent with folliculitis; the differential diagnosis included transient acantholytic dermatosis and miliaria rubra. Lymphoma was not in the initial clinical differential, and we only arrived at this diagnosis based on histopathologic evaluation.

The neoplastic cells typically are positive for CD20, CD79a, and BCL-6, and negative for BCL-2.⁴ Most cases of PCFCL do not express the t(14;18) translocation involving the BCL-2 locus, in contrast to systemic follicular lymphoma.¹ Systemic imaging and evaluation is needed to definitively differentiate PCFCL from systemic lymphoma with cutaneous involvement. Our patient was unusual in that BCL-2 was strongly staining in the setting of a negative systemic workup.

With regard to treatment of PCFCL, electron beam radiation therapy is highly effective and safe in patients with solitary lesions, as the remission rate is close to 100%.¹ For patients with multiple lesions confined to one area, electron beam radiation therapy also can be helpful, as in our patient. In patients with more extensive skin involvement, rituximab therapy may be preferable. Relapse following treatment with either radiation or rituximab occurs in approximately one-third of patients, but these relapses generally are limited to the skin.¹ The International Extranodal Lymphoma Study Group has noted that elevated lactate dehydrogenase, presence of more than 2 skin lesions, and presence of nodular lesions are negative prognostic factors in patients with PCFCL⁶; however, PCFCL has an excellent prognosis overall with a 5-year survival rate of 95%.¹

Other rare heterogeneous presentations of PCFCL have been reported in the literature. A large multinodular mass on the scalp with multifocal facial lesions has been described in a patient with essential thrombocytopenia.⁷ Another report identified a variant of PCFCL characterized by multiple erythematous firm papules that were distributed in a miliary pattern, predominantly on the forehead and cheeks.⁸ Barzilai et al⁹ described 4 patients with PCFCL who developed lesions that were clinically similar to rosacea or rhinophyma, including papulonodular eruptions on the cheeks; infiltrated erythematous nasal plaques; and small flesh-colored to erythematous papules on the cheeks, nose, helices, and upper back. Hodak et al¹⁰ identified 2 cases of PCFCL that manifested as anetoderma, a condition characterized by the focal loss of elastic tissue. In the setting of chronic lymphocytic leukemia, PCFCL has been observed as a red or violaceous nodule with a centrally depressed scar on the legs.¹¹ In one case, PCFCL manifested as recurrent episodes of extraorbital swelling and a multifocal red-blue macular lesion that extended from the inferior orbital rim to the nasojugal fold.¹² An interesting presentation of PCFCL was noted as a small, recurring, blood-filled blister on the cheek with perineural spread of the tumor along cranial nerves V2, V3, VII, and VIII.¹³ In the pediatric literature, PCFCL has been reported to present as an erythematous nodule with a smooth surface and a hard elastic consistency that appeared on the nose and nasolabial fold and spread to the ipsilateral cheek, maxillary sinus, and soft palate.¹⁴ In many of these unusual cases, the diagnosis of PCFCL was made after treatment with topical or systemic anti-inflammatory therapies failed.

Increased recognition of anomalous presentations of PCFCL among dermatologists can lead to more timely diagnoses and treatment. Based on our experience with this patient, we recommend considering biopsy for histopathologic evaluation when treating patients with presumed folliculitis or transient acantholytic dermatosis that does not improve with routine treatment or is accompanied by systemic symptoms.

The 2008 World Health Organization and European Organization for Treatment of Cancer joint classification has distinguished 3 categories of primary cutaneous B-cell lymphomas: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous diffuse large B-cell lymphoma, and primary cutaneous marginal zone lymphoma.^1-3 Primary cutaneous follicle center lymphoma is the most common type of cutaneous B-cell lymphoma, accounting for approximately 60% of cases worldwide.⁴ The median age at diagnosis is 60 years, and most lesions are located on the scalp, forehead, neck, and trunk.⁵ Histologically, PCFCL is characterized by dermal proliferation of centrocytes and centroblasts derived from germinal center B cells that are arranged in either a follicular, diffuse, or mixed growth pattern.¹ The cutaneous manifestations of PCFCL include solitary erythematous or violaceous plaques, nodules, or tumors of varying sizes.⁴ Grouped lesions also may be observed, but multifocal disease is rare.¹ We report a rare presentation of PCFCL mimicking folliculitis with multiple multifocal papules on the back.

Case Report

A 54-year-old woman presented with fever and leukocytosis of 4 days’ duration and was admitted to the hospital for presumed sepsis. She had a history of mastectomy for treatment of ductal carcinoma in situ of the right breast 5 years prior to the current presentation and endocrine therapy with tamoxifen. Her symptoms were thought to be a complication from a surgery for implantation of a tissue expander in the right breast 5 years prior to presentation.

During her hospital admission, she developed a papular and cystic eruption on the back that was clinically suggestive of folliculitis, transient acantholytic dermatosis (Grover disease), or miliaria rubra (Figure 1). This papular and cystic eruption initially was managed conservatively with observation as she recovered from an occult infection. Due to the persistent nature of the eruption on the back, an excisional biopsy of the cystic component was performed 2 months after her discharge from the hospital. Histologic studies showed a dense infiltrate of lymphocytes, which expanded into the deep dermis in a nodular and diffuse growth pattern that was accentuated in the periadnexal areas. The B lymphocytes were small and hyperchromatic with few scattered centroblasts (Figure 2). Further immunohistochemical studies demonstrated that the neoplastic cells were positive for CD20, CD79a, BCL-2, and BCL-6; CD3, CD5, and cyclin D1 were negative. Staining for antigen Ki-67 revealed a proliferation index of 15% to 20% among the neoplastic cells (Figure 3). These findings were consistent with either PCFCL or secondary cutaneous follicle center lymphoma.

Further evaluation for systemic disease was unremarkable. Positron emission tomography–computed tomography revealed no evidence of nodal lymphoma, and a bone marrow biopsy was negative. Other laboratory studies including lactate dehydrogenase were within reference range, which conferred a diagnosis of PCFCL. The patient was treated with localized electron beam radiation therapy to the skin of the mid back for a total dose of 24 Gy in 12 fractions at 2 Gy per fraction once daily over a 12-day period. She tolerated the treatment well and has remained clinically and radiographically without evidence of disease for more than 3 years.

Comment

Because the incidence of cutaneous B-cell lymphomas has been increasing, especially among males, non-Hispanic whites, and adults older than 50 years,¹ it is important for clinicians to have a high index of suspicion for this entity. In our patient, the clinical findings of a papular, largely asymptomatic eruption on the back with acute onset were initially thought to be consistent with folliculitis; the differential diagnosis included transient acantholytic dermatosis and miliaria rubra. Lymphoma was not in the initial clinical differential, and we only arrived at this diagnosis based on histopathologic evaluation.

The neoplastic cells typically are positive for CD20, CD79a, and BCL-6, and negative for BCL-2.⁴ Most cases of PCFCL do not express the t(14;18) translocation involving the BCL-2 locus, in contrast to systemic follicular lymphoma.¹ Systemic imaging and evaluation is needed to definitively differentiate PCFCL from systemic lymphoma with cutaneous involvement. Our patient was unusual in that BCL-2 was strongly staining in the setting of a negative systemic workup.

With regard to treatment of PCFCL, electron beam radiation therapy is highly effective and safe in patients with solitary lesions, as the remission rate is close to 100%.¹ For patients with multiple lesions confined to one area, electron beam radiation therapy also can be helpful, as in our patient. In patients with more extensive skin involvement, rituximab therapy may be preferable. Relapse following treatment with either radiation or rituximab occurs in approximately one-third of patients, but these relapses generally are limited to the skin.¹ The International Extranodal Lymphoma Study Group has noted that elevated lactate dehydrogenase, presence of more than 2 skin lesions, and presence of nodular lesions are negative prognostic factors in patients with PCFCL⁶; however, PCFCL has an excellent prognosis overall with a 5-year survival rate of 95%.¹

Other rare heterogeneous presentations of PCFCL have been reported in the literature. A large multinodular mass on the scalp with multifocal facial lesions has been described in a patient with essential thrombocytopenia.⁷ Another report identified a variant of PCFCL characterized by multiple erythematous firm papules that were distributed in a miliary pattern, predominantly on the forehead and cheeks.⁸ Barzilai et al⁹ described 4 patients with PCFCL who developed lesions that were clinically similar to rosacea or rhinophyma, including papulonodular eruptions on the cheeks; infiltrated erythematous nasal plaques; and small flesh-colored to erythematous papules on the cheeks, nose, helices, and upper back. Hodak et al¹⁰ identified 2 cases of PCFCL that manifested as anetoderma, a condition characterized by the focal loss of elastic tissue. In the setting of chronic lymphocytic leukemia, PCFCL has been observed as a red or violaceous nodule with a centrally depressed scar on the legs.¹¹ In one case, PCFCL manifested as recurrent episodes of extraorbital swelling and a multifocal red-blue macular lesion that extended from the inferior orbital rim to the nasojugal fold.¹² An interesting presentation of PCFCL was noted as a small, recurring, blood-filled blister on the cheek with perineural spread of the tumor along cranial nerves V2, V3, VII, and VIII.¹³ In the pediatric literature, PCFCL has been reported to present as an erythematous nodule with a smooth surface and a hard elastic consistency that appeared on the nose and nasolabial fold and spread to the ipsilateral cheek, maxillary sinus, and soft palate.¹⁴ In many of these unusual cases, the diagnosis of PCFCL was made after treatment with topical or systemic anti-inflammatory therapies failed.

Increased recognition of anomalous presentations of PCFCL among dermatologists can lead to more timely diagnoses and treatment. Based on our experience with this patient, we recommend considering biopsy for histopathologic evaluation when treating patients with presumed folliculitis or transient acantholytic dermatosis that does not improve with routine treatment or is accompanied by systemic symptoms.

Case

A 29-year-old man presented to the ED several hours after ingesting what he described as a “hefty” bottle of hand sanitizer. The patient stated that he ingested such a considerable quantity of liquid hand sanitizer because he was unable to obtain beer or liquor. He further admitted to drinking two 40-ounce beers daily for the past several years, noting that he last consumed drinking alcohol the preceding day.

The patient denied any other coingestants. He also denied nausea, vomiting, abdominal pain, or other somatic complaints. The patient’s medical history was significant for hypertension and hepatitis C, and his social history was significant for daily alcohol consumption, tobacco abuse, and former benzodiazepine, marijuana, and intravenous heroin abuse. His psychiatric history was significant for borderline personality disorder, major depression, and bulimia. The patient’s home medications included a daily multivitamin, folate, thiamine, sertraline, mirtazapine, and prazosin.

Initial vital signs at presentation were: blood pressure, 124/77 mm Hg; heart rate, 86 beats/min; respiratory rate, 15 breaths/min; and temperature, 98.0°F. On physical examination, he was noted to have slurred speech and nystagmus. His pupils were equal and reactive, without scleral icterus. The abdomen was nontender and nondistended, with regular bowel sounds, and without ascites or varicosities visualized. The rest of the examination was unremarkable. The patient did express thoughts of suicidality, but denied any homicidal ideation.

Laboratory studies revealed a serum ethanol concentration of 446 mg/dL. The patient’s basic metabolic panel was unremarkable, and liver function test results showed mildly elevated enzymes. The coagulation panel was within normal limits.

Is alcohol-based hand sanitizer consumption an emerging public health concern?

Excessive alcohol consumption is a recognized public health problem in the United States and is associated with an average of 88,000 deaths per year.¹ In a select population of patients, an untoward effect has developed from another public health target—that of hand hygiene.

Alcohol-based liquid hand sanitizers have become ubiquitous as a weapon in the antimicrobial arsenal with recommendations for its use as an alternative to soap and water in certain clinical settings. Liquid hand sanitizers are ideal for hospital or community use as they are faster, more effective, and less irritating to the skin than traditional hand-washing techniques.²

The downside to the widespread availability of hand sanitizers is that they offer easy access to individuals in search of clandestine sources of alcohol. Prior case reports have discussed the practice of consuming alcohol-based hand sanitizers for the purpose of intoxication in institutionalized persons, such as prisoners or patients in psychiatric facilities who are restricted to conventional sources of alcohol.

Children and confused elderly patients are also at risk for unintentional ingestions.^3,4 An article reviewed exposures reported to the American Association of Poison Control Center’s National Poison Data System over a 5-year period from 2005 to 2009.³ Of the 68,712 reported cases in this cohort, 80.5% were in children younger than 6 years of age. The investigators also noted an increased incidence of exposure over this period with an average of 1,894 additional cases per year.³There were 17,154 children aged 12 years and younger reported in 2017 to poison centers with exposures to hand sanitizers. Young children may be enticed by the bright colorful packaging and similarity to food and candy smells.⁵

What are the clinical manifestations of alcohol-based hand sanitizer ingestion?

Significant hazards exist from ingesting liquid hand sanitizer, including the high alcohol content, which varies from 40% to 85%.² Because isopropanol is commonly one of the components (if not the sole component) of many hand-sanitizer preparations, isopropanol toxicity may occur when ingested. The effects of isopropanol are similar to those of ethanol, with clinical effects reported after ingestion of as little as 100 mL of 70% isopropanol solution.⁴

Hand sanitizer formulations vary by manufacturer and contain different concentrations of ethanol and/or isopropanol, as well as additional potential inactive ingredients such as acetone, 1-propanol, 2-propanol, benzyl alcohol, hydrogen peroxide, glycerin, water, and different perfumes.^3,4

Persons who consume hand sanitizers recreationally are often unaware of the large alcohol content by volume that they are consuming. Recreational ingestion of hand sanitizer is believed to be the cause of at least one case of lethal ethanol intoxication. An articlereported a case of a male patient who suffered respiratory arrest after consuming an ethanol-based hand sanitizer.⁶ This patient was noted to have a serum ethanol of 536 mg/dL after consuming an unknown quantity of a 354 mL container of a 62% ethanol by volume hand sanitizer.⁶

Institutionalized individuals seeking alcohol through this source have discovered novel ways to yield a stronger product. Through the use of table salt and a cotton sock, it is possible to extract a liquid from a gel hand sanitizer preparation, yielding an alcohol context 30% higher by volume than the parent mixture.⁷

Alcohol intoxication poses a host of health effects. In nonhabituated individuals, a lethal load of alcohol can be achieved by consuming a volume of as little as 400 mL of an 80% alcohol-based solution.⁴ Symptoms from ingestion of an alcohol-based liquid hand sanitizer typically appear 1 to 2 hours after ingestion and mirror that of the alcohol toxidrome. Most commonly, this includes nausea, vomiting, epigastric pain, and varying degrees of central nervous system (CNS) depression.⁴ The life-threatening clinical manifestation of alcohol intoxication includes severe CNS and respiratory depression resulting in respiratory arrest, hypothermia, cardiac dysrhythmias with possible cardiac arrest, hypoglycemia, ketoacidosis, and hypotension.³

How is alcohol-based hand sanitizer ingestion managed?

The management of patients with alcohol-based hand sanitizer ingestion is the same as the management of alcohol ingestion from more socially acceptable sources and is mainly supportive.^3,4 These measures are directed at managing the patient’s airway with intubation and mechanical ventilation when appropriate, as well as supportive measures to address any underlying metabolic derangement or hypotension.² While hemodialysis has been used in some patients who had severe organ dysfunction and did not respond to supportive measures, it is usually not necessary.^1,3

Case Conclusion

The patient in this case was subsequently admitted to an intermediate level of care. He did not require intubation or further hemodynamic support during his initial acute intoxication. Later in the patient’s hospital course, he was noted to be in alcohol withdrawal, and proper management was initiated. He also required therapeutic one-to-one supervision after members of the nursing staff observed the patient consuming the hand sanitizer gel present in patient-care areas. He was later seen by psychiatry services. The psychiatrist recommended transfer to an inpatient psychiatric facility upon medical clearance for treatment of his psychiatric illness as well as alcohol dependence.

Case

A 29-year-old man presented to the ED several hours after ingesting what he described as a “hefty” bottle of hand sanitizer. The patient stated that he ingested such a considerable quantity of liquid hand sanitizer because he was unable to obtain beer or liquor. He further admitted to drinking two 40-ounce beers daily for the past several years, noting that he last consumed drinking alcohol the preceding day.

The patient denied any other coingestants. He also denied nausea, vomiting, abdominal pain, or other somatic complaints. The patient’s medical history was significant for hypertension and hepatitis C, and his social history was significant for daily alcohol consumption, tobacco abuse, and former benzodiazepine, marijuana, and intravenous heroin abuse. His psychiatric history was significant for borderline personality disorder, major depression, and bulimia. The patient’s home medications included a daily multivitamin, folate, thiamine, sertraline, mirtazapine, and prazosin.

Initial vital signs at presentation were: blood pressure, 124/77 mm Hg; heart rate, 86 beats/min; respiratory rate, 15 breaths/min; and temperature, 98.0°F. On physical examination, he was noted to have slurred speech and nystagmus. His pupils were equal and reactive, without scleral icterus. The abdomen was nontender and nondistended, with regular bowel sounds, and without ascites or varicosities visualized. The rest of the examination was unremarkable. The patient did express thoughts of suicidality, but denied any homicidal ideation.

Laboratory studies revealed a serum ethanol concentration of 446 mg/dL. The patient’s basic metabolic panel was unremarkable, and liver function test results showed mildly elevated enzymes. The coagulation panel was within normal limits.

Is alcohol-based hand sanitizer consumption an emerging public health concern?

Excessive alcohol consumption is a recognized public health problem in the United States and is associated with an average of 88,000 deaths per year.¹ In a select population of patients, an untoward effect has developed from another public health target—that of hand hygiene.

Alcohol-based liquid hand sanitizers have become ubiquitous as a weapon in the antimicrobial arsenal with recommendations for its use as an alternative to soap and water in certain clinical settings. Liquid hand sanitizers are ideal for hospital or community use as they are faster, more effective, and less irritating to the skin than traditional hand-washing techniques.²

The downside to the widespread availability of hand sanitizers is that they offer easy access to individuals in search of clandestine sources of alcohol. Prior case reports have discussed the practice of consuming alcohol-based hand sanitizers for the purpose of intoxication in institutionalized persons, such as prisoners or patients in psychiatric facilities who are restricted to conventional sources of alcohol.

Children and confused elderly patients are also at risk for unintentional ingestions.^3,4 An article reviewed exposures reported to the American Association of Poison Control Center’s National Poison Data System over a 5-year period from 2005 to 2009.³ Of the 68,712 reported cases in this cohort, 80.5% were in children younger than 6 years of age. The investigators also noted an increased incidence of exposure over this period with an average of 1,894 additional cases per year.³There were 17,154 children aged 12 years and younger reported in 2017 to poison centers with exposures to hand sanitizers. Young children may be enticed by the bright colorful packaging and similarity to food and candy smells.⁵

What are the clinical manifestations of alcohol-based hand sanitizer ingestion?

Significant hazards exist from ingesting liquid hand sanitizer, including the high alcohol content, which varies from 40% to 85%.² Because isopropanol is commonly one of the components (if not the sole component) of many hand-sanitizer preparations, isopropanol toxicity may occur when ingested. The effects of isopropanol are similar to those of ethanol, with clinical effects reported after ingestion of as little as 100 mL of 70% isopropanol solution.⁴

Hand sanitizer formulations vary by manufacturer and contain different concentrations of ethanol and/or isopropanol, as well as additional potential inactive ingredients such as acetone, 1-propanol, 2-propanol, benzyl alcohol, hydrogen peroxide, glycerin, water, and different perfumes.^3,4

Persons who consume hand sanitizers recreationally are often unaware of the large alcohol content by volume that they are consuming. Recreational ingestion of hand sanitizer is believed to be the cause of at least one case of lethal ethanol intoxication. An articlereported a case of a male patient who suffered respiratory arrest after consuming an ethanol-based hand sanitizer.⁶ This patient was noted to have a serum ethanol of 536 mg/dL after consuming an unknown quantity of a 354 mL container of a 62% ethanol by volume hand sanitizer.⁶

Institutionalized individuals seeking alcohol through this source have discovered novel ways to yield a stronger product. Through the use of table salt and a cotton sock, it is possible to extract a liquid from a gel hand sanitizer preparation, yielding an alcohol context 30% higher by volume than the parent mixture.⁷

Alcohol intoxication poses a host of health effects. In nonhabituated individuals, a lethal load of alcohol can be achieved by consuming a volume of as little as 400 mL of an 80% alcohol-based solution.⁴ Symptoms from ingestion of an alcohol-based liquid hand sanitizer typically appear 1 to 2 hours after ingestion and mirror that of the alcohol toxidrome. Most commonly, this includes nausea, vomiting, epigastric pain, and varying degrees of central nervous system (CNS) depression.⁴ The life-threatening clinical manifestation of alcohol intoxication includes severe CNS and respiratory depression resulting in respiratory arrest, hypothermia, cardiac dysrhythmias with possible cardiac arrest, hypoglycemia, ketoacidosis, and hypotension.³

How is alcohol-based hand sanitizer ingestion managed?

The management of patients with alcohol-based hand sanitizer ingestion is the same as the management of alcohol ingestion from more socially acceptable sources and is mainly supportive.^3,4 These measures are directed at managing the patient’s airway with intubation and mechanical ventilation when appropriate, as well as supportive measures to address any underlying metabolic derangement or hypotension.² While hemodialysis has been used in some patients who had severe organ dysfunction and did not respond to supportive measures, it is usually not necessary.^1,3

Case Conclusion

The patient in this case was subsequently admitted to an intermediate level of care. He did not require intubation or further hemodynamic support during his initial acute intoxication. Later in the patient’s hospital course, he was noted to be in alcohol withdrawal, and proper management was initiated. He also required therapeutic one-to-one supervision after members of the nursing staff observed the patient consuming the hand sanitizer gel present in patient-care areas. He was later seen by psychiatry services. The psychiatrist recommended transfer to an inpatient psychiatric facility upon medical clearance for treatment of his psychiatric illness as well as alcohol dependence.

Case

A 29-year-old man presented to the ED several hours after ingesting what he described as a “hefty” bottle of hand sanitizer. The patient stated that he ingested such a considerable quantity of liquid hand sanitizer because he was unable to obtain beer or liquor. He further admitted to drinking two 40-ounce beers daily for the past several years, noting that he last consumed drinking alcohol the preceding day.

The patient denied any other coingestants. He also denied nausea, vomiting, abdominal pain, or other somatic complaints. The patient’s medical history was significant for hypertension and hepatitis C, and his social history was significant for daily alcohol consumption, tobacco abuse, and former benzodiazepine, marijuana, and intravenous heroin abuse. His psychiatric history was significant for borderline personality disorder, major depression, and bulimia. The patient’s home medications included a daily multivitamin, folate, thiamine, sertraline, mirtazapine, and prazosin.

Initial vital signs at presentation were: blood pressure, 124/77 mm Hg; heart rate, 86 beats/min; respiratory rate, 15 breaths/min; and temperature, 98.0°F. On physical examination, he was noted to have slurred speech and nystagmus. His pupils were equal and reactive, without scleral icterus. The abdomen was nontender and nondistended, with regular bowel sounds, and without ascites or varicosities visualized. The rest of the examination was unremarkable. The patient did express thoughts of suicidality, but denied any homicidal ideation.

Laboratory studies revealed a serum ethanol concentration of 446 mg/dL. The patient’s basic metabolic panel was unremarkable, and liver function test results showed mildly elevated enzymes. The coagulation panel was within normal limits.

Is alcohol-based hand sanitizer consumption an emerging public health concern?

Excessive alcohol consumption is a recognized public health problem in the United States and is associated with an average of 88,000 deaths per year.¹ In a select population of patients, an untoward effect has developed from another public health target—that of hand hygiene.

