Cutis

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

The Diagnosis: Linear Lichen Planus

The patient was clinically diagnosed with linear lichen planus and was started on betamethasone dipropionate ointment 0.05% applied once daily with improvement in both the pruritus and appearance at 4-month follow-up. A biopsy was deferred based on the parents’ wishes.

Lichen planus is an inflammatory disorder involving the skin and oral mucosa. Cutaneous lichen planus classically presents as flat-topped, violaceous, pruritic, polygonal papules with overlying fine white or grey lines known as Wickham striae.¹ Postinflammatory hyperpigmentation is common, especially in patients with darker skin tones. Expected histologic findings include orthokeratosis, apoptotic keratinocytes, and bandlike lymphocytic infiltration at the dermoepidermal junction.¹

An estimated 5% of cases of cutaneous lichen planus occur in children.² A study of 316 children with lichen planus demonstrated that the classic morphology remained the most common presentation, while the linear variant was present in only 6.9% of pediatric cases.³ Linear lichen planus appears to be more common among children than adults. A study of 36 pediatric cases showed a greater representation of lichen planus in Black children (67% affected vs 21% cohort).²

Cutaneous lichen planus often clears spontaneously in approximately 1 year.⁴ Treatment in children primarily is focused on shortening the time to resolution and relieving pruritus, with topical corticosteroids as firstline therapy.^3,4 Oral corticosteroids have a faster clinical response; greater efficacy; and more effectively prevent residual hyperpigmentation, which is especially relevant in individuals with darker skin.³ Nonetheless, oral corticosteroids are considered a second-line treatment due to their unfavorable side-effect profile. Additional treatment options include oral aromatic retinoids (acitretin) and phototherapy.³

Incontinentia pigmenti is characterized by a defect in the inhibitor of nuclear factor–κB kinase regulatory subunit gamma, IKBKG, gene on the X chromosome. Incontinentia pigmenti usually is lethal in males; in females, it leads to ectodermal dysplasia associated with skin findings in a blaschkoid distribution occurring in 4 stages.⁵ The verrucous stage is preceded by the vesicular stage and expected to occur within the first few months of life, making it unlikely in our 5-year-old patient. Inflammatory linear verrucous epidermal nevus usually occurs in children younger than 5 years and is characterized by psoriasiform papules coalescing into a plaque with substantial scale instead of Wickham striae, as seen in our patient.⁶ Lichen striatus consists of smaller, pink to flesh-colored papules that rarely are pruritic.⁷ It is more common among atopic individuals and is associated with postinflammatory hypopigmentation.⁸ Linear psoriasis presents similarly to inflammatory linear verrucous epidermal nevus, with greater erythema and scale compared to the fine lacy Wickham striae that were seen in our patient.⁸

The Diagnosis: Linear Lichen Planus

The patient was clinically diagnosed with linear lichen planus and was started on betamethasone dipropionate ointment 0.05% applied once daily with improvement in both the pruritus and appearance at 4-month follow-up. A biopsy was deferred based on the parents’ wishes.

Lichen planus is an inflammatory disorder involving the skin and oral mucosa. Cutaneous lichen planus classically presents as flat-topped, violaceous, pruritic, polygonal papules with overlying fine white or grey lines known as Wickham striae.¹ Postinflammatory hyperpigmentation is common, especially in patients with darker skin tones. Expected histologic findings include orthokeratosis, apoptotic keratinocytes, and bandlike lymphocytic infiltration at the dermoepidermal junction.¹

An estimated 5% of cases of cutaneous lichen planus occur in children.² A study of 316 children with lichen planus demonstrated that the classic morphology remained the most common presentation, while the linear variant was present in only 6.9% of pediatric cases.³ Linear lichen planus appears to be more common among children than adults. A study of 36 pediatric cases showed a greater representation of lichen planus in Black children (67% affected vs 21% cohort).²

Cutaneous lichen planus often clears spontaneously in approximately 1 year.⁴ Treatment in children primarily is focused on shortening the time to resolution and relieving pruritus, with topical corticosteroids as firstline therapy.^3,4 Oral corticosteroids have a faster clinical response; greater efficacy; and more effectively prevent residual hyperpigmentation, which is especially relevant in individuals with darker skin.³ Nonetheless, oral corticosteroids are considered a second-line treatment due to their unfavorable side-effect profile. Additional treatment options include oral aromatic retinoids (acitretin) and phototherapy.³

