Cutis

As of 2018, the mean dermatologist to population ratio in the United States was 1.10 per 100,000 people, highlighting a shortage of dermatologists that is only predicted to increase in coming years.^1-4 This undersupply is fueled by both an increasing burden of dermatologic disease and population growth.⁴ Without readily available access to dermatologic care, many patients are left waiting for weeks to see a dermatologist, depending on geographic region.^5-7 It is not simply patients who perceive wait times to be prolonged; approximately half of dermatologists surveyed by the American Academy of Dermatology (AAD) reported an undersupply of dermatologists in their communities, a finding that strongly correlated with patient wait times.² Ensuring the dermatologic workforce is sufficient to fulfill patient needs requires innovation of current practice models. To address this unmet demand, many practices have begun incorporating physician extenders, a term that encompasses physicians not board certified in dermatology, physician assistants, and nurse practitioners.⁷ The evolving landscape of the dermatologic workforce raises questions about future practice models and patient outcomes.

Scope of Practice for Physician Extenders

In practice, the role of physician extenders is highly variable. Legislation involving the scope of practice for physician extenders constantly is changing and varies by state. As of November 2021, 24 states and the District of Columbia permit nurse practitioners “full practice” authority to triage patients, interpret diagnostic tests, and prescribe treatments without physician oversight, including controlled substances.^8,9 Even in states with “reduced practice” and “restricted practice” paradigms, which necessitate physician oversight, there remains ambiguity. Across the country, state regulatory bodies differ in statues governing licensing requirements, accessibility of the supervising physician, and ultimately culpability in the case of patient harm. Lack of consensus guidelines that clearly define roles and responsibilities has kindled controversy regarding extent of autonomy and liability for adverse outcomes.^10,11

With respect to procedures, the AAD has explicitly recommended that “only active and properly licensed doctors of medicine and osteopathy shall engage in the practice of medicine” but that “under appropriate circumstances, a physician may delegate certain procedures and services to appropriately trained nonphysician office personnel.”¹² This statement does not refer to or explicitly list the procedures that are appropriate for delegation to nonphysician personnel, and there is wide variability in how this recommendation is applied in daily practice. As it was originally intended, the AAD’s “Ethics in Medical Practice” position statement indicated that dermatologists must directly oversee physician extenders, a responsibility that is defined as being “present on-site, immediately available and able to respond promptly” to issues arising during the provision of health care services.¹²

Adverse Events From Cosmetic Procedures

The American Society for Dermatologic Surgery has documented a steady growth in the demand for cosmetic, medical, and surgical services,¹³ a trend that has heralded an increase in the number of procedures performed by physician extenders.^14,15 One study contrasted the risk for adverse events following minimally invasive cosmetic procedures performed by physicians or nonphysicians. Of 2116 patients surveyed, 50 adverse events were documented.¹⁴ The cohort treated by nonphysicians experienced a higher incidence of laser burns and dyspigmentation, and the use of improper technique was the most frequently implicated cause of developing an adverse event. Approximately 24.6% of American Society for Dermatologic Surgery members reported treating 10 or more complications of cosmetic procedures performed by nonphysicians.¹⁴ Beyond laser burns and dyspigmentation, this wide range of complications included inappropriately placed filler product, facial drooping, and scarring. These studies highlight the need for further investigation into the outcomes of procedures performed by physician extenders.

Training of Physician Extenders

Even with medical management, emphasis on proper training of personnel is key and remains a legitimate concern. The training of physician extenders in dermatology differs greatly by location; while some physician extenders operate under meticulous guidance and thus can expand their skill set, other physician extenders shadow dermatologists for an arbitrary amount of time before being thrust into practice.¹⁰ It would be a disservice to both patients and nonphysician providers alike to conflate the latter regimen with the 4 years of medical school, 1 year of internship, and 3 years of rigorous specialized dermatologic training that physicians undergo.

This stark discrepancy between the training of physicians and physician extenders raises difficult questions about the patient’s right to make an informed decision regarding how they receive health care. Indeed, the casually regulated autonomous practice of some nonphysician providers has ignited public shock and ire.¹¹

Reducing Health Care Expenditures

As legislatures deliberate over expanding scope of practice, policies should be based on evidence that prioritizes patient safety. In the appropriate setting, physician extenders can be instrumental to mitigating health care disparities; the use of physician extenders can diminish wait times for patients with routine visits for stable dermatologic disease.¹⁶ Moreover, reducing health care expenditures often is cited as a major benefit of increased utilization of physician extenders.¹⁴ It stands to reason that compensation of nonphysician providers is less expensive for a practice compared with physicians. Physician extenders participating in the management of stable chronic conditions or mild acute conditions may be cost-efficient in these circumstances; however, evidence suggests that physician extenders may incur greater costs than physicians with respect to the utilization of diagnostic tests or prescribing medications. For example, several studies have documented a substantial difference in the number of biopsies needed per malignant neoplasm by physicians compared to physician extenders.^17-19 Particularly in patients younger than 65 years and in patients without history of skin cancer, physician extenders had to perform a greater number of biopsies to diagnose malignant neoplasms vs physicians.¹⁸ In addition to increased utilization of diagnostic tests, nonphysician providers more frequently prescribe medications of varying classes.^20-22 Whether in outpatient offices, emergency departments, or hospital clinics, physician extenders more frequently prescribe antibiotics, which has concerning implications for antibiotic stewardship.^20,21 In states with independent prescription authority, physician extenders are more than 20 times more likely to overprescribeopioids compared to physician extenders in states requiring physician supervision.²³ These findings warrant additional investigation into how prescription patterns vary by provider type and how these differences impact patient outcomes.

Final Thoughts

Improving patient care is inherently a team endeavor, and the contributions of all members of the health care team are critical to success. Engaging physician extenders may help mitigate disparities in dermatologic care, with respect to surveillance of stable chronic conditions or the diagnosis of mild acute diseases. However, the exact scope of practice of physician extenders remains ambiguous, and their training regimens can vary drastically. Therefore, in the interest of patient safety, new patients or medically complex patients (ie, cutaneous lymphomas, nonstable autoimmune connective tissue disease) should be examined and managed by physicians. In either scenario, the patient should be informed of which providers are available and should be integrated into the decision-making process for their care. Through mutual respect, close collaboration, and candid assessments of patient complexity, different parties within the medical team can unite behind the mission to improve patient outcomes and champion equitable access to health care.

As of 2018, the mean dermatologist to population ratio in the United States was 1.10 per 100,000 people, highlighting a shortage of dermatologists that is only predicted to increase in coming years.^1-4 This undersupply is fueled by both an increasing burden of dermatologic disease and population growth.⁴ Without readily available access to dermatologic care, many patients are left waiting for weeks to see a dermatologist, depending on geographic region.^5-7 It is not simply patients who perceive wait times to be prolonged; approximately half of dermatologists surveyed by the American Academy of Dermatology (AAD) reported an undersupply of dermatologists in their communities, a finding that strongly correlated with patient wait times.² Ensuring the dermatologic workforce is sufficient to fulfill patient needs requires innovation of current practice models. To address this unmet demand, many practices have begun incorporating physician extenders, a term that encompasses physicians not board certified in dermatology, physician assistants, and nurse practitioners.⁷ The evolving landscape of the dermatologic workforce raises questions about future practice models and patient outcomes.

Scope of Practice for Physician Extenders

In practice, the role of physician extenders is highly variable. Legislation involving the scope of practice for physician extenders constantly is changing and varies by state. As of November 2021, 24 states and the District of Columbia permit nurse practitioners “full practice” authority to triage patients, interpret diagnostic tests, and prescribe treatments without physician oversight, including controlled substances.^8,9 Even in states with “reduced practice” and “restricted practice” paradigms, which necessitate physician oversight, there remains ambiguity. Across the country, state regulatory bodies differ in statues governing licensing requirements, accessibility of the supervising physician, and ultimately culpability in the case of patient harm. Lack of consensus guidelines that clearly define roles and responsibilities has kindled controversy regarding extent of autonomy and liability for adverse outcomes.^10,11

With respect to procedures, the AAD has explicitly recommended that “only active and properly licensed doctors of medicine and osteopathy shall engage in the practice of medicine” but that “under appropriate circumstances, a physician may delegate certain procedures and services to appropriately trained nonphysician office personnel.”¹² This statement does not refer to or explicitly list the procedures that are appropriate for delegation to nonphysician personnel, and there is wide variability in how this recommendation is applied in daily practice. As it was originally intended, the AAD’s “Ethics in Medical Practice” position statement indicated that dermatologists must directly oversee physician extenders, a responsibility that is defined as being “present on-site, immediately available and able to respond promptly” to issues arising during the provision of health care services.¹²

Adverse Events From Cosmetic Procedures

The American Society for Dermatologic Surgery has documented a steady growth in the demand for cosmetic, medical, and surgical services,¹³ a trend that has heralded an increase in the number of procedures performed by physician extenders.^14,15 One study contrasted the risk for adverse events following minimally invasive cosmetic procedures performed by physicians or nonphysicians. Of 2116 patients surveyed, 50 adverse events were documented.¹⁴ The cohort treated by nonphysicians experienced a higher incidence of laser burns and dyspigmentation, and the use of improper technique was the most frequently implicated cause of developing an adverse event. Approximately 24.6% of American Society for Dermatologic Surgery members reported treating 10 or more complications of cosmetic procedures performed by nonphysicians.¹⁴ Beyond laser burns and dyspigmentation, this wide range of complications included inappropriately placed filler product, facial drooping, and scarring. These studies highlight the need for further investigation into the outcomes of procedures performed by physician extenders.

Training of Physician Extenders

Even with medical management, emphasis on proper training of personnel is key and remains a legitimate concern. The training of physician extenders in dermatology differs greatly by location; while some physician extenders operate under meticulous guidance and thus can expand their skill set, other physician extenders shadow dermatologists for an arbitrary amount of time before being thrust into practice.¹⁰ It would be a disservice to both patients and nonphysician providers alike to conflate the latter regimen with the 4 years of medical school, 1 year of internship, and 3 years of rigorous specialized dermatologic training that physicians undergo.

This stark discrepancy between the training of physicians and physician extenders raises difficult questions about the patient’s right to make an informed decision regarding how they receive health care. Indeed, the casually regulated autonomous practice of some nonphysician providers has ignited public shock and ire.¹¹

Reducing Health Care Expenditures

As legislatures deliberate over expanding scope of practice, policies should be based on evidence that prioritizes patient safety. In the appropriate setting, physician extenders can be instrumental to mitigating health care disparities; the use of physician extenders can diminish wait times for patients with routine visits for stable dermatologic disease.¹⁶ Moreover, reducing health care expenditures often is cited as a major benefit of increased utilization of physician extenders.¹⁴ It stands to reason that compensation of nonphysician providers is less expensive for a practice compared with physicians. Physician extenders participating in the management of stable chronic conditions or mild acute conditions may be cost-efficient in these circumstances; however, evidence suggests that physician extenders may incur greater costs than physicians with respect to the utilization of diagnostic tests or prescribing medications. For example, several studies have documented a substantial difference in the number of biopsies needed per malignant neoplasm by physicians compared to physician extenders.^17-19 Particularly in patients younger than 65 years and in patients without history of skin cancer, physician extenders had to perform a greater number of biopsies to diagnose malignant neoplasms vs physicians.¹⁸ In addition to increased utilization of diagnostic tests, nonphysician providers more frequently prescribe medications of varying classes.^20-22 Whether in outpatient offices, emergency departments, or hospital clinics, physician extenders more frequently prescribe antibiotics, which has concerning implications for antibiotic stewardship.^20,21 In states with independent prescription authority, physician extenders are more than 20 times more likely to overprescribeopioids compared to physician extenders in states requiring physician supervision.²³ These findings warrant additional investigation into how prescription patterns vary by provider type and how these differences impact patient outcomes.

