Case Reports

A 45-year-old African American woman presented with painless fingernail detachment and cracks on her fingernails that had developed over the previous month. Her medical history was notable for an episode of Stevens-Johnson syndrome 2 months prior that required treatment with prednisone, IV immunoglobulin, etanercept, acetaminophen, and diphenhydramine.

A physical examination revealed multiple fingernails on both hands that exhibited 4 mm of proximal painless nail detachment with cream-colored discoloration, friability, and horizontal splitting (Figure). New, healthy nail was visible beneath the affected areas. Toenails were not affected.

• What is your diagnosis?
• How would you treat this patient?

Diagnosis

Based on the timing and characteristics of her nail detachment, the patient was diagnosed with onychomadesis, which is defined as painless detachment of the proximal nail plate from the nail matrix and nail bed after at least 40 days from an initial insult. Air beneath the detached nail plate causes a characteristic creamy-white discoloration. The severity of onychomadesis ranges from transverse furrows that affect a single nail without shedding, known as Beau lines, to multiple nails that are completely shed.^1,2 Nail plate shedding is typical because the nail matrix, the site of stem cells and the most proximal portion of the nail apparatus, is damaged and transiently arrested.

Various etiologies can halt nail plate production abruptly within the matrix. These typically manifest ≥ 40 days after the initial insult (the length of time for a fingernail to emerge from the proximal nail fold).² The annual incidence of these etiologies ranges from approximately 1 per 1 million people for Stevens-Johnson syndrome, a rare cause of onychomadesis, to 1 per 10 people for onychomycosis, one of the more common causes of onychomadesis.³ The Table compares the characteristics of the diagnoses that are most commonly associated with nail detachment and discoloration.

When a single nail is affected, the etiology of onychomadesis usually is primary and local, including mechanical nail trauma and fungal nail infections (onychomycosis).^1,2 Candida onychia is onychomycosis caused by Candida species typically Candida albicans, which result in localized nail darkening, chronic inflammation of the paronychial skin, and cuticle loss. The infection favors immunocompromised people; coinfections are common, and onychomadesis or onycholysis can occur. Unlike onychomadesis, onycholysis is defined by painless detachment of the distal nail plate from the nail bed, but nail shedding typically does not occur because the nail matrix is spared. The preferred treatment for Candida onychia is oral itraconazole, and guided screenings for immunodeficiencies and endocrinopathies, especially diabetes mellitus, should be completed.^3,4

Tinea unguium is another form of onychomycosis, but it is caused by dermatophytes, typically Trichophyton rubrum or Trichophyton mentagrophytes, which produce white and yellow nail discoloration followed by distal to proximal nail thickening and softening. Infection usually begins in toenails and demonstrates variable involvement in each nail as well as asymmetric distribution among digits.³ This condition also may eventuate in onychomadesis or onycholysis. Debridement followed by oral terbinafine is the treatment of choice.⁴

Two other causes of localized nail discoloration with or without nail detachment include melanonychia and nail bed infection by Pseudomonas aeruginosa (P aeruginosa). Melanonychia can be linear or diffuse brown discoloration of 1 or more nails caused by melanin deposition. Either pattern is a common finding in dark-skinned people, especially by age 50 years, but melanocyte hyperplasia should be excluded in all individuals along with drug adverse effects, exogenous pigments, infections, and systemic diseases.^3,5 P aeruginosa produces pyocyanin, the green pigment responsible for the discoloration seen in this opportunistic infection often localized to a single nail. Prior maceration of the nail apparatus by repeated water submersion is common among affected individuals. Avoidance of submerging fingernails in liquids followed by nail debridement and oral antipseudomonal antibiotics is the preferred treatment course.³

The etiology is usually secondary and systemic when multiple nails demonstrate onychomadesis, but the exact pathophysiology is poorly understood. One of the most studied infectious etiologies of onychomadesis is hand-foot-and-mouth disease (HFMD), which typically affects children aged < 10 years. Parents often will recall their child being ill 1 to 2 months prior to the nail findings. Scarlet fever and varicella also can result in onychomadesis. Although not common systemic causes, Stevens-Johnson syndrome and toxic epidermal necrolysis can trigger onychomadesis of multiple nails that usually resolves in several months, but other nail deformities often persist.^2,6 Onycholysis also can accompany this finding.⁷ Autoimmune etiologies of onychomadesis include alopecia areata and pemphigus vulgaris. Inciting medications that are toxic to the nail matrix include chemotherapy agents, valproic acid, carbamazepine, lithium, and azithromycin. Rare congenital disorders and birth trauma also can present with onychomadesis of multiple nails during infancy.²

Systemic etiologies typically affect fingernails more than toenails because of the faster growth rate of fingernails. Once the source of onychomadesis is controlled or eradicated, complete regrowth of fingernails can take from 4 to 6 months. Toenails can take twice as long and older age increases all regrowth periods.⁵

Our patient was treated with analgesics until her mucosal surfaces fully healed, and topical emollients and keratolytics were used to soften eschars from previous blisters and prevent further scar formation. Her affected fingernails shed and regrew after 6 months without additional interventions.

Conclusion

Although Stevens-Johnson syndrome is a rare cause of onychomadesis, and the pathophysiology of this sequela is poorly understood, this case illustrates a common nail abnormality with multiple potential etiologies that are discerned by an accurate history and thorough exam. In the absence of decorative nail polish, nails can be easily examined to provide helpful clues for past injuries or underlying diseases. An understanding of nail growth mechanics and associated terminology reveals the diagnostic and therapeutic implications of proximal vs distal nail detachment, the hue of nail discoloration, as well as single vs multiple affected nails.

Onychomadesis in single nails should prompt questions about nail trauma or risk factors for fungal infections. Depending on the etiology, manual activities need to be adjusted, or antifungals need to be initiated while investigating for an immunocompromised state. Onychomadesis in multiple nails in children should raise suspicion for HFMD or even birth trauma and congenital disorders. Multiple affected nails in adults should prompt guided questions for autoimmune diseases and inciting medications. For onycholysis, trauma, psoriasis, or certain infections should be the target. Green nails are easily recognized and treated with a defined regiment, whereas dark nails should be examined closely to differentiate Candida onychia from melanonychia. Whether from a rare cause in an adult to a common illness in a child, primary care providers have sufficient expertise to diagnose and treat various nail disorders and reassure worried patients and parents with an understanding of nail regrowth.

A 45-year-old African American woman presented with painless fingernail detachment and cracks on her fingernails that had developed over the previous month. Her medical history was notable for an episode of Stevens-Johnson syndrome 2 months prior that required treatment with prednisone, IV immunoglobulin, etanercept, acetaminophen, and diphenhydramine.

A physical examination revealed multiple fingernails on both hands that exhibited 4 mm of proximal painless nail detachment with cream-colored discoloration, friability, and horizontal splitting (Figure). New, healthy nail was visible beneath the affected areas. Toenails were not affected.

• What is your diagnosis?
• How would you treat this patient?

Diagnosis

Based on the timing and characteristics of her nail detachment, the patient was diagnosed with onychomadesis, which is defined as painless detachment of the proximal nail plate from the nail matrix and nail bed after at least 40 days from an initial insult. Air beneath the detached nail plate causes a characteristic creamy-white discoloration. The severity of onychomadesis ranges from transverse furrows that affect a single nail without shedding, known as Beau lines, to multiple nails that are completely shed.^1,2 Nail plate shedding is typical because the nail matrix, the site of stem cells and the most proximal portion of the nail apparatus, is damaged and transiently arrested.

Various etiologies can halt nail plate production abruptly within the matrix. These typically manifest ≥ 40 days after the initial insult (the length of time for a fingernail to emerge from the proximal nail fold).² The annual incidence of these etiologies ranges from approximately 1 per 1 million people for Stevens-Johnson syndrome, a rare cause of onychomadesis, to 1 per 10 people for onychomycosis, one of the more common causes of onychomadesis.³ The Table compares the characteristics of the diagnoses that are most commonly associated with nail detachment and discoloration.