Incontinentia pigmenti is characterized by a defect in the inhibitor of nuclear factor–κB kinase regulatory subunit gamma, IKBKG, gene on the X chromosome. Incontinentia pigmenti usually is lethal in males; in females, it leads to ectodermal dysplasia associated with skin findings in a blaschkoid distribution occurring in 4 stages.⁵ The verrucous stage is preceded by the vesicular stage and expected to occur within the first few months of life, making it unlikely in our 5-year-old patient. Inflammatory linear verrucous epidermal nevus usually occurs in children younger than 5 years and is characterized by psoriasiform papules coalescing into a plaque with substantial scale instead of Wickham striae, as seen in our patient.⁶ Lichen striatus consists of smaller, pink to flesh-colored papules that rarely are pruritic.⁷ It is more common among atopic individuals and is associated with postinflammatory hypopigmentation.⁸ Linear psoriasis presents similarly to inflammatory linear verrucous epidermal nevus, with greater erythema and scale compared to the fine lacy Wickham striae that were seen in our patient.⁸

The Diagnosis: Linear Lichen Planus

The patient was clinically diagnosed with linear lichen planus and was started on betamethasone dipropionate ointment 0.05% applied once daily with improvement in both the pruritus and appearance at 4-month follow-up. A biopsy was deferred based on the parents’ wishes.

Lichen planus is an inflammatory disorder involving the skin and oral mucosa. Cutaneous lichen planus classically presents as flat-topped, violaceous, pruritic, polygonal papules with overlying fine white or grey lines known as Wickham striae.¹ Postinflammatory hyperpigmentation is common, especially in patients with darker skin tones. Expected histologic findings include orthokeratosis, apoptotic keratinocytes, and bandlike lymphocytic infiltration at the dermoepidermal junction.¹

An estimated 5% of cases of cutaneous lichen planus occur in children.² A study of 316 children with lichen planus demonstrated that the classic morphology remained the most common presentation, while the linear variant was present in only 6.9% of pediatric cases.³ Linear lichen planus appears to be more common among children than adults. A study of 36 pediatric cases showed a greater representation of lichen planus in Black children (67% affected vs 21% cohort).²

Cutaneous lichen planus often clears spontaneously in approximately 1 year.⁴ Treatment in children primarily is focused on shortening the time to resolution and relieving pruritus, with topical corticosteroids as firstline therapy.^3,4 Oral corticosteroids have a faster clinical response; greater efficacy; and more effectively prevent residual hyperpigmentation, which is especially relevant in individuals with darker skin.³ Nonetheless, oral corticosteroids are considered a second-line treatment due to their unfavorable side-effect profile. Additional treatment options include oral aromatic retinoids (acitretin) and phototherapy.³

Incontinentia pigmenti is characterized by a defect in the inhibitor of nuclear factor–κB kinase regulatory subunit gamma, IKBKG, gene on the X chromosome. Incontinentia pigmenti usually is lethal in males; in females, it leads to ectodermal dysplasia associated with skin findings in a blaschkoid distribution occurring in 4 stages.⁵ The verrucous stage is preceded by the vesicular stage and expected to occur within the first few months of life, making it unlikely in our 5-year-old patient. Inflammatory linear verrucous epidermal nevus usually occurs in children younger than 5 years and is characterized by psoriasiform papules coalescing into a plaque with substantial scale instead of Wickham striae, as seen in our patient.⁶ Lichen striatus consists of smaller, pink to flesh-colored papules that rarely are pruritic.⁷ It is more common among atopic individuals and is associated with postinflammatory hypopigmentation.⁸ Linear psoriasis presents similarly to inflammatory linear verrucous epidermal nevus, with greater erythema and scale compared to the fine lacy Wickham striae that were seen in our patient.⁸

Pediatric dermatology is a relatively young subspecialty. The Society for Pediatric Dermatology (SPD) was established in 1975, followed by the creation of the journal Pediatric Dermatology in 1982 and the American Academy of Pediatrics Section on Dermatology in 1986.¹ In 2000, the Accreditation Council for Graduate Medical Education (ACGME) officially recognized pediatric dermatology as a unique subspecialty of the American Board of Dermatology (ABD). During that time, informal fellowship experiences emerged, and formal 1-year training programs approved by the ABD evolved by 2006. A subspecialty certification examination was created and has been administered every other year since 2004.¹ Data provided by the SPD indicate that approximately 431 US dermatologists have passed the ABD’s pediatric dermatology board certification examination thus far (unpublished data, September 2021).