Alcohol-based liquid hand sanitizers have become ubiquitous as a weapon in the antimicrobial arsenal with recommendations for its use as an alternative to soap and water in certain clinical settings. Liquid hand sanitizers are ideal for hospital or community use as they are faster, more effective, and less irritating to the skin than traditional hand-washing techniques.²

The downside to the widespread availability of hand sanitizers is that they offer easy access to individuals in search of clandestine sources of alcohol. Prior case reports have discussed the practice of consuming alcohol-based hand sanitizers for the purpose of intoxication in institutionalized persons, such as prisoners or patients in psychiatric facilities who are restricted to conventional sources of alcohol.

Children and confused elderly patients are also at risk for unintentional ingestions.^3,4 An article reviewed exposures reported to the American Association of Poison Control Center’s National Poison Data System over a 5-year period from 2005 to 2009.³ Of the 68,712 reported cases in this cohort, 80.5% were in children younger than 6 years of age. The investigators also noted an increased incidence of exposure over this period with an average of 1,894 additional cases per year.³There were 17,154 children aged 12 years and younger reported in 2017 to poison centers with exposures to hand sanitizers. Young children may be enticed by the bright colorful packaging and similarity to food and candy smells.⁵

What are the clinical manifestations of alcohol-based hand sanitizer ingestion?

Significant hazards exist from ingesting liquid hand sanitizer, including the high alcohol content, which varies from 40% to 85%.² Because isopropanol is commonly one of the components (if not the sole component) of many hand-sanitizer preparations, isopropanol toxicity may occur when ingested. The effects of isopropanol are similar to those of ethanol, with clinical effects reported after ingestion of as little as 100 mL of 70% isopropanol solution.⁴

Hand sanitizer formulations vary by manufacturer and contain different concentrations of ethanol and/or isopropanol, as well as additional potential inactive ingredients such as acetone, 1-propanol, 2-propanol, benzyl alcohol, hydrogen peroxide, glycerin, water, and different perfumes.^3,4

Persons who consume hand sanitizers recreationally are often unaware of the large alcohol content by volume that they are consuming. Recreational ingestion of hand sanitizer is believed to be the cause of at least one case of lethal ethanol intoxication. An articlereported a case of a male patient who suffered respiratory arrest after consuming an ethanol-based hand sanitizer.⁶ This patient was noted to have a serum ethanol of 536 mg/dL after consuming an unknown quantity of a 354 mL container of a 62% ethanol by volume hand sanitizer.⁶

Institutionalized individuals seeking alcohol through this source have discovered novel ways to yield a stronger product. Through the use of table salt and a cotton sock, it is possible to extract a liquid from a gel hand sanitizer preparation, yielding an alcohol context 30% higher by volume than the parent mixture.⁷

Alcohol intoxication poses a host of health effects. In nonhabituated individuals, a lethal load of alcohol can be achieved by consuming a volume of as little as 400 mL of an 80% alcohol-based solution.⁴ Symptoms from ingestion of an alcohol-based liquid hand sanitizer typically appear 1 to 2 hours after ingestion and mirror that of the alcohol toxidrome. Most commonly, this includes nausea, vomiting, epigastric pain, and varying degrees of central nervous system (CNS) depression.⁴ The life-threatening clinical manifestation of alcohol intoxication includes severe CNS and respiratory depression resulting in respiratory arrest, hypothermia, cardiac dysrhythmias with possible cardiac arrest, hypoglycemia, ketoacidosis, and hypotension.³

How is alcohol-based hand sanitizer ingestion managed?

The management of patients with alcohol-based hand sanitizer ingestion is the same as the management of alcohol ingestion from more socially acceptable sources and is mainly supportive.^3,4 These measures are directed at managing the patient’s airway with intubation and mechanical ventilation when appropriate, as well as supportive measures to address any underlying metabolic derangement or hypotension.² While hemodialysis has been used in some patients who had severe organ dysfunction and did not respond to supportive measures, it is usually not necessary.^1,3

Case Conclusion

The patient in this case was subsequently admitted to an intermediate level of care. He did not require intubation or further hemodynamic support during his initial acute intoxication. Later in the patient’s hospital course, he was noted to be in alcohol withdrawal, and proper management was initiated. He also required therapeutic one-to-one supervision after members of the nursing staff observed the patient consuming the hand sanitizer gel present in patient-care areas. He was later seen by psychiatry services. The psychiatrist recommended transfer to an inpatient psychiatric facility upon medical clearance for treatment of his psychiatric illness as well as alcohol dependence.

Mucorales fungi are ubiquitous organisms commonly inhabiting soil and can cause opportunistic infections. The majority of infections are caused by 3 genera: Rhizopus, Mucor, and Rhizomucor.¹ Infection occurs by inhalation or by direct contact with damaged skin. Mucorales infections can have cutaneous, rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations. Pulmonary mucormycosis is often rapidly progressive with angioinvasion and fulminant necrosis causing acute dyspnea, hemoptysis, and chest pain. More indolent pulmonary Mucorales infections can mimic a pulmonary mass with occasional cavitation found on imaging studies similar to other fungal infections (eg, Aspergillus).² Risk factors include severe uncontrolled diabetes mellitus (DM), recurrent diabetic ketoacidosis (DKA), immunosuppression due to congenital or acquired causes, hematologic malignancies, and chronic renal failure.³ The authors present a case of a patient with recurrent DKA and pulmonary mucormycosis.

Case Presentation

A 62-year-old male with DM and a more than 30-pack-year smoking history presented to the emergency department with abdominal pain and chest pain ongoing for about 1 week. The patient had a history of frequent admissions with DKA and medication nonadherence.

On admission, the patient was hemodynamically stable. His vital signs were: temperature 97.4° F, heart rate 89 bpm, respirations 24 breathes per minute, blood pressure 146/86 mm Hg, and oxygen saturation 94% on ambient air. The patient appeared ill but the physical examination was otherwise unremarkable. Laboratory results revealed a white blood cell count of 24,400 with neutrophilic predominance, blood glucose 658 mg/dL, creatinine clearance 2.16 mL/min/1.73 m², sodium level 124 mEq/L, bicarbonate 6 mEq/L, anion gap 27 mEq/L, 6.8 pH, partial pressure of CO₂ 11 mm Hg, and lactic acid 2.3 mmol/L.

The patient admitted for DKA management and placed on an insulin drip. Although he did not have a fever or cough productive of sputum or hemoptysis, there was concern that pneumonia might have precipitated DKA. A chest X-ray revealed a patchy, right suprahilar opacity (Figure 1).

The patient was placed on vancomycin 1,000 mg every 12 hours and cefepime 2,000 mg every 12 hours for possible hospital-acquired pneumonia because of his history of recent DKA hospitalization. Once the patient’s anion gap was closed and metabolic acidosis was resolved, the insulin drip was discontinued, and the patient was transferred to the general medical ward for further management. There, he continued to report having chest pain. A computed tomography (CT) scan without contrast of the chest (contrast was held due to recent acute kidney injury) revealed right hilar soft tissue density obstructing the bronchus intermidius, which had resulted in a right-lung collapse and right-sided pleural effusion (Figure 2). The left lung was clear, and there was no evidence of nodularity.

Given the patient’s extensive smoking history, the initial concern was for pulmonary malignancy. The decision was made to proceed with bronchoscopy with endobronchial ultrasound-guided transbronchial needle biopsy. Endobronchial brushings and biopsies of R11, 7, right bronchus intermedius, and right upper lobe were obtained. Gross inspection of the airway revealed markedly abnormal-appearing mucosa involving the take off to the right upper lobe and the entire bronchus intermedius with friable, cobblestoned, and edematous mucosa. Biopsies and immunostaining for occult carcinoma markers, including CD-56, TTF-1, Synaptophysin A, chromogranin, AE1/AE3, and CK-5/6, were negative for malignancy. Final microbiologic analysis was positive for Mucor. There was no evidence of bacterial or mycobacterial growth.

Due to continued suspicion for malignancy and lack of histologic yield, the patient underwent a repeat endobronchial ultrasound-guided needle biopsy. On this occasion, gross inspection revealed significant mucosal necrosis and extensive, extrinsic bronchial compression starting from the right bronchial division and notable throughout the right middle and lower lobes (Figure 3).

Bronchial washings revealed necrotic material with rare fungal hyphae present. Biopsies yielded necrotic material or lung tissue containing nonseptate hyphae with rare, right-angle branching consistent with Mucor (Figures 4 and 5). Malignancy was not present in the specimens obtained.

Based on the bronchoscopy results, thoracic surgery and infectious disease specialists were consulted. Surgical intervention was not recommended because of concerns for potential postoperative complications. The infectious disease specialists recommended initiation of liposomal amphotericin B at 10 mg/kg/d. Magnetic resonance imaging of the head showed parietal lobe enhancement with restricted diffusion most consistent with prior infarct. Paranasal sinus disease also was demonstrated. The latter findings prompted further evaluation. The patient underwent right and left endoscopic resection of concha bullosa as well as left maxillary endoscopic antrostomy. Gross examination showed thick mucosa in left concha bullosa, polypoid changes anterior to bulla ethmoidalis, and clear left maxillary sinus. The procedure had to be aborted when the patient experienced cardiac arrest secondary to ventricular fibrillation; he was successfully resuscitated.

Samples from the contents of right and left sinuses as well as left concha bullosa were submitted to pathology, showing benign respiratory mucosa with chronic inflammation and foci of bone without fungal elements. There was no other evidence of disseminated mucormycosis. The patient had a prolonged hospital course complicated by progressive hypoxemia, acute kidney injury, and toxic metabolic encephalopathy. Three months after his original diagnosis, he sustained another cardiac arrest in the hospital. Shortly after achieving return of spontaneous circulation and initiation of invasive mechanical ventilation, the family elected to withdraw care. The family declined an autopsy.

Discussion

This article describes a case of subacute pulmonary mucormycosis in a patient with recurrent DKA. Although patients with poorly controlled DM commonly present with the rhinocerebral form of mucormycosis, pulmonary involvement with a subacute course has been described. Determining the final diagnosis for the current patient was challenging due to the subtlety of his respiratory symptoms and the inconsistent initial findings on chest radiography. A pulmonary disease was finally suspected when a mass was found on the CT scan. However, the middle mediastinal mass was more suspicious for malignancy, particularly given the patient’s smoking history and persistent hyponatremia. In fact, the lack of any neoplastic findings on the initial endobronchial biopsy prompted the health care team to pursue a second biopsy that was consistent with mucormycosis.

This case demonstrates the challenges of prompt diagnosis and treatment of this potentially fatal infection. Furthermore, the extent of the disease at diagnosis precluded this patient from having a surgical intervention, which has been associated with better outcomes than those of medical management alone. Finally, it remains unknown whether the patient had an underlying malignancy, which could have increased the likelihood of pulmonary mucormycosis; the biopsy yield may have been confounded by repeated sampling of necrotic material caused by mucormycosis. Further investigation of any potential pulmonary neoplasm was limited by the patient’s clinical condition and the poor prognosis due to the extent of infection.

Mucorales is an order of fungi comprised of 6 main families that have potential to cause a variety of infections. The genera Mucor, Rhizopus, and Rhizomucor cause the majority of infections.¹ Mucormycosis (infection with Mucorales) is generally a rare fungal infection with an incidence of about 500 cases per year in the U.S. However, the incidence is increasing with an aging population, higher prevalence of DM and chronic kidney disease, and a growing population of immunocompromised patients due to advances in cancer therapy and transplantation. Risk factors for pulmonary mucormycosis include conditions associated with congenital and acquired immunodeficiency: hematologic malignancies, uncontrolled DM, solid tumors, and organ transplantation.²

Presentation

Notably, there seems to be an association between specific organ system involvement and predisposing conditions. Pulmonary mucormycosis occurs much less frequently than does the rhinocerebral form in patients with DKA but occurs more commonly in patients with neutropenia that is due to chemotherapy or hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.²

The mechanisms for preferential site infection are not well understood with current knowledge of mucormycosis pathogenesis. Current research demonstrates monocytes and neutrophils may play a vital role in the body’s defense against Mucor by both phagocytosis and oxidative damage. Chemotaxis and oxidative cell lysis seem to be compromised in states of hyperglycemia and acidosis. Iron metabolism repeatedly has been shown to play a role in the pathogenesis of mucormycosis. Specifically, patients receiving deferoxamine seem to have a predisposition to Mucorales infections, presumably due to the increased iron supply to the fungus.⁴ Notably, systemic acidosis also facilitates higher concentrations of available serum iron.

One of the main characteristics of mucormycosis is its ability to aggressively invade blood vessels, causing thrombosis and necrosis and subsequently disseminate hematogenously or through the lymphatic system. This property, at least in large part, depends on endothelial cell damage following phagocytosis of fungus by these cells.

Of note, some of the azole class of drugs (eg, voriconazole), which may be used for antifungal prophylaxis in patients with hematologic malignancies accompanied by neutropenia, have been implicated in predisposition to mucormycosis.² It also is commonly seen in patients undergoing HSCT. Patients with DM and DKA also can present with pulmonary mucormycosis but generally have a more indolent course unless they develop pulmonary hemorrhage.³ Infection usually occurs by inhalation.

Patients may report dyspnea, cough, and chest pain, which is sometimes accompanied by a fever. Presentation is generally indistinguishable from other causes of pneumonia, and the routinely obtained sputum cultures are usually not diagnostically significant.

Radiographic findings are variable and may include pulmonary nodules, consolidations, masses, and cavitary lesions.¹ Due to tissue invasion, a CT scan of the chest might demonstrate a mass crossing mediastinal tissue planes. Definitive diagnosis requires a biopsy with a demonstration of characteristic broad-based nonseptate hyphae with tissue invasion as well as a positive culture (Figures 4 and 5).⁵ Due to nonspecific symptoms as well as laboratory and imaging findings, a biopsy and, therefore, definitive diagnosis are often delayed. However, postponing medical and surgical therapy for mucormycosis has been associated with worse outcomes.⁶ With the absence of easily available serologic tests and unspecific symptoms in early disease, many mucormycosis cases are diagnosed postmortem.

Treatments

Recently described therapy advancements have indicated improved outcomes.⁷ Nevertheless, prognosis remains universally poor with 65% to 70% mortality for patients with cases of isolated pulmonary mucormycosis.⁸ Many of these patients succumb to sepsis, respiratory failure, and hemoptysis. Patients with pulmonary mucormycosis usually die of dissemination rather than of the sequelae of the pulmonary disease. In fact, pulmonary infection seems to have the highest incidence of dissemination in patients with neutropenia. Surgical therapy seems to have more favorable outcomes than treatment with antifungals alone, especially when considering infection primarily affecting 1 lung.⁸

Amphotericin B remains the first-line agent for treatment of pulmonary mucormycosis. Retrospective studies show that this agent remains one of the few with activity against Mucor with reported successful outcomes. Specifically, the liposomal formulation seems to have greater efficacy.⁹ Strong prospective data are lacking. An increasing body of evidence supports a potential benefit from adding echinocandins.¹⁰ Although these agents have minimal activity against mucormycosis in vitro, adjunctive therapy to amphotericin resulted in better survival. Alternative regimens include the combination of amphotericin with posaconazole or itraconazole. Both these agents seem to have in vitro activity against mucormycosis pathogens, although poor absorption of these agents puts the potential benefit of such combinations in question.

In patients unable to tolerate polyenes due to adverse effects (AEs), the use of posaconazole as monotherapy has been reported with positive results. One retrospective study reported treatment success in up to 60% and stable disease in 21% of patients at 12 weeks. This study included 24 out of 36 patients with pulmonary mucormycosis.¹¹ Significantly fewer AEs and oral administration makes posaconazole an attractive alternative treatment for mucormycosis and needs further prospective evaluation.

Novel therapies have been attempted, though without success thus far. One randomized clinical trial conducted on patients with mucormycosis attempted to determine whether capitalizing on iron metabolism by Mucor by providing adjunctive deferasirox, an iron chelator, would lead to an initial improvement in mortality. However, outcomes did not improve and resulted in higher mortality rates at 90 days in the intervention group.¹²

Reversal of underlying conditions remains the cornerstone of successful therapy. If possible, it is important to cease immunosuppression by avoiding corticosteroids, correcting acidosis and hyperglycemia, and discontinuing aluminum and iron chelators.¹³ This approach becomes problematic in patients with DM with poor glucose control due to nonadherence or lack of resources and in situations where the underlying condition is difficult to treat or the treatment puts patients at risk for mucormycosis (eg, malignancies). Surgery in addition to antifungal therapy should be pursued wherever possible for definitive therapy.

Mucorales fungi are ubiquitous organisms commonly inhabiting soil and can cause opportunistic infections. The majority of infections are caused by 3 genera: Rhizopus, Mucor, and Rhizomucor.¹ Infection occurs by inhalation or by direct contact with damaged skin. Mucorales infections can have cutaneous, rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations. Pulmonary mucormycosis is often rapidly progressive with angioinvasion and fulminant necrosis causing acute dyspnea, hemoptysis, and chest pain. More indolent pulmonary Mucorales infections can mimic a pulmonary mass with occasional cavitation found on imaging studies similar to other fungal infections (eg, Aspergillus).² Risk factors include severe uncontrolled diabetes mellitus (DM), recurrent diabetic ketoacidosis (DKA), immunosuppression due to congenital or acquired causes, hematologic malignancies, and chronic renal failure.³ The authors present a case of a patient with recurrent DKA and pulmonary mucormycosis.

Case Presentation

A 62-year-old male with DM and a more than 30-pack-year smoking history presented to the emergency department with abdominal pain and chest pain ongoing for about 1 week. The patient had a history of frequent admissions with DKA and medication nonadherence.

On admission, the patient was hemodynamically stable. His vital signs were: temperature 97.4° F, heart rate 89 bpm, respirations 24 breathes per minute, blood pressure 146/86 mm Hg, and oxygen saturation 94% on ambient air. The patient appeared ill but the physical examination was otherwise unremarkable. Laboratory results revealed a white blood cell count of 24,400 with neutrophilic predominance, blood glucose 658 mg/dL, creatinine clearance 2.16 mL/min/1.73 m², sodium level 124 mEq/L, bicarbonate 6 mEq/L, anion gap 27 mEq/L, 6.8 pH, partial pressure of CO₂ 11 mm Hg, and lactic acid 2.3 mmol/L.

The patient admitted for DKA management and placed on an insulin drip. Although he did not have a fever or cough productive of sputum or hemoptysis, there was concern that pneumonia might have precipitated DKA. A chest X-ray revealed a patchy, right suprahilar opacity (Figure 1).

The patient was placed on vancomycin 1,000 mg every 12 hours and cefepime 2,000 mg every 12 hours for possible hospital-acquired pneumonia because of his history of recent DKA hospitalization. Once the patient’s anion gap was closed and metabolic acidosis was resolved, the insulin drip was discontinued, and the patient was transferred to the general medical ward for further management. There, he continued to report having chest pain. A computed tomography (CT) scan without contrast of the chest (contrast was held due to recent acute kidney injury) revealed right hilar soft tissue density obstructing the bronchus intermidius, which had resulted in a right-lung collapse and right-sided pleural effusion (Figure 2). The left lung was clear, and there was no evidence of nodularity.

Given the patient’s extensive smoking history, the initial concern was for pulmonary malignancy. The decision was made to proceed with bronchoscopy with endobronchial ultrasound-guided transbronchial needle biopsy. Endobronchial brushings and biopsies of R11, 7, right bronchus intermedius, and right upper lobe were obtained. Gross inspection of the airway revealed markedly abnormal-appearing mucosa involving the take off to the right upper lobe and the entire bronchus intermedius with friable, cobblestoned, and edematous mucosa. Biopsies and immunostaining for occult carcinoma markers, including CD-56, TTF-1, Synaptophysin A, chromogranin, AE1/AE3, and CK-5/6, were negative for malignancy. Final microbiologic analysis was positive for Mucor. There was no evidence of bacterial or mycobacterial growth.

Due to continued suspicion for malignancy and lack of histologic yield, the patient underwent a repeat endobronchial ultrasound-guided needle biopsy. On this occasion, gross inspection revealed significant mucosal necrosis and extensive, extrinsic bronchial compression starting from the right bronchial division and notable throughout the right middle and lower lobes (Figure 3).

Bronchial washings revealed necrotic material with rare fungal hyphae present. Biopsies yielded necrotic material or lung tissue containing nonseptate hyphae with rare, right-angle branching consistent with Mucor (Figures 4 and 5). Malignancy was not present in the specimens obtained.

Based on the bronchoscopy results, thoracic surgery and infectious disease specialists were consulted. Surgical intervention was not recommended because of concerns for potential postoperative complications. The infectious disease specialists recommended initiation of liposomal amphotericin B at 10 mg/kg/d. Magnetic resonance imaging of the head showed parietal lobe enhancement with restricted diffusion most consistent with prior infarct. Paranasal sinus disease also was demonstrated. The latter findings prompted further evaluation. The patient underwent right and left endoscopic resection of concha bullosa as well as left maxillary endoscopic antrostomy. Gross examination showed thick mucosa in left concha bullosa, polypoid changes anterior to bulla ethmoidalis, and clear left maxillary sinus. The procedure had to be aborted when the patient experienced cardiac arrest secondary to ventricular fibrillation; he was successfully resuscitated.

Samples from the contents of right and left sinuses as well as left concha bullosa were submitted to pathology, showing benign respiratory mucosa with chronic inflammation and foci of bone without fungal elements. There was no other evidence of disseminated mucormycosis. The patient had a prolonged hospital course complicated by progressive hypoxemia, acute kidney injury, and toxic metabolic encephalopathy. Three months after his original diagnosis, he sustained another cardiac arrest in the hospital. Shortly after achieving return of spontaneous circulation and initiation of invasive mechanical ventilation, the family elected to withdraw care. The family declined an autopsy.

Discussion

This article describes a case of subacute pulmonary mucormycosis in a patient with recurrent DKA. Although patients with poorly controlled DM commonly present with the rhinocerebral form of mucormycosis, pulmonary involvement with a subacute course has been described. Determining the final diagnosis for the current patient was challenging due to the subtlety of his respiratory symptoms and the inconsistent initial findings on chest radiography. A pulmonary disease was finally suspected when a mass was found on the CT scan. However, the middle mediastinal mass was more suspicious for malignancy, particularly given the patient’s smoking history and persistent hyponatremia. In fact, the lack of any neoplastic findings on the initial endobronchial biopsy prompted the health care team to pursue a second biopsy that was consistent with mucormycosis.

This case demonstrates the challenges of prompt diagnosis and treatment of this potentially fatal infection. Furthermore, the extent of the disease at diagnosis precluded this patient from having a surgical intervention, which has been associated with better outcomes than those of medical management alone. Finally, it remains unknown whether the patient had an underlying malignancy, which could have increased the likelihood of pulmonary mucormycosis; the biopsy yield may have been confounded by repeated sampling of necrotic material caused by mucormycosis. Further investigation of any potential pulmonary neoplasm was limited by the patient’s clinical condition and the poor prognosis due to the extent of infection.

