Article

Key clinical point: Once-weekly exenatide was superior to placebo in improving glycemic control and was well tolerated in youth with type 2 diabetes (T2D) who were suboptimally controlled with current treatments. It had a safety profile similar to that in adults.

Major finding: At 24 weeks, the least squares mean change in the glycated hemoglobin level in the exenatide vs placebo group was −0.36% vs 0.49%, respectively, with a between-group difference of −0.85% (P  =  .012) showing the superiority of exenatide over placebo. Adverse events were reported by 61.0% and 73.9% of participants in the exenatide and placebo groups, respectively.

Study details: Findings are from a multicenter, parallel-group, phase 3 study including 72 patients with T2D suboptimally controlled with current treatments who were randomly assigned to receive once-weekly exenatide (n = 49) or placebo (n = 23).

Disclosures: This study was funded by AstraZeneca. N Shehadeh and O Doehring declared receiving support from AstraZeneca. The other authors declared being employees or holding stocks in AstraZeneca.

Source: Tamborlane WV et al. Once-weekly exenatide in youth with type 2 diabetes. Diabetes Care. 2022;45(8):1833–1840 (Jul 26). Doi: 10.2337/dc21-2275

Key clinical point: Once-weekly exenatide was superior to placebo in improving glycemic control and was well tolerated in youth with type 2 diabetes (T2D) who were suboptimally controlled with current treatments. It had a safety profile similar to that in adults.

Major finding: At 24 weeks, the least squares mean change in the glycated hemoglobin level in the exenatide vs placebo group was −0.36% vs 0.49%, respectively, with a between-group difference of −0.85% (P  =  .012) showing the superiority of exenatide over placebo. Adverse events were reported by 61.0% and 73.9% of participants in the exenatide and placebo groups, respectively.

Study details: Findings are from a multicenter, parallel-group, phase 3 study including 72 patients with T2D suboptimally controlled with current treatments who were randomly assigned to receive once-weekly exenatide (n = 49) or placebo (n = 23).

Disclosures: This study was funded by AstraZeneca. N Shehadeh and O Doehring declared receiving support from AstraZeneca. The other authors declared being employees or holding stocks in AstraZeneca.

Source: Tamborlane WV et al. Once-weekly exenatide in youth with type 2 diabetes. Diabetes Care. 2022;45(8):1833–1840 (Jul 26). Doi: 10.2337/dc21-2275

Key clinical point: Once-weekly exenatide was superior to placebo in improving glycemic control and was well tolerated in youth with type 2 diabetes (T2D) who were suboptimally controlled with current treatments. It had a safety profile similar to that in adults.

Major finding: At 24 weeks, the least squares mean change in the glycated hemoglobin level in the exenatide vs placebo group was −0.36% vs 0.49%, respectively, with a between-group difference of −0.85% (P  =  .012) showing the superiority of exenatide over placebo. Adverse events were reported by 61.0% and 73.9% of participants in the exenatide and placebo groups, respectively.

Study details: Findings are from a multicenter, parallel-group, phase 3 study including 72 patients with T2D suboptimally controlled with current treatments who were randomly assigned to receive once-weekly exenatide (n = 49) or placebo (n = 23).

Disclosures: This study was funded by AstraZeneca. N Shehadeh and O Doehring declared receiving support from AstraZeneca. The other authors declared being employees or holding stocks in AstraZeneca.

Source: Tamborlane WV et al. Once-weekly exenatide in youth with type 2 diabetes. Diabetes Care. 2022;45(8):1833–1840 (Jul 26). Doi: 10.2337/dc21-2275

Residents are confronted daily with situations in clinic that require a foundation in medical ethics to assist in decision-making. Attending physicians require health care services and at times may seek care from resident physicians. If the attending physician has direct oversight over the resident, however, the ethics of the resident treating them need to be addressed. Although patients have autonomy to choose whoever they want as a physician, nonmaleficence dictates that the resident may forego treatment due to concerns for providing suboptimal care; however, this same attending may be treated under specific circumstances. This column explores the ethical implications of both situations.

The Ethical Dilemma of Treating an Attending

Imagine this scenario: You are in your resident general dermatology clinic seeing patients with an attending overseeing your clinical decisions following each encounter. You look on your schedule and see that the next patient is one of your pediatric dermatology attendings for a total-body skin examination (TBSE). You have never treated a physician that oversees you, and you ponder whether you should perform the examination or fetch your attending to perform the encounter alone.

This conundrum then brings other questions to mind: Would changing the reason for the appointment (ie, an acute problem vs a TBSE) alter your decision as to whether or not you would treat this attending? Would the situation be different if this was an attending in a different department?

Ethics Curriculum for Residents

Medical providers face ethical dilemmas daily, and dermatologists and dermatology residents are not excluded. Dermatoethics can provide a framework for the best approach to this hypothetical situation. To equip residents with resources on ethics and a cognitive framework to approach similar situations, the American Board of Dermatology has created an ethics curriculum for residents to learn over their 3 years of training.¹

One study that analyzed the ethical themes portrayed in essays by fourth-year medical students showed that the most common themes included autonomy, social justice, nonmaleficence, beneficence, honesty, and respect.² These themes must be considered in different permutations throughout ethical conundrums.

In the situation of an attending physician who supervises a resident in another clinic voluntarily attending the resident clinic, the physician is aware of the resident’s skills and qualifications and knows that supervision is being provided by an attending physician, which allows informed consent to be made, as a study by Unruh et al³ shows. The patient’s autonomy allows them to choose their treating provider.

However, there are several reasons why the resident may be hesitant to enter the room. One concern may be that during a TBSE the provider usually examines the patient’s genitals, rectum, and breasts.⁴ Because the resident knows the individual personally, the patient and/or the provider may be uncomfortable checking these areas, leaving a portion of the examination unperformed. This neglect may harm the patient (eg, a genital melanoma is missed), violating the tenant of nonmaleficence.