In 1986, the first systematic evaluation of the US pediatric dermatology workforce revealed a total of 57 practicing pediatric dermatologists and concluded that job opportunities appeared to be limited at that time.² Since then, the demand for pediatric dermatology services has continued to grow steadily, and the number of board-certified pediatric dermatologists practicing in the United States has increased to at least 317 per data from a 2020 survey.³ However, given that there are more than 11,000 board-certified dermatologists in the United States, there continues to be a severe shortage of pediatric dermatologists.¹

Increased Demand for Pediatric Dermatologists

Approximately 10% to 30% of almost 200 million annual outpatient pediatric primary care visits involve a skin concern. Although many of these problems can be handled by primary care physicians, more than 80% of pediatricians report having difficulty accessing dermatology services for their patients.⁴ In surveys of pediatricians, pediatric dermatology has the third highest referral rate but has consistently ranked third among the specialties deemed most difficult to access.^5-7 In addition, it is not uncommon for the wait time to see a pediatric dermatologist to be 6 weeks or longer.^5,8

Recent population data estimate that there are 73 million children living in the United States.⁹ If there are roughly 317 practicing board-certified pediatric dermatologists, that translates into approximately 4.3 pediatric dermatologists per million children. This number is far smaller than the 4 general dermatologists per 100,000 individuals recommended by Glazer et al¹⁰ in 2017. To meet this suggested ratio goal, the workforce of pediatric dermatologists would have to increase to 2920. In addition to this severe workforce shortage, there is an additional problem with geographic maldistribution of pediatric dermatologists. More than 98% of pediatric dermatologists practice in metropolitan areas. At least 8 states and 95% of counties have no pediatric dermatologist, and there are no pediatric dermatologists practicing in rural counties.⁹ This disparity has considerable implications for barriers to care and lack of access for children living in underserved areas. Suggestions for attracting pediatric dermatologists to practice in these areas have included loan forgiveness programs as well as remote mentorship programs to provide professional support.^8,9

Training in Pediatrics

There currently are 38 ABD-approved pediatric dermatology fellowship training programs in the United States. Beginning in 2009, pediatric dermatology fellowship programs have participated in the SF Match program. Data provided by the SPD show that, since 2012, up to 27 programs have participated in the annual Match, offering a total number of positions ranging from 27 to 38; however, only 11 to 21 positions have been filled each year, leaving a large number of post-Match vacancies (unpublished data, September 2021).

Surveys have explored the reasons behind this lack of interest in pediatric dermatology training among dermatology residents. Factors that have been mentioned include lack of exposure and mentorship in medical school and residency, the financial hardship of an additional year of fellowship training, and historically lower salaries for pediatric dermatologists compared to general dermatologists.^3,6

A 2004 survey revealed that more than 75% of dermatology department chairs believed it was important to have a pediatric dermatologist on the faculty; however, at that time only 48% of dermatology programs reported having at least 1 full-time pediatric dermatology faculty member.¹¹ By 2008, a follow-up survey showed an increase to 70% of dermatology training programs reporting at least 1 full-time pediatric dermatologist; however, 43% of departments still had at least 1 open position, and 76% of those programs shared that they had been searching for more than 1 year.² Currently, the Accreditation Data System of the ACGME shows a total of 144 accredited US dermatology training programs. Of those, 117 programs have 1 or more board-certified pediatric dermatology faculty member, and 27 programs still have none (unpublished data, September 2021).

A shortage of pediatric dermatologists in training programs contributes to the lack of exposure and mentorship for medical students and residents during a critical time in professional development. Studies show that up to 91% of pediatric dermatologists decided to pursue training in pediatric dermatology during medical school, pediatrics residency, or dermatology residency. In one survey, 84% of respondents (N=109) cited early mentorship as the most important factor in their decision to pursue pediatric dermatology.⁶

A lack of pediatric dermatologists also results in suboptimal dermatology training for residents who care for children in primary care specialties, including pediatrics, combined internal medicine and pediatrics, and family practice. Multiple surveys have shown that many pediatricians feel they received inadequate training in dermatology during residency. Up to 38% have cited a need for more pediatric dermatology education (N=755).^5,6 In addition, studies show a wide disparity in diagnostic accuracy between dermatologists and pediatricians, with one concluding that more than one-third of referrals to pediatric dermatologists were initially misdiagnosed and/or incorrectly treated.^5,7

Recruitment Efforts for Pediatric Dermatologists

There are multiple strategies for recruiting trainees into the pediatric dermatology workforce. First, given the importance of early exposure to the field and role models/mentors, pediatric dermatologists must take advantage of every opportunity to interact with medical students and residents. They can share their genuine enthusiasm and love for the specialty while encouraging and supporting those who show interest. They also should seek opportunities for teaching, lecturing, and advising at every level of training. In addition, they can enhance visibility of the specialty by participating in career forums and/or assuming leadership roles within their departments or institutions.¹² Another suggestion is for dermatology training programs to consider giving priority to qualified applicants who express sincere interest in pursuing pediatric dermatology training (including those who have already completed pediatrics residency). Although a 2008 survey revealed that 39% of dermatology residency programs (N=80) favored giving priority to applicants demonstrating interest in pediatric dermatology, others were against it, citing issues such as lack of funding for additional residency training, lack of pediatric dermatology mentors within the program, and an overall mistrust of applicants’ sincerity.²