Final Thoughts

Improving patient care is inherently a team endeavor, and the contributions of all members of the health care team are critical to success. Engaging physician extenders may help mitigate disparities in dermatologic care, with respect to surveillance of stable chronic conditions or the diagnosis of mild acute diseases. However, the exact scope of practice of physician extenders remains ambiguous, and their training regimens can vary drastically. Therefore, in the interest of patient safety, new patients or medically complex patients (ie, cutaneous lymphomas, nonstable autoimmune connective tissue disease) should be examined and managed by physicians. In either scenario, the patient should be informed of which providers are available and should be integrated into the decision-making process for their care. Through mutual respect, close collaboration, and candid assessments of patient complexity, different parties within the medical team can unite behind the mission to improve patient outcomes and champion equitable access to health care.

As of 2018, the mean dermatologist to population ratio in the United States was 1.10 per 100,000 people, highlighting a shortage of dermatologists that is only predicted to increase in coming years.^1-4 This undersupply is fueled by both an increasing burden of dermatologic disease and population growth.⁴ Without readily available access to dermatologic care, many patients are left waiting for weeks to see a dermatologist, depending on geographic region.^5-7 It is not simply patients who perceive wait times to be prolonged; approximately half of dermatologists surveyed by the American Academy of Dermatology (AAD) reported an undersupply of dermatologists in their communities, a finding that strongly correlated with patient wait times.² Ensuring the dermatologic workforce is sufficient to fulfill patient needs requires innovation of current practice models. To address this unmet demand, many practices have begun incorporating physician extenders, a term that encompasses physicians not board certified in dermatology, physician assistants, and nurse practitioners.⁷ The evolving landscape of the dermatologic workforce raises questions about future practice models and patient outcomes.

Scope of Practice for Physician Extenders

In practice, the role of physician extenders is highly variable. Legislation involving the scope of practice for physician extenders constantly is changing and varies by state. As of November 2021, 24 states and the District of Columbia permit nurse practitioners “full practice” authority to triage patients, interpret diagnostic tests, and prescribe treatments without physician oversight, including controlled substances.^8,9 Even in states with “reduced practice” and “restricted practice” paradigms, which necessitate physician oversight, there remains ambiguity. Across the country, state regulatory bodies differ in statues governing licensing requirements, accessibility of the supervising physician, and ultimately culpability in the case of patient harm. Lack of consensus guidelines that clearly define roles and responsibilities has kindled controversy regarding extent of autonomy and liability for adverse outcomes.^10,11

With respect to procedures, the AAD has explicitly recommended that “only active and properly licensed doctors of medicine and osteopathy shall engage in the practice of medicine” but that “under appropriate circumstances, a physician may delegate certain procedures and services to appropriately trained nonphysician office personnel.”¹² This statement does not refer to or explicitly list the procedures that are appropriate for delegation to nonphysician personnel, and there is wide variability in how this recommendation is applied in daily practice. As it was originally intended, the AAD’s “Ethics in Medical Practice” position statement indicated that dermatologists must directly oversee physician extenders, a responsibility that is defined as being “present on-site, immediately available and able to respond promptly” to issues arising during the provision of health care services.¹²

Adverse Events From Cosmetic Procedures

The American Society for Dermatologic Surgery has documented a steady growth in the demand for cosmetic, medical, and surgical services,¹³ a trend that has heralded an increase in the number of procedures performed by physician extenders.^14,15 One study contrasted the risk for adverse events following minimally invasive cosmetic procedures performed by physicians or nonphysicians. Of 2116 patients surveyed, 50 adverse events were documented.¹⁴ The cohort treated by nonphysicians experienced a higher incidence of laser burns and dyspigmentation, and the use of improper technique was the most frequently implicated cause of developing an adverse event. Approximately 24.6% of American Society for Dermatologic Surgery members reported treating 10 or more complications of cosmetic procedures performed by nonphysicians.¹⁴ Beyond laser burns and dyspigmentation, this wide range of complications included inappropriately placed filler product, facial drooping, and scarring. These studies highlight the need for further investigation into the outcomes of procedures performed by physician extenders.

Training of Physician Extenders

Even with medical management, emphasis on proper training of personnel is key and remains a legitimate concern. The training of physician extenders in dermatology differs greatly by location; while some physician extenders operate under meticulous guidance and thus can expand their skill set, other physician extenders shadow dermatologists for an arbitrary amount of time before being thrust into practice.¹⁰ It would be a disservice to both patients and nonphysician providers alike to conflate the latter regimen with the 4 years of medical school, 1 year of internship, and 3 years of rigorous specialized dermatologic training that physicians undergo.

This stark discrepancy between the training of physicians and physician extenders raises difficult questions about the patient’s right to make an informed decision regarding how they receive health care. Indeed, the casually regulated autonomous practice of some nonphysician providers has ignited public shock and ire.¹¹

Reducing Health Care Expenditures

As legislatures deliberate over expanding scope of practice, policies should be based on evidence that prioritizes patient safety. In the appropriate setting, physician extenders can be instrumental to mitigating health care disparities; the use of physician extenders can diminish wait times for patients with routine visits for stable dermatologic disease.¹⁶ Moreover, reducing health care expenditures often is cited as a major benefit of increased utilization of physician extenders.¹⁴ It stands to reason that compensation of nonphysician providers is less expensive for a practice compared with physicians. Physician extenders participating in the management of stable chronic conditions or mild acute conditions may be cost-efficient in these circumstances; however, evidence suggests that physician extenders may incur greater costs than physicians with respect to the utilization of diagnostic tests or prescribing medications. For example, several studies have documented a substantial difference in the number of biopsies needed per malignant neoplasm by physicians compared to physician extenders.^17-19 Particularly in patients younger than 65 years and in patients without history of skin cancer, physician extenders had to perform a greater number of biopsies to diagnose malignant neoplasms vs physicians.¹⁸ In addition to increased utilization of diagnostic tests, nonphysician providers more frequently prescribe medications of varying classes.^20-22 Whether in outpatient offices, emergency departments, or hospital clinics, physician extenders more frequently prescribe antibiotics, which has concerning implications for antibiotic stewardship.^20,21 In states with independent prescription authority, physician extenders are more than 20 times more likely to overprescribeopioids compared to physician extenders in states requiring physician supervision.²³ These findings warrant additional investigation into how prescription patterns vary by provider type and how these differences impact patient outcomes.

Final Thoughts

Improving patient care is inherently a team endeavor, and the contributions of all members of the health care team are critical to success. Engaging physician extenders may help mitigate disparities in dermatologic care, with respect to surveillance of stable chronic conditions or the diagnosis of mild acute diseases. However, the exact scope of practice of physician extenders remains ambiguous, and their training regimens can vary drastically. Therefore, in the interest of patient safety, new patients or medically complex patients (ie, cutaneous lymphomas, nonstable autoimmune connective tissue disease) should be examined and managed by physicians. In either scenario, the patient should be informed of which providers are available and should be integrated into the decision-making process for their care. Through mutual respect, close collaboration, and candid assessments of patient complexity, different parties within the medical team can unite behind the mission to improve patient outcomes and champion equitable access to health care.

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

Secretan syndrome (SS) represents a recurrent or chronic form of factitious lymphedema, usually affecting the dorsal aspect of the hand.^1-3 It is accepted as a subtype of Munchausen syndrome whereby the patient self-inflicts and simulates lymphedema.^1,2 Historically, many of the cases reported with the term Charcot’s oedème bleu are now believed to represent clinical variants of SS.^4-6

Case Report

A 38-year-old Turkish woman presented with progressive swelling of the right hand of 2 years’ duration that had caused difficulty in manual work and reduction in manual dexterity. She previously had sought medical treatment for this condition by visiting several hospitals. According to her medical record, the following laboratory or radiologic tests had revealed negative or normal findings, except for obvious soft-tissue edema: bacterial and fungal cultures, plain radiography, Doppler ultrasonography, lymphoscintigraphy, magnetic resonance imaging, fine needle aspiration, and punch biopsy. Reflex sympathetic dystrophy, compartment syndrome, filariasis, tuberculosis, and lymphatic and venous obstruction were all excluded by appropriate testing. Our patient was in good health prior to onset of this disorder, and her medical history was unremarkable. There was no family history of a similar condition.

Dermatologic examination revealed brawny, soft, pitting edema; erythema; and crusts affecting the dorsal aspect of the right hand and proximal parts of the fingers (Figure 1). The yellow discoloration of the skin and nails was attributed to potassium permanganate wet dressings. Under an elastic bandage at the wrist, which the patient unrolled herself, a sharp line of demarcation was evident, separating the lymphedematous and normal parts of the arm. There was no axillary lymphadenopathy.

Comment

In 1901, Henri Francois Secretan, a Swiss physician, reported workmen who had persistent hard swellings on the dorsal aspect of the hands after minor work-related trauma for which they had compensation claims.⁷ In his original report, Secretan did not suggest self-inflicted trauma in the etiology of this disorder.^5,8,9 In 1890, Jean Martin Charcot, a French neurologist, described oedème bleu, a term that is now believed to denote a condition similar to SS.^4-6 Currently, SS is attributed to self-inflicted injury and is considered a form of factitious lymphedema.⁹ As in dermatitis artefacta, most patients with SS are young women, and male patients with the condition tend to be older.^3,8

The mechanism used to provoke this factitious lymphedema might be of traumatic or obstructive nature. Secretan syndrome either is induced by intermittent or constant application of a tourniquet, ligature, cord, elastic bandage, scarf, kerchief, rubber band, or compress around the affected extremity, or by repetitive blunt trauma, force, or skin irritation.^1,4,5,8-10 There was an underlying psychopathology in all reported cases.^1,8,11 Factitious lymphedema is unconsciously motivated and consciously produced.^4,12 The affected patient often is experiencing a serious emotional conflict and is unlikely to be a malingerer, although exaggeration of symptoms may occur, as in our patient.¹² Psychiatric evaluation in SS may uncover neurosis, hysteria, frank psychosis, schizophrenia, masochism, depression, or an abnormal personality disorder.^1,12

Patients with SS present with recurrent or chronic lymphedema, usually affecting the dominant hand.¹ Involvement usually is unilateral; bilateral cases are rare.^3,6 Secretan syndrome is not solely limited to the hands; it also may involve the upper and lower extremities, including the feet.^3,11 There may be a clear line of demarcation, a ring, sulcus, distinct circumferential linear bands of erythema, discoloration, or ecchymoses, separating the normal and lymphedematous parts of the extremity.^{1,4,6,8-10,12} Patients usually attempt to hide the constricted areas from sight.¹ Over time, flexion contractures may develop due to peritendinous fibrosis.⁶ Histopathology displays a hematoma with adhesions to the extensor tendons; a hematoma surrounded by a thickened scar; or changes similar to ganglion tissue with cystic areas of mucin, fibrosis, and myxoid degeneration.^4,6

Factitious lymphedema can only be definitively diagnosed when the patient confesses or is caught self-inflicting the injury. Nevertheless, a diagnosis by exclusion is possible.⁴ Lymphangiography, lymphoscintigraphy, vascular Doppler ultrasonography, and magnetic resonance imaging may be helpful in excluding congenital and acquired causes of lymphedema and venous obstruction.^1,3,9,11 Magnetic resonance imaging may show soft tissue and tendon edema as well as diffuse peritendinous fibrosis extending to the fascia of the dorsal interosseous muscles.^3,4