The effect of the medical hierarchy also should be considered. The de facto hierarchy of attendings supervising residents, interns, and medical students, with each group having some oversight over the next, can have positive effects on education and appropriate patient management but also can prove to be detrimental to the patient and provider in some circumstances. Studies have shown that residents may be less willing to disagree with their superior’s opinions for fear of negative reactions and harmful effects on their future careers.^5-7 The hierarchy of medicine also can affect a resident’s moral judgement by intimidating the practitioner to perform tasks or make diagnoses they may not wish to make.^5,6,8,9 For example, the resident may send a prescription for a medication that the attending requested despite no clear indication of need. This mingling of patient and supervisor roles can result in a resident treating their attending physician inconsistently with their standard of care.

Navigating the Ethics of Treating Family Members

The American Medical Association Code of Medical Ethics Opinions on Patient-Physician Relationships highlights treating family members as an important ethical topic. Although most residents and attendings are not biologically related, a familial-style relationship exists in many dermatology programs between attendings and residents due to the close-knit nature of dermatology programs. Diagnostic and treatment accuracy may be diminished by the discomfort or disbelief that a condition could affect someone the resident cares about.¹⁰

The American Medical Association also states that a physician can treat family members in an emergency situation or for short-term minor problems. If these 2 exceptions were to be extrapolated to apply to situations involving residents and attendings in addition to family, there would be situations where a dermatology resident could ethically treat their attending physician.¹⁰ If the attending physician was worried about a problem that was deemed potentially life-threatening, such as a rapidly progressive bullous eruption concerning for Stevens-Johnson syndrome following the initiation of a new medication, and they wanted an urgent evaluation and biopsy, an ethicist could argue that urgent treatment is medically indicated as deferring treatment could have negative consequences on the patient’s health. In addition, if the attending found a splinter in their finger following yardwork and needed assistance in removal, this also could be treated by their resident, as it is minimally invasive and has a finite conclusion.

Treating Nonsupervisory Attendings

In the case of performing a TBSE on an attending from another specialty, it would be acceptable and less ethically ambiguous if no close personal relationship existed between the two practitioners, as this patient would have no direct oversight over the resident physician.

Final Thoughts

Each situation that residents face may carry ethical implications with perspectives from the patient, provider, and bystanders. The above scenarios highlight specific instances that a dermatology resident may face and provide insight into how they may approach the situations. At the same time, it is important to remember that every situation is different and requires a unique approach. Fortunately,physicians—specifically dermatologists—are provided many resources to help navigate challenging scenarios.

Acknowledgments—The author thanks Jane M. Grant-Kels, MD (Farmington, Connecticut), for reviewing this paper and providing feedback to improve its content, as well as Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and article.

Residents are confronted daily with situations in clinic that require a foundation in medical ethics to assist in decision-making. Attending physicians require health care services and at times may seek care from resident physicians. If the attending physician has direct oversight over the resident, however, the ethics of the resident treating them need to be addressed. Although patients have autonomy to choose whoever they want as a physician, nonmaleficence dictates that the resident may forego treatment due to concerns for providing suboptimal care; however, this same attending may be treated under specific circumstances. This column explores the ethical implications of both situations.

The Ethical Dilemma of Treating an Attending

Imagine this scenario: You are in your resident general dermatology clinic seeing patients with an attending overseeing your clinical decisions following each encounter. You look on your schedule and see that the next patient is one of your pediatric dermatology attendings for a total-body skin examination (TBSE). You have never treated a physician that oversees you, and you ponder whether you should perform the examination or fetch your attending to perform the encounter alone.

This conundrum then brings other questions to mind: Would changing the reason for the appointment (ie, an acute problem vs a TBSE) alter your decision as to whether or not you would treat this attending? Would the situation be different if this was an attending in a different department?

Ethics Curriculum for Residents

Medical providers face ethical dilemmas daily, and dermatologists and dermatology residents are not excluded. Dermatoethics can provide a framework for the best approach to this hypothetical situation. To equip residents with resources on ethics and a cognitive framework to approach similar situations, the American Board of Dermatology has created an ethics curriculum for residents to learn over their 3 years of training.¹

One study that analyzed the ethical themes portrayed in essays by fourth-year medical students showed that the most common themes included autonomy, social justice, nonmaleficence, beneficence, honesty, and respect.² These themes must be considered in different permutations throughout ethical conundrums.

In the situation of an attending physician who supervises a resident in another clinic voluntarily attending the resident clinic, the physician is aware of the resident’s skills and qualifications and knows that supervision is being provided by an attending physician, which allows informed consent to be made, as a study by Unruh et al³ shows. The patient’s autonomy allows them to choose their treating provider.

However, there are several reasons why the resident may be hesitant to enter the room. One concern may be that during a TBSE the provider usually examines the patient’s genitals, rectum, and breasts.⁴ Because the resident knows the individual personally, the patient and/or the provider may be uncomfortable checking these areas, leaving a portion of the examination unperformed. This neglect may harm the patient (eg, a genital melanoma is missed), violating the tenant of nonmaleficence.

The effect of the medical hierarchy also should be considered. The de facto hierarchy of attendings supervising residents, interns, and medical students, with each group having some oversight over the next, can have positive effects on education and appropriate patient management but also can prove to be detrimental to the patient and provider in some circumstances. Studies have shown that residents may be less willing to disagree with their superior’s opinions for fear of negative reactions and harmful effects on their future careers.^5-7 The hierarchy of medicine also can affect a resident’s moral judgement by intimidating the practitioner to perform tasks or make diagnoses they may not wish to make.^5,6,8,9 For example, the resident may send a prescription for a medication that the attending requested despite no clear indication of need. This mingling of patient and supervisor roles can result in a resident treating their attending physician inconsistently with their standard of care.

Navigating the Ethics of Treating Family Members

The American Medical Association Code of Medical Ethics Opinions on Patient-Physician Relationships highlights treating family members as an important ethical topic. Although most residents and attendings are not biologically related, a familial-style relationship exists in many dermatology programs between attendings and residents due to the close-knit nature of dermatology programs. Diagnostic and treatment accuracy may be diminished by the discomfort or disbelief that a condition could affect someone the resident cares about.¹⁰

The American Medical Association also states that a physician can treat family members in an emergency situation or for short-term minor problems. If these 2 exceptions were to be extrapolated to apply to situations involving residents and attendings in addition to family, there would be situations where a dermatology resident could ethically treat their attending physician.¹⁰ If the attending physician was worried about a problem that was deemed potentially life-threatening, such as a rapidly progressive bullous eruption concerning for Stevens-Johnson syndrome following the initiation of a new medication, and they wanted an urgent evaluation and biopsy, an ethicist could argue that urgent treatment is medically indicated as deferring treatment could have negative consequences on the patient’s health. In addition, if the attending found a splinter in their finger following yardwork and needed assistance in removal, this also could be treated by their resident, as it is minimally invasive and has a finite conclusion.