When a single nail is affected, the etiology of onychomadesis usually is primary and local, including mechanical nail trauma and fungal nail infections (onychomycosis).^1,2 Candida onychia is onychomycosis caused by Candida species typically Candida albicans, which result in localized nail darkening, chronic inflammation of the paronychial skin, and cuticle loss. The infection favors immunocompromised people; coinfections are common, and onychomadesis or onycholysis can occur. Unlike onychomadesis, onycholysis is defined by painless detachment of the distal nail plate from the nail bed, but nail shedding typically does not occur because the nail matrix is spared. The preferred treatment for Candida onychia is oral itraconazole, and guided screenings for immunodeficiencies and endocrinopathies, especially diabetes mellitus, should be completed.^3,4

Tinea unguium is another form of onychomycosis, but it is caused by dermatophytes, typically Trichophyton rubrum or Trichophyton mentagrophytes, which produce white and yellow nail discoloration followed by distal to proximal nail thickening and softening. Infection usually begins in toenails and demonstrates variable involvement in each nail as well as asymmetric distribution among digits.³ This condition also may eventuate in onychomadesis or onycholysis. Debridement followed by oral terbinafine is the treatment of choice.⁴

Two other causes of localized nail discoloration with or without nail detachment include melanonychia and nail bed infection by Pseudomonas aeruginosa (P aeruginosa). Melanonychia can be linear or diffuse brown discoloration of 1 or more nails caused by melanin deposition. Either pattern is a common finding in dark-skinned people, especially by age 50 years, but melanocyte hyperplasia should be excluded in all individuals along with drug adverse effects, exogenous pigments, infections, and systemic diseases.^3,5 P aeruginosa produces pyocyanin, the green pigment responsible for the discoloration seen in this opportunistic infection often localized to a single nail. Prior maceration of the nail apparatus by repeated water submersion is common among affected individuals. Avoidance of submerging fingernails in liquids followed by nail debridement and oral antipseudomonal antibiotics is the preferred treatment course.³

The etiology is usually secondary and systemic when multiple nails demonstrate onychomadesis, but the exact pathophysiology is poorly understood. One of the most studied infectious etiologies of onychomadesis is hand-foot-and-mouth disease (HFMD), which typically affects children aged < 10 years. Parents often will recall their child being ill 1 to 2 months prior to the nail findings. Scarlet fever and varicella also can result in onychomadesis. Although not common systemic causes, Stevens-Johnson syndrome and toxic epidermal necrolysis can trigger onychomadesis of multiple nails that usually resolves in several months, but other nail deformities often persist.^2,6 Onycholysis also can accompany this finding.⁷ Autoimmune etiologies of onychomadesis include alopecia areata and pemphigus vulgaris. Inciting medications that are toxic to the nail matrix include chemotherapy agents, valproic acid, carbamazepine, lithium, and azithromycin. Rare congenital disorders and birth trauma also can present with onychomadesis of multiple nails during infancy.²

Systemic etiologies typically affect fingernails more than toenails because of the faster growth rate of fingernails. Once the source of onychomadesis is controlled or eradicated, complete regrowth of fingernails can take from 4 to 6 months. Toenails can take twice as long and older age increases all regrowth periods.⁵

Our patient was treated with analgesics until her mucosal surfaces fully healed, and topical emollients and keratolytics were used to soften eschars from previous blisters and prevent further scar formation. Her affected fingernails shed and regrew after 6 months without additional interventions.

Conclusion

Although Stevens-Johnson syndrome is a rare cause of onychomadesis, and the pathophysiology of this sequela is poorly understood, this case illustrates a common nail abnormality with multiple potential etiologies that are discerned by an accurate history and thorough exam. In the absence of decorative nail polish, nails can be easily examined to provide helpful clues for past injuries or underlying diseases. An understanding of nail growth mechanics and associated terminology reveals the diagnostic and therapeutic implications of proximal vs distal nail detachment, the hue of nail discoloration, as well as single vs multiple affected nails.

Onychomadesis in single nails should prompt questions about nail trauma or risk factors for fungal infections. Depending on the etiology, manual activities need to be adjusted, or antifungals need to be initiated while investigating for an immunocompromised state. Onychomadesis in multiple nails in children should raise suspicion for HFMD or even birth trauma and congenital disorders. Multiple affected nails in adults should prompt guided questions for autoimmune diseases and inciting medications. For onycholysis, trauma, psoriasis, or certain infections should be the target. Green nails are easily recognized and treated with a defined regiment, whereas dark nails should be examined closely to differentiate Candida onychia from melanonychia. Whether from a rare cause in an adult to a common illness in a child, primary care providers have sufficient expertise to diagnose and treat various nail disorders and reassure worried patients and parents with an understanding of nail regrowth.

A 45-year-old African American woman presented with painless fingernail detachment and cracks on her fingernails that had developed over the previous month. Her medical history was notable for an episode of Stevens-Johnson syndrome 2 months prior that required treatment with prednisone, IV immunoglobulin, etanercept, acetaminophen, and diphenhydramine.

A physical examination revealed multiple fingernails on both hands that exhibited 4 mm of proximal painless nail detachment with cream-colored discoloration, friability, and horizontal splitting (Figure). New, healthy nail was visible beneath the affected areas. Toenails were not affected.

• What is your diagnosis?
• How would you treat this patient?

Diagnosis

Based on the timing and characteristics of her nail detachment, the patient was diagnosed with onychomadesis, which is defined as painless detachment of the proximal nail plate from the nail matrix and nail bed after at least 40 days from an initial insult. Air beneath the detached nail plate causes a characteristic creamy-white discoloration. The severity of onychomadesis ranges from transverse furrows that affect a single nail without shedding, known as Beau lines, to multiple nails that are completely shed.^1,2 Nail plate shedding is typical because the nail matrix, the site of stem cells and the most proximal portion of the nail apparatus, is damaged and transiently arrested.

Various etiologies can halt nail plate production abruptly within the matrix. These typically manifest ≥ 40 days after the initial insult (the length of time for a fingernail to emerge from the proximal nail fold).² The annual incidence of these etiologies ranges from approximately 1 per 1 million people for Stevens-Johnson syndrome, a rare cause of onychomadesis, to 1 per 10 people for onychomycosis, one of the more common causes of onychomadesis.³ The Table compares the characteristics of the diagnoses that are most commonly associated with nail detachment and discoloration.

When a single nail is affected, the etiology of onychomadesis usually is primary and local, including mechanical nail trauma and fungal nail infections (onychomycosis).^1,2 Candida onychia is onychomycosis caused by Candida species typically Candida albicans, which result in localized nail darkening, chronic inflammation of the paronychial skin, and cuticle loss. The infection favors immunocompromised people; coinfections are common, and onychomadesis or onycholysis can occur. Unlike onychomadesis, onycholysis is defined by painless detachment of the distal nail plate from the nail bed, but nail shedding typically does not occur because the nail matrix is spared. The preferred treatment for Candida onychia is oral itraconazole, and guided screenings for immunodeficiencies and endocrinopathies, especially diabetes mellitus, should be completed.^3,4

Tinea unguium is another form of onychomycosis, but it is caused by dermatophytes, typically Trichophyton rubrum or Trichophyton mentagrophytes, which produce white and yellow nail discoloration followed by distal to proximal nail thickening and softening. Infection usually begins in toenails and demonstrates variable involvement in each nail as well as asymmetric distribution among digits.³ This condition also may eventuate in onychomadesis or onycholysis. Debridement followed by oral terbinafine is the treatment of choice.⁴

Two other causes of localized nail discoloration with or without nail detachment include melanonychia and nail bed infection by Pseudomonas aeruginosa (P aeruginosa). Melanonychia can be linear or diffuse brown discoloration of 1 or more nails caused by melanin deposition. Either pattern is a common finding in dark-skinned people, especially by age 50 years, but melanocyte hyperplasia should be excluded in all individuals along with drug adverse effects, exogenous pigments, infections, and systemic diseases.^3,5 P aeruginosa produces pyocyanin, the green pigment responsible for the discoloration seen in this opportunistic infection often localized to a single nail. Prior maceration of the nail apparatus by repeated water submersion is common among affected individuals. Avoidance of submerging fingernails in liquids followed by nail debridement and oral antipseudomonal antibiotics is the preferred treatment course.³

The etiology is usually secondary and systemic when multiple nails demonstrate onychomadesis, but the exact pathophysiology is poorly understood. One of the most studied infectious etiologies of onychomadesis is hand-foot-and-mouth disease (HFMD), which typically affects children aged < 10 years. Parents often will recall their child being ill 1 to 2 months prior to the nail findings. Scarlet fever and varicella also can result in onychomadesis. Although not common systemic causes, Stevens-Johnson syndrome and toxic epidermal necrolysis can trigger onychomadesis of multiple nails that usually resolves in several months, but other nail deformities often persist.^2,6 Onycholysis also can accompany this finding.⁷ Autoimmune etiologies of onychomadesis include alopecia areata and pemphigus vulgaris. Inciting medications that are toxic to the nail matrix include chemotherapy agents, valproic acid, carbamazepine, lithium, and azithromycin. Rare congenital disorders and birth trauma also can present with onychomadesis of multiple nails during infancy.²

Systemic etiologies typically affect fingernails more than toenails because of the faster growth rate of fingernails. Once the source of onychomadesis is controlled or eradicated, complete regrowth of fingernails can take from 4 to 6 months. Toenails can take twice as long and older age increases all regrowth periods.⁵

Our patient was treated with analgesics until her mucosal surfaces fully healed, and topical emollients and keratolytics were used to soften eschars from previous blisters and prevent further scar formation. Her affected fingernails shed and regrew after 6 months without additional interventions.

Conclusion

Although Stevens-Johnson syndrome is a rare cause of onychomadesis, and the pathophysiology of this sequela is poorly understood, this case illustrates a common nail abnormality with multiple potential etiologies that are discerned by an accurate history and thorough exam. In the absence of decorative nail polish, nails can be easily examined to provide helpful clues for past injuries or underlying diseases. An understanding of nail growth mechanics and associated terminology reveals the diagnostic and therapeutic implications of proximal vs distal nail detachment, the hue of nail discoloration, as well as single vs multiple affected nails.