Mucorales is an order of fungi comprised of 6 main families that have potential to cause a variety of infections. The genera Mucor, Rhizopus, and Rhizomucor cause the majority of infections.¹ Mucormycosis (infection with Mucorales) is generally a rare fungal infection with an incidence of about 500 cases per year in the U.S. However, the incidence is increasing with an aging population, higher prevalence of DM and chronic kidney disease, and a growing population of immunocompromised patients due to advances in cancer therapy and transplantation. Risk factors for pulmonary mucormycosis include conditions associated with congenital and acquired immunodeficiency: hematologic malignancies, uncontrolled DM, solid tumors, and organ transplantation.²

Presentation

Notably, there seems to be an association between specific organ system involvement and predisposing conditions. Pulmonary mucormycosis occurs much less frequently than does the rhinocerebral form in patients with DKA but occurs more commonly in patients with neutropenia that is due to chemotherapy or hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.²

The mechanisms for preferential site infection are not well understood with current knowledge of mucormycosis pathogenesis. Current research demonstrates monocytes and neutrophils may play a vital role in the body’s defense against Mucor by both phagocytosis and oxidative damage. Chemotaxis and oxidative cell lysis seem to be compromised in states of hyperglycemia and acidosis. Iron metabolism repeatedly has been shown to play a role in the pathogenesis of mucormycosis. Specifically, patients receiving deferoxamine seem to have a predisposition to Mucorales infections, presumably due to the increased iron supply to the fungus.⁴ Notably, systemic acidosis also facilitates higher concentrations of available serum iron.

One of the main characteristics of mucormycosis is its ability to aggressively invade blood vessels, causing thrombosis and necrosis and subsequently disseminate hematogenously or through the lymphatic system. This property, at least in large part, depends on endothelial cell damage following phagocytosis of fungus by these cells.

Of note, some of the azole class of drugs (eg, voriconazole), which may be used for antifungal prophylaxis in patients with hematologic malignancies accompanied by neutropenia, have been implicated in predisposition to mucormycosis.² It also is commonly seen in patients undergoing HSCT. Patients with DM and DKA also can present with pulmonary mucormycosis but generally have a more indolent course unless they develop pulmonary hemorrhage.³ Infection usually occurs by inhalation.

Patients may report dyspnea, cough, and chest pain, which is sometimes accompanied by a fever. Presentation is generally indistinguishable from other causes of pneumonia, and the routinely obtained sputum cultures are usually not diagnostically significant.

Radiographic findings are variable and may include pulmonary nodules, consolidations, masses, and cavitary lesions.¹ Due to tissue invasion, a CT scan of the chest might demonstrate a mass crossing mediastinal tissue planes. Definitive diagnosis requires a biopsy with a demonstration of characteristic broad-based nonseptate hyphae with tissue invasion as well as a positive culture (Figures 4 and 5).⁵ Due to nonspecific symptoms as well as laboratory and imaging findings, a biopsy and, therefore, definitive diagnosis are often delayed. However, postponing medical and surgical therapy for mucormycosis has been associated with worse outcomes.⁶ With the absence of easily available serologic tests and unspecific symptoms in early disease, many mucormycosis cases are diagnosed postmortem.

Treatments

Recently described therapy advancements have indicated improved outcomes.⁷ Nevertheless, prognosis remains universally poor with 65% to 70% mortality for patients with cases of isolated pulmonary mucormycosis.⁸ Many of these patients succumb to sepsis, respiratory failure, and hemoptysis. Patients with pulmonary mucormycosis usually die of dissemination rather than of the sequelae of the pulmonary disease. In fact, pulmonary infection seems to have the highest incidence of dissemination in patients with neutropenia. Surgical therapy seems to have more favorable outcomes than treatment with antifungals alone, especially when considering infection primarily affecting 1 lung.⁸

Amphotericin B remains the first-line agent for treatment of pulmonary mucormycosis. Retrospective studies show that this agent remains one of the few with activity against Mucor with reported successful outcomes. Specifically, the liposomal formulation seems to have greater efficacy.⁹ Strong prospective data are lacking. An increasing body of evidence supports a potential benefit from adding echinocandins.¹⁰ Although these agents have minimal activity against mucormycosis in vitro, adjunctive therapy to amphotericin resulted in better survival. Alternative regimens include the combination of amphotericin with posaconazole or itraconazole. Both these agents seem to have in vitro activity against mucormycosis pathogens, although poor absorption of these agents puts the potential benefit of such combinations in question.

In patients unable to tolerate polyenes due to adverse effects (AEs), the use of posaconazole as monotherapy has been reported with positive results. One retrospective study reported treatment success in up to 60% and stable disease in 21% of patients at 12 weeks. This study included 24 out of 36 patients with pulmonary mucormycosis.¹¹ Significantly fewer AEs and oral administration makes posaconazole an attractive alternative treatment for mucormycosis and needs further prospective evaluation.

Novel therapies have been attempted, though without success thus far. One randomized clinical trial conducted on patients with mucormycosis attempted to determine whether capitalizing on iron metabolism by Mucor by providing adjunctive deferasirox, an iron chelator, would lead to an initial improvement in mortality. However, outcomes did not improve and resulted in higher mortality rates at 90 days in the intervention group.¹²

Reversal of underlying conditions remains the cornerstone of successful therapy. If possible, it is important to cease immunosuppression by avoiding corticosteroids, correcting acidosis and hyperglycemia, and discontinuing aluminum and iron chelators.¹³ This approach becomes problematic in patients with DM with poor glucose control due to nonadherence or lack of resources and in situations where the underlying condition is difficult to treat or the treatment puts patients at risk for mucormycosis (eg, malignancies). Surgery in addition to antifungal therapy should be pursued wherever possible for definitive therapy.

Mucorales fungi are ubiquitous organisms commonly inhabiting soil and can cause opportunistic infections. The majority of infections are caused by 3 genera: Rhizopus, Mucor, and Rhizomucor.¹ Infection occurs by inhalation or by direct contact with damaged skin. Mucorales infections can have cutaneous, rhinocerebral, pulmonary, gastrointestinal, and central nervous system manifestations. Pulmonary mucormycosis is often rapidly progressive with angioinvasion and fulminant necrosis causing acute dyspnea, hemoptysis, and chest pain. More indolent pulmonary Mucorales infections can mimic a pulmonary mass with occasional cavitation found on imaging studies similar to other fungal infections (eg, Aspergillus).² Risk factors include severe uncontrolled diabetes mellitus (DM), recurrent diabetic ketoacidosis (DKA), immunosuppression due to congenital or acquired causes, hematologic malignancies, and chronic renal failure.³ The authors present a case of a patient with recurrent DKA and pulmonary mucormycosis.

Case Presentation

A 62-year-old male with DM and a more than 30-pack-year smoking history presented to the emergency department with abdominal pain and chest pain ongoing for about 1 week. The patient had a history of frequent admissions with DKA and medication nonadherence.

On admission, the patient was hemodynamically stable. His vital signs were: temperature 97.4° F, heart rate 89 bpm, respirations 24 breathes per minute, blood pressure 146/86 mm Hg, and oxygen saturation 94% on ambient air. The patient appeared ill but the physical examination was otherwise unremarkable. Laboratory results revealed a white blood cell count of 24,400 with neutrophilic predominance, blood glucose 658 mg/dL, creatinine clearance 2.16 mL/min/1.73 m², sodium level 124 mEq/L, bicarbonate 6 mEq/L, anion gap 27 mEq/L, 6.8 pH, partial pressure of CO₂ 11 mm Hg, and lactic acid 2.3 mmol/L.

The patient admitted for DKA management and placed on an insulin drip. Although he did not have a fever or cough productive of sputum or hemoptysis, there was concern that pneumonia might have precipitated DKA. A chest X-ray revealed a patchy, right suprahilar opacity (Figure 1).

The patient was placed on vancomycin 1,000 mg every 12 hours and cefepime 2,000 mg every 12 hours for possible hospital-acquired pneumonia because of his history of recent DKA hospitalization. Once the patient’s anion gap was closed and metabolic acidosis was resolved, the insulin drip was discontinued, and the patient was transferred to the general medical ward for further management. There, he continued to report having chest pain. A computed tomography (CT) scan without contrast of the chest (contrast was held due to recent acute kidney injury) revealed right hilar soft tissue density obstructing the bronchus intermidius, which had resulted in a right-lung collapse and right-sided pleural effusion (Figure 2). The left lung was clear, and there was no evidence of nodularity.

Given the patient’s extensive smoking history, the initial concern was for pulmonary malignancy. The decision was made to proceed with bronchoscopy with endobronchial ultrasound-guided transbronchial needle biopsy. Endobronchial brushings and biopsies of R11, 7, right bronchus intermedius, and right upper lobe were obtained. Gross inspection of the airway revealed markedly abnormal-appearing mucosa involving the take off to the right upper lobe and the entire bronchus intermedius with friable, cobblestoned, and edematous mucosa. Biopsies and immunostaining for occult carcinoma markers, including CD-56, TTF-1, Synaptophysin A, chromogranin, AE1/AE3, and CK-5/6, were negative for malignancy. Final microbiologic analysis was positive for Mucor. There was no evidence of bacterial or mycobacterial growth.

Due to continued suspicion for malignancy and lack of histologic yield, the patient underwent a repeat endobronchial ultrasound-guided needle biopsy. On this occasion, gross inspection revealed significant mucosal necrosis and extensive, extrinsic bronchial compression starting from the right bronchial division and notable throughout the right middle and lower lobes (Figure 3).

Bronchial washings revealed necrotic material with rare fungal hyphae present. Biopsies yielded necrotic material or lung tissue containing nonseptate hyphae with rare, right-angle branching consistent with Mucor (Figures 4 and 5). Malignancy was not present in the specimens obtained.

Based on the bronchoscopy results, thoracic surgery and infectious disease specialists were consulted. Surgical intervention was not recommended because of concerns for potential postoperative complications. The infectious disease specialists recommended initiation of liposomal amphotericin B at 10 mg/kg/d. Magnetic resonance imaging of the head showed parietal lobe enhancement with restricted diffusion most consistent with prior infarct. Paranasal sinus disease also was demonstrated. The latter findings prompted further evaluation. The patient underwent right and left endoscopic resection of concha bullosa as well as left maxillary endoscopic antrostomy. Gross examination showed thick mucosa in left concha bullosa, polypoid changes anterior to bulla ethmoidalis, and clear left maxillary sinus. The procedure had to be aborted when the patient experienced cardiac arrest secondary to ventricular fibrillation; he was successfully resuscitated.

Samples from the contents of right and left sinuses as well as left concha bullosa were submitted to pathology, showing benign respiratory mucosa with chronic inflammation and foci of bone without fungal elements. There was no other evidence of disseminated mucormycosis. The patient had a prolonged hospital course complicated by progressive hypoxemia, acute kidney injury, and toxic metabolic encephalopathy. Three months after his original diagnosis, he sustained another cardiac arrest in the hospital. Shortly after achieving return of spontaneous circulation and initiation of invasive mechanical ventilation, the family elected to withdraw care. The family declined an autopsy.

Discussion

This article describes a case of subacute pulmonary mucormycosis in a patient with recurrent DKA. Although patients with poorly controlled DM commonly present with the rhinocerebral form of mucormycosis, pulmonary involvement with a subacute course has been described. Determining the final diagnosis for the current patient was challenging due to the subtlety of his respiratory symptoms and the inconsistent initial findings on chest radiography. A pulmonary disease was finally suspected when a mass was found on the CT scan. However, the middle mediastinal mass was more suspicious for malignancy, particularly given the patient’s smoking history and persistent hyponatremia. In fact, the lack of any neoplastic findings on the initial endobronchial biopsy prompted the health care team to pursue a second biopsy that was consistent with mucormycosis.

This case demonstrates the challenges of prompt diagnosis and treatment of this potentially fatal infection. Furthermore, the extent of the disease at diagnosis precluded this patient from having a surgical intervention, which has been associated with better outcomes than those of medical management alone. Finally, it remains unknown whether the patient had an underlying malignancy, which could have increased the likelihood of pulmonary mucormycosis; the biopsy yield may have been confounded by repeated sampling of necrotic material caused by mucormycosis. Further investigation of any potential pulmonary neoplasm was limited by the patient’s clinical condition and the poor prognosis due to the extent of infection.

Mucorales is an order of fungi comprised of 6 main families that have potential to cause a variety of infections. The genera Mucor, Rhizopus, and Rhizomucor cause the majority of infections.¹ Mucormycosis (infection with Mucorales) is generally a rare fungal infection with an incidence of about 500 cases per year in the U.S. However, the incidence is increasing with an aging population, higher prevalence of DM and chronic kidney disease, and a growing population of immunocompromised patients due to advances in cancer therapy and transplantation. Risk factors for pulmonary mucormycosis include conditions associated with congenital and acquired immunodeficiency: hematologic malignancies, uncontrolled DM, solid tumors, and organ transplantation.²

Presentation

Notably, there seems to be an association between specific organ system involvement and predisposing conditions. Pulmonary mucormycosis occurs much less frequently than does the rhinocerebral form in patients with DKA but occurs more commonly in patients with neutropenia that is due to chemotherapy or hematopoietic stem cell transplantation (HSCT) for the treatment of hematologic malignancies.²

The mechanisms for preferential site infection are not well understood with current knowledge of mucormycosis pathogenesis. Current research demonstrates monocytes and neutrophils may play a vital role in the body’s defense against Mucor by both phagocytosis and oxidative damage. Chemotaxis and oxidative cell lysis seem to be compromised in states of hyperglycemia and acidosis. Iron metabolism repeatedly has been shown to play a role in the pathogenesis of mucormycosis. Specifically, patients receiving deferoxamine seem to have a predisposition to Mucorales infections, presumably due to the increased iron supply to the fungus.⁴ Notably, systemic acidosis also facilitates higher concentrations of available serum iron.

One of the main characteristics of mucormycosis is its ability to aggressively invade blood vessels, causing thrombosis and necrosis and subsequently disseminate hematogenously or through the lymphatic system. This property, at least in large part, depends on endothelial cell damage following phagocytosis of fungus by these cells.

Of note, some of the azole class of drugs (eg, voriconazole), which may be used for antifungal prophylaxis in patients with hematologic malignancies accompanied by neutropenia, have been implicated in predisposition to mucormycosis.² It also is commonly seen in patients undergoing HSCT. Patients with DM and DKA also can present with pulmonary mucormycosis but generally have a more indolent course unless they develop pulmonary hemorrhage.³ Infection usually occurs by inhalation.

Patients may report dyspnea, cough, and chest pain, which is sometimes accompanied by a fever. Presentation is generally indistinguishable from other causes of pneumonia, and the routinely obtained sputum cultures are usually not diagnostically significant.

Radiographic findings are variable and may include pulmonary nodules, consolidations, masses, and cavitary lesions.¹ Due to tissue invasion, a CT scan of the chest might demonstrate a mass crossing mediastinal tissue planes. Definitive diagnosis requires a biopsy with a demonstration of characteristic broad-based nonseptate hyphae with tissue invasion as well as a positive culture (Figures 4 and 5).⁵ Due to nonspecific symptoms as well as laboratory and imaging findings, a biopsy and, therefore, definitive diagnosis are often delayed. However, postponing medical and surgical therapy for mucormycosis has been associated with worse outcomes.⁶ With the absence of easily available serologic tests and unspecific symptoms in early disease, many mucormycosis cases are diagnosed postmortem.

Treatments

Recently described therapy advancements have indicated improved outcomes.⁷ Nevertheless, prognosis remains universally poor with 65% to 70% mortality for patients with cases of isolated pulmonary mucormycosis.⁸ Many of these patients succumb to sepsis, respiratory failure, and hemoptysis. Patients with pulmonary mucormycosis usually die of dissemination rather than of the sequelae of the pulmonary disease. In fact, pulmonary infection seems to have the highest incidence of dissemination in patients with neutropenia. Surgical therapy seems to have more favorable outcomes than treatment with antifungals alone, especially when considering infection primarily affecting 1 lung.⁸

Amphotericin B remains the first-line agent for treatment of pulmonary mucormycosis. Retrospective studies show that this agent remains one of the few with activity against Mucor with reported successful outcomes. Specifically, the liposomal formulation seems to have greater efficacy.⁹ Strong prospective data are lacking. An increasing body of evidence supports a potential benefit from adding echinocandins.¹⁰ Although these agents have minimal activity against mucormycosis in vitro, adjunctive therapy to amphotericin resulted in better survival. Alternative regimens include the combination of amphotericin with posaconazole or itraconazole. Both these agents seem to have in vitro activity against mucormycosis pathogens, although poor absorption of these agents puts the potential benefit of such combinations in question.

In patients unable to tolerate polyenes due to adverse effects (AEs), the use of posaconazole as monotherapy has been reported with positive results. One retrospective study reported treatment success in up to 60% and stable disease in 21% of patients at 12 weeks. This study included 24 out of 36 patients with pulmonary mucormycosis.¹¹ Significantly fewer AEs and oral administration makes posaconazole an attractive alternative treatment for mucormycosis and needs further prospective evaluation.

Novel therapies have been attempted, though without success thus far. One randomized clinical trial conducted on patients with mucormycosis attempted to determine whether capitalizing on iron metabolism by Mucor by providing adjunctive deferasirox, an iron chelator, would lead to an initial improvement in mortality. However, outcomes did not improve and resulted in higher mortality rates at 90 days in the intervention group.¹²

Reversal of underlying conditions remains the cornerstone of successful therapy. If possible, it is important to cease immunosuppression by avoiding corticosteroids, correcting acidosis and hyperglycemia, and discontinuing aluminum and iron chelators.¹³ This approach becomes problematic in patients with DM with poor glucose control due to nonadherence or lack of resources and in situations where the underlying condition is difficult to treat or the treatment puts patients at risk for mucormycosis (eg, malignancies). Surgery in addition to antifungal therapy should be pursued wherever possible for definitive therapy.

Dermoscopy increases diagnostic accuracy in the analysis of skin growths.^1,2 Recently the use of dermoscopy has broadened to include inflammatory dermatoses and skin infections.³ To substantiate the value of dermoscopy in assessing psoriasis, we performed a systematic review of the literature and briefly reviewed 31 articles. We also report a case that highlights the differences between psoriasis and basal cell carcinoma (BCC) under dermoscopic examination, and we discuss the literature on the dermoscopic findings of psoriasis with an emphasis on the relative sensitivities and specificities of dermoscopic findings for psoriasis and for BCC.

Case Report

A 63-year-old man with psoriasis and a history of BCC presented for follow-up of psoriasis, which was well-controlled on etanercept. The physical examination was remarkable for scaly pink papules scattered on the trunk and extremities. A new larger red-pink patch was located on the left lower back (Figure 1). Dermoscopic evaluation of the new patch revealed shiny white lines and branching blood vessels (Figure 2). Pathology results of a shave biopsy revealed superficial BCC. The skin cancer was treated with electrodesiccation and curettage.

Comment

The clinical morphology of psoriasis and BCC can be similar, and dermoscopy can help in differentiating between the 2 conditions.

Literature Search on Dermoscopy and Psoriasis
We performed a PubMed search of articles indexed for MEDLINE to review the published literature on dermoscopy and psoriasis. Two reviewers (C.H. and L.C.) searched for psoriasis paired with the terms dermoscopy or dermatoscopy or epiluminescence microscopy. Only English-language articles published between 1996 and 2016 were included in the search. Articles that focused solely on confocal microscopy were excluded. Article titles and abstracts were evaluated and articles that omitted mention of dermoscopy and psoriasis were excluded, yielding a total of 31 articles. Of these articles, only 2 discussed the specificity or sensitivity of the dermoscopic findings of psoriasis.^4,5 Most of the articles were case reports and descriptive cross-sectional studies. The reports addressed multiple subtypes of psoriasis, but reports on psoriasis vulgaris and scalp psoriasis were most common (Table). Lallas et al⁶ provided a comprehensive descriptive review of the main findings on dermoscopy for psoriasis and other inflammatory skin conditions, but it lacked a comparison between psoriasis and BCC or data on the sensitivity and specificity of the findings. Two studies reported sensitivity and specificity values for the dermoscopic findings of psoriasis.^4,5 Pan et al⁵ reported a 98% diagnostic probability of psoriasis if red dots, homogeneous vascular pattern, and a light red background are all present. Additionally, they reported that the presence of 4 of 6 criteria for BCC—scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background, and brown dots⁄globules—yielded a diagnostic probability of 99%.⁵ Similarly, Lallas et al⁶ demonstrated that the presence of dotted vessels alone is not sufficient to presume a diagnosis of psoriasis, as this finding can be seen in other inflammatory skin conditions. However, “the combination of regularly distributed dotted vessels over a light red background associated with diffuse white scales was highly predictive of [plaque psoriasis] and allowed a correct diagnosis with 88.0% specificity and 84.9% sensitivity.”⁴ Figure 3 shows a dermoscopic image of plaque psoriasis that demonstrates these findings. The remaining literature corroborated this evidence, with the most commonly reported dermoscopic findings of psoriasis being red dots, red globules, glomerular vessels (also known as twisted capillary loops), red globular rings, and white scale.^7-12

Dermoscopy and BCC
Much has been published on the dermoscopic findings of BCC.^5,13-15 The dermoscopic findings of BCC include large blue-gray ovoid nests, leaflike areas, spoke-wheel–like areas, arborizing vessels (telangiectasia), and ulceration.¹⁵ Superficial BCC is characterized by short fine or arborizing telangiectasia, shallow erosions, and shiny white areas.¹⁵ The positive predictive value of dermoscopy in BCC is as high as 97%.¹⁶ Additionally, multiple studies report a sensitivity of 95% to 99%^5,13,14 and a specificity of 79% to 99% in the use of dermoscopy for identifying BCC. According to Pan et al,⁵ the most sensitive finding for BCC is a scattered vascular pattern (97%), while the most specific finding is arborizing microvessels (99%).

Utility of Dermoscopy
Our case of a 63-year-old man with a history of psoriasis and BCC highlights the usefulness of dermoscopy in accurately determining the features of each condition. Additionally, dermoscopy aids in differentiating between psoriasis and squamous cell carcinoma. In contrast to the dotted vessels seen in psoriasis, squamous cell carcinomas often have peripheral hairpin (glomerular) vessels.¹⁷

If future reports confirm dermoscopy’s utility in accurately diagnosing psoriasis, fewer biopsies may be needed when evaluating patients with new rashes. Furthermore, dermoscopy may expedite treatment of psoriasis (as it can for malignant conditions) by obviating the wait for pathology results currently needed to initiate systemic treatment. For patients with psoriasis who also have sun-damaged skin, dermoscopy may assist in differentiating pink patches and plaques of psoriasis from skin cancer, such as superficial BCCs, which often have shiny white lines not seen in psoriasis.¹⁵

Dermoscopy increases diagnostic accuracy in the analysis of skin growths.^1,2 Recently the use of dermoscopy has broadened to include inflammatory dermatoses and skin infections.³ To substantiate the value of dermoscopy in assessing psoriasis, we performed a systematic review of the literature and briefly reviewed 31 articles. We also report a case that highlights the differences between psoriasis and basal cell carcinoma (BCC) under dermoscopic examination, and we discuss the literature on the dermoscopic findings of psoriasis with an emphasis on the relative sensitivities and specificities of dermoscopic findings for psoriasis and for BCC.

Case Report

A 63-year-old man with psoriasis and a history of BCC presented for follow-up of psoriasis, which was well-controlled on etanercept. The physical examination was remarkable for scaly pink papules scattered on the trunk and extremities. A new larger red-pink patch was located on the left lower back (Figure 1). Dermoscopic evaluation of the new patch revealed shiny white lines and branching blood vessels (Figure 2). Pathology results of a shave biopsy revealed superficial BCC. The skin cancer was treated with electrodesiccation and curettage.

Comment

The clinical morphology of psoriasis and BCC can be similar, and dermoscopy can help in differentiating between the 2 conditions.