Final Thoughts

The subspecialty of pediatric dermatology has experienced remarkable growth over the last 40 years; however, demand for pediatric dermatology services has continued to outpace supply, resulting in a persistent and notable workforce shortage. Overall, the current supply of pediatric dermatologists can neither meet the clinical demands of the pediatric population nor fulfill academic needs of existing training programs. We must continue to develop novel strategies for increasing the pool of students and residents who are interested in pursuing careers in pediatric dermatology. Ultimately, we also must create incentives and develop tactics to address the geographic maldistribution that exists within the specialty.

Pediatric dermatology is a relatively young subspecialty. The Society for Pediatric Dermatology (SPD) was established in 1975, followed by the creation of the journal Pediatric Dermatology in 1982 and the American Academy of Pediatrics Section on Dermatology in 1986.¹ In 2000, the Accreditation Council for Graduate Medical Education (ACGME) officially recognized pediatric dermatology as a unique subspecialty of the American Board of Dermatology (ABD). During that time, informal fellowship experiences emerged, and formal 1-year training programs approved by the ABD evolved by 2006. A subspecialty certification examination was created and has been administered every other year since 2004.¹ Data provided by the SPD indicate that approximately 431 US dermatologists have passed the ABD’s pediatric dermatology board certification examination thus far (unpublished data, September 2021).

In 1986, the first systematic evaluation of the US pediatric dermatology workforce revealed a total of 57 practicing pediatric dermatologists and concluded that job opportunities appeared to be limited at that time.² Since then, the demand for pediatric dermatology services has continued to grow steadily, and the number of board-certified pediatric dermatologists practicing in the United States has increased to at least 317 per data from a 2020 survey.³ However, given that there are more than 11,000 board-certified dermatologists in the United States, there continues to be a severe shortage of pediatric dermatologists.¹

Increased Demand for Pediatric Dermatologists

Approximately 10% to 30% of almost 200 million annual outpatient pediatric primary care visits involve a skin concern. Although many of these problems can be handled by primary care physicians, more than 80% of pediatricians report having difficulty accessing dermatology services for their patients.⁴ In surveys of pediatricians, pediatric dermatology has the third highest referral rate but has consistently ranked third among the specialties deemed most difficult to access.^5-7 In addition, it is not uncommon for the wait time to see a pediatric dermatologist to be 6 weeks or longer.^5,8

Recent population data estimate that there are 73 million children living in the United States.⁹ If there are roughly 317 practicing board-certified pediatric dermatologists, that translates into approximately 4.3 pediatric dermatologists per million children. This number is far smaller than the 4 general dermatologists per 100,000 individuals recommended by Glazer et al¹⁰ in 2017. To meet this suggested ratio goal, the workforce of pediatric dermatologists would have to increase to 2920. In addition to this severe workforce shortage, there is an additional problem with geographic maldistribution of pediatric dermatologists. More than 98% of pediatric dermatologists practice in metropolitan areas. At least 8 states and 95% of counties have no pediatric dermatologist, and there are no pediatric dermatologists practicing in rural counties.⁹ This disparity has considerable implications for barriers to care and lack of access for children living in underserved areas. Suggestions for attracting pediatric dermatologists to practice in these areas have included loan forgiveness programs as well as remote mentorship programs to provide professional support.^8,9

Training in Pediatrics

There currently are 38 ABD-approved pediatric dermatology fellowship training programs in the United States. Beginning in 2009, pediatric dermatology fellowship programs have participated in the SF Match program. Data provided by the SPD show that, since 2012, up to 27 programs have participated in the annual Match, offering a total number of positions ranging from 27 to 38; however, only 11 to 21 positions have been filled each year, leaving a large number of post-Match vacancies (unpublished data, September 2021).

Surveys have explored the reasons behind this lack of interest in pediatric dermatology training among dermatology residents. Factors that have been mentioned include lack of exposure and mentorship in medical school and residency, the financial hardship of an additional year of fellowship training, and historically lower salaries for pediatric dermatologists compared to general dermatologists.^3,6

A 2004 survey revealed that more than 75% of dermatology department chairs believed it was important to have a pediatric dermatologist on the faculty; however, at that time only 48% of dermatology programs reported having at least 1 full-time pediatric dermatology faculty member.¹¹ By 2008, a follow-up survey showed an increase to 70% of dermatology training programs reporting at least 1 full-time pediatric dermatologist; however, 43% of departments still had at least 1 open position, and 76% of those programs shared that they had been searching for more than 1 year.² Currently, the Accreditation Data System of the ACGME shows a total of 144 accredited US dermatology training programs. Of those, 117 programs have 1 or more board-certified pediatric dermatology faculty member, and 27 programs still have none (unpublished data, September 2021).