Onychomadesis in single nails should prompt questions about nail trauma or risk factors for fungal infections. Depending on the etiology, manual activities need to be adjusted, or antifungals need to be initiated while investigating for an immunocompromised state. Onychomadesis in multiple nails in children should raise suspicion for HFMD or even birth trauma and congenital disorders. Multiple affected nails in adults should prompt guided questions for autoimmune diseases and inciting medications. For onycholysis, trauma, psoriasis, or certain infections should be the target. Green nails are easily recognized and treated with a defined regiment, whereas dark nails should be examined closely to differentiate Candida onychia from melanonychia. Whether from a rare cause in an adult to a common illness in a child, primary care providers have sufficient expertise to diagnose and treat various nail disorders and reassure worried patients and parents with an understanding of nail regrowth.

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 22-year-old woman presented to our office complaining of headaches that started 6 weeks earlier. Initially the headache was throbbing, nonpositional, infrequent, and intermittent, lasting 15 to 45 minutes, often starting in the neck and migrating towards the right frontotemporal region. During the week prior to presentation, the headaches became daily and constant, with brief periods of relief after the patient took ibuprofen 400 mg 4 times a day as needed. The patient reported associated nausea, a sensation of pressure changes in the ears, and intermittent dimming of vision in the right eye (sometimes independent of headache). The patient denied photophobia and phonophobia. Her only medication was an oral contraceptive pill (OCP). She had no prior history of headaches.

Physical examination showed a blood pressure of 148/66 mm Hg, body mass index of 44.38, muscle tenderness in the neck and upper back, and no focal neurological findings. Funduscopic examination was unsuccessful. A working diagnosis of atypical migraine was made, but because of unilateral visual disturbance the patient was referred to Ophthalmology for further evaluation. The following day, ophthalmological consultation found bilateral papilledema and the patient was admitted to our hospitalist service via the Emergency Department. She subsequently was referred to inpatient Neurology.

THE DIAGNOSIS

Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was unremarkable. Magnetic resonance venography (MRV) with contrast of the brain showed possible stenosis at the junction of the transverse and sigmoid sinuses but no mass lesion nor venous sinus thrombosis. Lumbar puncture (LP) revealed an opening pressure of 650 mm H₂0 (reference range, 60–250 mm H₂O).¹ A diagnosis of idiopathic intracranial hypertension (IIH) was made.

DISCUSSION

IIH, previously known as pseudotumor cerebri and benign intracranial hypertension, is defined by signs and symptoms of elevated intracranial pressure (ICP) without obvious cause on neuroimaging (TABLE 1^2-5). It is well documented that IIH is consequential and can result in vision loss and intractable chronic headaches.^5,6 Older terms such as pseudotumor cerebri and benign intracranial hypertension are therefore no longer recommended because they are considered misleading and not reflective of the severity of potential injury caused by the condition^3,4,6 IIH is considered a diagnosis of exclusion requiring certain criteria to be met (TABLE 2²). Although the etiology of IIH is unclear, associations have been made between IIH and various medications and conditions^2-5,7 (TABLE 3^3,5).

Classically, IIH affects women who are obese and of childbearing age, but studies have shown that this condition also can affect men and children—albeit less frequently.^3,5-7 The incidence of IIH in the general population is between 0.03 to 2.36/100,000 people per year, but in women, the incidence is 0.65 to 4.65/100,000 per year.⁶ Furthermore, females who are obese have an incidence of 2.7 to 19.3/100,000 per year.⁶

Headache is the most common symptom of IIH. Unfortunately, the differential diagnosis of headache is vast; thus, a careful history is needed to narrow the field^3,5-7 (TABLE 4²). Associated symptoms of transient visual changes, pulsatile tinnitus, neck and back pain, nausea, vomiting, photo/phonophobia, and findings of abducens nerve palsy or papilledema—while nonspecific— should raise suspicion for elevated ICP and IIH, especially in women who are obese.^2-8 Once IIH is suspected, an urgent diagnosis and treatment is necessary to prevent permanent vision loss.^3,4,6

Headache with findings of papilledema warrants neuroimaging, preferably with MRI, to rule out intracranial mass and hydrocephalus.^1,2,5 MRV also is recommended to assess for intracranial venous thrombosis, an alternate cause for papilledema and increased ICP.^1,2,4,5

Continue to: Recently, a classification of IIH...

Recently, a classification of IIH without papilledema has been acknowledged by the International Headache Society.^2,8 Specific MRI findings have been suggested to help make this diagnosis^5,9 (TABLE 5⁵).

TREATMENT FOR IIH CAN BE MEDICAL OR SURGICAL

Medications associated with IIH should be discontinued.⁷ The first-line medication for IIH is acetazolamide, a carbonic anhydrase inhibitor that works in the choroid plexus to decrease cerebrospinal fluid (CSF) production and thus, lower ICP.^3,6 An adult dose of 1 to 2 g/day^3,4,6 is tolerated well, but can be increased to 4 g/day,¹⁰ if necessary. Weight loss via diet and exercise or bariatric surgery has been shown to be effective in patients who are obese and have been given a diagnosis of IIH.^3,4

Topiramate also has been suggested as a treatment option, based on its usefulness in weight loss and because of its action as a weak carbonic anhydrase inhibitor.^3,6 Also, LP has therapeutic merit—although relief is only short-term.^3,6 Patients who fail medical therapy and have intractable headache or progressive visual loss appear to benefit from optic nerve sheath fenestration.^3,7,8

Our patient experienced notable improvement in her headache after LP. Her OCP was discontinued, a diuretic regimen started, and weight loss counseling was provided. Prior to discharge, the patient was seen by a neuro-ophthalmologist for perimetry, a visual field test that assesses for acute vision loss and establishes a baseline for follow-up monitoring of vision.⁷

THE TAKEAWAY

Headache is a common condition that may be challenging to correctly diagnose. A thorough history and neurological examination, including fundoscopy, are essential in the evaluation of headache and suspected IIH. In the primary care setting, limited time, lack of mydriatic agents, suboptimal lighting, and practitioner inexperience may pose challenges for funduscopic examination. Ophthalmoscopes incorporating new technology to expand and magnify the examiner’s field of view may facilitate this exam.¹¹ A global rise in the prevalence of obesity underscores a need for primary care providers to be compulsive about their clinical evaluation when symptoms suspicious of IIH are present. Lastly, if IIH cannot be ruled out confidently, recommend a prompt evaluation by an ophthalmologist.

CORRESPONDENCE
Aarti Paltoo, MD, MSc, CCFP, Peel Village Medical Center, 28 Rambler Drive, Brampton, Ontario L6W 1E2 Canada; [email protected]

THE CASE

A 78-year-old woman with a history of anxiety and hypertension presented to our family medicine residency practice in Massachusetts with subacute polyarticular arthralgias that had been present for 2 months. She complained of pain and swelling of both ankles and the right knee. She noted that her symptoms had started on a recent trip to the Dominican Republic, where she developed generalized joint pain and a fever that lasted 1 to 2 weeks and subsequently resolved with the lingering polyarthralgias. She denied any rash, constitutional symptoms, photosensitivity, headaches, photophobia, or history of tick bite. Physical examination revealed normal vital signs, notable warmth and swelling of the bilateral ankles that was worse on the right side, and swelling of the right knee with effusion—but no tenderness—to palpation.

THE DIAGNOSIS

The patient’s labwork revealed a white blood cell count of 5900/mcL (reference range, 4500–11,000/mcL), hemoglobin count of 12.5 g/dL (reference range, 14–17.5 g/dL), and a platelet count of 230×10³/mcL. Electrolytes and renal function were normal. She had an elevated erythrocyte sedimentation rate of 34 mm/h (reference range, 0–20 mm/h) and a positive antinuclear antibody (ANA) test, but no titer was reported. Anti-chikungunya IgG and IgM antibodies were positive on enzyme-linked immunosorbent assay (ELISA) serologic testing.

DISCUSSION

Chikungunya is an infectious disease that is relatively rare in the United States. Chikungunya was rarely identified in American travelers prior to 2006, but incidence increased over the next decade. In 2014, a total of 2811 cases were reported.¹ Chikungunya is an RNA arbovirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is endemic to West Africa. Within the last 2 decades, there has been an increasing number of outbreaks in India, Asia, Europe, and the Americas, where the highest incidence is in South America, followed by Central America. In the United States, almost all reported cases of chikungunya infection have been in travelers returning from endemic areas.² The first 2 known cases of local transmission in the United States were reported in Florida in July 2014.³ Local transmission of chikungunya is significant in that it represents the possibility of a local reservoir for sustained transmission.

Disease presentation. Patients will initially complain of a high fever and severe distal polyarthralgias that usually are symmetric. The most common symptoms are polyarthralgias (87%–98% of patients), myalgias (46%–59%), and a maculopapular rash involving the palms and soles (40%–50%).⁴ Other associated symptoms include headaches, photophobia, and digestive symptoms. Respiratory symptoms are not present in chikungunya.⁵

The term chikungunya is derived from a Kimakonde (central Bantu) word meaning “that which bends up” because of the arthralgia caused by the disease. Fever usually lasts 3 to 7 days; polyarthralgia begins shortly after the onset of fever.⁴ Frank arthritis also may be present. Infection often exacerbates a previously damaged or diseased joint. Acute symptoms usually persist for 1 to 2 weeks, but arthralgias and arthritis can persist for months to years following resolution of the acute disease.⁶ In one study of 47 patients with acute chikungunya in Marseilles, France, the number of patients who were symptomatic declined from 88% to 86%, 48%, and 4% at 1, 3, 6, and 15 months, respectively.⁷

The differential diagnosis includes tropical infectious diseases (dengue, chikungunya, Zika, and leptospirosis) in patients who have recently traveled to the tropics and who complain of subacute polyarticular arthralgias or arthritis; locally acquired infections associated with arthralgia/arthritis such as Lyme disease and other tick-borne diseases and rickettsial infections; parvovirus B19 and other postinfectious arthritides; and rheumatologic conditions such as systemic lupus.