Literature Search on Dermoscopy and Psoriasis
We performed a PubMed search of articles indexed for MEDLINE to review the published literature on dermoscopy and psoriasis. Two reviewers (C.H. and L.C.) searched for psoriasis paired with the terms dermoscopy or dermatoscopy or epiluminescence microscopy. Only English-language articles published between 1996 and 2016 were included in the search. Articles that focused solely on confocal microscopy were excluded. Article titles and abstracts were evaluated and articles that omitted mention of dermoscopy and psoriasis were excluded, yielding a total of 31 articles. Of these articles, only 2 discussed the specificity or sensitivity of the dermoscopic findings of psoriasis.^4,5 Most of the articles were case reports and descriptive cross-sectional studies. The reports addressed multiple subtypes of psoriasis, but reports on psoriasis vulgaris and scalp psoriasis were most common (Table). Lallas et al⁶ provided a comprehensive descriptive review of the main findings on dermoscopy for psoriasis and other inflammatory skin conditions, but it lacked a comparison between psoriasis and BCC or data on the sensitivity and specificity of the findings. Two studies reported sensitivity and specificity values for the dermoscopic findings of psoriasis.^4,5 Pan et al⁵ reported a 98% diagnostic probability of psoriasis if red dots, homogeneous vascular pattern, and a light red background are all present. Additionally, they reported that the presence of 4 of 6 criteria for BCC—scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background, and brown dots⁄globules—yielded a diagnostic probability of 99%.⁵ Similarly, Lallas et al⁶ demonstrated that the presence of dotted vessels alone is not sufficient to presume a diagnosis of psoriasis, as this finding can be seen in other inflammatory skin conditions. However, “the combination of regularly distributed dotted vessels over a light red background associated with diffuse white scales was highly predictive of [plaque psoriasis] and allowed a correct diagnosis with 88.0% specificity and 84.9% sensitivity.”⁴ Figure 3 shows a dermoscopic image of plaque psoriasis that demonstrates these findings. The remaining literature corroborated this evidence, with the most commonly reported dermoscopic findings of psoriasis being red dots, red globules, glomerular vessels (also known as twisted capillary loops), red globular rings, and white scale.^7-12

Dermoscopy and BCC
Much has been published on the dermoscopic findings of BCC.^5,13-15 The dermoscopic findings of BCC include large blue-gray ovoid nests, leaflike areas, spoke-wheel–like areas, arborizing vessels (telangiectasia), and ulceration.¹⁵ Superficial BCC is characterized by short fine or arborizing telangiectasia, shallow erosions, and shiny white areas.¹⁵ The positive predictive value of dermoscopy in BCC is as high as 97%.¹⁶ Additionally, multiple studies report a sensitivity of 95% to 99%^5,13,14 and a specificity of 79% to 99% in the use of dermoscopy for identifying BCC. According to Pan et al,⁵ the most sensitive finding for BCC is a scattered vascular pattern (97%), while the most specific finding is arborizing microvessels (99%).

Utility of Dermoscopy
Our case of a 63-year-old man with a history of psoriasis and BCC highlights the usefulness of dermoscopy in accurately determining the features of each condition. Additionally, dermoscopy aids in differentiating between psoriasis and squamous cell carcinoma. In contrast to the dotted vessels seen in psoriasis, squamous cell carcinomas often have peripheral hairpin (glomerular) vessels.¹⁷

If future reports confirm dermoscopy’s utility in accurately diagnosing psoriasis, fewer biopsies may be needed when evaluating patients with new rashes. Furthermore, dermoscopy may expedite treatment of psoriasis (as it can for malignant conditions) by obviating the wait for pathology results currently needed to initiate systemic treatment. For patients with psoriasis who also have sun-damaged skin, dermoscopy may assist in differentiating pink patches and plaques of psoriasis from skin cancer, such as superficial BCCs, which often have shiny white lines not seen in psoriasis.¹⁵

Dermoscopy increases diagnostic accuracy in the analysis of skin growths.^1,2 Recently the use of dermoscopy has broadened to include inflammatory dermatoses and skin infections.³ To substantiate the value of dermoscopy in assessing psoriasis, we performed a systematic review of the literature and briefly reviewed 31 articles. We also report a case that highlights the differences between psoriasis and basal cell carcinoma (BCC) under dermoscopic examination, and we discuss the literature on the dermoscopic findings of psoriasis with an emphasis on the relative sensitivities and specificities of dermoscopic findings for psoriasis and for BCC.

Case Report

A 63-year-old man with psoriasis and a history of BCC presented for follow-up of psoriasis, which was well-controlled on etanercept. The physical examination was remarkable for scaly pink papules scattered on the trunk and extremities. A new larger red-pink patch was located on the left lower back (Figure 1). Dermoscopic evaluation of the new patch revealed shiny white lines and branching blood vessels (Figure 2). Pathology results of a shave biopsy revealed superficial BCC. The skin cancer was treated with electrodesiccation and curettage.

Comment

The clinical morphology of psoriasis and BCC can be similar, and dermoscopy can help in differentiating between the 2 conditions.

Literature Search on Dermoscopy and Psoriasis
We performed a PubMed search of articles indexed for MEDLINE to review the published literature on dermoscopy and psoriasis. Two reviewers (C.H. and L.C.) searched for psoriasis paired with the terms dermoscopy or dermatoscopy or epiluminescence microscopy. Only English-language articles published between 1996 and 2016 were included in the search. Articles that focused solely on confocal microscopy were excluded. Article titles and abstracts were evaluated and articles that omitted mention of dermoscopy and psoriasis were excluded, yielding a total of 31 articles. Of these articles, only 2 discussed the specificity or sensitivity of the dermoscopic findings of psoriasis.^4,5 Most of the articles were case reports and descriptive cross-sectional studies. The reports addressed multiple subtypes of psoriasis, but reports on psoriasis vulgaris and scalp psoriasis were most common (Table). Lallas et al⁶ provided a comprehensive descriptive review of the main findings on dermoscopy for psoriasis and other inflammatory skin conditions, but it lacked a comparison between psoriasis and BCC or data on the sensitivity and specificity of the findings. Two studies reported sensitivity and specificity values for the dermoscopic findings of psoriasis.^4,5 Pan et al⁵ reported a 98% diagnostic probability of psoriasis if red dots, homogeneous vascular pattern, and a light red background are all present. Additionally, they reported that the presence of 4 of 6 criteria for BCC—scattered vascular pattern, arborizing microvessels, telangiectatic or atypical vessels, milky-pink background, and brown dots⁄globules—yielded a diagnostic probability of 99%.⁵ Similarly, Lallas et al⁶ demonstrated that the presence of dotted vessels alone is not sufficient to presume a diagnosis of psoriasis, as this finding can be seen in other inflammatory skin conditions. However, “the combination of regularly distributed dotted vessels over a light red background associated with diffuse white scales was highly predictive of [plaque psoriasis] and allowed a correct diagnosis with 88.0% specificity and 84.9% sensitivity.”⁴ Figure 3 shows a dermoscopic image of plaque psoriasis that demonstrates these findings. The remaining literature corroborated this evidence, with the most commonly reported dermoscopic findings of psoriasis being red dots, red globules, glomerular vessels (also known as twisted capillary loops), red globular rings, and white scale.^7-12

Dermoscopy and BCC
Much has been published on the dermoscopic findings of BCC.^5,13-15 The dermoscopic findings of BCC include large blue-gray ovoid nests, leaflike areas, spoke-wheel–like areas, arborizing vessels (telangiectasia), and ulceration.¹⁵ Superficial BCC is characterized by short fine or arborizing telangiectasia, shallow erosions, and shiny white areas.¹⁵ The positive predictive value of dermoscopy in BCC is as high as 97%.¹⁶ Additionally, multiple studies report a sensitivity of 95% to 99%^5,13,14 and a specificity of 79% to 99% in the use of dermoscopy for identifying BCC. According to Pan et al,⁵ the most sensitive finding for BCC is a scattered vascular pattern (97%), while the most specific finding is arborizing microvessels (99%).

Utility of Dermoscopy
Our case of a 63-year-old man with a history of psoriasis and BCC highlights the usefulness of dermoscopy in accurately determining the features of each condition. Additionally, dermoscopy aids in differentiating between psoriasis and squamous cell carcinoma. In contrast to the dotted vessels seen in psoriasis, squamous cell carcinomas often have peripheral hairpin (glomerular) vessels.¹⁷

If future reports confirm dermoscopy’s utility in accurately diagnosing psoriasis, fewer biopsies may be needed when evaluating patients with new rashes. Furthermore, dermoscopy may expedite treatment of psoriasis (as it can for malignant conditions) by obviating the wait for pathology results currently needed to initiate systemic treatment. For patients with psoriasis who also have sun-damaged skin, dermoscopy may assist in differentiating pink patches and plaques of psoriasis from skin cancer, such as superficial BCCs, which often have shiny white lines not seen in psoriasis.¹⁵

THE CASE

A 41-year-old, right-hand dominant man sought care at our facility one day after trying to pull his boat out of the water. He’d tried to lift the boat with his hands while his forearms were fully supinated and his elbows were flexed to about 90°. He then felt a sharp burning sensation in his left anterior shoulder and was unable to lift the boat. The patient denied feeling a popping sensation at the time of the injury. He had mild pain at night, but was able to sleep. He said that he had mild diminished strength with elbow flexion, but denied having any numbness, tingling, or discoloration of his skin.

The patient said he did weightlifting and strength training of his upper and lower extremities 4 times/week. He was in good general health, was not taking any medications or supplements, and denied smoking or using illicit drugs. His surgical history was significant for a Bankart repair 8 years ago.

On physical examination, the patient had a scar from the previous surgery, a hollow area in his left anterior shoulder, and a prominent biceps muscle belly (FIGURE). His shoulder range of motion was normal. Left shoulder Neer, Hawkins-Kennedy, drop-arm, cross-arm, empty can, and apprehension tests were negative. A left Speed’s test (resisted elbow flexion when elbow is flexed 20° to 30° with the forearm in supination and the arm in about 60° of flexion) was positive for mild anterior shoulder pain. So, too, was a Yergason’s test (resisted forearm supination and elbow flexion when forearm is pronated and elbow is flexed to 90°). The patient’s elbow flexion strength was 4 out of 5, and his supination strength was 5 out of 5. Neurovascular and sensory examinations of his upper extremities, including radial and ulnar pulses, were normal.

THE DIAGNOSIS

A diagnostic musculoskeletal ultrasound revealed an empty tendon sheath of the long head of the biceps in the bicipital groove and a retracted echogenic stump with associated hematoma at the proximal musculotendinous junction. Based on the patient’s history, physical examination, and ultrasound, a diagnosis of an acute rupture of the left long head of the biceps brachii tendon was made.

DISCUSSION

Diagnosis of acute rupture is often made clinically based on a visually apparent defect proximally and a bulbous mass distally (“Popeye deformity”).¹ Ultrasound and magnetic resonance imaging (MRI) may aid in the diagnosis by demonstrating an absence of the long head in the bicipital groove or at its insertion.

The biceps brachii tendon functions in flexion and supination of the forearm. The long head of the biceps also plays a stabilizing role in the glenohumeral joint during elbow flexion and supination.² Injury to the biceps most often occurs in middle-aged men following a traumatic sudden eccentric bicipital contraction event, during which most patients describe a snapping or popping sensation.^3,4

Rupture of the proximal biceps tendon represents about 90% of all biceps ruptures, which almost exclusively involve the long head of the biceps.^3,5,6 Risk factors for tendon rupture include obesity, smoking, steroid injection in or around the tendon, and previous tendinopathy.^7-10

Functional limitations. It is generally thought that functional limitations following a proximal biceps rupture are relatively minimal, due to the work of other flexors and supinators, including the brachialis and brachioradialis. However, because strength and endurance of the muscle can decrease by about 25%, physical laborers and high-demand athletes may notice a degree of residual weakness with supination and elbow flexion.^11,12

Surgical repair is recommended for acute ruptures in patients with high physical demands and for whom a slight loss of flexion and su­pination strength would not be well tolerated.¹³ Tenotomy and tenodesis are the main techniques used to surgically repair a rupture of the long head of the biceps brachii tendon. Although there is no consensus on which technique is superior, it seems that there is less cosmetic deformity and better post-surgery biomechanical strength with tenodesis compared with tenotomy.¹⁴ However, tenodesis is associated with a higher likelihood of bicipital pain,¹⁴ and recent case reports have suggested it is associated with an increased risk of humeral fracture.¹⁵ Therefore, each patient should be treated on an individual case basis, taking into account age, activity level, and physical demand.¹⁴

For most patients, treatment remains conservative with typically excellent outcomes. Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder. Such exercises can be started almost immediately after injury. In one study, nonoperative management was recommended for patients with sedentary work, injury in the non-dominant arm, and acceptable cosmetic deformity. Researchers noted that patients who opt for a nonsurgical treatment generally do well with a home exercise program and rarely have stiffness.¹

Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder.

If the patient is a young athlete, if cosmetic deformity is unacceptable, or if the injury is in the dominant arm of a laborer, then the patient may want to consider tenodesis.¹ Tangari et al found that in high-demand athletes, biceps tenodesis resulted in excellent functional and cosmetic results with no clinically significant decrease in strength after an average follow-up of 7.6 years.¹³ In a case series of 5 patients who chose nonoperative treatment, Geaney and Mazzocca reported that patients experienced a 15% loss of supination strength at 4.5 years follow-up compared with the uninjured side.¹

Our patient elected to proceed with a tenodesis procedure. Two months after the surgery, he had fully recovered.

THE TAKEAWAY

Rupture of the biceps brachii tendon is relatively uncommon. In the vast majority of cases, it happens in the long head of the dominant arm of middle-aged men. Diagnosis is mainly clinical; however, ultrasound and MRI can confirm the diagnosis when there is doubt. Nonoperative management is appropriate for the majority of patients. Young athletes, patients who are concerned with cosmetic appearance, and labor workers with injury to their dominant arm should be referred to an orthopedic surgeon for possible surgery.

THE CASE

A 41-year-old, right-hand dominant man sought care at our facility one day after trying to pull his boat out of the water. He’d tried to lift the boat with his hands while his forearms were fully supinated and his elbows were flexed to about 90°. He then felt a sharp burning sensation in his left anterior shoulder and was unable to lift the boat. The patient denied feeling a popping sensation at the time of the injury. He had mild pain at night, but was able to sleep. He said that he had mild diminished strength with elbow flexion, but denied having any numbness, tingling, or discoloration of his skin.

The patient said he did weightlifting and strength training of his upper and lower extremities 4 times/week. He was in good general health, was not taking any medications or supplements, and denied smoking or using illicit drugs. His surgical history was significant for a Bankart repair 8 years ago.

On physical examination, the patient had a scar from the previous surgery, a hollow area in his left anterior shoulder, and a prominent biceps muscle belly (FIGURE). His shoulder range of motion was normal. Left shoulder Neer, Hawkins-Kennedy, drop-arm, cross-arm, empty can, and apprehension tests were negative. A left Speed’s test (resisted elbow flexion when elbow is flexed 20° to 30° with the forearm in supination and the arm in about 60° of flexion) was positive for mild anterior shoulder pain. So, too, was a Yergason’s test (resisted forearm supination and elbow flexion when forearm is pronated and elbow is flexed to 90°). The patient’s elbow flexion strength was 4 out of 5, and his supination strength was 5 out of 5. Neurovascular and sensory examinations of his upper extremities, including radial and ulnar pulses, were normal.

THE DIAGNOSIS

A diagnostic musculoskeletal ultrasound revealed an empty tendon sheath of the long head of the biceps in the bicipital groove and a retracted echogenic stump with associated hematoma at the proximal musculotendinous junction. Based on the patient’s history, physical examination, and ultrasound, a diagnosis of an acute rupture of the left long head of the biceps brachii tendon was made.

DISCUSSION

Diagnosis of acute rupture is often made clinically based on a visually apparent defect proximally and a bulbous mass distally (“Popeye deformity”).¹ Ultrasound and magnetic resonance imaging (MRI) may aid in the diagnosis by demonstrating an absence of the long head in the bicipital groove or at its insertion.

The biceps brachii tendon functions in flexion and supination of the forearm. The long head of the biceps also plays a stabilizing role in the glenohumeral joint during elbow flexion and supination.² Injury to the biceps most often occurs in middle-aged men following a traumatic sudden eccentric bicipital contraction event, during which most patients describe a snapping or popping sensation.^3,4

Rupture of the proximal biceps tendon represents about 90% of all biceps ruptures, which almost exclusively involve the long head of the biceps.^3,5,6 Risk factors for tendon rupture include obesity, smoking, steroid injection in or around the tendon, and previous tendinopathy.^7-10

Functional limitations. It is generally thought that functional limitations following a proximal biceps rupture are relatively minimal, due to the work of other flexors and supinators, including the brachialis and brachioradialis. However, because strength and endurance of the muscle can decrease by about 25%, physical laborers and high-demand athletes may notice a degree of residual weakness with supination and elbow flexion.^11,12

Surgical repair is recommended for acute ruptures in patients with high physical demands and for whom a slight loss of flexion and su­pination strength would not be well tolerated.¹³ Tenotomy and tenodesis are the main techniques used to surgically repair a rupture of the long head of the biceps brachii tendon. Although there is no consensus on which technique is superior, it seems that there is less cosmetic deformity and better post-surgery biomechanical strength with tenodesis compared with tenotomy.¹⁴ However, tenodesis is associated with a higher likelihood of bicipital pain,¹⁴ and recent case reports have suggested it is associated with an increased risk of humeral fracture.¹⁵ Therefore, each patient should be treated on an individual case basis, taking into account age, activity level, and physical demand.¹⁴

For most patients, treatment remains conservative with typically excellent outcomes. Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder. Such exercises can be started almost immediately after injury. In one study, nonoperative management was recommended for patients with sedentary work, injury in the non-dominant arm, and acceptable cosmetic deformity. Researchers noted that patients who opt for a nonsurgical treatment generally do well with a home exercise program and rarely have stiffness.¹

Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder.

If the patient is a young athlete, if cosmetic deformity is unacceptable, or if the injury is in the dominant arm of a laborer, then the patient may want to consider tenodesis.¹ Tangari et al found that in high-demand athletes, biceps tenodesis resulted in excellent functional and cosmetic results with no clinically significant decrease in strength after an average follow-up of 7.6 years.¹³ In a case series of 5 patients who chose nonoperative treatment, Geaney and Mazzocca reported that patients experienced a 15% loss of supination strength at 4.5 years follow-up compared with the uninjured side.¹

Our patient elected to proceed with a tenodesis procedure. Two months after the surgery, he had fully recovered.

THE TAKEAWAY

Rupture of the biceps brachii tendon is relatively uncommon. In the vast majority of cases, it happens in the long head of the dominant arm of middle-aged men. Diagnosis is mainly clinical; however, ultrasound and MRI can confirm the diagnosis when there is doubt. Nonoperative management is appropriate for the majority of patients. Young athletes, patients who are concerned with cosmetic appearance, and labor workers with injury to their dominant arm should be referred to an orthopedic surgeon for possible surgery.

THE CASE

A 41-year-old, right-hand dominant man sought care at our facility one day after trying to pull his boat out of the water. He’d tried to lift the boat with his hands while his forearms were fully supinated and his elbows were flexed to about 90°. He then felt a sharp burning sensation in his left anterior shoulder and was unable to lift the boat. The patient denied feeling a popping sensation at the time of the injury. He had mild pain at night, but was able to sleep. He said that he had mild diminished strength with elbow flexion, but denied having any numbness, tingling, or discoloration of his skin.

The patient said he did weightlifting and strength training of his upper and lower extremities 4 times/week. He was in good general health, was not taking any medications or supplements, and denied smoking or using illicit drugs. His surgical history was significant for a Bankart repair 8 years ago.

On physical examination, the patient had a scar from the previous surgery, a hollow area in his left anterior shoulder, and a prominent biceps muscle belly (FIGURE). His shoulder range of motion was normal. Left shoulder Neer, Hawkins-Kennedy, drop-arm, cross-arm, empty can, and apprehension tests were negative. A left Speed’s test (resisted elbow flexion when elbow is flexed 20° to 30° with the forearm in supination and the arm in about 60° of flexion) was positive for mild anterior shoulder pain. So, too, was a Yergason’s test (resisted forearm supination and elbow flexion when forearm is pronated and elbow is flexed to 90°). The patient’s elbow flexion strength was 4 out of 5, and his supination strength was 5 out of 5. Neurovascular and sensory examinations of his upper extremities, including radial and ulnar pulses, were normal.

THE DIAGNOSIS

A diagnostic musculoskeletal ultrasound revealed an empty tendon sheath of the long head of the biceps in the bicipital groove and a retracted echogenic stump with associated hematoma at the proximal musculotendinous junction. Based on the patient’s history, physical examination, and ultrasound, a diagnosis of an acute rupture of the left long head of the biceps brachii tendon was made.

DISCUSSION

Diagnosis of acute rupture is often made clinically based on a visually apparent defect proximally and a bulbous mass distally (“Popeye deformity”).¹ Ultrasound and magnetic resonance imaging (MRI) may aid in the diagnosis by demonstrating an absence of the long head in the bicipital groove or at its insertion.

The biceps brachii tendon functions in flexion and supination of the forearm. The long head of the biceps also plays a stabilizing role in the glenohumeral joint during elbow flexion and supination.² Injury to the biceps most often occurs in middle-aged men following a traumatic sudden eccentric bicipital contraction event, during which most patients describe a snapping or popping sensation.^3,4

Rupture of the proximal biceps tendon represents about 90% of all biceps ruptures, which almost exclusively involve the long head of the biceps.^3,5,6 Risk factors for tendon rupture include obesity, smoking, steroid injection in or around the tendon, and previous tendinopathy.^7-10

Functional limitations. It is generally thought that functional limitations following a proximal biceps rupture are relatively minimal, due to the work of other flexors and supinators, including the brachialis and brachioradialis. However, because strength and endurance of the muscle can decrease by about 25%, physical laborers and high-demand athletes may notice a degree of residual weakness with supination and elbow flexion.^11,12

Surgical repair is recommended for acute ruptures in patients with high physical demands and for whom a slight loss of flexion and su­pination strength would not be well tolerated.¹³ Tenotomy and tenodesis are the main techniques used to surgically repair a rupture of the long head of the biceps brachii tendon. Although there is no consensus on which technique is superior, it seems that there is less cosmetic deformity and better post-surgery biomechanical strength with tenodesis compared with tenotomy.¹⁴ However, tenodesis is associated with a higher likelihood of bicipital pain,¹⁴ and recent case reports have suggested it is associated with an increased risk of humeral fracture.¹⁵ Therefore, each patient should be treated on an individual case basis, taking into account age, activity level, and physical demand.¹⁴

For most patients, treatment remains conservative with typically excellent outcomes. Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder. Such exercises can be started almost immediately after injury. In one study, nonoperative management was recommended for patients with sedentary work, injury in the non-dominant arm, and acceptable cosmetic deformity. Researchers noted that patients who opt for a nonsurgical treatment generally do well with a home exercise program and rarely have stiffness.¹

Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder.

If the patient is a young athlete, if cosmetic deformity is unacceptable, or if the injury is in the dominant arm of a laborer, then the patient may want to consider tenodesis.¹ Tangari et al found that in high-demand athletes, biceps tenodesis resulted in excellent functional and cosmetic results with no clinically significant decrease in strength after an average follow-up of 7.6 years.¹³ In a case series of 5 patients who chose nonoperative treatment, Geaney and Mazzocca reported that patients experienced a 15% loss of supination strength at 4.5 years follow-up compared with the uninjured side.¹

Our patient elected to proceed with a tenodesis procedure. Two months after the surgery, he had fully recovered.

THE TAKEAWAY

Rupture of the biceps brachii tendon is relatively uncommon. In the vast majority of cases, it happens in the long head of the dominant arm of middle-aged men. Diagnosis is mainly clinical; however, ultrasound and MRI can confirm the diagnosis when there is doubt. Nonoperative management is appropriate for the majority of patients. Young athletes, patients who are concerned with cosmetic appearance, and labor workers with injury to their dominant arm should be referred to an orthopedic surgeon for possible surgery.