Factitious lymphedema should be suspected in all patients with recurrent or chronic unilateral lymphedema without an explicable or apparent predisposing factor.^4,11,12 Patients with SS typically visit several hospitals or institutions; see many physicians; and willingly accept, request, and undergo unnecessary extensive, invasive, and costly diagnostic and therapeutic procedures and prolonged hospitalizations.^1,2,5,12 The disorder promptly responds to immobilization and elevation of the limb.^2,4 Plaster casts may prove useful in prevention of compression and thus amelioration of the lymphedema.^1,4,6 Once the diagnosis is confirmed, direct confrontation should be avoided and ideally the patient should be referred for psychiatric evaluation.^1,2,4,5,8,12 If the patient admits self-inflicting behavior, psychotherapy and/or behavior modification therapy along with psychotropic medications may be helpful to relieve emotional and behavioral symptoms.¹² Unfortunately, if the patient denies a self-inflicting role in the occurrence of lymphedema and persists in self-injurious behavior, psychotherapy or psychotropic medications will be futile.⁹

Secretan syndrome (SS) represents a recurrent or chronic form of factitious lymphedema, usually affecting the dorsal aspect of the hand.^1-3 It is accepted as a subtype of Munchausen syndrome whereby the patient self-inflicts and simulates lymphedema.^1,2 Historically, many of the cases reported with the term Charcot’s oedème bleu are now believed to represent clinical variants of SS.^4-6

Case Report

A 38-year-old Turkish woman presented with progressive swelling of the right hand of 2 years’ duration that had caused difficulty in manual work and reduction in manual dexterity. She previously had sought medical treatment for this condition by visiting several hospitals. According to her medical record, the following laboratory or radiologic tests had revealed negative or normal findings, except for obvious soft-tissue edema: bacterial and fungal cultures, plain radiography, Doppler ultrasonography, lymphoscintigraphy, magnetic resonance imaging, fine needle aspiration, and punch biopsy. Reflex sympathetic dystrophy, compartment syndrome, filariasis, tuberculosis, and lymphatic and venous obstruction were all excluded by appropriate testing. Our patient was in good health prior to onset of this disorder, and her medical history was unremarkable. There was no family history of a similar condition.

Dermatologic examination revealed brawny, soft, pitting edema; erythema; and crusts affecting the dorsal aspect of the right hand and proximal parts of the fingers (Figure 1). The yellow discoloration of the skin and nails was attributed to potassium permanganate wet dressings. Under an elastic bandage at the wrist, which the patient unrolled herself, a sharp line of demarcation was evident, separating the lymphedematous and normal parts of the arm. There was no axillary lymphadenopathy.

Comment

In 1901, Henri Francois Secretan, a Swiss physician, reported workmen who had persistent hard swellings on the dorsal aspect of the hands after minor work-related trauma for which they had compensation claims.⁷ In his original report, Secretan did not suggest self-inflicted trauma in the etiology of this disorder.^5,8,9 In 1890, Jean Martin Charcot, a French neurologist, described oedème bleu, a term that is now believed to denote a condition similar to SS.^4-6 Currently, SS is attributed to self-inflicted injury and is considered a form of factitious lymphedema.⁹ As in dermatitis artefacta, most patients with SS are young women, and male patients with the condition tend to be older.^3,8

The mechanism used to provoke this factitious lymphedema might be of traumatic or obstructive nature. Secretan syndrome either is induced by intermittent or constant application of a tourniquet, ligature, cord, elastic bandage, scarf, kerchief, rubber band, or compress around the affected extremity, or by repetitive blunt trauma, force, or skin irritation.^1,4,5,8-10 There was an underlying psychopathology in all reported cases.^1,8,11 Factitious lymphedema is unconsciously motivated and consciously produced.^4,12 The affected patient often is experiencing a serious emotional conflict and is unlikely to be a malingerer, although exaggeration of symptoms may occur, as in our patient.¹² Psychiatric evaluation in SS may uncover neurosis, hysteria, frank psychosis, schizophrenia, masochism, depression, or an abnormal personality disorder.^1,12

Patients with SS present with recurrent or chronic lymphedema, usually affecting the dominant hand.¹ Involvement usually is unilateral; bilateral cases are rare.^3,6 Secretan syndrome is not solely limited to the hands; it also may involve the upper and lower extremities, including the feet.^3,11 There may be a clear line of demarcation, a ring, sulcus, distinct circumferential linear bands of erythema, discoloration, or ecchymoses, separating the normal and lymphedematous parts of the extremity.^{1,4,6,8-10,12} Patients usually attempt to hide the constricted areas from sight.¹ Over time, flexion contractures may develop due to peritendinous fibrosis.⁶ Histopathology displays a hematoma with adhesions to the extensor tendons; a hematoma surrounded by a thickened scar; or changes similar to ganglion tissue with cystic areas of mucin, fibrosis, and myxoid degeneration.^4,6

Factitious lymphedema can only be definitively diagnosed when the patient confesses or is caught self-inflicting the injury. Nevertheless, a diagnosis by exclusion is possible.⁴ Lymphangiography, lymphoscintigraphy, vascular Doppler ultrasonography, and magnetic resonance imaging may be helpful in excluding congenital and acquired causes of lymphedema and venous obstruction.^1,3,9,11 Magnetic resonance imaging may show soft tissue and tendon edema as well as diffuse peritendinous fibrosis extending to the fascia of the dorsal interosseous muscles.^3,4

Factitious lymphedema should be suspected in all patients with recurrent or chronic unilateral lymphedema without an explicable or apparent predisposing factor.^4,11,12 Patients with SS typically visit several hospitals or institutions; see many physicians; and willingly accept, request, and undergo unnecessary extensive, invasive, and costly diagnostic and therapeutic procedures and prolonged hospitalizations.^1,2,5,12 The disorder promptly responds to immobilization and elevation of the limb.^2,4 Plaster casts may prove useful in prevention of compression and thus amelioration of the lymphedema.^1,4,6 Once the diagnosis is confirmed, direct confrontation should be avoided and ideally the patient should be referred for psychiatric evaluation.^1,2,4,5,8,12 If the patient admits self-inflicting behavior, psychotherapy and/or behavior modification therapy along with psychotropic medications may be helpful to relieve emotional and behavioral symptoms.¹² Unfortunately, if the patient denies a self-inflicting role in the occurrence of lymphedema and persists in self-injurious behavior, psychotherapy or psychotropic medications will be futile.⁹

Secretan syndrome (SS) represents a recurrent or chronic form of factitious lymphedema, usually affecting the dorsal aspect of the hand.^1-3 It is accepted as a subtype of Munchausen syndrome whereby the patient self-inflicts and simulates lymphedema.^1,2 Historically, many of the cases reported with the term Charcot’s oedème bleu are now believed to represent clinical variants of SS.^4-6

Case Report

A 38-year-old Turkish woman presented with progressive swelling of the right hand of 2 years’ duration that had caused difficulty in manual work and reduction in manual dexterity. She previously had sought medical treatment for this condition by visiting several hospitals. According to her medical record, the following laboratory or radiologic tests had revealed negative or normal findings, except for obvious soft-tissue edema: bacterial and fungal cultures, plain radiography, Doppler ultrasonography, lymphoscintigraphy, magnetic resonance imaging, fine needle aspiration, and punch biopsy. Reflex sympathetic dystrophy, compartment syndrome, filariasis, tuberculosis, and lymphatic and venous obstruction were all excluded by appropriate testing. Our patient was in good health prior to onset of this disorder, and her medical history was unremarkable. There was no family history of a similar condition.

Dermatologic examination revealed brawny, soft, pitting edema; erythema; and crusts affecting the dorsal aspect of the right hand and proximal parts of the fingers (Figure 1). The yellow discoloration of the skin and nails was attributed to potassium permanganate wet dressings. Under an elastic bandage at the wrist, which the patient unrolled herself, a sharp line of demarcation was evident, separating the lymphedematous and normal parts of the arm. There was no axillary lymphadenopathy.

Comment

In 1901, Henri Francois Secretan, a Swiss physician, reported workmen who had persistent hard swellings on the dorsal aspect of the hands after minor work-related trauma for which they had compensation claims.⁷ In his original report, Secretan did not suggest self-inflicted trauma in the etiology of this disorder.^5,8,9 In 1890, Jean Martin Charcot, a French neurologist, described oedème bleu, a term that is now believed to denote a condition similar to SS.^4-6 Currently, SS is attributed to self-inflicted injury and is considered a form of factitious lymphedema.⁹ As in dermatitis artefacta, most patients with SS are young women, and male patients with the condition tend to be older.^3,8

The mechanism used to provoke this factitious lymphedema might be of traumatic or obstructive nature. Secretan syndrome either is induced by intermittent or constant application of a tourniquet, ligature, cord, elastic bandage, scarf, kerchief, rubber band, or compress around the affected extremity, or by repetitive blunt trauma, force, or skin irritation.^1,4,5,8-10 There was an underlying psychopathology in all reported cases.^1,8,11 Factitious lymphedema is unconsciously motivated and consciously produced.^4,12 The affected patient often is experiencing a serious emotional conflict and is unlikely to be a malingerer, although exaggeration of symptoms may occur, as in our patient.¹² Psychiatric evaluation in SS may uncover neurosis, hysteria, frank psychosis, schizophrenia, masochism, depression, or an abnormal personality disorder.^1,12

Patients with SS present with recurrent or chronic lymphedema, usually affecting the dominant hand.¹ Involvement usually is unilateral; bilateral cases are rare.^3,6 Secretan syndrome is not solely limited to the hands; it also may involve the upper and lower extremities, including the feet.^3,11 There may be a clear line of demarcation, a ring, sulcus, distinct circumferential linear bands of erythema, discoloration, or ecchymoses, separating the normal and lymphedematous parts of the extremity.^{1,4,6,8-10,12} Patients usually attempt to hide the constricted areas from sight.¹ Over time, flexion contractures may develop due to peritendinous fibrosis.⁶ Histopathology displays a hematoma with adhesions to the extensor tendons; a hematoma surrounded by a thickened scar; or changes similar to ganglion tissue with cystic areas of mucin, fibrosis, and myxoid degeneration.^4,6

Factitious lymphedema can only be definitively diagnosed when the patient confesses or is caught self-inflicting the injury. Nevertheless, a diagnosis by exclusion is possible.⁴ Lymphangiography, lymphoscintigraphy, vascular Doppler ultrasonography, and magnetic resonance imaging may be helpful in excluding congenital and acquired causes of lymphedema and venous obstruction.^1,3,9,11 Magnetic resonance imaging may show soft tissue and tendon edema as well as diffuse peritendinous fibrosis extending to the fascia of the dorsal interosseous muscles.^3,4

Factitious lymphedema should be suspected in all patients with recurrent or chronic unilateral lymphedema without an explicable or apparent predisposing factor.^4,11,12 Patients with SS typically visit several hospitals or institutions; see many physicians; and willingly accept, request, and undergo unnecessary extensive, invasive, and costly diagnostic and therapeutic procedures and prolonged hospitalizations.^1,2,5,12 The disorder promptly responds to immobilization and elevation of the limb.^2,4 Plaster casts may prove useful in prevention of compression and thus amelioration of the lymphedema.^1,4,6 Once the diagnosis is confirmed, direct confrontation should be avoided and ideally the patient should be referred for psychiatric evaluation.^1,2,4,5,8,12 If the patient admits self-inflicting behavior, psychotherapy and/or behavior modification therapy along with psychotropic medications may be helpful to relieve emotional and behavioral symptoms.¹² Unfortunately, if the patient denies a self-inflicting role in the occurrence of lymphedema and persists in self-injurious behavior, psychotherapy or psychotropic medications will be futile.⁹

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

To the Editor:

Blastomycosislike pyoderma (BLP), also commonly referred to as pyoderma vegetans, is a rare cutaneous bacterial infection that often mimics other fungal, inflammatory, or neoplastic disorders.¹ It is characterized by a collection of neutrophilic abscesses with pseudoepitheliomatous hyperplasia that coalesce into crusted plaques.