Chikungunya virus is increasingly common in American travelers returning from tropical and subtropical regions.

Clinical differentiation among dengue, chikungunya, and Zika may be difficult, although persistent frank arthritis is much more common in chikungunya than in dengue or Zika. Furthermore, conjunctivitis is present in Zika but is absent in chikungunya. Chikungunya also is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia than Zika or dengue. Dengue is more likely to cause lymphopenia and hemorrhagic consequences than is chikungunya or Zika.⁸

Continue to: In our patient...

In our patient, dengue titers were not obtained because the duration of symptoms was thought to be more consistent with chikungunya, but testing for dengue also would have been appropriate. If present, fever typically is low-grade in Zika and is shorter in duration than in chikungunya (approximately 2–3 days vs 5–7 days).⁹ Coinfection with chikungunya and Zika sometimes occurs because the same mosquito species transmit both diseases.

The most common test for diagnosing acute chikungunya is ELISA serologic testing for IgM antibodies, which develop toward the end of the first week of infection; earlier in that first week, serum testing for viral RNA may be performed by polymerase chain reaction.

Treatment is largely supportive

Treatment of acute chikungunya is largely supportive and includes anti-inflammatory agents. To our knowledge, no antiviral agents have been shown to be effective. Postacute or chronic symptoms may require treatment with glucocorticoids or other immunomodulatory medications. A 2017 literature review of treatments for chikungunya-associated rheumatic disorders showed evidence that chloroquine was more effective than placebo for chronic pain relief. Also, adding a disease-modifying antirheumatic agent in combination with chloroquine was more effective for controlling pain and reducing disability than hydroxychloroquine monotherapy.¹⁰

Our patient was treated with ibuprofen only and experienced resolution of joint symptoms several months after the initial presentation. A repeat ANA test 12 months later was negative.

A 2009 review of the medical literature revealed a single case report of chikungunya associated with positive ANA.⁸ Although a positive ANA may be associated with acute viral infections, significantly elevated ANA levels typically are associated with autoimmunity. Resolution of the patient’s serum ANA 1 year later suggested that the positive ANA was not secondary to a pre-existing rheumatologic condition but rather a consequence of her body’s response to the chikungunya infection itself. Our case raises the hypothesis that, at least in some cases, chikungunya somehow stimulates a temporary autoimmune response, which may help explain why immunomodulatory medications can be effective treatment options.

Continue to: THE TAKEAWAY

Chikungunya is increasingly common in tropical and subtropical regions. Family physicians practicing in the United States should become familiar with the common patterns of presentation of viruses such as chikungunya, dengue, and Zika. Obtaining a travel history for patients presenting with arthritis improves the differential diagnosis and may even reveal the cause of the condition.

CORRESPONDENCE
Jeremy Golding, MD, 279 Lincoln Street, Worcester, MA 01605; [email protected]

THE CASE

A 78-year-old woman with a history of anxiety and hypertension presented to our family medicine residency practice in Massachusetts with subacute polyarticular arthralgias that had been present for 2 months. She complained of pain and swelling of both ankles and the right knee. She noted that her symptoms had started on a recent trip to the Dominican Republic, where she developed generalized joint pain and a fever that lasted 1 to 2 weeks and subsequently resolved with the lingering polyarthralgias. She denied any rash, constitutional symptoms, photosensitivity, headaches, photophobia, or history of tick bite. Physical examination revealed normal vital signs, notable warmth and swelling of the bilateral ankles that was worse on the right side, and swelling of the right knee with effusion—but no tenderness—to palpation.

THE DIAGNOSIS

The patient’s labwork revealed a white blood cell count of 5900/mcL (reference range, 4500–11,000/mcL), hemoglobin count of 12.5 g/dL (reference range, 14–17.5 g/dL), and a platelet count of 230×10³/mcL. Electrolytes and renal function were normal. She had an elevated erythrocyte sedimentation rate of 34 mm/h (reference range, 0–20 mm/h) and a positive antinuclear antibody (ANA) test, but no titer was reported. Anti-chikungunya IgG and IgM antibodies were positive on enzyme-linked immunosorbent assay (ELISA) serologic testing.

DISCUSSION

Chikungunya is an infectious disease that is relatively rare in the United States. Chikungunya was rarely identified in American travelers prior to 2006, but incidence increased over the next decade. In 2014, a total of 2811 cases were reported.¹ Chikungunya is an RNA arbovirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is endemic to West Africa. Within the last 2 decades, there has been an increasing number of outbreaks in India, Asia, Europe, and the Americas, where the highest incidence is in South America, followed by Central America. In the United States, almost all reported cases of chikungunya infection have been in travelers returning from endemic areas.² The first 2 known cases of local transmission in the United States were reported in Florida in July 2014.³ Local transmission of chikungunya is significant in that it represents the possibility of a local reservoir for sustained transmission.

Disease presentation. Patients will initially complain of a high fever and severe distal polyarthralgias that usually are symmetric. The most common symptoms are polyarthralgias (87%–98% of patients), myalgias (46%–59%), and a maculopapular rash involving the palms and soles (40%–50%).⁴ Other associated symptoms include headaches, photophobia, and digestive symptoms. Respiratory symptoms are not present in chikungunya.⁵

The term chikungunya is derived from a Kimakonde (central Bantu) word meaning “that which bends up” because of the arthralgia caused by the disease. Fever usually lasts 3 to 7 days; polyarthralgia begins shortly after the onset of fever.⁴ Frank arthritis also may be present. Infection often exacerbates a previously damaged or diseased joint. Acute symptoms usually persist for 1 to 2 weeks, but arthralgias and arthritis can persist for months to years following resolution of the acute disease.⁶ In one study of 47 patients with acute chikungunya in Marseilles, France, the number of patients who were symptomatic declined from 88% to 86%, 48%, and 4% at 1, 3, 6, and 15 months, respectively.⁷

The differential diagnosis includes tropical infectious diseases (dengue, chikungunya, Zika, and leptospirosis) in patients who have recently traveled to the tropics and who complain of subacute polyarticular arthralgias or arthritis; locally acquired infections associated with arthralgia/arthritis such as Lyme disease and other tick-borne diseases and rickettsial infections; parvovirus B19 and other postinfectious arthritides; and rheumatologic conditions such as systemic lupus.

Chikungunya virus is increasingly common in American travelers returning from tropical and subtropical regions.

Clinical differentiation among dengue, chikungunya, and Zika may be difficult, although persistent frank arthritis is much more common in chikungunya than in dengue or Zika. Furthermore, conjunctivitis is present in Zika but is absent in chikungunya. Chikungunya also is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia than Zika or dengue. Dengue is more likely to cause lymphopenia and hemorrhagic consequences than is chikungunya or Zika.⁸

Continue to: In our patient...

In our patient, dengue titers were not obtained because the duration of symptoms was thought to be more consistent with chikungunya, but testing for dengue also would have been appropriate. If present, fever typically is low-grade in Zika and is shorter in duration than in chikungunya (approximately 2–3 days vs 5–7 days).⁹ Coinfection with chikungunya and Zika sometimes occurs because the same mosquito species transmit both diseases.

The most common test for diagnosing acute chikungunya is ELISA serologic testing for IgM antibodies, which develop toward the end of the first week of infection; earlier in that first week, serum testing for viral RNA may be performed by polymerase chain reaction.

Treatment is largely supportive

Treatment of acute chikungunya is largely supportive and includes anti-inflammatory agents. To our knowledge, no antiviral agents have been shown to be effective. Postacute or chronic symptoms may require treatment with glucocorticoids or other immunomodulatory medications. A 2017 literature review of treatments for chikungunya-associated rheumatic disorders showed evidence that chloroquine was more effective than placebo for chronic pain relief. Also, adding a disease-modifying antirheumatic agent in combination with chloroquine was more effective for controlling pain and reducing disability than hydroxychloroquine monotherapy.¹⁰

Our patient was treated with ibuprofen only and experienced resolution of joint symptoms several months after the initial presentation. A repeat ANA test 12 months later was negative.

A 2009 review of the medical literature revealed a single case report of chikungunya associated with positive ANA.⁸ Although a positive ANA may be associated with acute viral infections, significantly elevated ANA levels typically are associated with autoimmunity. Resolution of the patient’s serum ANA 1 year later suggested that the positive ANA was not secondary to a pre-existing rheumatologic condition but rather a consequence of her body’s response to the chikungunya infection itself. Our case raises the hypothesis that, at least in some cases, chikungunya somehow stimulates a temporary autoimmune response, which may help explain why immunomodulatory medications can be effective treatment options.