Many patients admitted to inpatient psychiatric hospitals present with delusions; however, the Capgras delusion is a rare type that often appears as a sequela of certain medical and neurologic conditions.¹ The Capgras delusion is a condition in which a person believes that either an individual or a group of people has been replaced by doubles or imposters.

In 1923, French psychiatrist Joseph Capgras first described the delusion. He and Jean Reboul-Lachaux coauthored a paper on a 53-year-old woman. The patient was a paranoid megalomaniac who “transformed everyone in her entourage, even those closest to her, such as her husband and daughter, into various and numerous doubles.”² She believed she was famous, wealthy, and of royal lineage. Although 3 of her children had died, she believed that they were abducted, and that her only surviving child was replaced by a look-alike.^2,3 Although the prevalence of such delusions in the general population has not been fully studied, a psychiatric hospital in Turkey found a 1.3% prevalence (1.8% women and 0.9% men) in 920 admissions over 5 years.⁴

The Capgras delusion is one of many delusions related to the misidentification of people, places, or objects; these delusions collectively are known as delusional misidentification syndrome (DMS).^5,6 The Fregoli delusion involves the belief that several different people are the same person in disguise. Intermetamorphosis is the belief that an individual has been transformed internally and externally to another person. Subjective doubles is the belief that a doppelganger of the afflicted person exists, living and functioning independently in the world. Reduplicative paramnesia is the belief that a person, place, or object has been duplicated. A rarer example of DMS is the Cotard delusion, which is the belief that the patient himself or herself is dead, putrefying, exsanguinating, or lacking internal organs.

The most common of the DMS is the Capgras delusion. One common presentation of Capgras delusion involves the spouse of the patient, who believes that an imposter of the same sex as their spouse has taken over his or her body. Rarer delusions are those in which a person misidentifies him or herself as the imposter.^3,5,6

Case Presentation

This case involved a 24-year-old male veteran who had received a wide range of mental health diagnoses in the past, including major depressive disorder (MDD) with psychotic features, generalized anxiety disorder, cannabis use disorder, adjustment disorder, and borderline personality disorder. He also had a medical history related to a motor vehicle accident with subsequent intestinal rupture and colostomy placement that had occurred a year and a half prior to presentation. He had no history of brain trauma.

The patient voluntarily presented to the hospital for increased suicidal thoughts and was admitted voluntarily for stabilization and self-harm prevention. He stated that “I feel everything is unreal. I feel suicidal and guilt” and endorsed a plan to either walk into traffic or shoot himself in the head due to increasingly distressing thoughts and memories. According to the patient, he had reported to the police that he raped his ex-girlfriend a year previously, although she denied the claim to the police.

The patient further disclosed that he did not believe his mother was real. “Last year my sister told me it was not 2016, but it was 2022,” he said. “She told me that I have hurt my mother with a padlock—that you could no longer identify her face. I don’t remember having done this. I have lived with her since that time, so I don’t think it’s really [my mother].” He believed that his mother was replaced by “government employees” who were sent to elicit confessions for his behavior while in the military. He expressed guilt over several actions he had performed while in military service, such as punching a wall during boot camp, stealing “soak-up” pads, and napping during work hours. His mother was contacted by a staff psychiatrist in the inpatient unit and denied that any assault had taken place.

The patient’s psychiatric review of systems was positive for visual hallucinations (specifically “blurs” next to his bed in the morning that disappeared as he tried to touch them), depressed mood, anxiety, hopelessness, and insomnia. Pertinent negatives of the review of systems included a denial of manic symptoms and auditory hallucinations. For additional details of his past psychiatric history, the patient admitted that his motor vehicle accident, intestinal rupture, and colostomy were the result of his 1 suicide attempt a year and a half prior after a verbal dispute with the same ex-girlfriend that he believed he had raped. After undergoing extensive medical and surgical treatment, he began seeing an outpatient psychiatrist as well as attending substance use counseling to curtail his marijuana use. He was prescribed a combination of duloxetine and risperidone as an outpatient, which he was taking with intermittent adherence.

Regarding substance use, the patient admitted to using marijuana regularly in the past but quit completely 1 month prior and denied any other drug use or alcohol use. He reported a family history of a sister who was undergoing treatment for bipolar disorder. In his social history, the patient disclosed that he was raised by both parents and described a good childhood with a life absent of abuse in any form. He was single with no children. Although he was unemployed, he lived off the funds from an insurance settlement from his motor vehicle accident. He was living in a trailer with his brother and mother. He also denied having access to firearms.

The patient was overweight, neatly groomed, had good eye contact, and was calm and cooperative. He seemed anxious as evidenced by his continuous shaking of his feet; although speech was normal in rate and tone. He reported his mood as “depressed and anxious” with congruent and tearful affect. His thought process was concrete, although his thought content contained delusions, suicidal ideation, and paranoia. He denied any homicidal thoughts or thoughts of harming others. He did not present with any auditory or visual hallucinations. Insight and judgment were poor. The mental status examination revealed no notable deficits in cognition.

The patient’s differential diagnosis included schizophreniform disorder, exacerbation of MDD with psychotic features, and the psychotic component of cannabis use disorder. His outpatient risperidone and duloxetine were not restarted. Aripiprazole 15 mg daily was prescribed for his delusions, paranoia, and visual hallucinations. The patient also received a prescription for hydroxyzine 50 mg every 6 hours as needed for anxiety.

Because of the nature of his delusions, comorbid medical and neurologic conditions were considered. Neurology consultation recommended a noncontrast head computer tomography (CT) scan and an electroencephalogram (EEG). Laboratory workup included HIV antibody, thyroid panel, chemistry panel, complete blood count, hepatitis B serum antigen, urine drug screen, hepatitis C virus, and rapid plasma reagin. All laboratory results were benign and unremarkable, and the urine drug screen was negative. The noncontrast CT revealed no acute findings, and the EEG revealed no recorded epileptiform abnormalities or seizures.

Throughout his hospital course, the patient remained cooperative with treatment. Three days into the hospitalization, he stated that he believed the entire family had been replaced by imposters. He began to distrust members of his family and was reticent to communicate with them when they attempted to contact him. He also experienced fragmented sleep during his hospital stay, and trazodone 50 mg at bedtime was added.

After aripiprazole was increased to 20 mg daily on hospital day 2 and then to 30 mg daily on hospital day 3 due to the patient’s delusions, he began to doubt the validity of his beliefs. After showing gradual improvement over 6 days, the patient reported that he no longer believed that those memories were real. His sleep, depressed mood, anxiety, and paranoia had markedly improved toward the end of the hospitalization and suicidal ideation/intent resolved. The patient was discharged home to his mother and brother after 6 days of hospitalization with aripiprazole 30 mg daily and trazodone 50 mg at bedtime.

Discussion

The Capgras delusion can present in several different contexts. A psychiatric differential diagnosis includes disorders in the schizophrenia spectrum (brief psychotic disorder, schizophreniform disorder, and schizophrenia), schizoaffective disorder, delusional disorder, and substance-induced psychotic disorder. In addition to psychiatric disorders, the Capgras delusion has been shown to occur in several medical conditions, which include stroke, central nervous system tumors, subarachnoid hemorrhage, vitamin B12 deficiency, hepatic encephalopathy, hypothyroidism, hyperparathyroidism, epilepsy, and dementia.^1,2,4,7

A 2007 retrospective study by Josephs examined 47 patients diagnosed with the Capgras delusion from several tertiary care centers. Of those patients, 38 (81%) had a neurodegenerative disease, most commonly Lewy body dementia (LBD).¹ In his review of the Josephs study, Devinsky proposed that the loss of striatal D2 receptors in LBD may be implicated in the manifestation of Capgras delusions.² The data suggest multiple brain regions may be involved, including the frontal lobes, right temporal lobe, right parietal lobe, parahippocampus, and amygdala.^1,2 Most patients in the Josephs study demonstrated global atrophy on imaging studies. One hypothesis is that it is the disconnection of the frontal lobe to other brain regions that may be implicated.^1,2,4 This results in intact recognition of facial features of familiar people, impaired emotional recognition, and impaired self-correction due to executive dysfunction.

Methamphetamine also has been implicated in a small number of cases of Capgras; the proposed mechanism involves dopaminergic neuronal impairment/loss.^1,2 Additionally, Capgras delusions have been described in cases of patients treated with antimalarial medications, such as chloroquine.⁸ Younger patients with the Capgras delusion were more likely to have purely psychiatric comorbidities—such as schizophrenia, substance-induced psychosis, or schizoaffective disorder—as opposed to underlying medical conditions.¹ In the case presented here, the Capgras delusion was thought to be due to a disorder in the schizophrenia spectrum, specifically schizophreniform disorder.

Because an increasing amount of evidence indicates that the Capgras delusion is associated with certain medical conditions, a workup should be performed to rule out underlying medical etiology. Of note, no official guidelines for the workup have been produced for the Capgras delusion. However, the workup may include brain imaging, such as magnetic resonance imaging and/or CT scan to rule out mass lesions, vascular malformations, stroke, or neuro-infectious processes; laboratory tests, such as vitamin B12, liver panel, HIV, rapid plasma reagin, hepatitis B and C viruses, parathyroid hormone levels, urine drug screen, and thyroid panel can be ordered to rule out other medical causes.^1,2,6,7,9

Consultations with internal medicine and neurology departments may be beneficial. Although treatment of the underlying condition may lead to an improvement in the symptoms, full remission in all cases has not been consistently demonstrated in the current literature.^5,7,9,10 Patients with the Capgras delusion are challenging to treat, because their delusions have been shown to be refractory to antipsychotic therapy. However, antipsychotics are currently the mainstay of treatment. Some case studies have shown efficacy with pimozide, tricyclic antidepressants, and mirtazapine.^6,9

One case study in 2014 in India of a 45-year-old woman who believed her husband and son were replaced by imposters out to kill her, showed a 40% to 50% reduction of paranoia, irritability, and suspicious scanning behaviors with a combination of risperidone and trihexyphenidyl. Despite the improvements, the woman continued to have delusions.⁷

A notable feature associated with those experiencing the Capgras delusion is the increased risk of violent behaviors, often because of suspiciousness and paranoia. A 2004 review suggested the risk of violence and homicidality is much higher in male patients compared with that of female patients with the Capgras delusion.⁹ This is despite evidence suggesting that the prevalence of the Capgras delusion seems to be greater in women.^6,9 Moreover, patients often demonstrated social withdrawal and self-isolation prior to violent acts. The victims often were family members or those who live with the patient, which is consistent with the evidence that those most familiar to patients are more likely to be misidentified.^1,2,7,9,10

A 1989 case series that examined 8 cases of the Capgras delusion listed the following violent behaviors: shot and killed father, pointed knife at mother, held knife to mother’s throat, punched parents, threatened to stab husband with scissors, nonspecifically threatened physical harm to family, injured mother with axe, and threatened to stab son with knife and burn him. Seven of the 8 patients lived with the misidentified persons, and 5 of the 8 patients were treatment resistant. The study posited that chronicity of the delusion, content of the delusion, and accessibility of misidentified persons seemed to increase the risk of violent behaviors. These authors went on to suggest that despite the appearance of stability, patients may react violently to minute changes.¹⁰ Overall literature seems to suggest the importance of performing a violence and homicidality assessment with special attention to assessment for themes of hostility toward misidentified individuals.^9,10

Conclusion

The Capgras delusion is an uncommon symptom associated with varied psychiatric, medical, iatrogenic, and neurologic conditions. Treatment of underlying medical conditions may improve or resolve the delusions. However, in this case, the patient did not seem to have any underlying medical conditions, and it was thought that he may have been experiencing a prodrome within the schizophrenia spectrum. This is consistent with the literature, which suggests that those with the delusions at younger ages may have a psychiatric etiology.

Although this patient was responsive to aripiprazole, the Capgras delusion has been known to be resistant to antipsychotic therapy. It is worth considering a medical and neurologic workup with the addition of a psychiatry referral. Further, while the patient in the presented case had the delusion that he had assaulted his mother, whom he misidentified as an imposter, the patient did not demonstrate any hostility and denied thoughts of harming her. However, given the increased risk of violence in patients with the Capgras delusion, a homicidality and violence assessment should be performed. While further recommendations are outside the scope of this article, the provider should be cognizant of local duty-to-warn and duty-to-protect laws regarding potentially homicidal patients.

Many patients admitted to inpatient psychiatric hospitals present with delusions; however, the Capgras delusion is a rare type that often appears as a sequela of certain medical and neurologic conditions.¹ The Capgras delusion is a condition in which a person believes that either an individual or a group of people has been replaced by doubles or imposters.

In 1923, French psychiatrist Joseph Capgras first described the delusion. He and Jean Reboul-Lachaux coauthored a paper on a 53-year-old woman. The patient was a paranoid megalomaniac who “transformed everyone in her entourage, even those closest to her, such as her husband and daughter, into various and numerous doubles.”² She believed she was famous, wealthy, and of royal lineage. Although 3 of her children had died, she believed that they were abducted, and that her only surviving child was replaced by a look-alike.^2,3 Although the prevalence of such delusions in the general population has not been fully studied, a psychiatric hospital in Turkey found a 1.3% prevalence (1.8% women and 0.9% men) in 920 admissions over 5 years.⁴

The Capgras delusion is one of many delusions related to the misidentification of people, places, or objects; these delusions collectively are known as delusional misidentification syndrome (DMS).^5,6 The Fregoli delusion involves the belief that several different people are the same person in disguise. Intermetamorphosis is the belief that an individual has been transformed internally and externally to another person. Subjective doubles is the belief that a doppelganger of the afflicted person exists, living and functioning independently in the world. Reduplicative paramnesia is the belief that a person, place, or object has been duplicated. A rarer example of DMS is the Cotard delusion, which is the belief that the patient himself or herself is dead, putrefying, exsanguinating, or lacking internal organs.

The most common of the DMS is the Capgras delusion. One common presentation of Capgras delusion involves the spouse of the patient, who believes that an imposter of the same sex as their spouse has taken over his or her body. Rarer delusions are those in which a person misidentifies him or herself as the imposter.^3,5,6

Case Presentation

This case involved a 24-year-old male veteran who had received a wide range of mental health diagnoses in the past, including major depressive disorder (MDD) with psychotic features, generalized anxiety disorder, cannabis use disorder, adjustment disorder, and borderline personality disorder. He also had a medical history related to a motor vehicle accident with subsequent intestinal rupture and colostomy placement that had occurred a year and a half prior to presentation. He had no history of brain trauma.

The patient voluntarily presented to the hospital for increased suicidal thoughts and was admitted voluntarily for stabilization and self-harm prevention. He stated that “I feel everything is unreal. I feel suicidal and guilt” and endorsed a plan to either walk into traffic or shoot himself in the head due to increasingly distressing thoughts and memories. According to the patient, he had reported to the police that he raped his ex-girlfriend a year previously, although she denied the claim to the police.

The patient further disclosed that he did not believe his mother was real. “Last year my sister told me it was not 2016, but it was 2022,” he said. “She told me that I have hurt my mother with a padlock—that you could no longer identify her face. I don’t remember having done this. I have lived with her since that time, so I don’t think it’s really [my mother].” He believed that his mother was replaced by “government employees” who were sent to elicit confessions for his behavior while in the military. He expressed guilt over several actions he had performed while in military service, such as punching a wall during boot camp, stealing “soak-up” pads, and napping during work hours. His mother was contacted by a staff psychiatrist in the inpatient unit and denied that any assault had taken place.

The patient’s psychiatric review of systems was positive for visual hallucinations (specifically “blurs” next to his bed in the morning that disappeared as he tried to touch them), depressed mood, anxiety, hopelessness, and insomnia. Pertinent negatives of the review of systems included a denial of manic symptoms and auditory hallucinations. For additional details of his past psychiatric history, the patient admitted that his motor vehicle accident, intestinal rupture, and colostomy were the result of his 1 suicide attempt a year and a half prior after a verbal dispute with the same ex-girlfriend that he believed he had raped. After undergoing extensive medical and surgical treatment, he began seeing an outpatient psychiatrist as well as attending substance use counseling to curtail his marijuana use. He was prescribed a combination of duloxetine and risperidone as an outpatient, which he was taking with intermittent adherence.

Regarding substance use, the patient admitted to using marijuana regularly in the past but quit completely 1 month prior and denied any other drug use or alcohol use. He reported a family history of a sister who was undergoing treatment for bipolar disorder. In his social history, the patient disclosed that he was raised by both parents and described a good childhood with a life absent of abuse in any form. He was single with no children. Although he was unemployed, he lived off the funds from an insurance settlement from his motor vehicle accident. He was living in a trailer with his brother and mother. He also denied having access to firearms.

The patient was overweight, neatly groomed, had good eye contact, and was calm and cooperative. He seemed anxious as evidenced by his continuous shaking of his feet; although speech was normal in rate and tone. He reported his mood as “depressed and anxious” with congruent and tearful affect. His thought process was concrete, although his thought content contained delusions, suicidal ideation, and paranoia. He denied any homicidal thoughts or thoughts of harming others. He did not present with any auditory or visual hallucinations. Insight and judgment were poor. The mental status examination revealed no notable deficits in cognition.

The patient’s differential diagnosis included schizophreniform disorder, exacerbation of MDD with psychotic features, and the psychotic component of cannabis use disorder. His outpatient risperidone and duloxetine were not restarted. Aripiprazole 15 mg daily was prescribed for his delusions, paranoia, and visual hallucinations. The patient also received a prescription for hydroxyzine 50 mg every 6 hours as needed for anxiety.

Because of the nature of his delusions, comorbid medical and neurologic conditions were considered. Neurology consultation recommended a noncontrast head computer tomography (CT) scan and an electroencephalogram (EEG). Laboratory workup included HIV antibody, thyroid panel, chemistry panel, complete blood count, hepatitis B serum antigen, urine drug screen, hepatitis C virus, and rapid plasma reagin. All laboratory results were benign and unremarkable, and the urine drug screen was negative. The noncontrast CT revealed no acute findings, and the EEG revealed no recorded epileptiform abnormalities or seizures.

Throughout his hospital course, the patient remained cooperative with treatment. Three days into the hospitalization, he stated that he believed the entire family had been replaced by imposters. He began to distrust members of his family and was reticent to communicate with them when they attempted to contact him. He also experienced fragmented sleep during his hospital stay, and trazodone 50 mg at bedtime was added.

After aripiprazole was increased to 20 mg daily on hospital day 2 and then to 30 mg daily on hospital day 3 due to the patient’s delusions, he began to doubt the validity of his beliefs. After showing gradual improvement over 6 days, the patient reported that he no longer believed that those memories were real. His sleep, depressed mood, anxiety, and paranoia had markedly improved toward the end of the hospitalization and suicidal ideation/intent resolved. The patient was discharged home to his mother and brother after 6 days of hospitalization with aripiprazole 30 mg daily and trazodone 50 mg at bedtime.

Discussion

The Capgras delusion can present in several different contexts. A psychiatric differential diagnosis includes disorders in the schizophrenia spectrum (brief psychotic disorder, schizophreniform disorder, and schizophrenia), schizoaffective disorder, delusional disorder, and substance-induced psychotic disorder. In addition to psychiatric disorders, the Capgras delusion has been shown to occur in several medical conditions, which include stroke, central nervous system tumors, subarachnoid hemorrhage, vitamin B12 deficiency, hepatic encephalopathy, hypothyroidism, hyperparathyroidism, epilepsy, and dementia.^1,2,4,7

A 2007 retrospective study by Josephs examined 47 patients diagnosed with the Capgras delusion from several tertiary care centers. Of those patients, 38 (81%) had a neurodegenerative disease, most commonly Lewy body dementia (LBD).¹ In his review of the Josephs study, Devinsky proposed that the loss of striatal D2 receptors in LBD may be implicated in the manifestation of Capgras delusions.² The data suggest multiple brain regions may be involved, including the frontal lobes, right temporal lobe, right parietal lobe, parahippocampus, and amygdala.^1,2 Most patients in the Josephs study demonstrated global atrophy on imaging studies. One hypothesis is that it is the disconnection of the frontal lobe to other brain regions that may be implicated.^1,2,4 This results in intact recognition of facial features of familiar people, impaired emotional recognition, and impaired self-correction due to executive dysfunction.

Methamphetamine also has been implicated in a small number of cases of Capgras; the proposed mechanism involves dopaminergic neuronal impairment/loss.^1,2 Additionally, Capgras delusions have been described in cases of patients treated with antimalarial medications, such as chloroquine.⁸ Younger patients with the Capgras delusion were more likely to have purely psychiatric comorbidities—such as schizophrenia, substance-induced psychosis, or schizoaffective disorder—as opposed to underlying medical conditions.¹ In the case presented here, the Capgras delusion was thought to be due to a disorder in the schizophrenia spectrum, specifically schizophreniform disorder.

Because an increasing amount of evidence indicates that the Capgras delusion is associated with certain medical conditions, a workup should be performed to rule out underlying medical etiology. Of note, no official guidelines for the workup have been produced for the Capgras delusion. However, the workup may include brain imaging, such as magnetic resonance imaging and/or CT scan to rule out mass lesions, vascular malformations, stroke, or neuro-infectious processes; laboratory tests, such as vitamin B12, liver panel, HIV, rapid plasma reagin, hepatitis B and C viruses, parathyroid hormone levels, urine drug screen, and thyroid panel can be ordered to rule out other medical causes.^1,2,6,7,9

Consultations with internal medicine and neurology departments may be beneficial. Although treatment of the underlying condition may lead to an improvement in the symptoms, full remission in all cases has not been consistently demonstrated in the current literature.^5,7,9,10 Patients with the Capgras delusion are challenging to treat, because their delusions have been shown to be refractory to antipsychotic therapy. However, antipsychotics are currently the mainstay of treatment. Some case studies have shown efficacy with pimozide, tricyclic antidepressants, and mirtazapine.^6,9

One case study in 2014 in India of a 45-year-old woman who believed her husband and son were replaced by imposters out to kill her, showed a 40% to 50% reduction of paranoia, irritability, and suspicious scanning behaviors with a combination of risperidone and trihexyphenidyl. Despite the improvements, the woman continued to have delusions.⁷

A notable feature associated with those experiencing the Capgras delusion is the increased risk of violent behaviors, often because of suspiciousness and paranoia. A 2004 review suggested the risk of violence and homicidality is much higher in male patients compared with that of female patients with the Capgras delusion.⁹ This is despite evidence suggesting that the prevalence of the Capgras delusion seems to be greater in women.^6,9 Moreover, patients often demonstrated social withdrawal and self-isolation prior to violent acts. The victims often were family members or those who live with the patient, which is consistent with the evidence that those most familiar to patients are more likely to be misidentified.^1,2,7,9,10

A 1989 case series that examined 8 cases of the Capgras delusion listed the following violent behaviors: shot and killed father, pointed knife at mother, held knife to mother’s throat, punched parents, threatened to stab husband with scissors, nonspecifically threatened physical harm to family, injured mother with axe, and threatened to stab son with knife and burn him. Seven of the 8 patients lived with the misidentified persons, and 5 of the 8 patients were treatment resistant. The study posited that chronicity of the delusion, content of the delusion, and accessibility of misidentified persons seemed to increase the risk of violent behaviors. These authors went on to suggest that despite the appearance of stability, patients may react violently to minute changes.¹⁰ Overall literature seems to suggest the importance of performing a violence and homicidality assessment with special attention to assessment for themes of hostility toward misidentified individuals.^9,10

Conclusion

The Capgras delusion is an uncommon symptom associated with varied psychiatric, medical, iatrogenic, and neurologic conditions. Treatment of underlying medical conditions may improve or resolve the delusions. However, in this case, the patient did not seem to have any underlying medical conditions, and it was thought that he may have been experiencing a prodrome within the schizophrenia spectrum. This is consistent with the literature, which suggests that those with the delusions at younger ages may have a psychiatric etiology.