Treating Nonsupervisory Attendings

In the case of performing a TBSE on an attending from another specialty, it would be acceptable and less ethically ambiguous if no close personal relationship existed between the two practitioners, as this patient would have no direct oversight over the resident physician.

Final Thoughts

Each situation that residents face may carry ethical implications with perspectives from the patient, provider, and bystanders. The above scenarios highlight specific instances that a dermatology resident may face and provide insight into how they may approach the situations. At the same time, it is important to remember that every situation is different and requires a unique approach. Fortunately,physicians—specifically dermatologists—are provided many resources to help navigate challenging scenarios.

Acknowledgments—The author thanks Jane M. Grant-Kels, MD (Farmington, Connecticut), for reviewing this paper and providing feedback to improve its content, as well as Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and article.

Residents are confronted daily with situations in clinic that require a foundation in medical ethics to assist in decision-making. Attending physicians require health care services and at times may seek care from resident physicians. If the attending physician has direct oversight over the resident, however, the ethics of the resident treating them need to be addressed. Although patients have autonomy to choose whoever they want as a physician, nonmaleficence dictates that the resident may forego treatment due to concerns for providing suboptimal care; however, this same attending may be treated under specific circumstances. This column explores the ethical implications of both situations.

The Ethical Dilemma of Treating an Attending

Imagine this scenario: You are in your resident general dermatology clinic seeing patients with an attending overseeing your clinical decisions following each encounter. You look on your schedule and see that the next patient is one of your pediatric dermatology attendings for a total-body skin examination (TBSE). You have never treated a physician that oversees you, and you ponder whether you should perform the examination or fetch your attending to perform the encounter alone.

This conundrum then brings other questions to mind: Would changing the reason for the appointment (ie, an acute problem vs a TBSE) alter your decision as to whether or not you would treat this attending? Would the situation be different if this was an attending in a different department?

Ethics Curriculum for Residents

Medical providers face ethical dilemmas daily, and dermatologists and dermatology residents are not excluded. Dermatoethics can provide a framework for the best approach to this hypothetical situation. To equip residents with resources on ethics and a cognitive framework to approach similar situations, the American Board of Dermatology has created an ethics curriculum for residents to learn over their 3 years of training.¹

One study that analyzed the ethical themes portrayed in essays by fourth-year medical students showed that the most common themes included autonomy, social justice, nonmaleficence, beneficence, honesty, and respect.² These themes must be considered in different permutations throughout ethical conundrums.

In the situation of an attending physician who supervises a resident in another clinic voluntarily attending the resident clinic, the physician is aware of the resident’s skills and qualifications and knows that supervision is being provided by an attending physician, which allows informed consent to be made, as a study by Unruh et al³ shows. The patient’s autonomy allows them to choose their treating provider.

However, there are several reasons why the resident may be hesitant to enter the room. One concern may be that during a TBSE the provider usually examines the patient’s genitals, rectum, and breasts.⁴ Because the resident knows the individual personally, the patient and/or the provider may be uncomfortable checking these areas, leaving a portion of the examination unperformed. This neglect may harm the patient (eg, a genital melanoma is missed), violating the tenant of nonmaleficence.

The effect of the medical hierarchy also should be considered. The de facto hierarchy of attendings supervising residents, interns, and medical students, with each group having some oversight over the next, can have positive effects on education and appropriate patient management but also can prove to be detrimental to the patient and provider in some circumstances. Studies have shown that residents may be less willing to disagree with their superior’s opinions for fear of negative reactions and harmful effects on their future careers.^5-7 The hierarchy of medicine also can affect a resident’s moral judgement by intimidating the practitioner to perform tasks or make diagnoses they may not wish to make.^5,6,8,9 For example, the resident may send a prescription for a medication that the attending requested despite no clear indication of need. This mingling of patient and supervisor roles can result in a resident treating their attending physician inconsistently with their standard of care.

Navigating the Ethics of Treating Family Members

The American Medical Association Code of Medical Ethics Opinions on Patient-Physician Relationships highlights treating family members as an important ethical topic. Although most residents and attendings are not biologically related, a familial-style relationship exists in many dermatology programs between attendings and residents due to the close-knit nature of dermatology programs. Diagnostic and treatment accuracy may be diminished by the discomfort or disbelief that a condition could affect someone the resident cares about.¹⁰

The American Medical Association also states that a physician can treat family members in an emergency situation or for short-term minor problems. If these 2 exceptions were to be extrapolated to apply to situations involving residents and attendings in addition to family, there would be situations where a dermatology resident could ethically treat their attending physician.¹⁰ If the attending physician was worried about a problem that was deemed potentially life-threatening, such as a rapidly progressive bullous eruption concerning for Stevens-Johnson syndrome following the initiation of a new medication, and they wanted an urgent evaluation and biopsy, an ethicist could argue that urgent treatment is medically indicated as deferring treatment could have negative consequences on the patient’s health. In addition, if the attending found a splinter in their finger following yardwork and needed assistance in removal, this also could be treated by their resident, as it is minimally invasive and has a finite conclusion.

Treating Nonsupervisory Attendings

In the case of performing a TBSE on an attending from another specialty, it would be acceptable and less ethically ambiguous if no close personal relationship existed between the two practitioners, as this patient would have no direct oversight over the resident physician.

Final Thoughts

Each situation that residents face may carry ethical implications with perspectives from the patient, provider, and bystanders. The above scenarios highlight specific instances that a dermatology resident may face and provide insight into how they may approach the situations. At the same time, it is important to remember that every situation is different and requires a unique approach. Fortunately,physicians—specifically dermatologists—are provided many resources to help navigate challenging scenarios.