Continue to: THE TAKEAWAY

Chikungunya is increasingly common in tropical and subtropical regions. Family physicians practicing in the United States should become familiar with the common patterns of presentation of viruses such as chikungunya, dengue, and Zika. Obtaining a travel history for patients presenting with arthritis improves the differential diagnosis and may even reveal the cause of the condition.

CORRESPONDENCE
Jeremy Golding, MD, 279 Lincoln Street, Worcester, MA 01605; [email protected]

THE CASE

A 78-year-old woman with a history of anxiety and hypertension presented to our family medicine residency practice in Massachusetts with subacute polyarticular arthralgias that had been present for 2 months. She complained of pain and swelling of both ankles and the right knee. She noted that her symptoms had started on a recent trip to the Dominican Republic, where she developed generalized joint pain and a fever that lasted 1 to 2 weeks and subsequently resolved with the lingering polyarthralgias. She denied any rash, constitutional symptoms, photosensitivity, headaches, photophobia, or history of tick bite. Physical examination revealed normal vital signs, notable warmth and swelling of the bilateral ankles that was worse on the right side, and swelling of the right knee with effusion—but no tenderness—to palpation.

THE DIAGNOSIS

The patient’s labwork revealed a white blood cell count of 5900/mcL (reference range, 4500–11,000/mcL), hemoglobin count of 12.5 g/dL (reference range, 14–17.5 g/dL), and a platelet count of 230×10³/mcL. Electrolytes and renal function were normal. She had an elevated erythrocyte sedimentation rate of 34 mm/h (reference range, 0–20 mm/h) and a positive antinuclear antibody (ANA) test, but no titer was reported. Anti-chikungunya IgG and IgM antibodies were positive on enzyme-linked immunosorbent assay (ELISA) serologic testing.

DISCUSSION

Chikungunya is an infectious disease that is relatively rare in the United States. Chikungunya was rarely identified in American travelers prior to 2006, but incidence increased over the next decade. In 2014, a total of 2811 cases were reported.¹ Chikungunya is an RNA arbovirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is endemic to West Africa. Within the last 2 decades, there has been an increasing number of outbreaks in India, Asia, Europe, and the Americas, where the highest incidence is in South America, followed by Central America. In the United States, almost all reported cases of chikungunya infection have been in travelers returning from endemic areas.² The first 2 known cases of local transmission in the United States were reported in Florida in July 2014.³ Local transmission of chikungunya is significant in that it represents the possibility of a local reservoir for sustained transmission.

Disease presentation. Patients will initially complain of a high fever and severe distal polyarthralgias that usually are symmetric. The most common symptoms are polyarthralgias (87%–98% of patients), myalgias (46%–59%), and a maculopapular rash involving the palms and soles (40%–50%).⁴ Other associated symptoms include headaches, photophobia, and digestive symptoms. Respiratory symptoms are not present in chikungunya.⁵

The term chikungunya is derived from a Kimakonde (central Bantu) word meaning “that which bends up” because of the arthralgia caused by the disease. Fever usually lasts 3 to 7 days; polyarthralgia begins shortly after the onset of fever.⁴ Frank arthritis also may be present. Infection often exacerbates a previously damaged or diseased joint. Acute symptoms usually persist for 1 to 2 weeks, but arthralgias and arthritis can persist for months to years following resolution of the acute disease.⁶ In one study of 47 patients with acute chikungunya in Marseilles, France, the number of patients who were symptomatic declined from 88% to 86%, 48%, and 4% at 1, 3, 6, and 15 months, respectively.⁷

The differential diagnosis includes tropical infectious diseases (dengue, chikungunya, Zika, and leptospirosis) in patients who have recently traveled to the tropics and who complain of subacute polyarticular arthralgias or arthritis; locally acquired infections associated with arthralgia/arthritis such as Lyme disease and other tick-borne diseases and rickettsial infections; parvovirus B19 and other postinfectious arthritides; and rheumatologic conditions such as systemic lupus.

Chikungunya virus is increasingly common in American travelers returning from tropical and subtropical regions.

Clinical differentiation among dengue, chikungunya, and Zika may be difficult, although persistent frank arthritis is much more common in chikungunya than in dengue or Zika. Furthermore, conjunctivitis is present in Zika but is absent in chikungunya. Chikungunya also is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia than Zika or dengue. Dengue is more likely to cause lymphopenia and hemorrhagic consequences than is chikungunya or Zika.⁸

Continue to: In our patient...

In our patient, dengue titers were not obtained because the duration of symptoms was thought to be more consistent with chikungunya, but testing for dengue also would have been appropriate. If present, fever typically is low-grade in Zika and is shorter in duration than in chikungunya (approximately 2–3 days vs 5–7 days).⁹ Coinfection with chikungunya and Zika sometimes occurs because the same mosquito species transmit both diseases.

The most common test for diagnosing acute chikungunya is ELISA serologic testing for IgM antibodies, which develop toward the end of the first week of infection; earlier in that first week, serum testing for viral RNA may be performed by polymerase chain reaction.

Treatment is largely supportive

Treatment of acute chikungunya is largely supportive and includes anti-inflammatory agents. To our knowledge, no antiviral agents have been shown to be effective. Postacute or chronic symptoms may require treatment with glucocorticoids or other immunomodulatory medications. A 2017 literature review of treatments for chikungunya-associated rheumatic disorders showed evidence that chloroquine was more effective than placebo for chronic pain relief. Also, adding a disease-modifying antirheumatic agent in combination with chloroquine was more effective for controlling pain and reducing disability than hydroxychloroquine monotherapy.¹⁰

Our patient was treated with ibuprofen only and experienced resolution of joint symptoms several months after the initial presentation. A repeat ANA test 12 months later was negative.

A 2009 review of the medical literature revealed a single case report of chikungunya associated with positive ANA.⁸ Although a positive ANA may be associated with acute viral infections, significantly elevated ANA levels typically are associated with autoimmunity. Resolution of the patient’s serum ANA 1 year later suggested that the positive ANA was not secondary to a pre-existing rheumatologic condition but rather a consequence of her body’s response to the chikungunya infection itself. Our case raises the hypothesis that, at least in some cases, chikungunya somehow stimulates a temporary autoimmune response, which may help explain why immunomodulatory medications can be effective treatment options.

Continue to: THE TAKEAWAY

Chikungunya is increasingly common in tropical and subtropical regions. Family physicians practicing in the United States should become familiar with the common patterns of presentation of viruses such as chikungunya, dengue, and Zika. Obtaining a travel history for patients presenting with arthritis improves the differential diagnosis and may even reveal the cause of the condition.

CORRESPONDENCE
Jeremy Golding, MD, 279 Lincoln Street, Worcester, MA 01605; [email protected]

Nivolumab, an immune checkpoint modulator, acts by binding to the programmed cell death 1 (PD-1) receptor on T cells, which blocks the inhibition of T cells. Nivolumab ultimately leads to stimulation of the T-cell response¹ and overcomes evasive adaptations of certain cancers. Cutaneous adverse events (AEs) have been reported in approximately 20% to 40% of patients treated with the anti–PD-1 class of drugs, including nivolumab.^2-4 The most common cutaneous AEs include pruritus; vitiligo; and various forms of rash, such as lichenoid dermatitis, psoriasiform eruptions, and bullous pemphigoid.^1-3,5-7 We report a patient with non–small cell lung cancer being treated with nivolumab who developed a bullous lichenoid eruption consistent with the diagnosis of lichen planus pemphigoides (LPP).

Case Report

An 87-year-old woman presented with a pruritic rash on the trunk and extremities of 3 weeks’ duration. Her medical history included stage IV non–small cell lung cancer, congestive heart failure, coronary artery disease, chronic kidney disease, and hypertension. Her long-term medications were ipratropium-albuterol, alendronate, amlodipine, aspirin, carvedilol, colesevelam, probiotic granules, and bumetanide. She was previously treated with carboplatin and docetaxel, which were discontinued secondary to fatigue, diarrhea, poor appetite, loss of taste, and a nonspecific rash. Six months later (approximately 3 months prior to the onset of cutaneous symptoms), she was started on nivolumab monotherapy every 14 days for a total of 9 infusions.

At the current presentation, physical examination revealed erythematous crusted erosions on the trunk and extremities and 1 flaccid bulla on the back. A punch biopsy revealed lichenoid dermatitis. The patient returned 2 weeks later with worsening of cutaneous manifestations, including more blisters and erosions. Figure 1 shows the clinical appearance of the eruption on the patient’s leg. At this time, additional biopsies revealed a subepidermal bullous lichenoid eruption with eosinophils (Figure 2). Direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) revealed weak linear staining for IgG antibodies along the basement membrane zone on monkey esophagus substrate. Examination of salt-split skin was noncontributory. The patient improved with a 2-week oral prednisone taper (starting at 40 mg daily). The dose was decreased incrementally over the course of 2 weeks from 40 mg to 20 mg to 0 mg. Because of the presumed grade 3 (severe) cutaneous drug eruption linked to nivolumab and further discussion with the medical oncology team, the patient decided to cease therapy. Since cessation of therapy, she has been seen twice for follow-up. At 2-month follow-up, she presented with drastic improvement of the eruption, and at 1 year she has continued to forego any further treatment for the stable and nonprogressing malignancy.