Although this patient was responsive to aripiprazole, the Capgras delusion has been known to be resistant to antipsychotic therapy. It is worth considering a medical and neurologic workup with the addition of a psychiatry referral. Further, while the patient in the presented case had the delusion that he had assaulted his mother, whom he misidentified as an imposter, the patient did not demonstrate any hostility and denied thoughts of harming her. However, given the increased risk of violence in patients with the Capgras delusion, a homicidality and violence assessment should be performed. While further recommendations are outside the scope of this article, the provider should be cognizant of local duty-to-warn and duty-to-protect laws regarding potentially homicidal patients.

Many patients admitted to inpatient psychiatric hospitals present with delusions; however, the Capgras delusion is a rare type that often appears as a sequela of certain medical and neurologic conditions.¹ The Capgras delusion is a condition in which a person believes that either an individual or a group of people has been replaced by doubles or imposters.

In 1923, French psychiatrist Joseph Capgras first described the delusion. He and Jean Reboul-Lachaux coauthored a paper on a 53-year-old woman. The patient was a paranoid megalomaniac who “transformed everyone in her entourage, even those closest to her, such as her husband and daughter, into various and numerous doubles.”² She believed she was famous, wealthy, and of royal lineage. Although 3 of her children had died, she believed that they were abducted, and that her only surviving child was replaced by a look-alike.^2,3 Although the prevalence of such delusions in the general population has not been fully studied, a psychiatric hospital in Turkey found a 1.3% prevalence (1.8% women and 0.9% men) in 920 admissions over 5 years.⁴

The Capgras delusion is one of many delusions related to the misidentification of people, places, or objects; these delusions collectively are known as delusional misidentification syndrome (DMS).^5,6 The Fregoli delusion involves the belief that several different people are the same person in disguise. Intermetamorphosis is the belief that an individual has been transformed internally and externally to another person. Subjective doubles is the belief that a doppelganger of the afflicted person exists, living and functioning independently in the world. Reduplicative paramnesia is the belief that a person, place, or object has been duplicated. A rarer example of DMS is the Cotard delusion, which is the belief that the patient himself or herself is dead, putrefying, exsanguinating, or lacking internal organs.

The most common of the DMS is the Capgras delusion. One common presentation of Capgras delusion involves the spouse of the patient, who believes that an imposter of the same sex as their spouse has taken over his or her body. Rarer delusions are those in which a person misidentifies him or herself as the imposter.^3,5,6

Case Presentation

This case involved a 24-year-old male veteran who had received a wide range of mental health diagnoses in the past, including major depressive disorder (MDD) with psychotic features, generalized anxiety disorder, cannabis use disorder, adjustment disorder, and borderline personality disorder. He also had a medical history related to a motor vehicle accident with subsequent intestinal rupture and colostomy placement that had occurred a year and a half prior to presentation. He had no history of brain trauma.

The patient voluntarily presented to the hospital for increased suicidal thoughts and was admitted voluntarily for stabilization and self-harm prevention. He stated that “I feel everything is unreal. I feel suicidal and guilt” and endorsed a plan to either walk into traffic or shoot himself in the head due to increasingly distressing thoughts and memories. According to the patient, he had reported to the police that he raped his ex-girlfriend a year previously, although she denied the claim to the police.

The patient further disclosed that he did not believe his mother was real. “Last year my sister told me it was not 2016, but it was 2022,” he said. “She told me that I have hurt my mother with a padlock—that you could no longer identify her face. I don’t remember having done this. I have lived with her since that time, so I don’t think it’s really [my mother].” He believed that his mother was replaced by “government employees” who were sent to elicit confessions for his behavior while in the military. He expressed guilt over several actions he had performed while in military service, such as punching a wall during boot camp, stealing “soak-up” pads, and napping during work hours. His mother was contacted by a staff psychiatrist in the inpatient unit and denied that any assault had taken place.

The patient’s psychiatric review of systems was positive for visual hallucinations (specifically “blurs” next to his bed in the morning that disappeared as he tried to touch them), depressed mood, anxiety, hopelessness, and insomnia. Pertinent negatives of the review of systems included a denial of manic symptoms and auditory hallucinations. For additional details of his past psychiatric history, the patient admitted that his motor vehicle accident, intestinal rupture, and colostomy were the result of his 1 suicide attempt a year and a half prior after a verbal dispute with the same ex-girlfriend that he believed he had raped. After undergoing extensive medical and surgical treatment, he began seeing an outpatient psychiatrist as well as attending substance use counseling to curtail his marijuana use. He was prescribed a combination of duloxetine and risperidone as an outpatient, which he was taking with intermittent adherence.

Regarding substance use, the patient admitted to using marijuana regularly in the past but quit completely 1 month prior and denied any other drug use or alcohol use. He reported a family history of a sister who was undergoing treatment for bipolar disorder. In his social history, the patient disclosed that he was raised by both parents and described a good childhood with a life absent of abuse in any form. He was single with no children. Although he was unemployed, he lived off the funds from an insurance settlement from his motor vehicle accident. He was living in a trailer with his brother and mother. He also denied having access to firearms.

The patient was overweight, neatly groomed, had good eye contact, and was calm and cooperative. He seemed anxious as evidenced by his continuous shaking of his feet; although speech was normal in rate and tone. He reported his mood as “depressed and anxious” with congruent and tearful affect. His thought process was concrete, although his thought content contained delusions, suicidal ideation, and paranoia. He denied any homicidal thoughts or thoughts of harming others. He did not present with any auditory or visual hallucinations. Insight and judgment were poor. The mental status examination revealed no notable deficits in cognition.

The patient’s differential diagnosis included schizophreniform disorder, exacerbation of MDD with psychotic features, and the psychotic component of cannabis use disorder. His outpatient risperidone and duloxetine were not restarted. Aripiprazole 15 mg daily was prescribed for his delusions, paranoia, and visual hallucinations. The patient also received a prescription for hydroxyzine 50 mg every 6 hours as needed for anxiety.

Because of the nature of his delusions, comorbid medical and neurologic conditions were considered. Neurology consultation recommended a noncontrast head computer tomography (CT) scan and an electroencephalogram (EEG). Laboratory workup included HIV antibody, thyroid panel, chemistry panel, complete blood count, hepatitis B serum antigen, urine drug screen, hepatitis C virus, and rapid plasma reagin. All laboratory results were benign and unremarkable, and the urine drug screen was negative. The noncontrast CT revealed no acute findings, and the EEG revealed no recorded epileptiform abnormalities or seizures.

Throughout his hospital course, the patient remained cooperative with treatment. Three days into the hospitalization, he stated that he believed the entire family had been replaced by imposters. He began to distrust members of his family and was reticent to communicate with them when they attempted to contact him. He also experienced fragmented sleep during his hospital stay, and trazodone 50 mg at bedtime was added.

After aripiprazole was increased to 20 mg daily on hospital day 2 and then to 30 mg daily on hospital day 3 due to the patient’s delusions, he began to doubt the validity of his beliefs. After showing gradual improvement over 6 days, the patient reported that he no longer believed that those memories were real. His sleep, depressed mood, anxiety, and paranoia had markedly improved toward the end of the hospitalization and suicidal ideation/intent resolved. The patient was discharged home to his mother and brother after 6 days of hospitalization with aripiprazole 30 mg daily and trazodone 50 mg at bedtime.

Discussion

The Capgras delusion can present in several different contexts. A psychiatric differential diagnosis includes disorders in the schizophrenia spectrum (brief psychotic disorder, schizophreniform disorder, and schizophrenia), schizoaffective disorder, delusional disorder, and substance-induced psychotic disorder. In addition to psychiatric disorders, the Capgras delusion has been shown to occur in several medical conditions, which include stroke, central nervous system tumors, subarachnoid hemorrhage, vitamin B12 deficiency, hepatic encephalopathy, hypothyroidism, hyperparathyroidism, epilepsy, and dementia.^1,2,4,7

A 2007 retrospective study by Josephs examined 47 patients diagnosed with the Capgras delusion from several tertiary care centers. Of those patients, 38 (81%) had a neurodegenerative disease, most commonly Lewy body dementia (LBD).¹ In his review of the Josephs study, Devinsky proposed that the loss of striatal D2 receptors in LBD may be implicated in the manifestation of Capgras delusions.² The data suggest multiple brain regions may be involved, including the frontal lobes, right temporal lobe, right parietal lobe, parahippocampus, and amygdala.^1,2 Most patients in the Josephs study demonstrated global atrophy on imaging studies. One hypothesis is that it is the disconnection of the frontal lobe to other brain regions that may be implicated.^1,2,4 This results in intact recognition of facial features of familiar people, impaired emotional recognition, and impaired self-correction due to executive dysfunction.

Methamphetamine also has been implicated in a small number of cases of Capgras; the proposed mechanism involves dopaminergic neuronal impairment/loss.^1,2 Additionally, Capgras delusions have been described in cases of patients treated with antimalarial medications, such as chloroquine.⁸ Younger patients with the Capgras delusion were more likely to have purely psychiatric comorbidities—such as schizophrenia, substance-induced psychosis, or schizoaffective disorder—as opposed to underlying medical conditions.¹ In the case presented here, the Capgras delusion was thought to be due to a disorder in the schizophrenia spectrum, specifically schizophreniform disorder.

Because an increasing amount of evidence indicates that the Capgras delusion is associated with certain medical conditions, a workup should be performed to rule out underlying medical etiology. Of note, no official guidelines for the workup have been produced for the Capgras delusion. However, the workup may include brain imaging, such as magnetic resonance imaging and/or CT scan to rule out mass lesions, vascular malformations, stroke, or neuro-infectious processes; laboratory tests, such as vitamin B12, liver panel, HIV, rapid plasma reagin, hepatitis B and C viruses, parathyroid hormone levels, urine drug screen, and thyroid panel can be ordered to rule out other medical causes.^1,2,6,7,9

Consultations with internal medicine and neurology departments may be beneficial. Although treatment of the underlying condition may lead to an improvement in the symptoms, full remission in all cases has not been consistently demonstrated in the current literature.^5,7,9,10 Patients with the Capgras delusion are challenging to treat, because their delusions have been shown to be refractory to antipsychotic therapy. However, antipsychotics are currently the mainstay of treatment. Some case studies have shown efficacy with pimozide, tricyclic antidepressants, and mirtazapine.^6,9

One case study in 2014 in India of a 45-year-old woman who believed her husband and son were replaced by imposters out to kill her, showed a 40% to 50% reduction of paranoia, irritability, and suspicious scanning behaviors with a combination of risperidone and trihexyphenidyl. Despite the improvements, the woman continued to have delusions.⁷

A notable feature associated with those experiencing the Capgras delusion is the increased risk of violent behaviors, often because of suspiciousness and paranoia. A 2004 review suggested the risk of violence and homicidality is much higher in male patients compared with that of female patients with the Capgras delusion.⁹ This is despite evidence suggesting that the prevalence of the Capgras delusion seems to be greater in women.^6,9 Moreover, patients often demonstrated social withdrawal and self-isolation prior to violent acts. The victims often were family members or those who live with the patient, which is consistent with the evidence that those most familiar to patients are more likely to be misidentified.^1,2,7,9,10

A 1989 case series that examined 8 cases of the Capgras delusion listed the following violent behaviors: shot and killed father, pointed knife at mother, held knife to mother’s throat, punched parents, threatened to stab husband with scissors, nonspecifically threatened physical harm to family, injured mother with axe, and threatened to stab son with knife and burn him. Seven of the 8 patients lived with the misidentified persons, and 5 of the 8 patients were treatment resistant. The study posited that chronicity of the delusion, content of the delusion, and accessibility of misidentified persons seemed to increase the risk of violent behaviors. These authors went on to suggest that despite the appearance of stability, patients may react violently to minute changes.¹⁰ Overall literature seems to suggest the importance of performing a violence and homicidality assessment with special attention to assessment for themes of hostility toward misidentified individuals.^9,10

Conclusion

The Capgras delusion is an uncommon symptom associated with varied psychiatric, medical, iatrogenic, and neurologic conditions. Treatment of underlying medical conditions may improve or resolve the delusions. However, in this case, the patient did not seem to have any underlying medical conditions, and it was thought that he may have been experiencing a prodrome within the schizophrenia spectrum. This is consistent with the literature, which suggests that those with the delusions at younger ages may have a psychiatric etiology.

Although this patient was responsive to aripiprazole, the Capgras delusion has been known to be resistant to antipsychotic therapy. It is worth considering a medical and neurologic workup with the addition of a psychiatry referral. Further, while the patient in the presented case had the delusion that he had assaulted his mother, whom he misidentified as an imposter, the patient did not demonstrate any hostility and denied thoughts of harming her. However, given the increased risk of violence in patients with the Capgras delusion, a homicidality and violence assessment should be performed. While further recommendations are outside the scope of this article, the provider should be cognizant of local duty-to-warn and duty-to-protect laws regarding potentially homicidal patients.

Take-Home Points

• Malignant transformation of a benign GCT is extremely rare.
• It is difficult to distinguish between an early malignant transformation and an overlooked malignancy.
• The most common clinical presentation of transformation of GCT into malignancy is pain, often with swelling.
• Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation.
• Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the wound site.

Giant cell tumors (GCTs) of bone account for about 5% of all primary bone tumors in adults, with a predominance in the third decade in life.¹ Clinically, GCT of bone often presents with pain, pathologic fracture, and/or soft- tissue expansion in the epiphysis of long bones. However, GCT of bone also has been reported in non-long bones, such as the talus and the calcaneus.^2,3 Histologically, GCT of bone consists of neoplastic stromal cells, mononuclear histiocytic cells, and multinucleated giant cells that resemble osteoclasts.⁴ The radiologic appearance of GCT is often described as a lytic, eccentrically located bony lesion that extends near the articular surface in patients with closed physes. Many GCTs have aggressive radiologic features with possible extensive bony destruction and soft-tissue extension. 

Although categorized as a benign lesion, GCT can be locally aggressive, with a variable local recurrence rate of 0% to 65%, depending on treatment modality and skeletal location. Given the aggressiveness of GCT of bone, recommendations for operative intervention include intralesional curettage with adjuvant therapy (eg, cryotherapy, phenol, argon beam, electrocautery) and placement of bone void fillers (eg, bone graft polymethylmethacrylate). Wide resection is recommended when the articular surface is no longer viable for reconstruction secondary to extensive destruction. Some authors have reported that surgical margin is the only risk factor in local recurrence,^5,6 and thus complete resection may be needed for tumor eradication. In addition, about 3% of GCTs demonstrate benign pulmonary implants, which have been cited as cause of death in 16% to 25% of reported cases of pulmonary spread.^7,8

The literature includes few reports of primary or secondary malignant transformation of GCT. Hutter and colleagues⁹ defined primary malignant GCT as GCT with sarcomatous tissue juxtaposed with zones of typical benign GCT cells. Secondary malignant GCT is a sarcomatous lesion at the site of a previously documented benign GCT. Secondary malignant GCT of bone histologically has been classified as a fibrosarcoma, malignant fibrous histiocytoma, or osteosarcoma transformation.¹⁰ 

Most malignant transformations of GCT of bone have been attributed to previous irradiation of the lesion.^11,12 However, there are some case reports of benign bone GCT malignant transformation in situ without any other medical intervention. It was reported that non-radiation-induced secondary transformations occur relatively early after GCT treatment.¹³ During the early stages of tumor recurrence, however, it is difficult to distinguish between malignant transformation and primary disease overlooked as a result of sampling error.

We report a case of secondary malignant transformation of GCT of bone 11 years after surgical curettage, cryotherapy, and cementation without adjuvant radiation therapy. To our knowledge, this case report is the first to describe transformation of a nonirradiated benign GCT into an aggressive, high-grade epithelioid angiosarcoma, a very rare vascular bone tumor. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In July 2003, a 46-year-old woman presented with left heel pain of several months’ duration. Plain radiographs showed a nonaggressive-appearing lytic lesion of the superior aspect of the posterior calcaneal tuberosity with a small cortical incongruity along the superior margin of the lesion (Figures 1A-1D).

A postoperative splint was placed, and weight-bearing progressed over 6 weeks. The patient was followed at 2- to 3-month intervals over the first 5 postoperative years. She was able to work and perform activities of daily living, but her postoperative course was complicated by significant chronic pain in multiple extremities and long-term treatment by the chronic pain service. At no time did postoperative imaging—magnetic resonance imaging (MRI) at 6 years, whole-body bone scan at 7 years, plain radiographs at 10 years—show evidence of recurrence.

Radiographs showed stable postoperative changes with a small radiolucent area (with sclerotic rim) surrounding the cement-bone interface. Given its proximity to the Achilles tendon and more motion than usual at the wound site, the radiolucency likely was caused by small movements of the interface. The radiolucent area remained stable over a 15-month period.

Whole-body bone scan showed a small area of osteoblastic activity in the left calcaneus, consistent with inflammation surrounding the bone- cement interface, but the uptake was minor relative to other areas of signal, and there were no significant inflammatory reactive changes on MRI (Figures 3A, 3B).

Over 11 years, regular 6- to 12-month follow-up examinations revealed no significant changes in the left foot or in plain radiographs of the chest. In addition, physical examinations revealed no evidence of a palpable mass of the left foot.

In July 2014 (11 years after curettage and cementation), the patient presented to her pain clinic appointment with severe left foot pain. She said that, over a few weeks, she experienced a significant increase in pain and developed posterolateral foot swelling, which limited her ability to ambulate. Plain radiographs showed a significant soft-tissue prominence around the posterior calcaneus, increased lucency around the bone-cement interface in the calcaneus with elevation, and a cortical break of the superior margin of the posterior calcaneus (Figures 3C, 3D). MRI showed a large lobular mass in the calcaneus and surrounding soft tissue with T1 and T2 signal heterogeneity and enhancement after administration of gadolinium (Figures 4A-4D). There was a large extraosseous extension of the calcaneus-based mass laterally and superiorly with edema in the surrounding hindfoot region (Figure 4).

Physical examination revealed exquisite tenderness along the lateral and posterior aspects of the left hindfoot. The patient was unable to bear weight and had soft-tissue swelling throughout the foot and mid calf as well as a palpable mass in the posterior heel. She was otherwise neurovascularly intact through all distributions of the left lower extremity. It was unclear if the GCT of the calcaneus had recurred or if there was a new, secondary tumor. Given her severe pain and morbidity, the patient decided to proceed with open biopsy and a pathology-pending plan for possible amputation in the near future.

In August 2014, an open biopsy with intraoperative frozen evaluation yielded a diagnosis of malignant neoplasm not otherwise specified. Permanent sections showed a proliferation of malignant epithelioid cells with extensive necrosis, hemorrhage, and hemosiderin deposition but no multinucleated giant cells.

Transformation of the GCT into a high-grade epithelioid angiosarcoma prompted presentation of the patient’s case to a multidisciplinary board of physicians with a focused clinical practice in sarcoma management. The board included board-certified specialists in orthopedic oncology, pathology, musculoskeletal radiology, medical oncology, and radiation oncology. Although discussion included pre-resection use of neoadjuvant chemotherapy to evaluate for disease response, the patient’s severe pain led her to forgo this treatment and proceed directly to below-knee amputation.

Amputation revealed a 7.7-cm hemorrhagic necrotic mass composed of a highly cellular spindle and epithelioid malignancy with abundant hemosiderin deposition (Figure 5). In addition, several atypical mitotic figures and malignant multinucleated tumor giant cells were randomly scattered throughout the neoplasm.

At first follow-up, the patient reported significant pain relief and asked to begin titrating off her chronic pain medicine. Clinical staging, which involved performing whole-body positron emission tomography/computed tomography, revealed nothing concerning for metastases. When this report was being written, the patient was being monitored for recurrent disease in accordance with National Comprehensive Cancer Network guidelines. In the absence of residual sarcoma, our medical oncology team discussed adjuvant chemotherapy options with her. Subsequently, however, she proceeded only with observation and periodic imaging.

Malignant transformation of a benign GCT is extremely rare, especially in cases in which the tumor bed has not previously undergone radiation therapy. Although the literature includes historical case reports, primary and secondary malignant GCTs comprise <9% of all GCTs.^11,13,14 Primary bone epithelioid angiosarcoma is also extremely rare, especially in the calcaneus; only 1 case is described in the literature.¹⁵ In this article, we report on a benign GCT of bone that transformed into an epithelioid angiosarcoma more than a decade after the GCT was treated with curettage and cementation.

The fact that the malignant areas of a previous tumor may have been missed because of sampling error is important for benign GCT of bone in the early postoperative period, as distinguishing between early malignant transformation and an overlooked malignancy may not be possible. However, transformation is more likely the case when a benign GCT becomes a high-grade malignancy after a long disease-free interval. Several authors have indicated that a benign GCT tumor recurring with a secondary malignancy 2 to 5 years after initial GCT treatment suggests malignant transformation.¹⁶ Grote and colleagues¹⁰ compiled reports of malignant transformation of GCT of bone and described the clinicopathologic features of secondary malignant transformation of GCTs. The data they compiled and data from several other studies indicate a poor prognosis after malignant transformation of GCT; 4 years after diagnosis, mean survival is 40% to 50%.^10,16 The most common clinical presentation of transformation of GCT into malignancy is pain, often with coincident swelling of the native wound bed. However, a few cases have been identified with radiologic imaging alone and without a period of clinical symptoms.¹⁶

To our knowledge, this case report is the first to describe a longitudinal assessment of the transformation of a benign GCT of bone into an epithelioid angiosarcoma. Whereas an earlier reported GCT of bone transformed into epithelioid angiosarcoma after irradiation,¹² our patient’s GCT of bone transformed without irradiation. GCTs of bone are locally aggressive benign tumors and are relatively rare. Malignant transformation of a benign bone tumor a decade after initial, definitive treatment is concerning, especially given the poor prognosis after malignant transformation in this clinical scenario. Current adjuvant treatments have not changed the prognosis. The literature includes a wide variety of histologic transformations, including high-grade sarcomas, after a long disease-free interval. Although malignant transformation of benign GCTs is rare, clinicians should be aware of the potential. Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation—pain or swelling in the wound bed—and patients should know to immediately inform their physician of any changes in pain level or local wound bed. Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the site of a previously treated GCT of bone with a disease-free interval of several years.

Take-Home Points

• Malignant transformation of a benign GCT is extremely rare.
• It is difficult to distinguish between an early malignant transformation and an overlooked malignancy.
• The most common clinical presentation of transformation of GCT into malignancy is pain, often with swelling.
• Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation.
• Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the wound site.

Giant cell tumors (GCTs) of bone account for about 5% of all primary bone tumors in adults, with a predominance in the third decade in life.¹ Clinically, GCT of bone often presents with pain, pathologic fracture, and/or soft- tissue expansion in the epiphysis of long bones. However, GCT of bone also has been reported in non-long bones, such as the talus and the calcaneus.^2,3 Histologically, GCT of bone consists of neoplastic stromal cells, mononuclear histiocytic cells, and multinucleated giant cells that resemble osteoclasts.⁴ The radiologic appearance of GCT is often described as a lytic, eccentrically located bony lesion that extends near the articular surface in patients with closed physes. Many GCTs have aggressive radiologic features with possible extensive bony destruction and soft-tissue extension. 