Acknowledgments—The author thanks Jane M. Grant-Kels, MD (Farmington, Connecticut), for reviewing this paper and providing feedback to improve its content, as well as Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and article.

The Diagnosis: Scleromyxedema

A punch biopsy of the upper back performed at an outside institution revealed increased histiocytes and abundant interstitial mucin confined to the papillary dermis (Figures 1 and 2), consistent with the lichen myxedematosus (LM) papules that may be seen in scleromyxedema. Serum protein electrophoresis revealed the presence of a protein of restricted mobility on the gamma region that occupied 5.3% of the total protein (0.3 g/dL). Urine protein electrophoresis showed free kappa light chain monoclonal protein in the gamma region. Immunofixation electrophoresis revealed the presence of IgG kappa monoclonal protein in the gamma region with 10% monotype kappa cells. The presence of Raynaud phenomenon and positive antinuclear antibody (1:320, speckled) was noted. Laboratory studies for thyroid-stimulating hormone, C-reactive protein, Scl-70 antibody, myositis panel, ribonucleoprotein antibody, Smith antibody, Sjögren syndrome–related antigens A and B antibodies, rheumatoid factor, and RNA polymerase III antibody all were within reference range. Our patient was treated with monthly intravenous immunoglobulin (IVIG), and he noted substantial improvement in skin findings after 3 months of IVIG.

Localized lichen myxedematosus is a rare idiopathic cutaneous disease that clinically is characterized by waxy indurated papules and histologically is characterized by diffuse mucin deposition and fibroblast proliferation in the upper dermis.¹ Scleromyxedema is a diffuse variant of LM in which the papules and plaques of LM are associated with skin thickening involving almost the entire body and associated systemic disease. The exact mechanism of this disease is unknown, but the most widely accepted hypothesis is that immunoglobulins and cytokines contribute to the synthesis of glycosaminoglycans and thereby the deposition of mucin in the dermis.² Scleromyxedema has a chronic course and generally responds poorly to existing treatments.¹ Partial improvement has been demonstrated in treatment with topical calcineurin inhibitors and topical steroids.²

The differential diagnosis in our patient included scleromyxedema, scleredema, scleroderma, LM, and reticular erythematosus mucinosis. He was diagnosed with scleromyxedema with kappa monoclonal gammopathy. Scleromyxedema is a rare disorder involving the deposition of mucinous material in the papillary dermis that causes the formation of infiltrative skin lesions.³ The etiology is unknown, but the presence of a monoclonal protein is an important characteristic of this disorder. It is important to rule out thyroid disease as a possible etiology before concluding that the disease process is driven by the monoclonal gammopathy; this will help determine appropriate therapies.^4,5 Usually the monoclonal protein is associated with the IgG lambda subtype. Intravenous immunoglobulin often is considered as a first-line treatment of scleromyxedema and usually is administered at a dosage of 2 g/kg divided over 2 to 5 consecutive days per month.³ Previously, our patient had been treated with IVIG for 3 years for chronic inflammatory demyelinating polyneuropathy and had stopped 1 to 2 years before his cutaneous symptoms started. Generally, scleromyxedema patients must stay on IVIG long-term to prevent relapse, typically every 6 to 8 weeks. Second-line treatments for scleromyxedema include systemic corticosteroids and thalidomide.⁶ Scleromyxedema and LM have several clinical and histopathologic features in common. Our patient’s biopsy revealed increased mucin deposition associated with fibroblast proliferation confined to the superficial dermis. These histologic changes can be seen in the setting of either LM or scleromyxedema. Our patient’s diffuse skin thickening and monoclonal gammopathy were more characteristic of scleromyxedema. In contrast, LM is a localized eruption with no internal organ manifestations and no associated systemic disease, such as monoclonal gammopathy and thyroid disease.

Scleredema adultorum of Buschke (also referred to as scleredema) is a rare idiopathic dermatologic condition characterized by thickening and tightening of the skin that leads to firm, nonpitting, woody edema that initially involves the upper back and neck but can spread to the face, scalp, and shoulders; importantly, scleredema spares the hands and feet.⁷ Scleredema has been associated with type 2 diabetes mellitus, streptococcal upper respiratory tract infections, and monoclonal gammopathy.⁸ Although our patient did have a monoclonal gammopathy, he also experienced prominent hand involvement with diffuse skin thickening, which is not typical of scleredema. Additionally, biopsy of scleredema would show increased mucin but would not show the proliferation of fibroblasts that was seen in our patient’s biopsy. Furthermore, scleredema has more profound diffuse superficial and deep mucin deposition compared to scleromyxedema. Scleroderma is an autoimmune cutaneous condition that is divided into 2 categories: localized scleroderma and systemic sclerosis (SSc).⁹ Localized scleroderma (also called morphea) often is characterized by indurated hyperpigmented or hypopigmented lesions. There is an absence of Raynaud phenomenon, telangiectasia, and systemic disease.⁹ Systemic sclerosis is further divided into 2 categories—limited cutaneous and diffuse cutaneous—which are differentiated by the extent of organ system involvement. Limited cutaneous SSc involves calcinosis, Raynaud phenomenon, esophageal dysmotility, skin sclerosis distal to the elbows and knees, and telangiectasia.⁹ Diffuse cutaneous SSc is characterized by Raynaud phenomenon; cutaneous sclerosis proximal to the elbows and knees; and fibrosis of the gastrointestinal, pulmonary, renal, and cardiac systems.9 Scl-70 antibodies are specific for diffuse cutaneous SSc, and centromere antibodies are specific for limited cutaneous SSc. Scleromyxedema shares many of the same clinical symptoms as scleroderma; therefore, histopathologic examination is important for differentiating these disorders. Histologically, scleroderma is characterized by thickened collagen bundles associated with a variable degree of perivascular and interstitial lymphoplasmacytic inflammation. No increased dermal mucin is present.⁹ Our patient did not have the clinical cutaneous features of localized scleroderma and lacked the signs of internal organ involvement that typically are found in SSc. He did have Raynaud phenomenon but did not have matlike telangiectases or Scl-70 or centromere antibodies.