Comment

Immunotherapy
The interaction between the PD-1 receptor and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2, is an immune checkpoint.^8,9 Under normal physiologic conditions, this checkpoint serves to prevent autoimmunity.¹⁰ When the PD-1 receptor is left unbound, T cells are more inclined to mount an immune response. If the receptor is ligand bound, the response of T cells is suppressed via mechanisms such as anergy or apoptosis.⁸ Tumor cells are known to produce PD-L1 as an adaptive resistance mechanism to evade immunity.⁸ Nivolumab is a human monoclonal antibody that targets the PD-1 receptor, thereby preventing the interaction with its ligand and allowing for unsuppressed activity of T cells.¹⁰ This therapy ultimately blocks the tumor’s local immune suppression mechanisms, which allows T cells to recognize cancer antigens.¹⁰

Adverse Events
Dermatologic AEs are among the most common with nivolumab treatment. In a pooled retrospective analysis of melanoma patients, Weber et al⁹ found that 34% of 576 patients experience cutaneous any-grade AEs associated with nivolumab treatment, most commonly pruritus. It has been well documented that anti–PD-1 therapy AEs of the skin as well as other organ systems have a delayed onset of at least 1 month.⁹ The average time of onset for bullous eruptions associated with anti–PD-1 therapy has been reported to be approximately 12 weeks, with a range of 7 to 16.1 weeks.¹¹ Our patient had a bullous eruption with an onset of 12 weeks following initiation of treatment.

Although lichenoid reactions appear to be relatively common AEs of anti–PD-1 therapy,^2,5,6 only a small number of cases of bullous pemphigoid eruptions have been reported.⁷ It has been hypothesized that blockade of the PD-1/PD-L1 pathway increases production of hemidesmosomal protein BP180 autoantibody, which is involved in the pathogenesis of LPP.⁷ Bullous eruptions have not been reported in the use of anticytotoxic T-lymphocyte–associated protein 4 agents, which could indicate that such eruptions are specific to the anti–PD-1 class of drugs.⁷

Diagnosis
Our patient represents a rare drug reaction involving both lichenoid and bullous components. Our differential diagnosis included drug-induced bullous lichen planus (BLP) and drug-induced LPP. Differentiation of these diagnoses can be difficult. In fact, in 2017 Fujii et al¹² found reason to reprise the hypothesis that BLP is a transitional step toward LPP. The histologic evaluation of LPP differs depending on the type of lesion biopsied and can be indistinguishable from BLP as well as bullous pemphigoid. Therefore, clinical history and immunofluorescence should be used to make a diagnosis. Lichen planus pemphigoides typically will have linear IgG deposition along the basement membrane zone on both DIF and IIF, findings that will be negative in patients with BLP.¹³ Direct immunofluorescence findings in BLP include shaggy deposits of fibrin along the basement membrane zone. In this patient, DIF was negative, which may have been caused by variability among lesions in LPP, but IIF was positive. Given the clinicopathologic correlation, the diagnosis of LPP was made. Further studies, such as immunoblot and enzyme-linked immunosorbent assay, also can be used to aid diagnosis.

A similar presentation has been documented in a patient with metastatic melanoma.¹⁴ The diagnosis in this patient was LPP induced by pembrolizumab, which is another agent within the anti–PD-1 class. The Naranjo probability scale scored our patient’s eruption as a possible adverse drug reaction.¹⁵ Thus, other etiologies, such as a paraneoplastic process, cannot be completely ruled out. However, our patient has not had recurrence after 1 year, and the timing of the eruption appeared to be related to drug therapy, making alternative etiologies less likely.

Management
Cessation of nivolumab therapy and a short course of oral corticosteroid therapy led to marked improvement of symptoms. Given the emergent treatment of our patient, the resolution of her symptoms cannot be solely attributed to the cessation of nivolumab or to treatment with prednisone. Oral rather than topical corticosteroids were chosen because of the severity of the eruption. Topical corticosteroids and oral antihistamines can provide relief in less severe cases of bullous reactions to anti–PD-1 therapy.^7,11 This regimen also has proven to be effective in lichenoid dermatitis induced by anti–PD-1.²

Conclusion

We hope this case report will contribute to the growing body of evidence regarding recognition and management of unique reactions to cancer immunotherapies.

Nivolumab, an immune checkpoint modulator, acts by binding to the programmed cell death 1 (PD-1) receptor on T cells, which blocks the inhibition of T cells. Nivolumab ultimately leads to stimulation of the T-cell response¹ and overcomes evasive adaptations of certain cancers. Cutaneous adverse events (AEs) have been reported in approximately 20% to 40% of patients treated with the anti–PD-1 class of drugs, including nivolumab.^2-4 The most common cutaneous AEs include pruritus; vitiligo; and various forms of rash, such as lichenoid dermatitis, psoriasiform eruptions, and bullous pemphigoid.^1-3,5-7 We report a patient with non–small cell lung cancer being treated with nivolumab who developed a bullous lichenoid eruption consistent with the diagnosis of lichen planus pemphigoides (LPP).

Case Report

An 87-year-old woman presented with a pruritic rash on the trunk and extremities of 3 weeks’ duration. Her medical history included stage IV non–small cell lung cancer, congestive heart failure, coronary artery disease, chronic kidney disease, and hypertension. Her long-term medications were ipratropium-albuterol, alendronate, amlodipine, aspirin, carvedilol, colesevelam, probiotic granules, and bumetanide. She was previously treated with carboplatin and docetaxel, which were discontinued secondary to fatigue, diarrhea, poor appetite, loss of taste, and a nonspecific rash. Six months later (approximately 3 months prior to the onset of cutaneous symptoms), she was started on nivolumab monotherapy every 14 days for a total of 9 infusions.

At the current presentation, physical examination revealed erythematous crusted erosions on the trunk and extremities and 1 flaccid bulla on the back. A punch biopsy revealed lichenoid dermatitis. The patient returned 2 weeks later with worsening of cutaneous manifestations, including more blisters and erosions. Figure 1 shows the clinical appearance of the eruption on the patient’s leg. At this time, additional biopsies revealed a subepidermal bullous lichenoid eruption with eosinophils (Figure 2). Direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) revealed weak linear staining for IgG antibodies along the basement membrane zone on monkey esophagus substrate. Examination of salt-split skin was noncontributory. The patient improved with a 2-week oral prednisone taper (starting at 40 mg daily). The dose was decreased incrementally over the course of 2 weeks from 40 mg to 20 mg to 0 mg. Because of the presumed grade 3 (severe) cutaneous drug eruption linked to nivolumab and further discussion with the medical oncology team, the patient decided to cease therapy. Since cessation of therapy, she has been seen twice for follow-up. At 2-month follow-up, she presented with drastic improvement of the eruption, and at 1 year she has continued to forego any further treatment for the stable and nonprogressing malignancy.

Comment

Immunotherapy
The interaction between the PD-1 receptor and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2, is an immune checkpoint.^8,9 Under normal physiologic conditions, this checkpoint serves to prevent autoimmunity.¹⁰ When the PD-1 receptor is left unbound, T cells are more inclined to mount an immune response. If the receptor is ligand bound, the response of T cells is suppressed via mechanisms such as anergy or apoptosis.⁸ Tumor cells are known to produce PD-L1 as an adaptive resistance mechanism to evade immunity.⁸ Nivolumab is a human monoclonal antibody that targets the PD-1 receptor, thereby preventing the interaction with its ligand and allowing for unsuppressed activity of T cells.¹⁰ This therapy ultimately blocks the tumor’s local immune suppression mechanisms, which allows T cells to recognize cancer antigens.¹⁰

Adverse Events
Dermatologic AEs are among the most common with nivolumab treatment. In a pooled retrospective analysis of melanoma patients, Weber et al⁹ found that 34% of 576 patients experience cutaneous any-grade AEs associated with nivolumab treatment, most commonly pruritus. It has been well documented that anti–PD-1 therapy AEs of the skin as well as other organ systems have a delayed onset of at least 1 month.⁹ The average time of onset for bullous eruptions associated with anti–PD-1 therapy has been reported to be approximately 12 weeks, with a range of 7 to 16.1 weeks.¹¹ Our patient had a bullous eruption with an onset of 12 weeks following initiation of treatment.

Although lichenoid reactions appear to be relatively common AEs of anti–PD-1 therapy,^2,5,6 only a small number of cases of bullous pemphigoid eruptions have been reported.⁷ It has been hypothesized that blockade of the PD-1/PD-L1 pathway increases production of hemidesmosomal protein BP180 autoantibody, which is involved in the pathogenesis of LPP.⁷ Bullous eruptions have not been reported in the use of anticytotoxic T-lymphocyte–associated protein 4 agents, which could indicate that such eruptions are specific to the anti–PD-1 class of drugs.⁷

Diagnosis
Our patient represents a rare drug reaction involving both lichenoid and bullous components. Our differential diagnosis included drug-induced bullous lichen planus (BLP) and drug-induced LPP. Differentiation of these diagnoses can be difficult. In fact, in 2017 Fujii et al¹² found reason to reprise the hypothesis that BLP is a transitional step toward LPP. The histologic evaluation of LPP differs depending on the type of lesion biopsied and can be indistinguishable from BLP as well as bullous pemphigoid. Therefore, clinical history and immunofluorescence should be used to make a diagnosis. Lichen planus pemphigoides typically will have linear IgG deposition along the basement membrane zone on both DIF and IIF, findings that will be negative in patients with BLP.¹³ Direct immunofluorescence findings in BLP include shaggy deposits of fibrin along the basement membrane zone. In this patient, DIF was negative, which may have been caused by variability among lesions in LPP, but IIF was positive. Given the clinicopathologic correlation, the diagnosis of LPP was made. Further studies, such as immunoblot and enzyme-linked immunosorbent assay, also can be used to aid diagnosis.