A shortage of pediatric dermatologists in training programs contributes to the lack of exposure and mentorship for medical students and residents during a critical time in professional development. Studies show that up to 91% of pediatric dermatologists decided to pursue training in pediatric dermatology during medical school, pediatrics residency, or dermatology residency. In one survey, 84% of respondents (N=109) cited early mentorship as the most important factor in their decision to pursue pediatric dermatology.⁶

A lack of pediatric dermatologists also results in suboptimal dermatology training for residents who care for children in primary care specialties, including pediatrics, combined internal medicine and pediatrics, and family practice. Multiple surveys have shown that many pediatricians feel they received inadequate training in dermatology during residency. Up to 38% have cited a need for more pediatric dermatology education (N=755).^5,6 In addition, studies show a wide disparity in diagnostic accuracy between dermatologists and pediatricians, with one concluding that more than one-third of referrals to pediatric dermatologists were initially misdiagnosed and/or incorrectly treated.^5,7

Recruitment Efforts for Pediatric Dermatologists

There are multiple strategies for recruiting trainees into the pediatric dermatology workforce. First, given the importance of early exposure to the field and role models/mentors, pediatric dermatologists must take advantage of every opportunity to interact with medical students and residents. They can share their genuine enthusiasm and love for the specialty while encouraging and supporting those who show interest. They also should seek opportunities for teaching, lecturing, and advising at every level of training. In addition, they can enhance visibility of the specialty by participating in career forums and/or assuming leadership roles within their departments or institutions.¹² Another suggestion is for dermatology training programs to consider giving priority to qualified applicants who express sincere interest in pursuing pediatric dermatology training (including those who have already completed pediatrics residency). Although a 2008 survey revealed that 39% of dermatology residency programs (N=80) favored giving priority to applicants demonstrating interest in pediatric dermatology, others were against it, citing issues such as lack of funding for additional residency training, lack of pediatric dermatology mentors within the program, and an overall mistrust of applicants’ sincerity.²

Final Thoughts

The subspecialty of pediatric dermatology has experienced remarkable growth over the last 40 years; however, demand for pediatric dermatology services has continued to outpace supply, resulting in a persistent and notable workforce shortage. Overall, the current supply of pediatric dermatologists can neither meet the clinical demands of the pediatric population nor fulfill academic needs of existing training programs. We must continue to develop novel strategies for increasing the pool of students and residents who are interested in pursuing careers in pediatric dermatology. Ultimately, we also must create incentives and develop tactics to address the geographic maldistribution that exists within the specialty.

Pediatric dermatology is a relatively young subspecialty. The Society for Pediatric Dermatology (SPD) was established in 1975, followed by the creation of the journal Pediatric Dermatology in 1982 and the American Academy of Pediatrics Section on Dermatology in 1986.¹ In 2000, the Accreditation Council for Graduate Medical Education (ACGME) officially recognized pediatric dermatology as a unique subspecialty of the American Board of Dermatology (ABD). During that time, informal fellowship experiences emerged, and formal 1-year training programs approved by the ABD evolved by 2006. A subspecialty certification examination was created and has been administered every other year since 2004.¹ Data provided by the SPD indicate that approximately 431 US dermatologists have passed the ABD’s pediatric dermatology board certification examination thus far (unpublished data, September 2021).

In 1986, the first systematic evaluation of the US pediatric dermatology workforce revealed a total of 57 practicing pediatric dermatologists and concluded that job opportunities appeared to be limited at that time.² Since then, the demand for pediatric dermatology services has continued to grow steadily, and the number of board-certified pediatric dermatologists practicing in the United States has increased to at least 317 per data from a 2020 survey.³ However, given that there are more than 11,000 board-certified dermatologists in the United States, there continues to be a severe shortage of pediatric dermatologists.¹

Increased Demand for Pediatric Dermatologists

Approximately 10% to 30% of almost 200 million annual outpatient pediatric primary care visits involve a skin concern. Although many of these problems can be handled by primary care physicians, more than 80% of pediatricians report having difficulty accessing dermatology services for their patients.⁴ In surveys of pediatricians, pediatric dermatology has the third highest referral rate but has consistently ranked third among the specialties deemed most difficult to access.^5-7 In addition, it is not uncommon for the wait time to see a pediatric dermatologist to be 6 weeks or longer.^5,8