A 15-year-old adolescent girl with a history of type 1 diabetes mellitus was admitted for diabetic ketoacidosis. The patient presented with bilateral pretibial lesions of 6 years’ duration that developed after swimming in a pool following reported trauma to the site. These pruritic plaques had grown slowly and were occasionally tender. Of note, with episodes of hyperglycemia, the lesions developed purulent drainage.

Upon admission to the hospital and subsequent dermatology consultation, physical examination revealed the right pretibial shin had a 15×5-cm, gray-brown, hyperpigmented, verrucous, tender plaque with purulent drainage and overlying crust (Figure 1). The left pretibial shin had a similar smaller lesion (Figure 2). Laboratory test results were notable for a white blood cell count of 41.84 cells/µL (reference range, 3.8–10.5 cells/µL), blood glucose level of 586 mg/dL (reference range, 70–99 mg/dL), and hemoglobin A_1c of 11.7% (reference range, 4.0%–5.6%). A biopsy specimen from the right pretibial shin was stained with hematoxylin and eosin for dermatopathologic evaluation as well as sent for tissue culture. Tissue and wound cultures grew Staphylococcus aureus and group B Streptococcus with no fungal or acid-fast bacilli growth.

To the Editor:

Blastomycosislike pyoderma (BLP), also commonly referred to as pyoderma vegetans, is a rare cutaneous bacterial infection that often mimics other fungal, inflammatory, or neoplastic disorders.¹ It is characterized by a collection of neutrophilic abscesses with pseudoepitheliomatous hyperplasia that coalesce into crusted plaques.

A 15-year-old adolescent girl with a history of type 1 diabetes mellitus was admitted for diabetic ketoacidosis. The patient presented with bilateral pretibial lesions of 6 years’ duration that developed after swimming in a pool following reported trauma to the site. These pruritic plaques had grown slowly and were occasionally tender. Of note, with episodes of hyperglycemia, the lesions developed purulent drainage.

Upon admission to the hospital and subsequent dermatology consultation, physical examination revealed the right pretibial shin had a 15×5-cm, gray-brown, hyperpigmented, verrucous, tender plaque with purulent drainage and overlying crust (Figure 1). The left pretibial shin had a similar smaller lesion (Figure 2). Laboratory test results were notable for a white blood cell count of 41.84 cells/µL (reference range, 3.8–10.5 cells/µL), blood glucose level of 586 mg/dL (reference range, 70–99 mg/dL), and hemoglobin A_1c of 11.7% (reference range, 4.0%–5.6%). A biopsy specimen from the right pretibial shin was stained with hematoxylin and eosin for dermatopathologic evaluation as well as sent for tissue culture. Tissue and wound cultures grew Staphylococcus aureus and group B Streptococcus with no fungal or acid-fast bacilli growth.

To the Editor:

Blastomycosislike pyoderma (BLP), also commonly referred to as pyoderma vegetans, is a rare cutaneous bacterial infection that often mimics other fungal, inflammatory, or neoplastic disorders.¹ It is characterized by a collection of neutrophilic abscesses with pseudoepitheliomatous hyperplasia that coalesce into crusted plaques.

A 15-year-old adolescent girl with a history of type 1 diabetes mellitus was admitted for diabetic ketoacidosis. The patient presented with bilateral pretibial lesions of 6 years’ duration that developed after swimming in a pool following reported trauma to the site. These pruritic plaques had grown slowly and were occasionally tender. Of note, with episodes of hyperglycemia, the lesions developed purulent drainage.

Upon admission to the hospital and subsequent dermatology consultation, physical examination revealed the right pretibial shin had a 15×5-cm, gray-brown, hyperpigmented, verrucous, tender plaque with purulent drainage and overlying crust (Figure 1). The left pretibial shin had a similar smaller lesion (Figure 2). Laboratory test results were notable for a white blood cell count of 41.84 cells/µL (reference range, 3.8–10.5 cells/µL), blood glucose level of 586 mg/dL (reference range, 70–99 mg/dL), and hemoglobin A_1c of 11.7% (reference range, 4.0%–5.6%). A biopsy specimen from the right pretibial shin was stained with hematoxylin and eosin for dermatopathologic evaluation as well as sent for tissue culture. Tissue and wound cultures grew Staphylococcus aureus and group B Streptococcus with no fungal or acid-fast bacilli growth.

To the Editor:

A 34-year-old pregnant woman at 5 weeks’ gestation was transferred to dermatology from an outside hospital with a full-body rash. Three days after noting a fever and generalized body aches, she developed a painful rash on the legs that had gradually spread to the arms, trunk, and face. Symptoms of eyelid pruritus and edema initially were improved with intravenous (IV) steroids at an emergency department visit, but they started to flare soon thereafter with worsening mucosal involvement and dysphagia. After a second visit to the emergency department and repeat treatment with IV steroids, she was transferred to our institution for a higher level of care.

The patient denied taking any new medications in the 2 months prior to the onset of the rash. Her medication history only consisted of over-the-counter prenatal vitamins, a single use of over-the-counter migraine medication (containing acetaminophen, aspirin, and caffeine as active ingredients), and a possible use of ibuprofen or acetaminophen separately. She reported ocular discomfort and blurriness, dysphagia, dysuria, and vaginal discomfort. Physical examination revealed dusky red to violaceous macules and patches that involved approximately 65% of the body surface area (BSA), with bullae involving approximately 10% BSA. The face was diffusely red and edematous with crusted erosions and scattered bullae on the cheeks. Mucosal involvement was notable for injected conjunctivae and erosions present on the upper hard palate of the mouth and lips (Figure, A). Erythematous macules with dusky centers coalescing into patches with overlying vesicles and bullae were scattered on the arms (Figure, B), hands, trunk (Figure, C), and legs. The Nikolsky sign was positive. The vulva was swollen and covered with erythematous macules with dusky centers.

To the Editor:

A 34-year-old pregnant woman at 5 weeks’ gestation was transferred to dermatology from an outside hospital with a full-body rash. Three days after noting a fever and generalized body aches, she developed a painful rash on the legs that had gradually spread to the arms, trunk, and face. Symptoms of eyelid pruritus and edema initially were improved with intravenous (IV) steroids at an emergency department visit, but they started to flare soon thereafter with worsening mucosal involvement and dysphagia. After a second visit to the emergency department and repeat treatment with IV steroids, she was transferred to our institution for a higher level of care.

The patient denied taking any new medications in the 2 months prior to the onset of the rash. Her medication history only consisted of over-the-counter prenatal vitamins, a single use of over-the-counter migraine medication (containing acetaminophen, aspirin, and caffeine as active ingredients), and a possible use of ibuprofen or acetaminophen separately. She reported ocular discomfort and blurriness, dysphagia, dysuria, and vaginal discomfort. Physical examination revealed dusky red to violaceous macules and patches that involved approximately 65% of the body surface area (BSA), with bullae involving approximately 10% BSA. The face was diffusely red and edematous with crusted erosions and scattered bullae on the cheeks. Mucosal involvement was notable for injected conjunctivae and erosions present on the upper hard palate of the mouth and lips (Figure, A). Erythematous macules with dusky centers coalescing into patches with overlying vesicles and bullae were scattered on the arms (Figure, B), hands, trunk (Figure, C), and legs. The Nikolsky sign was positive. The vulva was swollen and covered with erythematous macules with dusky centers.

To the Editor:

A 34-year-old pregnant woman at 5 weeks’ gestation was transferred to dermatology from an outside hospital with a full-body rash. Three days after noting a fever and generalized body aches, she developed a painful rash on the legs that had gradually spread to the arms, trunk, and face. Symptoms of eyelid pruritus and edema initially were improved with intravenous (IV) steroids at an emergency department visit, but they started to flare soon thereafter with worsening mucosal involvement and dysphagia. After a second visit to the emergency department and repeat treatment with IV steroids, she was transferred to our institution for a higher level of care.

The patient denied taking any new medications in the 2 months prior to the onset of the rash. Her medication history only consisted of over-the-counter prenatal vitamins, a single use of over-the-counter migraine medication (containing acetaminophen, aspirin, and caffeine as active ingredients), and a possible use of ibuprofen or acetaminophen separately. She reported ocular discomfort and blurriness, dysphagia, dysuria, and vaginal discomfort. Physical examination revealed dusky red to violaceous macules and patches that involved approximately 65% of the body surface area (BSA), with bullae involving approximately 10% BSA. The face was diffusely red and edematous with crusted erosions and scattered bullae on the cheeks. Mucosal involvement was notable for injected conjunctivae and erosions present on the upper hard palate of the mouth and lips (Figure, A). Erythematous macules with dusky centers coalescing into patches with overlying vesicles and bullae were scattered on the arms (Figure, B), hands, trunk (Figure, C), and legs. The Nikolsky sign was positive. The vulva was swollen and covered with erythematous macules with dusky centers.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

Case Report

A 70-year-old man living in Esna, Luxor, Egypt presented to the Department of Rheumatology and Rehabilitation with widespread gangrenous skin lesions associated with ulcers of 2 weeks’ duration. One year prior, the patient had an insidious onset of nocturnal fever, bilateral leg edema, and numbness and a tingling sensation in both hands. He presented some laboratory and radiologic investigations that were performed at another hospital prior to the current presentation, which revealed thrombocytopenia, mild splenomegaly, and generalized lymphadenopathy. An excisional left axillary lymph node biopsy was performed at another hospital prior to the current presentation, and the pathology report provided by the patient described a reactive, foamy, histiocyte-rich lesion, suggesting a diagnosis of hemophagocytic lymphohistiocytosis. The patient had no diabetes or hypertension and no history of deep vein thrombosis, stroke, or unintentional weight loss. No medications were taken prior to the onset of the skin lesions, and his family history was irrelevant.

General examination at the current presentation revealed a fever (temperature, 101.3 °F [38.5 °C]), a normal heart rate (90 beats per minute), normal blood pressure (120/80 mmHg), normal respiratory rate (14 breaths per minute), accentuated heart sounds, and normal vesicular breathing without adventitious sounds. He had saddle nose, loss of the outer third of the eyebrows, and marked reduction in the density of the eyelashes (madarosis). Bilateral pitting edema of the legs also was present. Neurologic examination revealed hypoesthesia in a glove-and-stocking pattern, thickened peripheral nerves, and trophic changes over both hands; however, he had normal muscle power and deep reflexes. Joint examination revealed no abnormalities. Skin examination revealed widespread, reticulated, necrotizing, purpuric lesions on the arms, legs, abdomen, and ears, some associated with gangrenous ulcerations and hemorrhagic blisters. Scattered vasculitic ulcers and gangrenous patches were seen on the fingers. A gangrenous ulcer mimicking Fournier gangrene was seen involving the scrotal skin in addition to a gangrenous lesion on the glans penis (Figure 1–3). Unaffected skin appeared smooth, shiny, and edematous and showed no nodular lesions. Peripheral pulsations were intact.