Reticular erythematosus mucinosis (REM) is a rare inflammatory cutaneous disease that is characterized by diffuse reticular erythematous macules or papules that may be asymptomatic or associated with pruritus.¹⁰ Reticular erythematosus mucinosis most frequently affects middle-aged women and appears on the trunk.⁹ Our patient was not part of the demographic group most frequently affected by REM. More importantly, our patient’s lesions were not erythematous or reticular in appearance, making the diagnosis of REM unlikely. Furthermore, REM has no associated cutaneous sclerosis or induration.

The Diagnosis: Scleromyxedema

A punch biopsy of the upper back performed at an outside institution revealed increased histiocytes and abundant interstitial mucin confined to the papillary dermis (Figures 1 and 2), consistent with the lichen myxedematosus (LM) papules that may be seen in scleromyxedema. Serum protein electrophoresis revealed the presence of a protein of restricted mobility on the gamma region that occupied 5.3% of the total protein (0.3 g/dL). Urine protein electrophoresis showed free kappa light chain monoclonal protein in the gamma region. Immunofixation electrophoresis revealed the presence of IgG kappa monoclonal protein in the gamma region with 10% monotype kappa cells. The presence of Raynaud phenomenon and positive antinuclear antibody (1:320, speckled) was noted. Laboratory studies for thyroid-stimulating hormone, C-reactive protein, Scl-70 antibody, myositis panel, ribonucleoprotein antibody, Smith antibody, Sjögren syndrome–related antigens A and B antibodies, rheumatoid factor, and RNA polymerase III antibody all were within reference range. Our patient was treated with monthly intravenous immunoglobulin (IVIG), and he noted substantial improvement in skin findings after 3 months of IVIG.

Localized lichen myxedematosus is a rare idiopathic cutaneous disease that clinically is characterized by waxy indurated papules and histologically is characterized by diffuse mucin deposition and fibroblast proliferation in the upper dermis.¹ Scleromyxedema is a diffuse variant of LM in which the papules and plaques of LM are associated with skin thickening involving almost the entire body and associated systemic disease. The exact mechanism of this disease is unknown, but the most widely accepted hypothesis is that immunoglobulins and cytokines contribute to the synthesis of glycosaminoglycans and thereby the deposition of mucin in the dermis.² Scleromyxedema has a chronic course and generally responds poorly to existing treatments.¹ Partial improvement has been demonstrated in treatment with topical calcineurin inhibitors and topical steroids.²

The differential diagnosis in our patient included scleromyxedema, scleredema, scleroderma, LM, and reticular erythematosus mucinosis. He was diagnosed with scleromyxedema with kappa monoclonal gammopathy. Scleromyxedema is a rare disorder involving the deposition of mucinous material in the papillary dermis that causes the formation of infiltrative skin lesions.³ The etiology is unknown, but the presence of a monoclonal protein is an important characteristic of this disorder. It is important to rule out thyroid disease as a possible etiology before concluding that the disease process is driven by the monoclonal gammopathy; this will help determine appropriate therapies.^4,5 Usually the monoclonal protein is associated with the IgG lambda subtype. Intravenous immunoglobulin often is considered as a first-line treatment of scleromyxedema and usually is administered at a dosage of 2 g/kg divided over 2 to 5 consecutive days per month.³ Previously, our patient had been treated with IVIG for 3 years for chronic inflammatory demyelinating polyneuropathy and had stopped 1 to 2 years before his cutaneous symptoms started. Generally, scleromyxedema patients must stay on IVIG long-term to prevent relapse, typically every 6 to 8 weeks. Second-line treatments for scleromyxedema include systemic corticosteroids and thalidomide.⁶ Scleromyxedema and LM have several clinical and histopathologic features in common. Our patient’s biopsy revealed increased mucin deposition associated with fibroblast proliferation confined to the superficial dermis. These histologic changes can be seen in the setting of either LM or scleromyxedema. Our patient’s diffuse skin thickening and monoclonal gammopathy were more characteristic of scleromyxedema. In contrast, LM is a localized eruption with no internal organ manifestations and no associated systemic disease, such as monoclonal gammopathy and thyroid disease.

Scleredema adultorum of Buschke (also referred to as scleredema) is a rare idiopathic dermatologic condition characterized by thickening and tightening of the skin that leads to firm, nonpitting, woody edema that initially involves the upper back and neck but can spread to the face, scalp, and shoulders; importantly, scleredema spares the hands and feet.⁷ Scleredema has been associated with type 2 diabetes mellitus, streptococcal upper respiratory tract infections, and monoclonal gammopathy.⁸ Although our patient did have a monoclonal gammopathy, he also experienced prominent hand involvement with diffuse skin thickening, which is not typical of scleredema. Additionally, biopsy of scleredema would show increased mucin but would not show the proliferation of fibroblasts that was seen in our patient’s biopsy. Furthermore, scleredema has more profound diffuse superficial and deep mucin deposition compared to scleromyxedema. Scleroderma is an autoimmune cutaneous condition that is divided into 2 categories: localized scleroderma and systemic sclerosis (SSc).⁹ Localized scleroderma (also called morphea) often is characterized by indurated hyperpigmented or hypopigmented lesions. There is an absence of Raynaud phenomenon, telangiectasia, and systemic disease.⁹ Systemic sclerosis is further divided into 2 categories—limited cutaneous and diffuse cutaneous—which are differentiated by the extent of organ system involvement. Limited cutaneous SSc involves calcinosis, Raynaud phenomenon, esophageal dysmotility, skin sclerosis distal to the elbows and knees, and telangiectasia.⁹ Diffuse cutaneous SSc is characterized by Raynaud phenomenon; cutaneous sclerosis proximal to the elbows and knees; and fibrosis of the gastrointestinal, pulmonary, renal, and cardiac systems.9 Scl-70 antibodies are specific for diffuse cutaneous SSc, and centromere antibodies are specific for limited cutaneous SSc. Scleromyxedema shares many of the same clinical symptoms as scleroderma; therefore, histopathologic examination is important for differentiating these disorders. Histologically, scleroderma is characterized by thickened collagen bundles associated with a variable degree of perivascular and interstitial lymphoplasmacytic inflammation. No increased dermal mucin is present.⁹ Our patient did not have the clinical cutaneous features of localized scleroderma and lacked the signs of internal organ involvement that typically are found in SSc. He did have Raynaud phenomenon but did not have matlike telangiectases or Scl-70 or centromere antibodies.