Recent population data estimate that there are 73 million children living in the United States.⁹ If there are roughly 317 practicing board-certified pediatric dermatologists, that translates into approximately 4.3 pediatric dermatologists per million children. This number is far smaller than the 4 general dermatologists per 100,000 individuals recommended by Glazer et al¹⁰ in 2017. To meet this suggested ratio goal, the workforce of pediatric dermatologists would have to increase to 2920. In addition to this severe workforce shortage, there is an additional problem with geographic maldistribution of pediatric dermatologists. More than 98% of pediatric dermatologists practice in metropolitan areas. At least 8 states and 95% of counties have no pediatric dermatologist, and there are no pediatric dermatologists practicing in rural counties.⁹ This disparity has considerable implications for barriers to care and lack of access for children living in underserved areas. Suggestions for attracting pediatric dermatologists to practice in these areas have included loan forgiveness programs as well as remote mentorship programs to provide professional support.^8,9

Training in Pediatrics

There currently are 38 ABD-approved pediatric dermatology fellowship training programs in the United States. Beginning in 2009, pediatric dermatology fellowship programs have participated in the SF Match program. Data provided by the SPD show that, since 2012, up to 27 programs have participated in the annual Match, offering a total number of positions ranging from 27 to 38; however, only 11 to 21 positions have been filled each year, leaving a large number of post-Match vacancies (unpublished data, September 2021).

Surveys have explored the reasons behind this lack of interest in pediatric dermatology training among dermatology residents. Factors that have been mentioned include lack of exposure and mentorship in medical school and residency, the financial hardship of an additional year of fellowship training, and historically lower salaries for pediatric dermatologists compared to general dermatologists.^3,6

A 2004 survey revealed that more than 75% of dermatology department chairs believed it was important to have a pediatric dermatologist on the faculty; however, at that time only 48% of dermatology programs reported having at least 1 full-time pediatric dermatology faculty member.¹¹ By 2008, a follow-up survey showed an increase to 70% of dermatology training programs reporting at least 1 full-time pediatric dermatologist; however, 43% of departments still had at least 1 open position, and 76% of those programs shared that they had been searching for more than 1 year.² Currently, the Accreditation Data System of the ACGME shows a total of 144 accredited US dermatology training programs. Of those, 117 programs have 1 or more board-certified pediatric dermatology faculty member, and 27 programs still have none (unpublished data, September 2021).

A shortage of pediatric dermatologists in training programs contributes to the lack of exposure and mentorship for medical students and residents during a critical time in professional development. Studies show that up to 91% of pediatric dermatologists decided to pursue training in pediatric dermatology during medical school, pediatrics residency, or dermatology residency. In one survey, 84% of respondents (N=109) cited early mentorship as the most important factor in their decision to pursue pediatric dermatology.⁶

A lack of pediatric dermatologists also results in suboptimal dermatology training for residents who care for children in primary care specialties, including pediatrics, combined internal medicine and pediatrics, and family practice. Multiple surveys have shown that many pediatricians feel they received inadequate training in dermatology during residency. Up to 38% have cited a need for more pediatric dermatology education (N=755).^5,6 In addition, studies show a wide disparity in diagnostic accuracy between dermatologists and pediatricians, with one concluding that more than one-third of referrals to pediatric dermatologists were initially misdiagnosed and/or incorrectly treated.^5,7

Recruitment Efforts for Pediatric Dermatologists

There are multiple strategies for recruiting trainees into the pediatric dermatology workforce. First, given the importance of early exposure to the field and role models/mentors, pediatric dermatologists must take advantage of every opportunity to interact with medical students and residents. They can share their genuine enthusiasm and love for the specialty while encouraging and supporting those who show interest. They also should seek opportunities for teaching, lecturing, and advising at every level of training. In addition, they can enhance visibility of the specialty by participating in career forums and/or assuming leadership roles within their departments or institutions.¹² Another suggestion is for dermatology training programs to consider giving priority to qualified applicants who express sincere interest in pursuing pediatric dermatology training (including those who have already completed pediatrics residency). Although a 2008 survey revealed that 39% of dermatology residency programs (N=80) favored giving priority to applicants demonstrating interest in pediatric dermatology, others were against it, citing issues such as lack of funding for additional residency training, lack of pediatric dermatology mentors within the program, and an overall mistrust of applicants’ sincerity.²

Final Thoughts

The subspecialty of pediatric dermatology has experienced remarkable growth over the last 40 years; however, demand for pediatric dermatology services has continued to outpace supply, resulting in a persistent and notable workforce shortage. Overall, the current supply of pediatric dermatologists can neither meet the clinical demands of the pediatric population nor fulfill academic needs of existing training programs. We must continue to develop novel strategies for increasing the pool of students and residents who are interested in pursuing careers in pediatric dermatology. Ultimately, we also must create incentives and develop tactics to address the geographic maldistribution that exists within the specialty.