Positive findings from a wide panel of laboratory investigations included an elevated erythrocyte sedimentation rate (103 mm for the first hour [reference range, 0–22 mm]), high C-reactive protein (50.7 mg/L [reference range, up to 6 mg/L]), anemia (hemoglobin count, 7.3 g/dL [reference range, 13.5–17.5 g/dL]), thrombocytopenia (45×10³/mm³ [reference range, 150×10³/mm³), low serum albumin (2.3 g/dL [reference range, 3.4–5.4 g/dL]), elevated IgG and IgM anticardiolipin antibodies (IgG, 21.4 IgG phospholipid [GPL] units [reference range, <10 IgG phospholipid (GPL) units]; IgM, 59.4 IgM phospholipid (MPL) units [reference range, <7 IgM phospholipid (MPL) units]), positive lupus anticoagulant panel test, elevated anti-β2 glycoprotein antibodies (IgG, 17.5 µ/mL [reference range, <8 µ/mL]; IgM, 124.8 µ/mL [reference range, <8 µ/mL]), and low complement C3 (78 IU [reference range, 90–180 IU]). White blood cell count, liver and kidney functions, triglycerides, serum ferritin, and complement C4 all were normal. Hepatitis B surface antigen, hepatitis C viral antibody, HIV, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies C and P (ANCA-C&P), and venereal disease research laboratory tests all were negative.

Nerve conduction velocity showed axonal sensory polyneuropathy. Motor nerve conduction studies for median and ulnar nerves were within normal range. Lower-limb nerves assessment was limited by the ulcerated areas and marked edema. Echocardiography was unremarkable. Arterial Doppler studies were only available for the upper limbs and were unremarkable.

A punch biopsy was taken from one of the necrotizing purpuric lesions on the legs, and histopathologic examination revealed foci of epidermal necrosis and subepidermal separation and superficial and deep perivascular and periadnexal infiltrates extending into the fat lobules. The infiltrates were mainly made up of foamy macrophages, and some contained globi (lepra cells), in addition to lymphocytes and many neutrophils with nuclear dust. Blood vessels in the superficial and deep dermis and in the subcutaneous fat showed fibrinoid necrosis in their walls with neutrophils infiltrating the walls and thrombi in the lumens (Figure 4). Modified Ziehl-Neelsen staining revealed clumps of acid-fast lepra bacilli inside vascular lumina and endothelial cell lining and within the foamy macrophages (Figure 5). Slit-skin smear examination was performed twice and yielded negative results. The slide and paraffin block of the already performed lymph node biopsy were retrieved. Examination revealed aggregates of foamy histiocytes surrounded by lymphocytes and plasma cells replacing normal lymphoid follicles. Modified Ziehl-Neelsen stain was performed, and clusters of acid-fast bacilli were detected within the foamy histiocytic infiltrate (Figure 6).

Comment

Despite a decrease in its prevalence through a World Health Organization (WHO)–empowered eradication program, leprosy still represents a health problem in endemic areas.^1,2 It is characterized by a wide range of immune responses to Mycobacterium leprae, displaying a spectrum of clinical and histopathologic manifestations that vary from the tuberculoid or paucibacillary pole with a strong cell-mediated immune response and fewer organisms to the lepromatous or multibacillary pole with weaker cell-mediated immune response and higher loads of organisms.³ In addition to its well-known cutaneous and neurologic manifestations, leprosy can present with a variety of manifestations, including constitutional symptoms, musculoskeletal manifestations, and serologic abnormalities; thus, leprosy can mimic rheumatoid arthritis, spondyloarthritis, and vasculitis—a pitfall that may result in misdiagnosis as a rheumatologic disorder.^3-7

The chronic course of leprosy can be disrupted by acute, immunologically mediated reactions known as lepra reactions, of which there are 3 types.⁸ Type I lepra reactions are cell mediated and occur mainly in patients with borderline disease, often representing an upgrade toward the tuberculoid pole; less often they represent a downgrade reaction. Nerves become painful and swollen with possible loss of function, and skin lesions become edematous and tender; sometimes arthritis develops.⁹ Type II lepra reactions, also known as erythema nodosum leprosum (ENL), occur in borderline lepromatous and lepromatous patients with a high bacillary load. They are characterized by fever, body aches, tender cutaneous/subcutaneous nodules that may ulcerate, possible bullous lesions, painful nerve swellings, swollen joints, iritis, lymphadenitis, glomerulonephritis, epididymo-orchitis, and hepatic affection. Both immune-complex and delayed hypersensitivity reactions play a role in ENL.^8,10 The third reaction is a rare aggressive type known as Lucio phenomenon or Lucio leprosy, which presents with irregular-shaped, angulated, or stellar necrotizing purpuric lesions (hemorrhagic infacrtions) developing mainly on the extremities. The lesions evolve into ulcers that heal with atrophic scarring.^2,11 Lucio phenomenon develops as a result of thrombotic vascular occlusion secondary to massive invasion of vascular endothelial cells by lepra bacilli.^2,11-14 Involvement of the scrotal skin, such as in our patient, is rare.

Lucio phenomenon mainly is seen in Mexico and Central America, and few cases have been documented in Cuba, South America, the United States, India, Polynesia, South Africa, and Southeast Asia.^15-17 It specifically occurs in patients with untreated, diffuse, nonnodular lepromatous leprosy (pure and primitive diffuse lepromatous leprosy (DLL)/diffuse leprosy of Lucio and Latapí). This type of leprosy was first described by Lucio and Alvarado¹⁸ in 1852 as a distinct form of lepromatous leprosy characterized by widespread and dense infiltration of the whole skin by lepra bacilli without the typical nodular lesions of leprosy, rendering its diagnosis challenging, especially in sporadic cases. Other manifestations of DLL include complete alopecia of the eyebrows and eyelashes, destructive rhinitis, and areas of anhidrosis and dyesthesia.²

Latapí and Chévez-Zomora¹⁹ defined Lucio phenomenon in 1948 as a form of histopathologic vasculitis restricted to patients with DLL. Histopathologically, in addition to the infiltration of the skin with acid-fast bacilli–laden foamy histiocytes, lesions of Lucio phenomenon show features of necrotizing (leukocytoclastic) vasculitis with fibrinoid necrosis²⁰ or vascular thrombi with minimal perivascular lymphocytic infiltrate and no evidence of vasculitis.¹¹ Medium to large vessels in the deep dermis and subcutaneous tissue show infiltration of their walls with a large number of macrophages laden with acid-fast bacilli.¹¹ Cases with histopathologic features mimicking antiphospholipid syndrome with endothelial cell proliferation, thrombosis, and mild mononuclear cell infiltrate also may be seen.²⁰ In all cases, ischemic epidermal necrosis is seen, as well as acid-fast bacilli, both singly and in clusters (globi) within endothelial cells and inside blood vessel lumina.

Although Lucio phenomenon initially was thought to be immune-complex mediated like ENL, it has been suggested that the main trigger is thrombotic vascular occlusion secondary to massive invasion of the vascular endothelial cells by the lepra bacilli, resulting in necrosis.¹⁴ Bacterial lipopolysaccharides promote the release of IL-1 and tumor necrosis factor α, which in turn stimulate the production of prostaglandins, IL-6, and coagulation factor III, leading to vascular thrombosis and tissue necrosis.^21,22 Moreover, antiphospholipid antibodies, which have been found to be induced in response to certain infectious agents in genetically predisposed individuals,²³ have been reported in patients with leprosy, mainly in association with lepromatous leprosy. The reported prevalence of anticardiolipin antibodies ranged from 37% to 98%, whereas anti-β2-glycoprotein I antibodies ranged from 3% to 19%, and antiprothrombin antibodies ranged from 6% to 45%.^24,25 Antiphospholipid antibodies have been reported to play a role in the pathogenesis of Lucio phenomenon.^11,13,15,26 Our case supports this hypothesis with positive anticardiolipin antibodies, anti-β2 glycoprotein antibodies, and positive lupus anticoagulant.

In accordance with Curi et al,² who reported 5 cases of DLL with Lucio phenomenon, our patient showed a similar presentation with positive inflammatory markers in association with a negative autoimmune profile (ANA, ANCA-C&P) and negative venereal disease research laboratory test. It is important to mention that a positive autoimmune profile (ANA, ANCA-C&P) can be present in leprotic patients, causing possible diagnostic confusion with collagen diseases.^27,28

An interesting finding in our case was the negative slit-skin smear results. Although the specificity of slit-skin smear is 100%, as it directly demonstrates the presence of acid-fast bacilli,²⁹ its sensitivity is low and varies from 10% to 50%.³⁰ The detection of acid-fast bacilli in tissue sections is reported to be a better method for confirming the diagnosis of leprosy.³¹

The provisional impression of hemophagocytic lymphohistiocytosis in the lymph node biopsy in our patient was excluded upon detection of acid-fast bacilli in the foamy histiocytes infiltrating the lymph node; moreover, the normal serum lipids and serum ferritin argued against this diagnosis.³² Leprosy tends to involve the lymph nodes, particularly in borderline, borderline lepromatous, and lepromatous forms.³³ The incidence of lymph node involvement accompanied by skin lesions with the presence of acid-fast bacilli in the lymph nodes is 92.2%.³⁴

Our patient showed an excellent response to antileprotic treatment, which was administered according to the WHO multidrug therapy guidelines for multibacillary leprosy,³⁵ combined with low-dose prednisolone, acetylsalicylic acid, and anticoagulant treatment. Thalidomide and high-dose prednisolone (60 mg/d) combined with antileprotic treatment also have been reported to be successful in managing recurrent infarctions in leprosy.³⁶ The Fournier-like gangrenous ulcer of the scrotum was managed by surgical debridement and vacuum therapy.

It is noteworthy that the WHO elimination goal for leprosy was to reduce the prevalence to less than 1 case per 10,000 population. Egypt is among the first countries in North Africa and the Middle East regions to achieve this target supervised by the National Leprosy Control Program as early as 1994; this was further reduced to 0.33 cases per 10,000 population in 2004, and reduced again in 2009; however, certain foci showed a prevalence rate more than the elimination target, particularly in the cities of Qena (1.12) and Sohag (2.47).³⁷ Esna, where our patient is from, is an endemic area in Egypt.³⁸

Conclusion

Leprosy is a great mimicker of many connective tissue diseases, including vasculitis. Antiphospholipid antibodies are involved in Lucio phenomenon. Recognition of Lucio phenomenon is important to initiate prompt treatment and avoid morbidity and mortality. We report a rare case of diffuse nonnodular lepromatous leprosy in Egypt in which Lucio phenomenon was the first diagnostic presentation. Scrotal involvement with Lucio phenomenon was not previously reported in any case of Lucio leprosy.

Case Report

A 70-year-old man living in Esna, Luxor, Egypt presented to the Department of Rheumatology and Rehabilitation with widespread gangrenous skin lesions associated with ulcers of 2 weeks’ duration. One year prior, the patient had an insidious onset of nocturnal fever, bilateral leg edema, and numbness and a tingling sensation in both hands. He presented some laboratory and radiologic investigations that were performed at another hospital prior to the current presentation, which revealed thrombocytopenia, mild splenomegaly, and generalized lymphadenopathy. An excisional left axillary lymph node biopsy was performed at another hospital prior to the current presentation, and the pathology report provided by the patient described a reactive, foamy, histiocyte-rich lesion, suggesting a diagnosis of hemophagocytic lymphohistiocytosis. The patient had no diabetes or hypertension and no history of deep vein thrombosis, stroke, or unintentional weight loss. No medications were taken prior to the onset of the skin lesions, and his family history was irrelevant.