Although categorized as a benign lesion, GCT can be locally aggressive, with a variable local recurrence rate of 0% to 65%, depending on treatment modality and skeletal location. Given the aggressiveness of GCT of bone, recommendations for operative intervention include intralesional curettage with adjuvant therapy (eg, cryotherapy, phenol, argon beam, electrocautery) and placement of bone void fillers (eg, bone graft polymethylmethacrylate). Wide resection is recommended when the articular surface is no longer viable for reconstruction secondary to extensive destruction. Some authors have reported that surgical margin is the only risk factor in local recurrence,^5,6 and thus complete resection may be needed for tumor eradication. In addition, about 3% of GCTs demonstrate benign pulmonary implants, which have been cited as cause of death in 16% to 25% of reported cases of pulmonary spread.^7,8

The literature includes few reports of primary or secondary malignant transformation of GCT. Hutter and colleagues⁹ defined primary malignant GCT as GCT with sarcomatous tissue juxtaposed with zones of typical benign GCT cells. Secondary malignant GCT is a sarcomatous lesion at the site of a previously documented benign GCT. Secondary malignant GCT of bone histologically has been classified as a fibrosarcoma, malignant fibrous histiocytoma, or osteosarcoma transformation.¹⁰ 

Most malignant transformations of GCT of bone have been attributed to previous irradiation of the lesion.^11,12 However, there are some case reports of benign bone GCT malignant transformation in situ without any other medical intervention. It was reported that non-radiation-induced secondary transformations occur relatively early after GCT treatment.¹³ During the early stages of tumor recurrence, however, it is difficult to distinguish between malignant transformation and primary disease overlooked as a result of sampling error.

We report a case of secondary malignant transformation of GCT of bone 11 years after surgical curettage, cryotherapy, and cementation without adjuvant radiation therapy. To our knowledge, this case report is the first to describe transformation of a nonirradiated benign GCT into an aggressive, high-grade epithelioid angiosarcoma, a very rare vascular bone tumor. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In July 2003, a 46-year-old woman presented with left heel pain of several months’ duration. Plain radiographs showed a nonaggressive-appearing lytic lesion of the superior aspect of the posterior calcaneal tuberosity with a small cortical incongruity along the superior margin of the lesion (Figures 1A-1D).

A postoperative splint was placed, and weight-bearing progressed over 6 weeks. The patient was followed at 2- to 3-month intervals over the first 5 postoperative years. She was able to work and perform activities of daily living, but her postoperative course was complicated by significant chronic pain in multiple extremities and long-term treatment by the chronic pain service. At no time did postoperative imaging—magnetic resonance imaging (MRI) at 6 years, whole-body bone scan at 7 years, plain radiographs at 10 years—show evidence of recurrence.

Radiographs showed stable postoperative changes with a small radiolucent area (with sclerotic rim) surrounding the cement-bone interface. Given its proximity to the Achilles tendon and more motion than usual at the wound site, the radiolucency likely was caused by small movements of the interface. The radiolucent area remained stable over a 15-month period.

Whole-body bone scan showed a small area of osteoblastic activity in the left calcaneus, consistent with inflammation surrounding the bone- cement interface, but the uptake was minor relative to other areas of signal, and there were no significant inflammatory reactive changes on MRI (Figures 3A, 3B).

Over 11 years, regular 6- to 12-month follow-up examinations revealed no significant changes in the left foot or in plain radiographs of the chest. In addition, physical examinations revealed no evidence of a palpable mass of the left foot.

In July 2014 (11 years after curettage and cementation), the patient presented to her pain clinic appointment with severe left foot pain. She said that, over a few weeks, she experienced a significant increase in pain and developed posterolateral foot swelling, which limited her ability to ambulate. Plain radiographs showed a significant soft-tissue prominence around the posterior calcaneus, increased lucency around the bone-cement interface in the calcaneus with elevation, and a cortical break of the superior margin of the posterior calcaneus (Figures 3C, 3D). MRI showed a large lobular mass in the calcaneus and surrounding soft tissue with T1 and T2 signal heterogeneity and enhancement after administration of gadolinium (Figures 4A-4D). There was a large extraosseous extension of the calcaneus-based mass laterally and superiorly with edema in the surrounding hindfoot region (Figure 4).

Physical examination revealed exquisite tenderness along the lateral and posterior aspects of the left hindfoot. The patient was unable to bear weight and had soft-tissue swelling throughout the foot and mid calf as well as a palpable mass in the posterior heel. She was otherwise neurovascularly intact through all distributions of the left lower extremity. It was unclear if the GCT of the calcaneus had recurred or if there was a new, secondary tumor. Given her severe pain and morbidity, the patient decided to proceed with open biopsy and a pathology-pending plan for possible amputation in the near future.

In August 2014, an open biopsy with intraoperative frozen evaluation yielded a diagnosis of malignant neoplasm not otherwise specified. Permanent sections showed a proliferation of malignant epithelioid cells with extensive necrosis, hemorrhage, and hemosiderin deposition but no multinucleated giant cells.

Transformation of the GCT into a high-grade epithelioid angiosarcoma prompted presentation of the patient’s case to a multidisciplinary board of physicians with a focused clinical practice in sarcoma management. The board included board-certified specialists in orthopedic oncology, pathology, musculoskeletal radiology, medical oncology, and radiation oncology. Although discussion included pre-resection use of neoadjuvant chemotherapy to evaluate for disease response, the patient’s severe pain led her to forgo this treatment and proceed directly to below-knee amputation.

Amputation revealed a 7.7-cm hemorrhagic necrotic mass composed of a highly cellular spindle and epithelioid malignancy with abundant hemosiderin deposition (Figure 5). In addition, several atypical mitotic figures and malignant multinucleated tumor giant cells were randomly scattered throughout the neoplasm.

At first follow-up, the patient reported significant pain relief and asked to begin titrating off her chronic pain medicine. Clinical staging, which involved performing whole-body positron emission tomography/computed tomography, revealed nothing concerning for metastases. When this report was being written, the patient was being monitored for recurrent disease in accordance with National Comprehensive Cancer Network guidelines. In the absence of residual sarcoma, our medical oncology team discussed adjuvant chemotherapy options with her. Subsequently, however, she proceeded only with observation and periodic imaging.

Malignant transformation of a benign GCT is extremely rare, especially in cases in which the tumor bed has not previously undergone radiation therapy. Although the literature includes historical case reports, primary and secondary malignant GCTs comprise <9% of all GCTs.^11,13,14 Primary bone epithelioid angiosarcoma is also extremely rare, especially in the calcaneus; only 1 case is described in the literature.¹⁵ In this article, we report on a benign GCT of bone that transformed into an epithelioid angiosarcoma more than a decade after the GCT was treated with curettage and cementation.

The fact that the malignant areas of a previous tumor may have been missed because of sampling error is important for benign GCT of bone in the early postoperative period, as distinguishing between early malignant transformation and an overlooked malignancy may not be possible. However, transformation is more likely the case when a benign GCT becomes a high-grade malignancy after a long disease-free interval. Several authors have indicated that a benign GCT tumor recurring with a secondary malignancy 2 to 5 years after initial GCT treatment suggests malignant transformation.¹⁶ Grote and colleagues¹⁰ compiled reports of malignant transformation of GCT of bone and described the clinicopathologic features of secondary malignant transformation of GCTs. The data they compiled and data from several other studies indicate a poor prognosis after malignant transformation of GCT; 4 years after diagnosis, mean survival is 40% to 50%.^10,16 The most common clinical presentation of transformation of GCT into malignancy is pain, often with coincident swelling of the native wound bed. However, a few cases have been identified with radiologic imaging alone and without a period of clinical symptoms.¹⁶

To our knowledge, this case report is the first to describe a longitudinal assessment of the transformation of a benign GCT of bone into an epithelioid angiosarcoma. Whereas an earlier reported GCT of bone transformed into epithelioid angiosarcoma after irradiation,¹² our patient’s GCT of bone transformed without irradiation. GCTs of bone are locally aggressive benign tumors and are relatively rare. Malignant transformation of a benign bone tumor a decade after initial, definitive treatment is concerning, especially given the poor prognosis after malignant transformation in this clinical scenario. Current adjuvant treatments have not changed the prognosis. The literature includes a wide variety of histologic transformations, including high-grade sarcomas, after a long disease-free interval. Although malignant transformation of benign GCTs is rare, clinicians should be aware of the potential. Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation—pain or swelling in the wound bed—and patients should know to immediately inform their physician of any changes in pain level or local wound bed. Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the site of a previously treated GCT of bone with a disease-free interval of several years.

Take-Home Points

• Malignant transformation of a benign GCT is extremely rare.
• It is difficult to distinguish between an early malignant transformation and an overlooked malignancy.
• The most common clinical presentation of transformation of GCT into malignancy is pain, often with swelling.
• Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation.
• Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the wound site.

Giant cell tumors (GCTs) of bone account for about 5% of all primary bone tumors in adults, with a predominance in the third decade in life.¹ Clinically, GCT of bone often presents with pain, pathologic fracture, and/or soft- tissue expansion in the epiphysis of long bones. However, GCT of bone also has been reported in non-long bones, such as the talus and the calcaneus.^2,3 Histologically, GCT of bone consists of neoplastic stromal cells, mononuclear histiocytic cells, and multinucleated giant cells that resemble osteoclasts.⁴ The radiologic appearance of GCT is often described as a lytic, eccentrically located bony lesion that extends near the articular surface in patients with closed physes. Many GCTs have aggressive radiologic features with possible extensive bony destruction and soft-tissue extension. 

Although categorized as a benign lesion, GCT can be locally aggressive, with a variable local recurrence rate of 0% to 65%, depending on treatment modality and skeletal location. Given the aggressiveness of GCT of bone, recommendations for operative intervention include intralesional curettage with adjuvant therapy (eg, cryotherapy, phenol, argon beam, electrocautery) and placement of bone void fillers (eg, bone graft polymethylmethacrylate). Wide resection is recommended when the articular surface is no longer viable for reconstruction secondary to extensive destruction. Some authors have reported that surgical margin is the only risk factor in local recurrence,^5,6 and thus complete resection may be needed for tumor eradication. In addition, about 3% of GCTs demonstrate benign pulmonary implants, which have been cited as cause of death in 16% to 25% of reported cases of pulmonary spread.^7,8

The literature includes few reports of primary or secondary malignant transformation of GCT. Hutter and colleagues⁹ defined primary malignant GCT as GCT with sarcomatous tissue juxtaposed with zones of typical benign GCT cells. Secondary malignant GCT is a sarcomatous lesion at the site of a previously documented benign GCT. Secondary malignant GCT of bone histologically has been classified as a fibrosarcoma, malignant fibrous histiocytoma, or osteosarcoma transformation.¹⁰ 

Most malignant transformations of GCT of bone have been attributed to previous irradiation of the lesion.^11,12 However, there are some case reports of benign bone GCT malignant transformation in situ without any other medical intervention. It was reported that non-radiation-induced secondary transformations occur relatively early after GCT treatment.¹³ During the early stages of tumor recurrence, however, it is difficult to distinguish between malignant transformation and primary disease overlooked as a result of sampling error.

We report a case of secondary malignant transformation of GCT of bone 11 years after surgical curettage, cryotherapy, and cementation without adjuvant radiation therapy. To our knowledge, this case report is the first to describe transformation of a nonirradiated benign GCT into an aggressive, high-grade epithelioid angiosarcoma, a very rare vascular bone tumor. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In July 2003, a 46-year-old woman presented with left heel pain of several months’ duration. Plain radiographs showed a nonaggressive-appearing lytic lesion of the superior aspect of the posterior calcaneal tuberosity with a small cortical incongruity along the superior margin of the lesion (Figures 1A-1D).

A postoperative splint was placed, and weight-bearing progressed over 6 weeks. The patient was followed at 2- to 3-month intervals over the first 5 postoperative years. She was able to work and perform activities of daily living, but her postoperative course was complicated by significant chronic pain in multiple extremities and long-term treatment by the chronic pain service. At no time did postoperative imaging—magnetic resonance imaging (MRI) at 6 years, whole-body bone scan at 7 years, plain radiographs at 10 years—show evidence of recurrence.

Radiographs showed stable postoperative changes with a small radiolucent area (with sclerotic rim) surrounding the cement-bone interface. Given its proximity to the Achilles tendon and more motion than usual at the wound site, the radiolucency likely was caused by small movements of the interface. The radiolucent area remained stable over a 15-month period.

Whole-body bone scan showed a small area of osteoblastic activity in the left calcaneus, consistent with inflammation surrounding the bone- cement interface, but the uptake was minor relative to other areas of signal, and there were no significant inflammatory reactive changes on MRI (Figures 3A, 3B).

Over 11 years, regular 6- to 12-month follow-up examinations revealed no significant changes in the left foot or in plain radiographs of the chest. In addition, physical examinations revealed no evidence of a palpable mass of the left foot.

In July 2014 (11 years after curettage and cementation), the patient presented to her pain clinic appointment with severe left foot pain. She said that, over a few weeks, she experienced a significant increase in pain and developed posterolateral foot swelling, which limited her ability to ambulate. Plain radiographs showed a significant soft-tissue prominence around the posterior calcaneus, increased lucency around the bone-cement interface in the calcaneus with elevation, and a cortical break of the superior margin of the posterior calcaneus (Figures 3C, 3D). MRI showed a large lobular mass in the calcaneus and surrounding soft tissue with T1 and T2 signal heterogeneity and enhancement after administration of gadolinium (Figures 4A-4D). There was a large extraosseous extension of the calcaneus-based mass laterally and superiorly with edema in the surrounding hindfoot region (Figure 4).

Physical examination revealed exquisite tenderness along the lateral and posterior aspects of the left hindfoot. The patient was unable to bear weight and had soft-tissue swelling throughout the foot and mid calf as well as a palpable mass in the posterior heel. She was otherwise neurovascularly intact through all distributions of the left lower extremity. It was unclear if the GCT of the calcaneus had recurred or if there was a new, secondary tumor. Given her severe pain and morbidity, the patient decided to proceed with open biopsy and a pathology-pending plan for possible amputation in the near future.

In August 2014, an open biopsy with intraoperative frozen evaluation yielded a diagnosis of malignant neoplasm not otherwise specified. Permanent sections showed a proliferation of malignant epithelioid cells with extensive necrosis, hemorrhage, and hemosiderin deposition but no multinucleated giant cells.

Transformation of the GCT into a high-grade epithelioid angiosarcoma prompted presentation of the patient’s case to a multidisciplinary board of physicians with a focused clinical practice in sarcoma management. The board included board-certified specialists in orthopedic oncology, pathology, musculoskeletal radiology, medical oncology, and radiation oncology. Although discussion included pre-resection use of neoadjuvant chemotherapy to evaluate for disease response, the patient’s severe pain led her to forgo this treatment and proceed directly to below-knee amputation.

Amputation revealed a 7.7-cm hemorrhagic necrotic mass composed of a highly cellular spindle and epithelioid malignancy with abundant hemosiderin deposition (Figure 5). In addition, several atypical mitotic figures and malignant multinucleated tumor giant cells were randomly scattered throughout the neoplasm.

At first follow-up, the patient reported significant pain relief and asked to begin titrating off her chronic pain medicine. Clinical staging, which involved performing whole-body positron emission tomography/computed tomography, revealed nothing concerning for metastases. When this report was being written, the patient was being monitored for recurrent disease in accordance with National Comprehensive Cancer Network guidelines. In the absence of residual sarcoma, our medical oncology team discussed adjuvant chemotherapy options with her. Subsequently, however, she proceeded only with observation and periodic imaging.

Malignant transformation of a benign GCT is extremely rare, especially in cases in which the tumor bed has not previously undergone radiation therapy. Although the literature includes historical case reports, primary and secondary malignant GCTs comprise <9% of all GCTs.^11,13,14 Primary bone epithelioid angiosarcoma is also extremely rare, especially in the calcaneus; only 1 case is described in the literature.¹⁵ In this article, we report on a benign GCT of bone that transformed into an epithelioid angiosarcoma more than a decade after the GCT was treated with curettage and cementation.

The fact that the malignant areas of a previous tumor may have been missed because of sampling error is important for benign GCT of bone in the early postoperative period, as distinguishing between early malignant transformation and an overlooked malignancy may not be possible. However, transformation is more likely the case when a benign GCT becomes a high-grade malignancy after a long disease-free interval. Several authors have indicated that a benign GCT tumor recurring with a secondary malignancy 2 to 5 years after initial GCT treatment suggests malignant transformation.¹⁶ Grote and colleagues¹⁰ compiled reports of malignant transformation of GCT of bone and described the clinicopathologic features of secondary malignant transformation of GCTs. The data they compiled and data from several other studies indicate a poor prognosis after malignant transformation of GCT; 4 years after diagnosis, mean survival is 40% to 50%.^10,16 The most common clinical presentation of transformation of GCT into malignancy is pain, often with coincident swelling of the native wound bed. However, a few cases have been identified with radiologic imaging alone and without a period of clinical symptoms.¹⁶

To our knowledge, this case report is the first to describe a longitudinal assessment of the transformation of a benign GCT of bone into an epithelioid angiosarcoma. Whereas an earlier reported GCT of bone transformed into epithelioid angiosarcoma after irradiation,¹² our patient’s GCT of bone transformed without irradiation. GCTs of bone are locally aggressive benign tumors and are relatively rare. Malignant transformation of a benign bone tumor a decade after initial, definitive treatment is concerning, especially given the poor prognosis after malignant transformation in this clinical scenario. Current adjuvant treatments have not changed the prognosis. The literature includes a wide variety of histologic transformations, including high-grade sarcomas, after a long disease-free interval. Although malignant transformation of benign GCTs is rare, clinicians should be aware of the potential. Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation—pain or swelling in the wound bed—and patients should know to immediately inform their physician of any changes in pain level or local wound bed. Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the site of a previously treated GCT of bone with a disease-free interval of several years.

Pseudomyogenic hemangioendothelioma (PMHE), also referred to as epithelioid sarcoma–like hemangioendothelioma,¹ is a rare soft tissue tumor that was described in 1992 by Mirra et al² as a fibromalike variant of epithelioid sarcoma. It predominantly affects males between the second and fifth decades of life and most commonly presents as multiple nodules that may involve either the superficial or deep soft tissues of the legs and less often the arms. It also can arise on the trunk. We present a case of PMHE occurring in a young man and briefly review the literature on clinical presentation and histologic differentiation of this unique tumor, comparing these findings to its mimickers.

Case Report

A 20-year-old man presented with skin lesions on the left leg that had been present for 1 year. The patient described the lesions as tender pimples that would drain yellow discharge on occasion but had now transformed into large brown plaques. Physical examination showed 4 verrucous plaques ranging in size from 1 to 3 cm with hyperpigmentation and a central crust (Figure 1). Initially, the patient thought the lesions appeared due to shaving his legs for sports. He presented to the emergency department multiple times over the past year; pain control was provided and local skin care was recommended. Culture of the discharge had been performed 6 months prior to biopsy with negative results. No biopsy was performed on initial presentation and the lesions were diagnosed in the emergency department clinically as boils.

After failing to improve, the patient was seen by an outside dermatologist and the clinical differential diagnosis included deep fungal infection, atypical mycobacterial infection, and keloids. A 4-mm punch biopsy was taken from the periphery of one of the lesions and demonstrated hyperkeratosis, papillomatosis, and acanthosis (Figure 2). Within the superficial and deep dermis and focally extending into the subcutaneous tissue, there were sheets of spindled to epithelioid-appearing cells with moderate cytologic atypia (Figure 3). The tumor showed infiltrative margins. There was moderate cellularity. The individual cells had a rhabdoid appearance with large eccentric vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm (Figure 4). No definitive evidence of glandular, squamous, or vascular differentiation was present. There was an associated moderate inflammatory host response composed of neutrophils and lymphocytes. Occasional extravasated red blood cells were present. Immunohistochemistry staining was performed and the atypical cells demonstrated diffuse positive staining for friend leukemia integration 1 transcription factor (FLI-1), erythroblastosis virus E26 transforming sequence-related gene (ERG)(Figure 5), CD31, and CD68. There was patchy positive staining for cytokeratin AE1/AE3, CD10, and factor VIII. There was no remarkable staining for human herpesvirus 8, epithelial membrane antigen, S-100, CD34, cytokeratin 903, and desmin. Overall, the histologic features in conjunction with the immunohistochemistry staining were consistent with a diagnosis of PMHE.

Magnetic resonance imaging was then performed to evaluate the depth and extent of the lesions for surgical excision planning (Figure 6), which showed 5 nodular lesions within the dermis and subcutis adjacent to the proximal aspect of the left tibia and medial aspect of the left knee. An additional lesion was noted between the sartorius and semimembranosus muscles, which was thought to represent either a lymph node or an additional neoplastic lesion. Chest computed tomography also displayed indeterminate lesions in the lungs.

Excision of the superficial lesions was performed. All of the lesions demonstrated similar histologic changes to the previously described biopsy specimen. The tumor was limited to the dermis and subcutaneous tissue. The patient was lost to follow-up and the etiology of the lung lesions was unknown.

Comment

Nomenclature
Pseudomyogenic hemangioendothelioma is a relatively new type of vascular tumor that has been included in the updated 2013 edition of the World Health Organization classification as an intermediate malignant tumor that rarely metastasizes.³ It typically involves multiple tissue planes, most notably the dermis and subcutaneous layers but also muscle and bone.⁴ The term pseudomyogenic refers to the histologic resemblance of some of the cells to rhabdomyoblasts; however, these tumors are negative for all immunohistochemical muscle markers, most notably myogenin, desmin, and α-smooth muscle actin.⁵

Clinical Presentation
Gross features of PMHE typically include multiple firm nodules with ill-defined margins. The tumor was initially described in 1992 by Mirra et al² as a fibromalike variant of epithelioid sarcoma. In 2003, a series of 7 cases of PMHE was reported by Billings et al⁶ under the term epithelioid sarcomalike hemangioendothelioma. Other than the predominance of an epithelioid morphology, the cases reported as epithelioid sarcomalike hemangioendothelioma had similar clinical features and immunophenotype to what has been reported as PMHE.

Based on a PubMed search of articles indexed for MEDLINE using the term pseudomyogenic hemangioendothelioma, the 2 largest case series were reported by Pradhan et al⁷ (N=8) in 2017 and Hornick and Fletcher⁴ (N=50) in 2011. Hornick and Fletcher⁴ reported a male (41/50 [82.0%]) to female (9/50 [18.0%]) ratio of 4.6 to 1, and an average age at presentation of 31 years with 82% (41/50) of patients 40 years or younger. Pradhan et al⁷ also reported a male predominance (7/8 [87.5%]) with a similar average age at presentation of 29 years (age range, 9–62 years). The size of individual tumors ranged from 0.3 to 5.5 cm (mean size, 1.9 cm) in the series by Hornick and Fletcher⁴ and 0.3 to 6.0 com in the series by Pradhan et al.⁷ Hornick and Fletcher⁴ reported the most common site of involvement was the leg (27/50 [54.0%]), followed by the arm (12/50 [24.0%]), trunk (9/50 [18.0%]), and head and neck (2/50 [4.0%]). The leg (6/8 [75.0%]) also was the most common site of involvement in the series by Pradhan et al,⁷ with 2 cases occurring on the arm. In the series by Hornick and Fletcher,⁴ the tumors typically involved the dermis and subcutaneous tissue (26/50 [52%]) with a smaller number involving skeletal muscle (17/50 [34%]) and bone (7/50 [14%]). They reported 66% of their patients (33/50) had multifocal disease at presentation.⁴ Pradhan et al⁷ also reported 2 (25.0%) cases being limited to the superficial soft tissue, 2 (25.0%) being limited to the deep soft tissue, and 4 (50.0%) involving the bone; 5 (62.5%) patients had multifocal disease at presentation. The presentation of our patient in regards to gender, age, and tumor characteristics is consistent with other published cases.^5-10

Histopathology
Microscopic features of PMHE include sheets of spindled to epithelioid-appearing cells with mild to moderate nuclear atypia and eosinophilic cytoplasm. The tumor has an infiltrative growth pattern. Some of the cells may resemble rhabdomyoblastlike cells, hence the moniker pseudomyogenic. There is no recapitulation of vascular structures or remarkable cytoplasmic vacuolization. Mitotic rate is low and there is no tumor necrosis.⁴ The tumor cells do not appear to arise from a vessel or display an angiocentric growth pattern. Many cases report the presence of an inflammatory infiltrate containing neutrophils interspersed within the tumor.^4,5,7 The overlying epidermis will commonly show hyperkeratosis, epidermal hyperplasia, and acanthosis.^4,11

Differential Diagnosis
The histopathologic differential diagnosis would include epithelioid sarcoma, epithelioid hemangioendothelioma, and to a lesser extent dermatofibrosarcoma protuberans (DFSP) and rhabdomyosarcoma. Dermatofibrosarcoma protuberans is the most commonly encountered of these tumors. Histologically, DFSP is characterized by a cellular proliferation of small spindle cells with plump nuclei arranged in a storiform or cartwheel pattern. Dermatofibrosarcoma protuberans tends to be limited to the dermis and subcutaneous tissue and only rarely involves underlying skeletal muscle. The presence of the storiform growth pattern in conjunction with the lack of rhabdoid changes would favor a diagnosis of DFSP. Another characteristic histologic finding typically only associated with DFSP is the interdigitating growth pattern of the spindle cells within the lobules of the subcutaneous tissue, creating a lacelike or honeycomb appearance.