Practice Gap

Frictional, symmetric, asymptomatic, erythematous macules of the hands and feet can be mistaken for perniolike lesions associated with COVID-19, commonly known as COVID toes. However, in a low-risk setting without other associated symptoms or concerning findings on examination, consider and inquire about frequent use of a swimming pool. This activity can lead to localized pressure- and friction-induced erythema on palmar and plantar surfaces, called “pool palms and feet,” expanding on the already-named lesion “pool palms”—an entity that is distinct from COVID toes.

Technique for Diagnosis

We evaluated 4 patients in the outpatient setting who presented with localized, patterned, erythematous lesions of the hands or feet, or both, during the COVID-19 pandemic. The parents of our patients were concerned that the rash represented “COVID fingers and toes,” which are perniolike lesions seen in patients with suspected or confirmed current or prior COVID-19.¹

Pernio, also known as chilblains, is a superficial inflammatory vascular response, usually in the setting of exposure to cold.² This phenomenon usually appears as erythematous or violaceous macules and papules on acral skin, particularly on the dorsum and sides of the fingers and toes, with edema, vesiculation, and ulceration in more severe cases. Initially, it is pruritic and painful at times.

With COVID toes, there often is a delayed presentation of perniolike lesions after the onset of other COVID-19 symptoms, such as fever, cough, headache, and sore throat.^2,3 It has been described more often in younger patients and those with milder disease. However, because our patients had no known exposure to SARS-CoV-2 or other associated symptoms, our suspicion was low.

The 4 patients we evaluated—aged 4 to 12 years and in their usual good health—had blanchable erythema of the palmar fingers, palmar eminences of both hands, and plantar surfaces of both feet (Figure). There was no swelling or tenderness, and the lesions had no violaceous coloration, vesiculation, or ulceration. There was no associated pruritus or pain. One patient reported rough texture and mild peeling of the hands.

Upon further inquiry, the patients reported a history of extended time spent in home swimming pools, including holding on to the edge of the pool, due to limitation of activities because of COVID restrictions. One parent noted that the pool that caused the rash had a rough nonslip surface, whereas other pools that the children used, which had a smoother surface, caused no problems.

The morphology of symmetric blanching erythema in areas of pressure and friction, in the absence of a notable medical history, signs, or symptoms, was consistent with a diagnosis of pool palms, which has been described in the medical literature.^4-9 Pool palms can affect the palms and soles, which are subject to substantial friction, especially when a person is getting in and out of the pool. There is a general consensus that pool palms is a frictional dermatitis affecting children because the greater fragility of their skin is exacerbated by immersion in water.^4-9

Pool palms and feet is benign. Only supportive care, with cessation of swimming and application of emollients, is necessary.

Apart from COVID-19, other conditions to consider in a patient with erythematous lesions of the palms and soles include eczematous dermatitis; neutrophilic eccrine hidradenitis; and, if lesions are vesicular, hand-foot-and-mouth disease. Juvenile plantar dermatosis, which is thought to be due to moisture with occlusion in shoes, also might be considered but is distinguished by more scales and fissures that can be painful.

Location of the lesions is a critical variable. The patients we evaluated had lesions primarily on palmar and plantar surfaces where contact with pool surfaces was greatest, such as at bony prominences, which supported a diagnosis of frictional dermatitis, such as pool palms and feet. A thorough history and physical examination are helpful in determining the diagnosis.

Practical Implications

It is important to consider and recognize this localized pressure phenomenon of pool palms and feet, thus obviating an unnecessary workup or therapeutic interventions. Specifically, a finding of erythematous asymptomatic macules, with or without scaling, on bony prominences of the palms and soles is more consistent with pool palms and feet.

Pernio and COVID toes both present as erythematous to violaceous papules and macules, with edema, vesiculation, and ulceration in severe cases, often on the dorsum and sides of fingers and toes; typically the conditions are pruritic and painful at times.

Explaining the diagnosis of pool palms and feet and sharing one’s experience with similar cases might help alleviate parental fear and anxiety during the COVID-19 pandemic.

Practice Gap

Frictional, symmetric, asymptomatic, erythematous macules of the hands and feet can be mistaken for perniolike lesions associated with COVID-19, commonly known as COVID toes. However, in a low-risk setting without other associated symptoms or concerning findings on examination, consider and inquire about frequent use of a swimming pool. This activity can lead to localized pressure- and friction-induced erythema on palmar and plantar surfaces, called “pool palms and feet,” expanding on the already-named lesion “pool palms”—an entity that is distinct from COVID toes.