General examination at the current presentation revealed a fever (temperature, 101.3 °F [38.5 °C]), a normal heart rate (90 beats per minute), normal blood pressure (120/80 mmHg), normal respiratory rate (14 breaths per minute), accentuated heart sounds, and normal vesicular breathing without adventitious sounds. He had saddle nose, loss of the outer third of the eyebrows, and marked reduction in the density of the eyelashes (madarosis). Bilateral pitting edema of the legs also was present. Neurologic examination revealed hypoesthesia in a glove-and-stocking pattern, thickened peripheral nerves, and trophic changes over both hands; however, he had normal muscle power and deep reflexes. Joint examination revealed no abnormalities. Skin examination revealed widespread, reticulated, necrotizing, purpuric lesions on the arms, legs, abdomen, and ears, some associated with gangrenous ulcerations and hemorrhagic blisters. Scattered vasculitic ulcers and gangrenous patches were seen on the fingers. A gangrenous ulcer mimicking Fournier gangrene was seen involving the scrotal skin in addition to a gangrenous lesion on the glans penis (Figure 1–3). Unaffected skin appeared smooth, shiny, and edematous and showed no nodular lesions. Peripheral pulsations were intact.

Positive findings from a wide panel of laboratory investigations included an elevated erythrocyte sedimentation rate (103 mm for the first hour [reference range, 0–22 mm]), high C-reactive protein (50.7 mg/L [reference range, up to 6 mg/L]), anemia (hemoglobin count, 7.3 g/dL [reference range, 13.5–17.5 g/dL]), thrombocytopenia (45×10³/mm³ [reference range, 150×10³/mm³), low serum albumin (2.3 g/dL [reference range, 3.4–5.4 g/dL]), elevated IgG and IgM anticardiolipin antibodies (IgG, 21.4 IgG phospholipid [GPL] units [reference range, <10 IgG phospholipid (GPL) units]; IgM, 59.4 IgM phospholipid (MPL) units [reference range, <7 IgM phospholipid (MPL) units]), positive lupus anticoagulant panel test, elevated anti-β2 glycoprotein antibodies (IgG, 17.5 µ/mL [reference range, <8 µ/mL]; IgM, 124.8 µ/mL [reference range, <8 µ/mL]), and low complement C3 (78 IU [reference range, 90–180 IU]). White blood cell count, liver and kidney functions, triglycerides, serum ferritin, and complement C4 all were normal. Hepatitis B surface antigen, hepatitis C viral antibody, HIV, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies C and P (ANCA-C&P), and venereal disease research laboratory tests all were negative.

Nerve conduction velocity showed axonal sensory polyneuropathy. Motor nerve conduction studies for median and ulnar nerves were within normal range. Lower-limb nerves assessment was limited by the ulcerated areas and marked edema. Echocardiography was unremarkable. Arterial Doppler studies were only available for the upper limbs and were unremarkable.

A punch biopsy was taken from one of the necrotizing purpuric lesions on the legs, and histopathologic examination revealed foci of epidermal necrosis and subepidermal separation and superficial and deep perivascular and periadnexal infiltrates extending into the fat lobules. The infiltrates were mainly made up of foamy macrophages, and some contained globi (lepra cells), in addition to lymphocytes and many neutrophils with nuclear dust. Blood vessels in the superficial and deep dermis and in the subcutaneous fat showed fibrinoid necrosis in their walls with neutrophils infiltrating the walls and thrombi in the lumens (Figure 4). Modified Ziehl-Neelsen staining revealed clumps of acid-fast lepra bacilli inside vascular lumina and endothelial cell lining and within the foamy macrophages (Figure 5). Slit-skin smear examination was performed twice and yielded negative results. The slide and paraffin block of the already performed lymph node biopsy were retrieved. Examination revealed aggregates of foamy histiocytes surrounded by lymphocytes and plasma cells replacing normal lymphoid follicles. Modified Ziehl-Neelsen stain was performed, and clusters of acid-fast bacilli were detected within the foamy histiocytic infiltrate (Figure 6).

Comment

Despite a decrease in its prevalence through a World Health Organization (WHO)–empowered eradication program, leprosy still represents a health problem in endemic areas.^1,2 It is characterized by a wide range of immune responses to Mycobacterium leprae, displaying a spectrum of clinical and histopathologic manifestations that vary from the tuberculoid or paucibacillary pole with a strong cell-mediated immune response and fewer organisms to the lepromatous or multibacillary pole with weaker cell-mediated immune response and higher loads of organisms.³ In addition to its well-known cutaneous and neurologic manifestations, leprosy can present with a variety of manifestations, including constitutional symptoms, musculoskeletal manifestations, and serologic abnormalities; thus, leprosy can mimic rheumatoid arthritis, spondyloarthritis, and vasculitis—a pitfall that may result in misdiagnosis as a rheumatologic disorder.^3-7

The chronic course of leprosy can be disrupted by acute, immunologically mediated reactions known as lepra reactions, of which there are 3 types.⁸ Type I lepra reactions are cell mediated and occur mainly in patients with borderline disease, often representing an upgrade toward the tuberculoid pole; less often they represent a downgrade reaction. Nerves become painful and swollen with possible loss of function, and skin lesions become edematous and tender; sometimes arthritis develops.⁹ Type II lepra reactions, also known as erythema nodosum leprosum (ENL), occur in borderline lepromatous and lepromatous patients with a high bacillary load. They are characterized by fever, body aches, tender cutaneous/subcutaneous nodules that may ulcerate, possible bullous lesions, painful nerve swellings, swollen joints, iritis, lymphadenitis, glomerulonephritis, epididymo-orchitis, and hepatic affection. Both immune-complex and delayed hypersensitivity reactions play a role in ENL.^8,10 The third reaction is a rare aggressive type known as Lucio phenomenon or Lucio leprosy, which presents with irregular-shaped, angulated, or stellar necrotizing purpuric lesions (hemorrhagic infacrtions) developing mainly on the extremities. The lesions evolve into ulcers that heal with atrophic scarring.^2,11 Lucio phenomenon develops as a result of thrombotic vascular occlusion secondary to massive invasion of vascular endothelial cells by lepra bacilli.^2,11-14 Involvement of the scrotal skin, such as in our patient, is rare.

Lucio phenomenon mainly is seen in Mexico and Central America, and few cases have been documented in Cuba, South America, the United States, India, Polynesia, South Africa, and Southeast Asia.^15-17 It specifically occurs in patients with untreated, diffuse, nonnodular lepromatous leprosy (pure and primitive diffuse lepromatous leprosy (DLL)/diffuse leprosy of Lucio and Latapí). This type of leprosy was first described by Lucio and Alvarado¹⁸ in 1852 as a distinct form of lepromatous leprosy characterized by widespread and dense infiltration of the whole skin by lepra bacilli without the typical nodular lesions of leprosy, rendering its diagnosis challenging, especially in sporadic cases. Other manifestations of DLL include complete alopecia of the eyebrows and eyelashes, destructive rhinitis, and areas of anhidrosis and dyesthesia.²

Latapí and Chévez-Zomora¹⁹ defined Lucio phenomenon in 1948 as a form of histopathologic vasculitis restricted to patients with DLL. Histopathologically, in addition to the infiltration of the skin with acid-fast bacilli–laden foamy histiocytes, lesions of Lucio phenomenon show features of necrotizing (leukocytoclastic) vasculitis with fibrinoid necrosis²⁰ or vascular thrombi with minimal perivascular lymphocytic infiltrate and no evidence of vasculitis.¹¹ Medium to large vessels in the deep dermis and subcutaneous tissue show infiltration of their walls with a large number of macrophages laden with acid-fast bacilli.¹¹ Cases with histopathologic features mimicking antiphospholipid syndrome with endothelial cell proliferation, thrombosis, and mild mononuclear cell infiltrate also may be seen.²⁰ In all cases, ischemic epidermal necrosis is seen, as well as acid-fast bacilli, both singly and in clusters (globi) within endothelial cells and inside blood vessel lumina.

Although Lucio phenomenon initially was thought to be immune-complex mediated like ENL, it has been suggested that the main trigger is thrombotic vascular occlusion secondary to massive invasion of the vascular endothelial cells by the lepra bacilli, resulting in necrosis.¹⁴ Bacterial lipopolysaccharides promote the release of IL-1 and tumor necrosis factor α, which in turn stimulate the production of prostaglandins, IL-6, and coagulation factor III, leading to vascular thrombosis and tissue necrosis.^21,22 Moreover, antiphospholipid antibodies, which have been found to be induced in response to certain infectious agents in genetically predisposed individuals,²³ have been reported in patients with leprosy, mainly in association with lepromatous leprosy. The reported prevalence of anticardiolipin antibodies ranged from 37% to 98%, whereas anti-β2-glycoprotein I antibodies ranged from 3% to 19%, and antiprothrombin antibodies ranged from 6% to 45%.^24,25 Antiphospholipid antibodies have been reported to play a role in the pathogenesis of Lucio phenomenon.^11,13,15,26 Our case supports this hypothesis with positive anticardiolipin antibodies, anti-β2 glycoprotein antibodies, and positive lupus anticoagulant.

In accordance with Curi et al,² who reported 5 cases of DLL with Lucio phenomenon, our patient showed a similar presentation with positive inflammatory markers in association with a negative autoimmune profile (ANA, ANCA-C&P) and negative venereal disease research laboratory test. It is important to mention that a positive autoimmune profile (ANA, ANCA-C&P) can be present in leprotic patients, causing possible diagnostic confusion with collagen diseases.^27,28

An interesting finding in our case was the negative slit-skin smear results. Although the specificity of slit-skin smear is 100%, as it directly demonstrates the presence of acid-fast bacilli,²⁹ its sensitivity is low and varies from 10% to 50%.³⁰ The detection of acid-fast bacilli in tissue sections is reported to be a better method for confirming the diagnosis of leprosy.³¹

The provisional impression of hemophagocytic lymphohistiocytosis in the lymph node biopsy in our patient was excluded upon detection of acid-fast bacilli in the foamy histiocytes infiltrating the lymph node; moreover, the normal serum lipids and serum ferritin argued against this diagnosis.³² Leprosy tends to involve the lymph nodes, particularly in borderline, borderline lepromatous, and lepromatous forms.³³ The incidence of lymph node involvement accompanied by skin lesions with the presence of acid-fast bacilli in the lymph nodes is 92.2%.³⁴

Our patient showed an excellent response to antileprotic treatment, which was administered according to the WHO multidrug therapy guidelines for multibacillary leprosy,³⁵ combined with low-dose prednisolone, acetylsalicylic acid, and anticoagulant treatment. Thalidomide and high-dose prednisolone (60 mg/d) combined with antileprotic treatment also have been reported to be successful in managing recurrent infarctions in leprosy.³⁶ The Fournier-like gangrenous ulcer of the scrotum was managed by surgical debridement and vacuum therapy.

It is noteworthy that the WHO elimination goal for leprosy was to reduce the prevalence to less than 1 case per 10,000 population. Egypt is among the first countries in North Africa and the Middle East regions to achieve this target supervised by the National Leprosy Control Program as early as 1994; this was further reduced to 0.33 cases per 10,000 population in 2004, and reduced again in 2009; however, certain foci showed a prevalence rate more than the elimination target, particularly in the cities of Qena (1.12) and Sohag (2.47).³⁷ Esna, where our patient is from, is an endemic area in Egypt.³⁸

Conclusion

Leprosy is a great mimicker of many connective tissue diseases, including vasculitis. Antiphospholipid antibodies are involved in Lucio phenomenon. Recognition of Lucio phenomenon is important to initiate prompt treatment and avoid morbidity and mortality. We report a rare case of diffuse nonnodular lepromatous leprosy in Egypt in which Lucio phenomenon was the first diagnostic presentation. Scrotal involvement with Lucio phenomenon was not previously reported in any case of Lucio leprosy.