Reticular erythematosus mucinosis (REM) is a rare inflammatory cutaneous disease that is characterized by diffuse reticular erythematous macules or papules that may be asymptomatic or associated with pruritus.¹⁰ Reticular erythematosus mucinosis most frequently affects middle-aged women and appears on the trunk.⁹ Our patient was not part of the demographic group most frequently affected by REM. More importantly, our patient’s lesions were not erythematous or reticular in appearance, making the diagnosis of REM unlikely. Furthermore, REM has no associated cutaneous sclerosis or induration.

The Diagnosis: Scleromyxedema

A punch biopsy of the upper back performed at an outside institution revealed increased histiocytes and abundant interstitial mucin confined to the papillary dermis (Figures 1 and 2), consistent with the lichen myxedematosus (LM) papules that may be seen in scleromyxedema. Serum protein electrophoresis revealed the presence of a protein of restricted mobility on the gamma region that occupied 5.3% of the total protein (0.3 g/dL). Urine protein electrophoresis showed free kappa light chain monoclonal protein in the gamma region. Immunofixation electrophoresis revealed the presence of IgG kappa monoclonal protein in the gamma region with 10% monotype kappa cells. The presence of Raynaud phenomenon and positive antinuclear antibody (1:320, speckled) was noted. Laboratory studies for thyroid-stimulating hormone, C-reactive protein, Scl-70 antibody, myositis panel, ribonucleoprotein antibody, Smith antibody, Sjögren syndrome–related antigens A and B antibodies, rheumatoid factor, and RNA polymerase III antibody all were within reference range. Our patient was treated with monthly intravenous immunoglobulin (IVIG), and he noted substantial improvement in skin findings after 3 months of IVIG.

Localized lichen myxedematosus is a rare idiopathic cutaneous disease that clinically is characterized by waxy indurated papules and histologically is characterized by diffuse mucin deposition and fibroblast proliferation in the upper dermis.¹ Scleromyxedema is a diffuse variant of LM in which the papules and plaques of LM are associated with skin thickening involving almost the entire body and associated systemic disease. The exact mechanism of this disease is unknown, but the most widely accepted hypothesis is that immunoglobulins and cytokines contribute to the synthesis of glycosaminoglycans and thereby the deposition of mucin in the dermis.² Scleromyxedema has a chronic course and generally responds poorly to existing treatments.¹ Partial improvement has been demonstrated in treatment with topical calcineurin inhibitors and topical steroids.²

The differential diagnosis in our patient included scleromyxedema, scleredema, scleroderma, LM, and reticular erythematosus mucinosis. He was diagnosed with scleromyxedema with kappa monoclonal gammopathy. Scleromyxedema is a rare disorder involving the deposition of mucinous material in the papillary dermis that causes the formation of infiltrative skin lesions.³ The etiology is unknown, but the presence of a monoclonal protein is an important characteristic of this disorder. It is important to rule out thyroid disease as a possible etiology before concluding that the disease process is driven by the monoclonal gammopathy; this will help determine appropriate therapies.^4,5 Usually the monoclonal protein is associated with the IgG lambda subtype. Intravenous immunoglobulin often is considered as a first-line treatment of scleromyxedema and usually is administered at a dosage of 2 g/kg divided over 2 to 5 consecutive days per month.³ Previously, our patient had been treated with IVIG for 3 years for chronic inflammatory demyelinating polyneuropathy and had stopped 1 to 2 years before his cutaneous symptoms started. Generally, scleromyxedema patients must stay on IVIG long-term to prevent relapse, typically every 6 to 8 weeks. Second-line treatments for scleromyxedema include systemic corticosteroids and thalidomide.⁶ Scleromyxedema and LM have several clinical and histopathologic features in common. Our patient’s biopsy revealed increased mucin deposition associated with fibroblast proliferation confined to the superficial dermis. These histologic changes can be seen in the setting of either LM or scleromyxedema. Our patient’s diffuse skin thickening and monoclonal gammopathy were more characteristic of scleromyxedema. In contrast, LM is a localized eruption with no internal organ manifestations and no associated systemic disease, such as monoclonal gammopathy and thyroid disease.

Scleredema adultorum of Buschke (also referred to as scleredema) is a rare idiopathic dermatologic condition characterized by thickening and tightening of the skin that leads to firm, nonpitting, woody edema that initially involves the upper back and neck but can spread to the face, scalp, and shoulders; importantly, scleredema spares the hands and feet.⁷ Scleredema has been associated with type 2 diabetes mellitus, streptococcal upper respiratory tract infections, and monoclonal gammopathy.⁸ Although our patient did have a monoclonal gammopathy, he also experienced prominent hand involvement with diffuse skin thickening, which is not typical of scleredema. Additionally, biopsy of scleredema would show increased mucin but would not show the proliferation of fibroblasts that was seen in our patient’s biopsy. Furthermore, scleredema has more profound diffuse superficial and deep mucin deposition compared to scleromyxedema. Scleroderma is an autoimmune cutaneous condition that is divided into 2 categories: localized scleroderma and systemic sclerosis (SSc).⁹ Localized scleroderma (also called morphea) often is characterized by indurated hyperpigmented or hypopigmented lesions. There is an absence of Raynaud phenomenon, telangiectasia, and systemic disease.⁹ Systemic sclerosis is further divided into 2 categories—limited cutaneous and diffuse cutaneous—which are differentiated by the extent of organ system involvement. Limited cutaneous SSc involves calcinosis, Raynaud phenomenon, esophageal dysmotility, skin sclerosis distal to the elbows and knees, and telangiectasia.⁹ Diffuse cutaneous SSc is characterized by Raynaud phenomenon; cutaneous sclerosis proximal to the elbows and knees; and fibrosis of the gastrointestinal, pulmonary, renal, and cardiac systems.9 Scl-70 antibodies are specific for diffuse cutaneous SSc, and centromere antibodies are specific for limited cutaneous SSc. Scleromyxedema shares many of the same clinical symptoms as scleroderma; therefore, histopathologic examination is important for differentiating these disorders. Histologically, scleroderma is characterized by thickened collagen bundles associated with a variable degree of perivascular and interstitial lymphoplasmacytic inflammation. No increased dermal mucin is present.⁹ Our patient did not have the clinical cutaneous features of localized scleroderma and lacked the signs of internal organ involvement that typically are found in SSc. He did have Raynaud phenomenon but did not have matlike telangiectases or Scl-70 or centromere antibodies.