Immunohistochemistry staining is necessary to help differentiate PMHE from other tumors in the differential diagnosis. Pseudomyogenic hemangioendothelioma stains positive for cytokeratin AE1/AE3; integrase interactor 1; and vascular markers FLI-1, CD31, and ERG, and negative for CD34.^4,6,12-15 In contrast to epithelioid hemangioendothelioma, DFSP, and to a lesser extent epithelioid sarcoma, all of which are positive for CD34, epithelioid sarcoma is negative for both CD31 and integrase interactor 1. Dermatofibrosarcoma protuberans is negative for cytokeratin AE1/AE3. Rhabdomyosarcomas are positive for myogenic markers such as MyoD1 and myogenin, unlike any of the other tumors mentioned. Histologically, epithelioid sarcomas will tend to have a granulomalike growth pattern with central necrosis, unlike PMHE.¹² Epithelioid hemangioendothelioma often will have a cordlike growth pattern in a myxochondroid background. Unlike PMHE, these tumors often will appear to be arising from vessels, and intracytoplasmic vacuoles are common. Three cases of PMHE have been reported to have a t(7;19)(q22;q13) chromosomal anomaly, which is not consistent with every case.¹⁶

Treatment Options
Standard treatment typically includes wide excision of the lesions, as was done in our case. Because of the substantial risk of local recurrence, which was up to 58% in the series by Hornick and Fletcher,⁴ adjuvant therapy may be considered if positive margins are found on excision. Metastasis to lymph nodes and the lungs has been reported but is rare.^2,4 Most cases have been shown to have a favorable prognosis; however, local recurrence seems to be common. Rarely, amputation of the limb may be required.⁵ In contrast, epithelioid sarcomas have been found to spread to lymph nodes and the lungs in up to 50% of cases with a 5-year survival rate of 10% to 30%.¹³

Conclusion

In summary, we describe a case of PMHE involving the lower leg in a 20-year-old man. These tumors often are multinodular and multiplanar, with the dermis and subcutaneous tissues being the most common areas affected. It has a high rate of local recurrence but rarely has distant metastasis. Pseudomyogenic hemangioendothelioma, similar to other soft tissue tumors, can be difficult to diagnose on shave biopsy or superficial punch biopsy not extending into subcutaneous tissue. Deep incisional or punch biopsies are required to more definitively diagnose these types of tumors. The diagnosis of PMHE versus other soft tissue tumors requires correlation of histology and immunohistochemistry staining with clinical information and radiographic findings.

Pseudomyogenic hemangioendothelioma (PMHE), also referred to as epithelioid sarcoma–like hemangioendothelioma,¹ is a rare soft tissue tumor that was described in 1992 by Mirra et al² as a fibromalike variant of epithelioid sarcoma. It predominantly affects males between the second and fifth decades of life and most commonly presents as multiple nodules that may involve either the superficial or deep soft tissues of the legs and less often the arms. It also can arise on the trunk. We present a case of PMHE occurring in a young man and briefly review the literature on clinical presentation and histologic differentiation of this unique tumor, comparing these findings to its mimickers.

Case Report

A 20-year-old man presented with skin lesions on the left leg that had been present for 1 year. The patient described the lesions as tender pimples that would drain yellow discharge on occasion but had now transformed into large brown plaques. Physical examination showed 4 verrucous plaques ranging in size from 1 to 3 cm with hyperpigmentation and a central crust (Figure 1). Initially, the patient thought the lesions appeared due to shaving his legs for sports. He presented to the emergency department multiple times over the past year; pain control was provided and local skin care was recommended. Culture of the discharge had been performed 6 months prior to biopsy with negative results. No biopsy was performed on initial presentation and the lesions were diagnosed in the emergency department clinically as boils.

After failing to improve, the patient was seen by an outside dermatologist and the clinical differential diagnosis included deep fungal infection, atypical mycobacterial infection, and keloids. A 4-mm punch biopsy was taken from the periphery of one of the lesions and demonstrated hyperkeratosis, papillomatosis, and acanthosis (Figure 2). Within the superficial and deep dermis and focally extending into the subcutaneous tissue, there were sheets of spindled to epithelioid-appearing cells with moderate cytologic atypia (Figure 3). The tumor showed infiltrative margins. There was moderate cellularity. The individual cells had a rhabdoid appearance with large eccentric vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm (Figure 4). No definitive evidence of glandular, squamous, or vascular differentiation was present. There was an associated moderate inflammatory host response composed of neutrophils and lymphocytes. Occasional extravasated red blood cells were present. Immunohistochemistry staining was performed and the atypical cells demonstrated diffuse positive staining for friend leukemia integration 1 transcription factor (FLI-1), erythroblastosis virus E26 transforming sequence-related gene (ERG)(Figure 5), CD31, and CD68. There was patchy positive staining for cytokeratin AE1/AE3, CD10, and factor VIII. There was no remarkable staining for human herpesvirus 8, epithelial membrane antigen, S-100, CD34, cytokeratin 903, and desmin. Overall, the histologic features in conjunction with the immunohistochemistry staining were consistent with a diagnosis of PMHE.

Magnetic resonance imaging was then performed to evaluate the depth and extent of the lesions for surgical excision planning (Figure 6), which showed 5 nodular lesions within the dermis and subcutis adjacent to the proximal aspect of the left tibia and medial aspect of the left knee. An additional lesion was noted between the sartorius and semimembranosus muscles, which was thought to represent either a lymph node or an additional neoplastic lesion. Chest computed tomography also displayed indeterminate lesions in the lungs.

Excision of the superficial lesions was performed. All of the lesions demonstrated similar histologic changes to the previously described biopsy specimen. The tumor was limited to the dermis and subcutaneous tissue. The patient was lost to follow-up and the etiology of the lung lesions was unknown.

Comment

Nomenclature
Pseudomyogenic hemangioendothelioma is a relatively new type of vascular tumor that has been included in the updated 2013 edition of the World Health Organization classification as an intermediate malignant tumor that rarely metastasizes.³ It typically involves multiple tissue planes, most notably the dermis and subcutaneous layers but also muscle and bone.⁴ The term pseudomyogenic refers to the histologic resemblance of some of the cells to rhabdomyoblasts; however, these tumors are negative for all immunohistochemical muscle markers, most notably myogenin, desmin, and α-smooth muscle actin.⁵

Clinical Presentation
Gross features of PMHE typically include multiple firm nodules with ill-defined margins. The tumor was initially described in 1992 by Mirra et al² as a fibromalike variant of epithelioid sarcoma. In 2003, a series of 7 cases of PMHE was reported by Billings et al⁶ under the term epithelioid sarcomalike hemangioendothelioma. Other than the predominance of an epithelioid morphology, the cases reported as epithelioid sarcomalike hemangioendothelioma had similar clinical features and immunophenotype to what has been reported as PMHE.

Based on a PubMed search of articles indexed for MEDLINE using the term pseudomyogenic hemangioendothelioma, the 2 largest case series were reported by Pradhan et al⁷ (N=8) in 2017 and Hornick and Fletcher⁴ (N=50) in 2011. Hornick and Fletcher⁴ reported a male (41/50 [82.0%]) to female (9/50 [18.0%]) ratio of 4.6 to 1, and an average age at presentation of 31 years with 82% (41/50) of patients 40 years or younger. Pradhan et al⁷ also reported a male predominance (7/8 [87.5%]) with a similar average age at presentation of 29 years (age range, 9–62 years). The size of individual tumors ranged from 0.3 to 5.5 cm (mean size, 1.9 cm) in the series by Hornick and Fletcher⁴ and 0.3 to 6.0 com in the series by Pradhan et al.⁷ Hornick and Fletcher⁴ reported the most common site of involvement was the leg (27/50 [54.0%]), followed by the arm (12/50 [24.0%]), trunk (9/50 [18.0%]), and head and neck (2/50 [4.0%]). The leg (6/8 [75.0%]) also was the most common site of involvement in the series by Pradhan et al,⁷ with 2 cases occurring on the arm. In the series by Hornick and Fletcher,⁴ the tumors typically involved the dermis and subcutaneous tissue (26/50 [52%]) with a smaller number involving skeletal muscle (17/50 [34%]) and bone (7/50 [14%]). They reported 66% of their patients (33/50) had multifocal disease at presentation.⁴ Pradhan et al⁷ also reported 2 (25.0%) cases being limited to the superficial soft tissue, 2 (25.0%) being limited to the deep soft tissue, and 4 (50.0%) involving the bone; 5 (62.5%) patients had multifocal disease at presentation. The presentation of our patient in regards to gender, age, and tumor characteristics is consistent with other published cases.^5-10

Histopathology
Microscopic features of PMHE include sheets of spindled to epithelioid-appearing cells with mild to moderate nuclear atypia and eosinophilic cytoplasm. The tumor has an infiltrative growth pattern. Some of the cells may resemble rhabdomyoblastlike cells, hence the moniker pseudomyogenic. There is no recapitulation of vascular structures or remarkable cytoplasmic vacuolization. Mitotic rate is low and there is no tumor necrosis.⁴ The tumor cells do not appear to arise from a vessel or display an angiocentric growth pattern. Many cases report the presence of an inflammatory infiltrate containing neutrophils interspersed within the tumor.^4,5,7 The overlying epidermis will commonly show hyperkeratosis, epidermal hyperplasia, and acanthosis.^4,11

Differential Diagnosis
The histopathologic differential diagnosis would include epithelioid sarcoma, epithelioid hemangioendothelioma, and to a lesser extent dermatofibrosarcoma protuberans (DFSP) and rhabdomyosarcoma. Dermatofibrosarcoma protuberans is the most commonly encountered of these tumors. Histologically, DFSP is characterized by a cellular proliferation of small spindle cells with plump nuclei arranged in a storiform or cartwheel pattern. Dermatofibrosarcoma protuberans tends to be limited to the dermis and subcutaneous tissue and only rarely involves underlying skeletal muscle. The presence of the storiform growth pattern in conjunction with the lack of rhabdoid changes would favor a diagnosis of DFSP. Another characteristic histologic finding typically only associated with DFSP is the interdigitating growth pattern of the spindle cells within the lobules of the subcutaneous tissue, creating a lacelike or honeycomb appearance.

Immunohistochemistry staining is necessary to help differentiate PMHE from other tumors in the differential diagnosis. Pseudomyogenic hemangioendothelioma stains positive for cytokeratin AE1/AE3; integrase interactor 1; and vascular markers FLI-1, CD31, and ERG, and negative for CD34.^4,6,12-15 In contrast to epithelioid hemangioendothelioma, DFSP, and to a lesser extent epithelioid sarcoma, all of which are positive for CD34, epithelioid sarcoma is negative for both CD31 and integrase interactor 1. Dermatofibrosarcoma protuberans is negative for cytokeratin AE1/AE3. Rhabdomyosarcomas are positive for myogenic markers such as MyoD1 and myogenin, unlike any of the other tumors mentioned. Histologically, epithelioid sarcomas will tend to have a granulomalike growth pattern with central necrosis, unlike PMHE.¹² Epithelioid hemangioendothelioma often will have a cordlike growth pattern in a myxochondroid background. Unlike PMHE, these tumors often will appear to be arising from vessels, and intracytoplasmic vacuoles are common. Three cases of PMHE have been reported to have a t(7;19)(q22;q13) chromosomal anomaly, which is not consistent with every case.¹⁶

Treatment Options
Standard treatment typically includes wide excision of the lesions, as was done in our case. Because of the substantial risk of local recurrence, which was up to 58% in the series by Hornick and Fletcher,⁴ adjuvant therapy may be considered if positive margins are found on excision. Metastasis to lymph nodes and the lungs has been reported but is rare.^2,4 Most cases have been shown to have a favorable prognosis; however, local recurrence seems to be common. Rarely, amputation of the limb may be required.⁵ In contrast, epithelioid sarcomas have been found to spread to lymph nodes and the lungs in up to 50% of cases with a 5-year survival rate of 10% to 30%.¹³

Conclusion

In summary, we describe a case of PMHE involving the lower leg in a 20-year-old man. These tumors often are multinodular and multiplanar, with the dermis and subcutaneous tissues being the most common areas affected. It has a high rate of local recurrence but rarely has distant metastasis. Pseudomyogenic hemangioendothelioma, similar to other soft tissue tumors, can be difficult to diagnose on shave biopsy or superficial punch biopsy not extending into subcutaneous tissue. Deep incisional or punch biopsies are required to more definitively diagnose these types of tumors. The diagnosis of PMHE versus other soft tissue tumors requires correlation of histology and immunohistochemistry staining with clinical information and radiographic findings.

Pseudomyogenic hemangioendothelioma (PMHE), also referred to as epithelioid sarcoma–like hemangioendothelioma,¹ is a rare soft tissue tumor that was described in 1992 by Mirra et al² as a fibromalike variant of epithelioid sarcoma. It predominantly affects males between the second and fifth decades of life and most commonly presents as multiple nodules that may involve either the superficial or deep soft tissues of the legs and less often the arms. It also can arise on the trunk. We present a case of PMHE occurring in a young man and briefly review the literature on clinical presentation and histologic differentiation of this unique tumor, comparing these findings to its mimickers.

Case Report

A 20-year-old man presented with skin lesions on the left leg that had been present for 1 year. The patient described the lesions as tender pimples that would drain yellow discharge on occasion but had now transformed into large brown plaques. Physical examination showed 4 verrucous plaques ranging in size from 1 to 3 cm with hyperpigmentation and a central crust (Figure 1). Initially, the patient thought the lesions appeared due to shaving his legs for sports. He presented to the emergency department multiple times over the past year; pain control was provided and local skin care was recommended. Culture of the discharge had been performed 6 months prior to biopsy with negative results. No biopsy was performed on initial presentation and the lesions were diagnosed in the emergency department clinically as boils.

After failing to improve, the patient was seen by an outside dermatologist and the clinical differential diagnosis included deep fungal infection, atypical mycobacterial infection, and keloids. A 4-mm punch biopsy was taken from the periphery of one of the lesions and demonstrated hyperkeratosis, papillomatosis, and acanthosis (Figure 2). Within the superficial and deep dermis and focally extending into the subcutaneous tissue, there were sheets of spindled to epithelioid-appearing cells with moderate cytologic atypia (Figure 3). The tumor showed infiltrative margins. There was moderate cellularity. The individual cells had a rhabdoid appearance with large eccentric vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm (Figure 4). No definitive evidence of glandular, squamous, or vascular differentiation was present. There was an associated moderate inflammatory host response composed of neutrophils and lymphocytes. Occasional extravasated red blood cells were present. Immunohistochemistry staining was performed and the atypical cells demonstrated diffuse positive staining for friend leukemia integration 1 transcription factor (FLI-1), erythroblastosis virus E26 transforming sequence-related gene (ERG)(Figure 5), CD31, and CD68. There was patchy positive staining for cytokeratin AE1/AE3, CD10, and factor VIII. There was no remarkable staining for human herpesvirus 8, epithelial membrane antigen, S-100, CD34, cytokeratin 903, and desmin. Overall, the histologic features in conjunction with the immunohistochemistry staining were consistent with a diagnosis of PMHE.

Magnetic resonance imaging was then performed to evaluate the depth and extent of the lesions for surgical excision planning (Figure 6), which showed 5 nodular lesions within the dermis and subcutis adjacent to the proximal aspect of the left tibia and medial aspect of the left knee. An additional lesion was noted between the sartorius and semimembranosus muscles, which was thought to represent either a lymph node or an additional neoplastic lesion. Chest computed tomography also displayed indeterminate lesions in the lungs.

Excision of the superficial lesions was performed. All of the lesions demonstrated similar histologic changes to the previously described biopsy specimen. The tumor was limited to the dermis and subcutaneous tissue. The patient was lost to follow-up and the etiology of the lung lesions was unknown.

Comment

Nomenclature
Pseudomyogenic hemangioendothelioma is a relatively new type of vascular tumor that has been included in the updated 2013 edition of the World Health Organization classification as an intermediate malignant tumor that rarely metastasizes.³ It typically involves multiple tissue planes, most notably the dermis and subcutaneous layers but also muscle and bone.⁴ The term pseudomyogenic refers to the histologic resemblance of some of the cells to rhabdomyoblasts; however, these tumors are negative for all immunohistochemical muscle markers, most notably myogenin, desmin, and α-smooth muscle actin.⁵

Clinical Presentation
Gross features of PMHE typically include multiple firm nodules with ill-defined margins. The tumor was initially described in 1992 by Mirra et al² as a fibromalike variant of epithelioid sarcoma. In 2003, a series of 7 cases of PMHE was reported by Billings et al⁶ under the term epithelioid sarcomalike hemangioendothelioma. Other than the predominance of an epithelioid morphology, the cases reported as epithelioid sarcomalike hemangioendothelioma had similar clinical features and immunophenotype to what has been reported as PMHE.

Based on a PubMed search of articles indexed for MEDLINE using the term pseudomyogenic hemangioendothelioma, the 2 largest case series were reported by Pradhan et al⁷ (N=8) in 2017 and Hornick and Fletcher⁴ (N=50) in 2011. Hornick and Fletcher⁴ reported a male (41/50 [82.0%]) to female (9/50 [18.0%]) ratio of 4.6 to 1, and an average age at presentation of 31 years with 82% (41/50) of patients 40 years or younger. Pradhan et al⁷ also reported a male predominance (7/8 [87.5%]) with a similar average age at presentation of 29 years (age range, 9–62 years). The size of individual tumors ranged from 0.3 to 5.5 cm (mean size, 1.9 cm) in the series by Hornick and Fletcher⁴ and 0.3 to 6.0 com in the series by Pradhan et al.⁷ Hornick and Fletcher⁴ reported the most common site of involvement was the leg (27/50 [54.0%]), followed by the arm (12/50 [24.0%]), trunk (9/50 [18.0%]), and head and neck (2/50 [4.0%]). The leg (6/8 [75.0%]) also was the most common site of involvement in the series by Pradhan et al,⁷ with 2 cases occurring on the arm. In the series by Hornick and Fletcher,⁴ the tumors typically involved the dermis and subcutaneous tissue (26/50 [52%]) with a smaller number involving skeletal muscle (17/50 [34%]) and bone (7/50 [14%]). They reported 66% of their patients (33/50) had multifocal disease at presentation.⁴ Pradhan et al⁷ also reported 2 (25.0%) cases being limited to the superficial soft tissue, 2 (25.0%) being limited to the deep soft tissue, and 4 (50.0%) involving the bone; 5 (62.5%) patients had multifocal disease at presentation. The presentation of our patient in regards to gender, age, and tumor characteristics is consistent with other published cases.^5-10

Histopathology
Microscopic features of PMHE include sheets of spindled to epithelioid-appearing cells with mild to moderate nuclear atypia and eosinophilic cytoplasm. The tumor has an infiltrative growth pattern. Some of the cells may resemble rhabdomyoblastlike cells, hence the moniker pseudomyogenic. There is no recapitulation of vascular structures or remarkable cytoplasmic vacuolization. Mitotic rate is low and there is no tumor necrosis.⁴ The tumor cells do not appear to arise from a vessel or display an angiocentric growth pattern. Many cases report the presence of an inflammatory infiltrate containing neutrophils interspersed within the tumor.^4,5,7 The overlying epidermis will commonly show hyperkeratosis, epidermal hyperplasia, and acanthosis.^4,11

Differential Diagnosis
The histopathologic differential diagnosis would include epithelioid sarcoma, epithelioid hemangioendothelioma, and to a lesser extent dermatofibrosarcoma protuberans (DFSP) and rhabdomyosarcoma. Dermatofibrosarcoma protuberans is the most commonly encountered of these tumors. Histologically, DFSP is characterized by a cellular proliferation of small spindle cells with plump nuclei arranged in a storiform or cartwheel pattern. Dermatofibrosarcoma protuberans tends to be limited to the dermis and subcutaneous tissue and only rarely involves underlying skeletal muscle. The presence of the storiform growth pattern in conjunction with the lack of rhabdoid changes would favor a diagnosis of DFSP. Another characteristic histologic finding typically only associated with DFSP is the interdigitating growth pattern of the spindle cells within the lobules of the subcutaneous tissue, creating a lacelike or honeycomb appearance.

Immunohistochemistry staining is necessary to help differentiate PMHE from other tumors in the differential diagnosis. Pseudomyogenic hemangioendothelioma stains positive for cytokeratin AE1/AE3; integrase interactor 1; and vascular markers FLI-1, CD31, and ERG, and negative for CD34.^4,6,12-15 In contrast to epithelioid hemangioendothelioma, DFSP, and to a lesser extent epithelioid sarcoma, all of which are positive for CD34, epithelioid sarcoma is negative for both CD31 and integrase interactor 1. Dermatofibrosarcoma protuberans is negative for cytokeratin AE1/AE3. Rhabdomyosarcomas are positive for myogenic markers such as MyoD1 and myogenin, unlike any of the other tumors mentioned. Histologically, epithelioid sarcomas will tend to have a granulomalike growth pattern with central necrosis, unlike PMHE.¹² Epithelioid hemangioendothelioma often will have a cordlike growth pattern in a myxochondroid background. Unlike PMHE, these tumors often will appear to be arising from vessels, and intracytoplasmic vacuoles are common. Three cases of PMHE have been reported to have a t(7;19)(q22;q13) chromosomal anomaly, which is not consistent with every case.¹⁶

Treatment Options
Standard treatment typically includes wide excision of the lesions, as was done in our case. Because of the substantial risk of local recurrence, which was up to 58% in the series by Hornick and Fletcher,⁴ adjuvant therapy may be considered if positive margins are found on excision. Metastasis to lymph nodes and the lungs has been reported but is rare.^2,4 Most cases have been shown to have a favorable prognosis; however, local recurrence seems to be common. Rarely, amputation of the limb may be required.⁵ In contrast, epithelioid sarcomas have been found to spread to lymph nodes and the lungs in up to 50% of cases with a 5-year survival rate of 10% to 30%.¹³

Conclusion

In summary, we describe a case of PMHE involving the lower leg in a 20-year-old man. These tumors often are multinodular and multiplanar, with the dermis and subcutaneous tissues being the most common areas affected. It has a high rate of local recurrence but rarely has distant metastasis. Pseudomyogenic hemangioendothelioma, similar to other soft tissue tumors, can be difficult to diagnose on shave biopsy or superficial punch biopsy not extending into subcutaneous tissue. Deep incisional or punch biopsies are required to more definitively diagnose these types of tumors. The diagnosis of PMHE versus other soft tissue tumors requires correlation of histology and immunohistochemistry staining with clinical information and radiographic findings.