A similar presentation has been documented in a patient with metastatic melanoma.¹⁴ The diagnosis in this patient was LPP induced by pembrolizumab, which is another agent within the anti–PD-1 class. The Naranjo probability scale scored our patient’s eruption as a possible adverse drug reaction.¹⁵ Thus, other etiologies, such as a paraneoplastic process, cannot be completely ruled out. However, our patient has not had recurrence after 1 year, and the timing of the eruption appeared to be related to drug therapy, making alternative etiologies less likely.

Management
Cessation of nivolumab therapy and a short course of oral corticosteroid therapy led to marked improvement of symptoms. Given the emergent treatment of our patient, the resolution of her symptoms cannot be solely attributed to the cessation of nivolumab or to treatment with prednisone. Oral rather than topical corticosteroids were chosen because of the severity of the eruption. Topical corticosteroids and oral antihistamines can provide relief in less severe cases of bullous reactions to anti–PD-1 therapy.^7,11 This regimen also has proven to be effective in lichenoid dermatitis induced by anti–PD-1.²

Conclusion

We hope this case report will contribute to the growing body of evidence regarding recognition and management of unique reactions to cancer immunotherapies.

Nivolumab, an immune checkpoint modulator, acts by binding to the programmed cell death 1 (PD-1) receptor on T cells, which blocks the inhibition of T cells. Nivolumab ultimately leads to stimulation of the T-cell response¹ and overcomes evasive adaptations of certain cancers. Cutaneous adverse events (AEs) have been reported in approximately 20% to 40% of patients treated with the anti–PD-1 class of drugs, including nivolumab.^2-4 The most common cutaneous AEs include pruritus; vitiligo; and various forms of rash, such as lichenoid dermatitis, psoriasiform eruptions, and bullous pemphigoid.^1-3,5-7 We report a patient with non–small cell lung cancer being treated with nivolumab who developed a bullous lichenoid eruption consistent with the diagnosis of lichen planus pemphigoides (LPP).

Case Report

An 87-year-old woman presented with a pruritic rash on the trunk and extremities of 3 weeks’ duration. Her medical history included stage IV non–small cell lung cancer, congestive heart failure, coronary artery disease, chronic kidney disease, and hypertension. Her long-term medications were ipratropium-albuterol, alendronate, amlodipine, aspirin, carvedilol, colesevelam, probiotic granules, and bumetanide. She was previously treated with carboplatin and docetaxel, which were discontinued secondary to fatigue, diarrhea, poor appetite, loss of taste, and a nonspecific rash. Six months later (approximately 3 months prior to the onset of cutaneous symptoms), she was started on nivolumab monotherapy every 14 days for a total of 9 infusions.

At the current presentation, physical examination revealed erythematous crusted erosions on the trunk and extremities and 1 flaccid bulla on the back. A punch biopsy revealed lichenoid dermatitis. The patient returned 2 weeks later with worsening of cutaneous manifestations, including more blisters and erosions. Figure 1 shows the clinical appearance of the eruption on the patient’s leg. At this time, additional biopsies revealed a subepidermal bullous lichenoid eruption with eosinophils (Figure 2). Direct immunofluorescence (DIF) was negative; however, indirect immunofluorescence (IIF) revealed weak linear staining for IgG antibodies along the basement membrane zone on monkey esophagus substrate. Examination of salt-split skin was noncontributory. The patient improved with a 2-week oral prednisone taper (starting at 40 mg daily). The dose was decreased incrementally over the course of 2 weeks from 40 mg to 20 mg to 0 mg. Because of the presumed grade 3 (severe) cutaneous drug eruption linked to nivolumab and further discussion with the medical oncology team, the patient decided to cease therapy. Since cessation of therapy, she has been seen twice for follow-up. At 2-month follow-up, she presented with drastic improvement of the eruption, and at 1 year she has continued to forego any further treatment for the stable and nonprogressing malignancy.

Comment

Immunotherapy
The interaction between the PD-1 receptor and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2, is an immune checkpoint.^8,9 Under normal physiologic conditions, this checkpoint serves to prevent autoimmunity.¹⁰ When the PD-1 receptor is left unbound, T cells are more inclined to mount an immune response. If the receptor is ligand bound, the response of T cells is suppressed via mechanisms such as anergy or apoptosis.⁸ Tumor cells are known to produce PD-L1 as an adaptive resistance mechanism to evade immunity.⁸ Nivolumab is a human monoclonal antibody that targets the PD-1 receptor, thereby preventing the interaction with its ligand and allowing for unsuppressed activity of T cells.¹⁰ This therapy ultimately blocks the tumor’s local immune suppression mechanisms, which allows T cells to recognize cancer antigens.¹⁰

Adverse Events
Dermatologic AEs are among the most common with nivolumab treatment. In a pooled retrospective analysis of melanoma patients, Weber et al⁹ found that 34% of 576 patients experience cutaneous any-grade AEs associated with nivolumab treatment, most commonly pruritus. It has been well documented that anti–PD-1 therapy AEs of the skin as well as other organ systems have a delayed onset of at least 1 month.⁹ The average time of onset for bullous eruptions associated with anti–PD-1 therapy has been reported to be approximately 12 weeks, with a range of 7 to 16.1 weeks.¹¹ Our patient had a bullous eruption with an onset of 12 weeks following initiation of treatment.

Although lichenoid reactions appear to be relatively common AEs of anti–PD-1 therapy,^2,5,6 only a small number of cases of bullous pemphigoid eruptions have been reported.⁷ It has been hypothesized that blockade of the PD-1/PD-L1 pathway increases production of hemidesmosomal protein BP180 autoantibody, which is involved in the pathogenesis of LPP.⁷ Bullous eruptions have not been reported in the use of anticytotoxic T-lymphocyte–associated protein 4 agents, which could indicate that such eruptions are specific to the anti–PD-1 class of drugs.⁷

Diagnosis
Our patient represents a rare drug reaction involving both lichenoid and bullous components. Our differential diagnosis included drug-induced bullous lichen planus (BLP) and drug-induced LPP. Differentiation of these diagnoses can be difficult. In fact, in 2017 Fujii et al¹² found reason to reprise the hypothesis that BLP is a transitional step toward LPP. The histologic evaluation of LPP differs depending on the type of lesion biopsied and can be indistinguishable from BLP as well as bullous pemphigoid. Therefore, clinical history and immunofluorescence should be used to make a diagnosis. Lichen planus pemphigoides typically will have linear IgG deposition along the basement membrane zone on both DIF and IIF, findings that will be negative in patients with BLP.¹³ Direct immunofluorescence findings in BLP include shaggy deposits of fibrin along the basement membrane zone. In this patient, DIF was negative, which may have been caused by variability among lesions in LPP, but IIF was positive. Given the clinicopathologic correlation, the diagnosis of LPP was made. Further studies, such as immunoblot and enzyme-linked immunosorbent assay, also can be used to aid diagnosis.

A similar presentation has been documented in a patient with metastatic melanoma.¹⁴ The diagnosis in this patient was LPP induced by pembrolizumab, which is another agent within the anti–PD-1 class. The Naranjo probability scale scored our patient’s eruption as a possible adverse drug reaction.¹⁵ Thus, other etiologies, such as a paraneoplastic process, cannot be completely ruled out. However, our patient has not had recurrence after 1 year, and the timing of the eruption appeared to be related to drug therapy, making alternative etiologies less likely.

Management
Cessation of nivolumab therapy and a short course of oral corticosteroid therapy led to marked improvement of symptoms. Given the emergent treatment of our patient, the resolution of her symptoms cannot be solely attributed to the cessation of nivolumab or to treatment with prednisone. Oral rather than topical corticosteroids were chosen because of the severity of the eruption. Topical corticosteroids and oral antihistamines can provide relief in less severe cases of bullous reactions to anti–PD-1 therapy.^7,11 This regimen also has proven to be effective in lichenoid dermatitis induced by anti–PD-1.²

Conclusion

We hope this case report will contribute to the growing body of evidence regarding recognition and management of unique reactions to cancer immunotherapies.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Case Report

A 62-year-old woman presented with multiple large friable tumors of the abdominal panniculus. The patient also reported an unintentional 75-lb weight loss over the last 9 months as well as vaginal bleeding and fecal discharge from the vagina of 2 weeks’ duration. The patient had a surgical and medical history of a robotic-assisted hysterectomy and bilateral salpingo-oophorectomy performed 4 years prior to presentation. Final surgical pathology showed complex atypical endometrial hyperplasia with no adenocarcinoma identified.