Case Report

A 70-year-old man living in Esna, Luxor, Egypt presented to the Department of Rheumatology and Rehabilitation with widespread gangrenous skin lesions associated with ulcers of 2 weeks’ duration. One year prior, the patient had an insidious onset of nocturnal fever, bilateral leg edema, and numbness and a tingling sensation in both hands. He presented some laboratory and radiologic investigations that were performed at another hospital prior to the current presentation, which revealed thrombocytopenia, mild splenomegaly, and generalized lymphadenopathy. An excisional left axillary lymph node biopsy was performed at another hospital prior to the current presentation, and the pathology report provided by the patient described a reactive, foamy, histiocyte-rich lesion, suggesting a diagnosis of hemophagocytic lymphohistiocytosis. The patient had no diabetes or hypertension and no history of deep vein thrombosis, stroke, or unintentional weight loss. No medications were taken prior to the onset of the skin lesions, and his family history was irrelevant.

General examination at the current presentation revealed a fever (temperature, 101.3 °F [38.5 °C]), a normal heart rate (90 beats per minute), normal blood pressure (120/80 mmHg), normal respiratory rate (14 breaths per minute), accentuated heart sounds, and normal vesicular breathing without adventitious sounds. He had saddle nose, loss of the outer third of the eyebrows, and marked reduction in the density of the eyelashes (madarosis). Bilateral pitting edema of the legs also was present. Neurologic examination revealed hypoesthesia in a glove-and-stocking pattern, thickened peripheral nerves, and trophic changes over both hands; however, he had normal muscle power and deep reflexes. Joint examination revealed no abnormalities. Skin examination revealed widespread, reticulated, necrotizing, purpuric lesions on the arms, legs, abdomen, and ears, some associated with gangrenous ulcerations and hemorrhagic blisters. Scattered vasculitic ulcers and gangrenous patches were seen on the fingers. A gangrenous ulcer mimicking Fournier gangrene was seen involving the scrotal skin in addition to a gangrenous lesion on the glans penis (Figure 1–3). Unaffected skin appeared smooth, shiny, and edematous and showed no nodular lesions. Peripheral pulsations were intact.

Positive findings from a wide panel of laboratory investigations included an elevated erythrocyte sedimentation rate (103 mm for the first hour [reference range, 0–22 mm]), high C-reactive protein (50.7 mg/L [reference range, up to 6 mg/L]), anemia (hemoglobin count, 7.3 g/dL [reference range, 13.5–17.5 g/dL]), thrombocytopenia (45×10³/mm³ [reference range, 150×10³/mm³), low serum albumin (2.3 g/dL [reference range, 3.4–5.4 g/dL]), elevated IgG and IgM anticardiolipin antibodies (IgG, 21.4 IgG phospholipid [GPL] units [reference range, <10 IgG phospholipid (GPL) units]; IgM, 59.4 IgM phospholipid (MPL) units [reference range, <7 IgM phospholipid (MPL) units]), positive lupus anticoagulant panel test, elevated anti-β2 glycoprotein antibodies (IgG, 17.5 µ/mL [reference range, <8 µ/mL]; IgM, 124.8 µ/mL [reference range, <8 µ/mL]), and low complement C3 (78 IU [reference range, 90–180 IU]). White blood cell count, liver and kidney functions, triglycerides, serum ferritin, and complement C4 all were normal. Hepatitis B surface antigen, hepatitis C viral antibody, HIV, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies C and P (ANCA-C&P), and venereal disease research laboratory tests all were negative.

Nerve conduction velocity showed axonal sensory polyneuropathy. Motor nerve conduction studies for median and ulnar nerves were within normal range. Lower-limb nerves assessment was limited by the ulcerated areas and marked edema. Echocardiography was unremarkable. Arterial Doppler studies were only available for the upper limbs and were unremarkable.

A punch biopsy was taken from one of the necrotizing purpuric lesions on the legs, and histopathologic examination revealed foci of epidermal necrosis and subepidermal separation and superficial and deep perivascular and periadnexal infiltrates extending into the fat lobules. The infiltrates were mainly made up of foamy macrophages, and some contained globi (lepra cells), in addition to lymphocytes and many neutrophils with nuclear dust. Blood vessels in the superficial and deep dermis and in the subcutaneous fat showed fibrinoid necrosis in their walls with neutrophils infiltrating the walls and thrombi in the lumens (Figure 4). Modified Ziehl-Neelsen staining revealed clumps of acid-fast lepra bacilli inside vascular lumina and endothelial cell lining and within the foamy macrophages (Figure 5). Slit-skin smear examination was performed twice and yielded negative results. The slide and paraffin block of the already performed lymph node biopsy were retrieved. Examination revealed aggregates of foamy histiocytes surrounded by lymphocytes and plasma cells replacing normal lymphoid follicles. Modified Ziehl-Neelsen stain was performed, and clusters of acid-fast bacilli were detected within the foamy histiocytic infiltrate (Figure 6).

Comment

Despite a decrease in its prevalence through a World Health Organization (WHO)–empowered eradication program, leprosy still represents a health problem in endemic areas.^1,2 It is characterized by a wide range of immune responses to Mycobacterium leprae, displaying a spectrum of clinical and histopathologic manifestations that vary from the tuberculoid or paucibacillary pole with a strong cell-mediated immune response and fewer organisms to the lepromatous or multibacillary pole with weaker cell-mediated immune response and higher loads of organisms.³ In addition to its well-known cutaneous and neurologic manifestations, leprosy can present with a variety of manifestations, including constitutional symptoms, musculoskeletal manifestations, and serologic abnormalities; thus, leprosy can mimic rheumatoid arthritis, spondyloarthritis, and vasculitis—a pitfall that may result in misdiagnosis as a rheumatologic disorder.^3-7

The chronic course of leprosy can be disrupted by acute, immunologically mediated reactions known as lepra reactions, of which there are 3 types.⁸ Type I lepra reactions are cell mediated and occur mainly in patients with borderline disease, often representing an upgrade toward the tuberculoid pole; less often they represent a downgrade reaction. Nerves become painful and swollen with possible loss of function, and skin lesions become edematous and tender; sometimes arthritis develops.⁹ Type II lepra reactions, also known as erythema nodosum leprosum (ENL), occur in borderline lepromatous and lepromatous patients with a high bacillary load. They are characterized by fever, body aches, tender cutaneous/subcutaneous nodules that may ulcerate, possible bullous lesions, painful nerve swellings, swollen joints, iritis, lymphadenitis, glomerulonephritis, epididymo-orchitis, and hepatic affection. Both immune-complex and delayed hypersensitivity reactions play a role in ENL.^8,10 The third reaction is a rare aggressive type known as Lucio phenomenon or Lucio leprosy, which presents with irregular-shaped, angulated, or stellar necrotizing purpuric lesions (hemorrhagic infacrtions) developing mainly on the extremities. The lesions evolve into ulcers that heal with atrophic scarring.^2,11 Lucio phenomenon develops as a result of thrombotic vascular occlusion secondary to massive invasion of vascular endothelial cells by lepra bacilli.^2,11-14 Involvement of the scrotal skin, such as in our patient, is rare.

Lucio phenomenon mainly is seen in Mexico and Central America, and few cases have been documented in Cuba, South America, the United States, India, Polynesia, South Africa, and Southeast Asia.^15-17 It specifically occurs in patients with untreated, diffuse, nonnodular lepromatous leprosy (pure and primitive diffuse lepromatous leprosy (DLL)/diffuse leprosy of Lucio and Latapí). This type of leprosy was first described by Lucio and Alvarado¹⁸ in 1852 as a distinct form of lepromatous leprosy characterized by widespread and dense infiltration of the whole skin by lepra bacilli without the typical nodular lesions of leprosy, rendering its diagnosis challenging, especially in sporadic cases. Other manifestations of DLL include complete alopecia of the eyebrows and eyelashes, destructive rhinitis, and areas of anhidrosis and dyesthesia.²

Latapí and Chévez-Zomora¹⁹ defined Lucio phenomenon in 1948 as a form of histopathologic vasculitis restricted to patients with DLL. Histopathologically, in addition to the infiltration of the skin with acid-fast bacilli–laden foamy histiocytes, lesions of Lucio phenomenon show features of necrotizing (leukocytoclastic) vasculitis with fibrinoid necrosis²⁰ or vascular thrombi with minimal perivascular lymphocytic infiltrate and no evidence of vasculitis.¹¹ Medium to large vessels in the deep dermis and subcutaneous tissue show infiltration of their walls with a large number of macrophages laden with acid-fast bacilli.¹¹ Cases with histopathologic features mimicking antiphospholipid syndrome with endothelial cell proliferation, thrombosis, and mild mononuclear cell infiltrate also may be seen.²⁰ In all cases, ischemic epidermal necrosis is seen, as well as acid-fast bacilli, both singly and in clusters (globi) within endothelial cells and inside blood vessel lumina.

Although Lucio phenomenon initially was thought to be immune-complex mediated like ENL, it has been suggested that the main trigger is thrombotic vascular occlusion secondary to massive invasion of the vascular endothelial cells by the lepra bacilli, resulting in necrosis.¹⁴ Bacterial lipopolysaccharides promote the release of IL-1 and tumor necrosis factor α, which in turn stimulate the production of prostaglandins, IL-6, and coagulation factor III, leading to vascular thrombosis and tissue necrosis.^21,22 Moreover, antiphospholipid antibodies, which have been found to be induced in response to certain infectious agents in genetically predisposed individuals,²³ have been reported in patients with leprosy, mainly in association with lepromatous leprosy. The reported prevalence of anticardiolipin antibodies ranged from 37% to 98%, whereas anti-β2-glycoprotein I antibodies ranged from 3% to 19%, and antiprothrombin antibodies ranged from 6% to 45%.^24,25 Antiphospholipid antibodies have been reported to play a role in the pathogenesis of Lucio phenomenon.^11,13,15,26 Our case supports this hypothesis with positive anticardiolipin antibodies, anti-β2 glycoprotein antibodies, and positive lupus anticoagulant.

In accordance with Curi et al,² who reported 5 cases of DLL with Lucio phenomenon, our patient showed a similar presentation with positive inflammatory markers in association with a negative autoimmune profile (ANA, ANCA-C&P) and negative venereal disease research laboratory test. It is important to mention that a positive autoimmune profile (ANA, ANCA-C&P) can be present in leprotic patients, causing possible diagnostic confusion with collagen diseases.^27,28

An interesting finding in our case was the negative slit-skin smear results. Although the specificity of slit-skin smear is 100%, as it directly demonstrates the presence of acid-fast bacilli,²⁹ its sensitivity is low and varies from 10% to 50%.³⁰ The detection of acid-fast bacilli in tissue sections is reported to be a better method for confirming the diagnosis of leprosy.³¹

The provisional impression of hemophagocytic lymphohistiocytosis in the lymph node biopsy in our patient was excluded upon detection of acid-fast bacilli in the foamy histiocytes infiltrating the lymph node; moreover, the normal serum lipids and serum ferritin argued against this diagnosis.³² Leprosy tends to involve the lymph nodes, particularly in borderline, borderline lepromatous, and lepromatous forms.³³ The incidence of lymph node involvement accompanied by skin lesions with the presence of acid-fast bacilli in the lymph nodes is 92.2%.³⁴

Our patient showed an excellent response to antileprotic treatment, which was administered according to the WHO multidrug therapy guidelines for multibacillary leprosy,³⁵ combined with low-dose prednisolone, acetylsalicylic acid, and anticoagulant treatment. Thalidomide and high-dose prednisolone (60 mg/d) combined with antileprotic treatment also have been reported to be successful in managing recurrent infarctions in leprosy.³⁶ The Fournier-like gangrenous ulcer of the scrotum was managed by surgical debridement and vacuum therapy.