Reticular erythematosus mucinosis (REM) is a rare inflammatory cutaneous disease that is characterized by diffuse reticular erythematous macules or papules that may be asymptomatic or associated with pruritus.¹⁰ Reticular erythematosus mucinosis most frequently affects middle-aged women and appears on the trunk.⁹ Our patient was not part of the demographic group most frequently affected by REM. More importantly, our patient’s lesions were not erythematous or reticular in appearance, making the diagnosis of REM unlikely. Furthermore, REM has no associated cutaneous sclerosis or induration.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Background

Ketogenic diet (KD) is a high-fat and low carbohydrate diet that has been reported as a treatment option for patients with cancer. KD creates a metabolic state in which blood glucose levels are reduced and ketone bodies are elevated. Cancer cells are unable to use ketone bodies for energy and metabolism due to mitochondrial dysfunction. We published the efficacy of KD in patients with cancer after failure of chemotherapy. 1 This case report is presented to evaluate the feasibility of KD concurrent with chemoimmunotherapy.

Case Report

Patient is a 69-year-old male who presented with iron deficiency anemia in 2018. Colonoscopy and biopsy showed colon adenocarcinoma. He underwent resection which confirmed stage IIIC disease. He received adjuvant treatment with FOLFOX but quickly developed pancreatic and omental metastasis. He was started on FOLFIRI + bevacizumab followed by pancreatic mass resection in 2019. Molecular testing revealed wild type KRAS, positive BRAF V600E, and high MSI. He received encorafenib + cetuximab until disease progression. Treatment was changed to pembrolizumab until PET scan showed progression. His CEA increased to 1031 in January 2021. He was subsequently started on KD concurrent with trifluridine + tipiracil + bevacizumab. He progressed after 10 months. Therapy was changed to ipilimumab + nivolumab with continuation of KD. He was strictly adherent to KD with low Glucose Ketone Index of 8.2 (confirming ketosis) but in 2022 his GKI level started to rise. His CEA, however, significantly decreased to 20 in March 2022 and PET scan showed stable disease. He presently is on maintenance nivolumab + KD while maintaining an excellent quality of life by EORTC QLQ scores.

Conclusions

The use of KD concurrently with chemotherapy and immunotherapy is still under investigation. Our case report shows that KD is tolerable with treatment and can possibly contribute to controlling progression of metastatic cancer. We are starting an investigator initiative KD trial that received a grant from R&D at VACCHCS. We will present the study protocol in poster presentation.

Background

Ketogenic diet (KD) is a high-fat and low carbohydrate diet that has been reported as a treatment option for patients with cancer. KD creates a metabolic state in which blood glucose levels are reduced and ketone bodies are elevated. Cancer cells are unable to use ketone bodies for energy and metabolism due to mitochondrial dysfunction. We published the efficacy of KD in patients with cancer after failure of chemotherapy. 1 This case report is presented to evaluate the feasibility of KD concurrent with chemoimmunotherapy.

Case Report

Patient is a 69-year-old male who presented with iron deficiency anemia in 2018. Colonoscopy and biopsy showed colon adenocarcinoma. He underwent resection which confirmed stage IIIC disease. He received adjuvant treatment with FOLFOX but quickly developed pancreatic and omental metastasis. He was started on FOLFIRI + bevacizumab followed by pancreatic mass resection in 2019. Molecular testing revealed wild type KRAS, positive BRAF V600E, and high MSI. He received encorafenib + cetuximab until disease progression. Treatment was changed to pembrolizumab until PET scan showed progression. His CEA increased to 1031 in January 2021. He was subsequently started on KD concurrent with trifluridine + tipiracil + bevacizumab. He progressed after 10 months. Therapy was changed to ipilimumab + nivolumab with continuation of KD. He was strictly adherent to KD with low Glucose Ketone Index of 8.2 (confirming ketosis) but in 2022 his GKI level started to rise. His CEA, however, significantly decreased to 20 in March 2022 and PET scan showed stable disease. He presently is on maintenance nivolumab + KD while maintaining an excellent quality of life by EORTC QLQ scores.

Conclusions

The use of KD concurrently with chemotherapy and immunotherapy is still under investigation. Our case report shows that KD is tolerable with treatment and can possibly contribute to controlling progression of metastatic cancer. We are starting an investigator initiative KD trial that received a grant from R&D at VACCHCS. We will present the study protocol in poster presentation.

Background

Ketogenic diet (KD) is a high-fat and low carbohydrate diet that has been reported as a treatment option for patients with cancer. KD creates a metabolic state in which blood glucose levels are reduced and ketone bodies are elevated. Cancer cells are unable to use ketone bodies for energy and metabolism due to mitochondrial dysfunction. We published the efficacy of KD in patients with cancer after failure of chemotherapy. 1 This case report is presented to evaluate the feasibility of KD concurrent with chemoimmunotherapy.

Case Report

Patient is a 69-year-old male who presented with iron deficiency anemia in 2018. Colonoscopy and biopsy showed colon adenocarcinoma. He underwent resection which confirmed stage IIIC disease. He received adjuvant treatment with FOLFOX but quickly developed pancreatic and omental metastasis. He was started on FOLFIRI + bevacizumab followed by pancreatic mass resection in 2019. Molecular testing revealed wild type KRAS, positive BRAF V600E, and high MSI. He received encorafenib + cetuximab until disease progression. Treatment was changed to pembrolizumab until PET scan showed progression. His CEA increased to 1031 in January 2021. He was subsequently started on KD concurrent with trifluridine + tipiracil + bevacizumab. He progressed after 10 months. Therapy was changed to ipilimumab + nivolumab with continuation of KD. He was strictly adherent to KD with low Glucose Ketone Index of 8.2 (confirming ketosis) but in 2022 his GKI level started to rise. His CEA, however, significantly decreased to 20 in March 2022 and PET scan showed stable disease. He presently is on maintenance nivolumab + KD while maintaining an excellent quality of life by EORTC QLQ scores.