Physical examination revealed multiple large, friable, exophytic tumors of the left side of the lower abdominal panniculus within close vicinity of the patient’s abdominal hysterectomy scars (Figure 1). The largest lesion measured approximately 6 cm in length. Laboratory values were elevated for carcinoembryonic antigen (5.9 ng/mL [reference range, <3.0 ng/mL]) and cancer antigen 125 (202 U/mL [reference range, <35 U/mL]). Computed tomography of the abdomen and pelvis revealed diffuse metastatic disease.

Comment

Incidence and Pathogenesis
Endometrial carcinoma is the most common gynecologic malignancy in the United States, but it rarely progresses to disseminated disease because of routine gynecologic examinations and the low threshold for surgical intervention. Cutaneous metastases represent one of the rarest presentations of disseminated disease, occurring in only 0.8% of those diagnosed with endometrial carcinoma.¹ Cutaneous metastases occur almost exclusively in women older than 50 years and typically appear several months to years after hysterectomy. Although the exact pathogenesis is unknown, it is theorized that small foci of malignant cells may be seeded during surgery, leading to visceral and cutaneous involvement.

Clinical Presentation
Lesions vary morphologically, most commonly presenting as nonspecific, painless, hemorrhagic nodules. Lesions typically present in areas of direct local extension; prior radiotherapy; or areas of initial surgery, as was the case with our patient.² Approximately 20 cases of umbilical involvement (Sister Mary Joseph nodule) have been reported in the literature. These cases are thought to occur from direct local spread of disease from the peritoneum.³ Hematogenous and lymphatic spread to distant sites such as the scalp and mandible also have been reported. More than 50% of patients will have underlying visceral metastatic disease at the time of diagnosis.³

Histopathologic Findings
Histopathology varies with the morphology of the underlying primary tumor, with endometrioid adenocarcinoma being the most common form associated with cutaneous metastasis, as was the case with our patient.⁴ Histology is characterized by dermal proliferation of atypical glandular epithelium with diffuse hemorrhage. Staining typically is positive for CK7 and negative for CK20 and CDX2.⁵ Histopathology and immunohistochemical staining are not specific for diagnosis and must be correlated with clinical history.

Management and Prognosis
Similar to cutaneous metastasis in other internal malignancies, prognosis is poor, as widespread dissemination of the underlying malignancy typically is present. Mean life expectancy is 4 to 12 months.⁶ Treatment is primarily palliative, as chemotherapy and radiotherapy are largely ineffective.

Conclusion

Our patient represents a dramatic form of cutaneous extension of a common disease. Dermatologists often are consulted because of the nonspecific nature of the lesions and must be conscious of this entity. As with other cutaneous metastases, a thorough medical and surgical history in conjunction with histopathology are necessary for an accurate diagnosis.

Case Report

A 62-year-old woman presented with multiple large friable tumors of the abdominal panniculus. The patient also reported an unintentional 75-lb weight loss over the last 9 months as well as vaginal bleeding and fecal discharge from the vagina of 2 weeks’ duration. The patient had a surgical and medical history of a robotic-assisted hysterectomy and bilateral salpingo-oophorectomy performed 4 years prior to presentation. Final surgical pathology showed complex atypical endometrial hyperplasia with no adenocarcinoma identified.

Physical examination revealed multiple large, friable, exophytic tumors of the left side of the lower abdominal panniculus within close vicinity of the patient’s abdominal hysterectomy scars (Figure 1). The largest lesion measured approximately 6 cm in length. Laboratory values were elevated for carcinoembryonic antigen (5.9 ng/mL [reference range, <3.0 ng/mL]) and cancer antigen 125 (202 U/mL [reference range, <35 U/mL]). Computed tomography of the abdomen and pelvis revealed diffuse metastatic disease.

Comment

Incidence and Pathogenesis
Endometrial carcinoma is the most common gynecologic malignancy in the United States, but it rarely progresses to disseminated disease because of routine gynecologic examinations and the low threshold for surgical intervention. Cutaneous metastases represent one of the rarest presentations of disseminated disease, occurring in only 0.8% of those diagnosed with endometrial carcinoma.¹ Cutaneous metastases occur almost exclusively in women older than 50 years and typically appear several months to years after hysterectomy. Although the exact pathogenesis is unknown, it is theorized that small foci of malignant cells may be seeded during surgery, leading to visceral and cutaneous involvement.

Clinical Presentation
Lesions vary morphologically, most commonly presenting as nonspecific, painless, hemorrhagic nodules. Lesions typically present in areas of direct local extension; prior radiotherapy; or areas of initial surgery, as was the case with our patient.² Approximately 20 cases of umbilical involvement (Sister Mary Joseph nodule) have been reported in the literature. These cases are thought to occur from direct local spread of disease from the peritoneum.³ Hematogenous and lymphatic spread to distant sites such as the scalp and mandible also have been reported. More than 50% of patients will have underlying visceral metastatic disease at the time of diagnosis.³

Histopathologic Findings
Histopathology varies with the morphology of the underlying primary tumor, with endometrioid adenocarcinoma being the most common form associated with cutaneous metastasis, as was the case with our patient.⁴ Histology is characterized by dermal proliferation of atypical glandular epithelium with diffuse hemorrhage. Staining typically is positive for CK7 and negative for CK20 and CDX2.⁵ Histopathology and immunohistochemical staining are not specific for diagnosis and must be correlated with clinical history.

Management and Prognosis
Similar to cutaneous metastasis in other internal malignancies, prognosis is poor, as widespread dissemination of the underlying malignancy typically is present. Mean life expectancy is 4 to 12 months.⁶ Treatment is primarily palliative, as chemotherapy and radiotherapy are largely ineffective.

Conclusion

Our patient represents a dramatic form of cutaneous extension of a common disease. Dermatologists often are consulted because of the nonspecific nature of the lesions and must be conscious of this entity. As with other cutaneous metastases, a thorough medical and surgical history in conjunction with histopathology are necessary for an accurate diagnosis.

Case Report

A 62-year-old woman presented with multiple large friable tumors of the abdominal panniculus. The patient also reported an unintentional 75-lb weight loss over the last 9 months as well as vaginal bleeding and fecal discharge from the vagina of 2 weeks’ duration. The patient had a surgical and medical history of a robotic-assisted hysterectomy and bilateral salpingo-oophorectomy performed 4 years prior to presentation. Final surgical pathology showed complex atypical endometrial hyperplasia with no adenocarcinoma identified.

Physical examination revealed multiple large, friable, exophytic tumors of the left side of the lower abdominal panniculus within close vicinity of the patient’s abdominal hysterectomy scars (Figure 1). The largest lesion measured approximately 6 cm in length. Laboratory values were elevated for carcinoembryonic antigen (5.9 ng/mL [reference range, <3.0 ng/mL]) and cancer antigen 125 (202 U/mL [reference range, <35 U/mL]). Computed tomography of the abdomen and pelvis revealed diffuse metastatic disease.

Comment

Incidence and Pathogenesis
Endometrial carcinoma is the most common gynecologic malignancy in the United States, but it rarely progresses to disseminated disease because of routine gynecologic examinations and the low threshold for surgical intervention. Cutaneous metastases represent one of the rarest presentations of disseminated disease, occurring in only 0.8% of those diagnosed with endometrial carcinoma.¹ Cutaneous metastases occur almost exclusively in women older than 50 years and typically appear several months to years after hysterectomy. Although the exact pathogenesis is unknown, it is theorized that small foci of malignant cells may be seeded during surgery, leading to visceral and cutaneous involvement.

Clinical Presentation
Lesions vary morphologically, most commonly presenting as nonspecific, painless, hemorrhagic nodules. Lesions typically present in areas of direct local extension; prior radiotherapy; or areas of initial surgery, as was the case with our patient.² Approximately 20 cases of umbilical involvement (Sister Mary Joseph nodule) have been reported in the literature. These cases are thought to occur from direct local spread of disease from the peritoneum.³ Hematogenous and lymphatic spread to distant sites such as the scalp and mandible also have been reported. More than 50% of patients will have underlying visceral metastatic disease at the time of diagnosis.³

Histopathologic Findings
Histopathology varies with the morphology of the underlying primary tumor, with endometrioid adenocarcinoma being the most common form associated with cutaneous metastasis, as was the case with our patient.⁴ Histology is characterized by dermal proliferation of atypical glandular epithelium with diffuse hemorrhage. Staining typically is positive for CK7 and negative for CK20 and CDX2.⁵ Histopathology and immunohistochemical staining are not specific for diagnosis and must be correlated with clinical history.

Management and Prognosis
Similar to cutaneous metastasis in other internal malignancies, prognosis is poor, as widespread dissemination of the underlying malignancy typically is present. Mean life expectancy is 4 to 12 months.⁶ Treatment is primarily palliative, as chemotherapy and radiotherapy are largely ineffective.

Conclusion

Our patient represents a dramatic form of cutaneous extension of a common disease. Dermatologists often are consulted because of the nonspecific nature of the lesions and must be conscious of this entity. As with other cutaneous metastases, a thorough medical and surgical history in conjunction with histopathology are necessary for an accurate diagnosis.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; [email protected]

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; [email protected]

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; [email protected]