It is noteworthy that the WHO elimination goal for leprosy was to reduce the prevalence to less than 1 case per 10,000 population. Egypt is among the first countries in North Africa and the Middle East regions to achieve this target supervised by the National Leprosy Control Program as early as 1994; this was further reduced to 0.33 cases per 10,000 population in 2004, and reduced again in 2009; however, certain foci showed a prevalence rate more than the elimination target, particularly in the cities of Qena (1.12) and Sohag (2.47).³⁷ Esna, where our patient is from, is an endemic area in Egypt.³⁸

Conclusion

Leprosy is a great mimicker of many connective tissue diseases, including vasculitis. Antiphospholipid antibodies are involved in Lucio phenomenon. Recognition of Lucio phenomenon is important to initiate prompt treatment and avoid morbidity and mortality. We report a rare case of diffuse nonnodular lepromatous leprosy in Egypt in which Lucio phenomenon was the first diagnostic presentation. Scrotal involvement with Lucio phenomenon was not previously reported in any case of Lucio leprosy.

To the Editor:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by bilateral, symmetrical, proximal muscle weakness and classic cutaneous manifestations.¹ Patients with antibodies directed against melanoma differentiation–associated gene 5, MDA5, have a distinct presentation due to vasculopathy with more severe cutaneous ulcerations, palmar papules, alopecia, and an elevated risk of rapidly progressive interstitial lung disease.² A ferritin level greater than 1600 ng/mL portends an increased risk for pulmonary disease and therefore can be of prognostic value.³ Further, patients with anti-MDA5 DM are at a lower risk of malignancy and are more likely to test negative for antinuclear antibodies in comparison to other patients with DM.^2,4

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a potentially lethal condition whereby uncontrolled activation of histiocytes in the reticuloendothelial system causes hemophagocytosis and a hyperinflammatory state. Patients present with fever, splenomegaly, cytopenia, and hyperferritinemia.⁵ Autoimmune‐associated hemophagocytic syndrome (AAHS) describes HLH that develops in association with autoimmune conditions, most commonly systemic lupus erythematosus and adult-onset Still disease. Cases reported in association with DM exist but are few in number, and there is no standard-of-care treatment.⁶ We report a case of a woman with anti-MDA5 DM complicated by HLH and DM-associated liver injury.

A 50-year-old woman presented as a direct admit from the rheumatology clinic for diffuse muscle weakness of 8 months’ duration, 40-pound unintentional weight loss, pruritic rash, bilateral joint pains, dry eyes, dry mouth, and altered mental status. Four months prior, she presented to an outside hospital and was given a diagnosis of probable Sjögren syndrome and autoimmune hepatitis vs drug-induced liver injury. At that time, a workup was notable for antibodies against Sjögren syndrome–related antigen A, anti–smooth muscle antibodies, and transaminitis. Ultrasonography of the right upper quadrant revealed hepatic steatosis. The patient was started on oral prednisone and pilocarpine but had been off all medications for 1 month when she presented to our hospital.

On hospital admission, physical examination revealed a violaceous heliotrope rash; a v-sign on the chest; shawl sign; palmar papules with pits at the fingertips; and periungual erythema and ulcerations along the metacarpophalangeal joints, elbows, lateral feet, and upper eyelids (Figure 1). Laboratory workup showed the following results: white blood cell count, 4100/μL (reference range, 4000–11,000/μL); hemoglobin, 11.6 g/dL (reference range, 12–16 g/dL); platelet count, 100,000/μL (reference range, 150,000–450,000/μL); lactate dehydrogenase, 510 U/L (reference range, 80–225 U/L); alkaline phosphatase (ALP), 766 U/L (reference range, 30–120 U/L); alanine aminotransferase (ALT), 88 U/L (reference range, 10–40 U/L); aspartate aminotransferase (AST), 544 U/L (reference range, 10–40 U/L); total bilirubin, 4.2 mg/dL (reference range, 0.3–1.0 mg/dL); direct bilirubin, 3.7 mg/dL (reference range, 0.1–0.3 mg/dL); aldolase, 20.2 U/L (reference range, 1–7.5 U/L), creatine kinase, 180 U/L (reference range, 30–135 U/L); γ-glutamyltransferase (GGT), 2743 U/L (reference range, 8–40 U/L); high sensitivity C-reactive protein, 122.9 mg/L (low-risk reference range, <1.0 mg/L); triglycerides, 534 mg/dL (reference range, <150 mg/dL); ferritin, 3784 ng/mL (reference range, 24–307 ng/mL); antinuclear antibody, negative titer; antimitochondrial antibody, negative titer; soluble IL-2 receptor (CD25), 7000 U/mL (reference range, 189–846 U/mL); anti-Sjögren syndrome–related antigen A antibody, positive.

To the Editor:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by bilateral, symmetrical, proximal muscle weakness and classic cutaneous manifestations.¹ Patients with antibodies directed against melanoma differentiation–associated gene 5, MDA5, have a distinct presentation due to vasculopathy with more severe cutaneous ulcerations, palmar papules, alopecia, and an elevated risk of rapidly progressive interstitial lung disease.² A ferritin level greater than 1600 ng/mL portends an increased risk for pulmonary disease and therefore can be of prognostic value.³ Further, patients with anti-MDA5 DM are at a lower risk of malignancy and are more likely to test negative for antinuclear antibodies in comparison to other patients with DM.^2,4

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a potentially lethal condition whereby uncontrolled activation of histiocytes in the reticuloendothelial system causes hemophagocytosis and a hyperinflammatory state. Patients present with fever, splenomegaly, cytopenia, and hyperferritinemia.⁵ Autoimmune‐associated hemophagocytic syndrome (AAHS) describes HLH that develops in association with autoimmune conditions, most commonly systemic lupus erythematosus and adult-onset Still disease. Cases reported in association with DM exist but are few in number, and there is no standard-of-care treatment.⁶ We report a case of a woman with anti-MDA5 DM complicated by HLH and DM-associated liver injury.

A 50-year-old woman presented as a direct admit from the rheumatology clinic for diffuse muscle weakness of 8 months’ duration, 40-pound unintentional weight loss, pruritic rash, bilateral joint pains, dry eyes, dry mouth, and altered mental status. Four months prior, she presented to an outside hospital and was given a diagnosis of probable Sjögren syndrome and autoimmune hepatitis vs drug-induced liver injury. At that time, a workup was notable for antibodies against Sjögren syndrome–related antigen A, anti–smooth muscle antibodies, and transaminitis. Ultrasonography of the right upper quadrant revealed hepatic steatosis. The patient was started on oral prednisone and pilocarpine but had been off all medications for 1 month when she presented to our hospital.

On hospital admission, physical examination revealed a violaceous heliotrope rash; a v-sign on the chest; shawl sign; palmar papules with pits at the fingertips; and periungual erythema and ulcerations along the metacarpophalangeal joints, elbows, lateral feet, and upper eyelids (Figure 1). Laboratory workup showed the following results: white blood cell count, 4100/μL (reference range, 4000–11,000/μL); hemoglobin, 11.6 g/dL (reference range, 12–16 g/dL); platelet count, 100,000/μL (reference range, 150,000–450,000/μL); lactate dehydrogenase, 510 U/L (reference range, 80–225 U/L); alkaline phosphatase (ALP), 766 U/L (reference range, 30–120 U/L); alanine aminotransferase (ALT), 88 U/L (reference range, 10–40 U/L); aspartate aminotransferase (AST), 544 U/L (reference range, 10–40 U/L); total bilirubin, 4.2 mg/dL (reference range, 0.3–1.0 mg/dL); direct bilirubin, 3.7 mg/dL (reference range, 0.1–0.3 mg/dL); aldolase, 20.2 U/L (reference range, 1–7.5 U/L), creatine kinase, 180 U/L (reference range, 30–135 U/L); γ-glutamyltransferase (GGT), 2743 U/L (reference range, 8–40 U/L); high sensitivity C-reactive protein, 122.9 mg/L (low-risk reference range, <1.0 mg/L); triglycerides, 534 mg/dL (reference range, <150 mg/dL); ferritin, 3784 ng/mL (reference range, 24–307 ng/mL); antinuclear antibody, negative titer; antimitochondrial antibody, negative titer; soluble IL-2 receptor (CD25), 7000 U/mL (reference range, 189–846 U/mL); anti-Sjögren syndrome–related antigen A antibody, positive.

To the Editor:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by bilateral, symmetrical, proximal muscle weakness and classic cutaneous manifestations.¹ Patients with antibodies directed against melanoma differentiation–associated gene 5, MDA5, have a distinct presentation due to vasculopathy with more severe cutaneous ulcerations, palmar papules, alopecia, and an elevated risk of rapidly progressive interstitial lung disease.² A ferritin level greater than 1600 ng/mL portends an increased risk for pulmonary disease and therefore can be of prognostic value.³ Further, patients with anti-MDA5 DM are at a lower risk of malignancy and are more likely to test negative for antinuclear antibodies in comparison to other patients with DM.^2,4

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a potentially lethal condition whereby uncontrolled activation of histiocytes in the reticuloendothelial system causes hemophagocytosis and a hyperinflammatory state. Patients present with fever, splenomegaly, cytopenia, and hyperferritinemia.⁵ Autoimmune‐associated hemophagocytic syndrome (AAHS) describes HLH that develops in association with autoimmune conditions, most commonly systemic lupus erythematosus and adult-onset Still disease. Cases reported in association with DM exist but are few in number, and there is no standard-of-care treatment.⁶ We report a case of a woman with anti-MDA5 DM complicated by HLH and DM-associated liver injury.

A 50-year-old woman presented as a direct admit from the rheumatology clinic for diffuse muscle weakness of 8 months’ duration, 40-pound unintentional weight loss, pruritic rash, bilateral joint pains, dry eyes, dry mouth, and altered mental status. Four months prior, she presented to an outside hospital and was given a diagnosis of probable Sjögren syndrome and autoimmune hepatitis vs drug-induced liver injury. At that time, a workup was notable for antibodies against Sjögren syndrome–related antigen A, anti–smooth muscle antibodies, and transaminitis. Ultrasonography of the right upper quadrant revealed hepatic steatosis. The patient was started on oral prednisone and pilocarpine but had been off all medications for 1 month when she presented to our hospital.

On hospital admission, physical examination revealed a violaceous heliotrope rash; a v-sign on the chest; shawl sign; palmar papules with pits at the fingertips; and periungual erythema and ulcerations along the metacarpophalangeal joints, elbows, lateral feet, and upper eyelids (Figure 1). Laboratory workup showed the following results: white blood cell count, 4100/μL (reference range, 4000–11,000/μL); hemoglobin, 11.6 g/dL (reference range, 12–16 g/dL); platelet count, 100,000/μL (reference range, 150,000–450,000/μL); lactate dehydrogenase, 510 U/L (reference range, 80–225 U/L); alkaline phosphatase (ALP), 766 U/L (reference range, 30–120 U/L); alanine aminotransferase (ALT), 88 U/L (reference range, 10–40 U/L); aspartate aminotransferase (AST), 544 U/L (reference range, 10–40 U/L); total bilirubin, 4.2 mg/dL (reference range, 0.3–1.0 mg/dL); direct bilirubin, 3.7 mg/dL (reference range, 0.1–0.3 mg/dL); aldolase, 20.2 U/L (reference range, 1–7.5 U/L), creatine kinase, 180 U/L (reference range, 30–135 U/L); γ-glutamyltransferase (GGT), 2743 U/L (reference range, 8–40 U/L); high sensitivity C-reactive protein, 122.9 mg/L (low-risk reference range, <1.0 mg/L); triglycerides, 534 mg/dL (reference range, <150 mg/dL); ferritin, 3784 ng/mL (reference range, 24–307 ng/mL); antinuclear antibody, negative titer; antimitochondrial antibody, negative titer; soluble IL-2 receptor (CD25), 7000 U/mL (reference range, 189–846 U/mL); anti-Sjögren syndrome–related antigen A antibody, positive.