Conclusions

The use of KD concurrently with chemotherapy and immunotherapy is still under investigation. Our case report shows that KD is tolerable with treatment and can possibly contribute to controlling progression of metastatic cancer. We are starting an investigator initiative KD trial that received a grant from R&D at VACCHCS. We will present the study protocol in poster presentation.

Purpose

Examine the impact of different definitions of castration resistance used to identify patients with castration-resistant prostate cancer (CRPC) using electronic health records (EHR).

Background

CRPC is a form of prostate cancer that is resistant to treatment with androgen deprivation therapy (ADT) and is associated with higher morbidity and mortality. Widely used guidelines like the Prostate Cancer Working Group 3 (PCWG 3), the American Urological Association (AUA), and many others differ in their definitions of castration-resistance. Until now, the feasibility of identifying CRPC using different definitions from EHR data has not been studied.

Methods/Data Analyisis

EHR data from the Veterans Health Administration (01/2006-12/2020) were used to identify veterans with CRPC according to the following criteria: 1) PCWG 3—a PSA increase ?25% from the nadir with a minimum rise of 2 ng/mL, while castrate (testosterone < 50 ng/mL); 2) AUA—2 consecutive PSA rises of ?0.2 ng/mL; 3) CRPC screening—a PSA rise of > 0.0 ng/mL within a window of 7–90 days.

Results

36,101 unique patients were identified using 1 of (or a combination of) the 3 CRPC criteria. Approximately 12,775 (35%) patients met all 3 criteria, while 8,589 (24%) were identified by AUA, 4,785 (13%) by CRPC screening, and 145 (0.4%) by PCWG3. A total of 8,377 (23%) patients met both the AUA and CRPC screening criteria, 1,219 (3%) patients met the AUA and PCWG3 criteria, and 211 (1%) met the PCWG3 and CRPC screening criteria.

Conculsions/Implications

Although several definitions can be used to identify CRPC patients, a combination of these definitions results in the greatest yield of CRPC patients identified using EHR data. Even though the PCWG3 criterion is frequently used in both clinical trials research and retrospective observational research, PCWG3 may miss many patients meeting other criteria and should not be used by itself when studying patients with CRPC identified from EHR data.

Purpose

Examine the impact of different definitions of castration resistance used to identify patients with castration-resistant prostate cancer (CRPC) using electronic health records (EHR).

Background

CRPC is a form of prostate cancer that is resistant to treatment with androgen deprivation therapy (ADT) and is associated with higher morbidity and mortality. Widely used guidelines like the Prostate Cancer Working Group 3 (PCWG 3), the American Urological Association (AUA), and many others differ in their definitions of castration-resistance. Until now, the feasibility of identifying CRPC using different definitions from EHR data has not been studied.

Methods/Data Analyisis

EHR data from the Veterans Health Administration (01/2006-12/2020) were used to identify veterans with CRPC according to the following criteria: 1) PCWG 3—a PSA increase ?25% from the nadir with a minimum rise of 2 ng/mL, while castrate (testosterone < 50 ng/mL); 2) AUA—2 consecutive PSA rises of ?0.2 ng/mL; 3) CRPC screening—a PSA rise of > 0.0 ng/mL within a window of 7–90 days.

Results

36,101 unique patients were identified using 1 of (or a combination of) the 3 CRPC criteria. Approximately 12,775 (35%) patients met all 3 criteria, while 8,589 (24%) were identified by AUA, 4,785 (13%) by CRPC screening, and 145 (0.4%) by PCWG3. A total of 8,377 (23%) patients met both the AUA and CRPC screening criteria, 1,219 (3%) patients met the AUA and PCWG3 criteria, and 211 (1%) met the PCWG3 and CRPC screening criteria.

Conculsions/Implications

Although several definitions can be used to identify CRPC patients, a combination of these definitions results in the greatest yield of CRPC patients identified using EHR data. Even though the PCWG3 criterion is frequently used in both clinical trials research and retrospective observational research, PCWG3 may miss many patients meeting other criteria and should not be used by itself when studying patients with CRPC identified from EHR data.

Purpose

Examine the impact of different definitions of castration resistance used to identify patients with castration-resistant prostate cancer (CRPC) using electronic health records (EHR).

Background

CRPC is a form of prostate cancer that is resistant to treatment with androgen deprivation therapy (ADT) and is associated with higher morbidity and mortality. Widely used guidelines like the Prostate Cancer Working Group 3 (PCWG 3), the American Urological Association (AUA), and many others differ in their definitions of castration-resistance. Until now, the feasibility of identifying CRPC using different definitions from EHR data has not been studied.

Methods/Data Analyisis

EHR data from the Veterans Health Administration (01/2006-12/2020) were used to identify veterans with CRPC according to the following criteria: 1) PCWG 3—a PSA increase ?25% from the nadir with a minimum rise of 2 ng/mL, while castrate (testosterone < 50 ng/mL); 2) AUA—2 consecutive PSA rises of ?0.2 ng/mL; 3) CRPC screening—a PSA rise of > 0.0 ng/mL within a window of 7–90 days.

Results

36,101 unique patients were identified using 1 of (or a combination of) the 3 CRPC criteria. Approximately 12,775 (35%) patients met all 3 criteria, while 8,589 (24%) were identified by AUA, 4,785 (13%) by CRPC screening, and 145 (0.4%) by PCWG3. A total of 8,377 (23%) patients met both the AUA and CRPC screening criteria, 1,219 (3%) patients met the AUA and PCWG3 criteria, and 211 (1%) met the PCWG3 and CRPC screening criteria.

Conculsions/Implications

Although several definitions can be used to identify CRPC patients, a combination of these definitions results in the greatest yield of CRPC patients identified using EHR data. Even though the PCWG3 criterion is frequently used in both clinical trials research and retrospective observational research, PCWG3 may miss many patients meeting other criteria and should not be used by itself when studying patients with CRPC identified from EHR data.