Technique for Diagnosis

We evaluated 4 patients in the outpatient setting who presented with localized, patterned, erythematous lesions of the hands or feet, or both, during the COVID-19 pandemic. The parents of our patients were concerned that the rash represented “COVID fingers and toes,” which are perniolike lesions seen in patients with suspected or confirmed current or prior COVID-19.¹

Pernio, also known as chilblains, is a superficial inflammatory vascular response, usually in the setting of exposure to cold.² This phenomenon usually appears as erythematous or violaceous macules and papules on acral skin, particularly on the dorsum and sides of the fingers and toes, with edema, vesiculation, and ulceration in more severe cases. Initially, it is pruritic and painful at times.

With COVID toes, there often is a delayed presentation of perniolike lesions after the onset of other COVID-19 symptoms, such as fever, cough, headache, and sore throat.^2,3 It has been described more often in younger patients and those with milder disease. However, because our patients had no known exposure to SARS-CoV-2 or other associated symptoms, our suspicion was low.

The 4 patients we evaluated—aged 4 to 12 years and in their usual good health—had blanchable erythema of the palmar fingers, palmar eminences of both hands, and plantar surfaces of both feet (Figure). There was no swelling or tenderness, and the lesions had no violaceous coloration, vesiculation, or ulceration. There was no associated pruritus or pain. One patient reported rough texture and mild peeling of the hands.

Upon further inquiry, the patients reported a history of extended time spent in home swimming pools, including holding on to the edge of the pool, due to limitation of activities because of COVID restrictions. One parent noted that the pool that caused the rash had a rough nonslip surface, whereas other pools that the children used, which had a smoother surface, caused no problems.

The morphology of symmetric blanching erythema in areas of pressure and friction, in the absence of a notable medical history, signs, or symptoms, was consistent with a diagnosis of pool palms, which has been described in the medical literature.^4-9 Pool palms can affect the palms and soles, which are subject to substantial friction, especially when a person is getting in and out of the pool. There is a general consensus that pool palms is a frictional dermatitis affecting children because the greater fragility of their skin is exacerbated by immersion in water.^4-9

Pool palms and feet is benign. Only supportive care, with cessation of swimming and application of emollients, is necessary.

Apart from COVID-19, other conditions to consider in a patient with erythematous lesions of the palms and soles include eczematous dermatitis; neutrophilic eccrine hidradenitis; and, if lesions are vesicular, hand-foot-and-mouth disease. Juvenile plantar dermatosis, which is thought to be due to moisture with occlusion in shoes, also might be considered but is distinguished by more scales and fissures that can be painful.

Location of the lesions is a critical variable. The patients we evaluated had lesions primarily on palmar and plantar surfaces where contact with pool surfaces was greatest, such as at bony prominences, which supported a diagnosis of frictional dermatitis, such as pool palms and feet. A thorough history and physical examination are helpful in determining the diagnosis.

Practical Implications

It is important to consider and recognize this localized pressure phenomenon of pool palms and feet, thus obviating an unnecessary workup or therapeutic interventions. Specifically, a finding of erythematous asymptomatic macules, with or without scaling, on bony prominences of the palms and soles is more consistent with pool palms and feet.

Pernio and COVID toes both present as erythematous to violaceous papules and macules, with edema, vesiculation, and ulceration in severe cases, often on the dorsum and sides of fingers and toes; typically the conditions are pruritic and painful at times.

Explaining the diagnosis of pool palms and feet and sharing one’s experience with similar cases might help alleviate parental fear and anxiety during the COVID-19 pandemic.

Practice Gap

Frictional, symmetric, asymptomatic, erythematous macules of the hands and feet can be mistaken for perniolike lesions associated with COVID-19, commonly known as COVID toes. However, in a low-risk setting without other associated symptoms or concerning findings on examination, consider and inquire about frequent use of a swimming pool. This activity can lead to localized pressure- and friction-induced erythema on palmar and plantar surfaces, called “pool palms and feet,” expanding on the already-named lesion “pool palms”—an entity that is distinct from COVID toes.

Technique for Diagnosis

We evaluated 4 patients in the outpatient setting who presented with localized, patterned, erythematous lesions of the hands or feet, or both, during the COVID-19 pandemic. The parents of our patients were concerned that the rash represented “COVID fingers and toes,” which are perniolike lesions seen in patients with suspected or confirmed current or prior COVID-19.¹

Pernio, also known as chilblains, is a superficial inflammatory vascular response, usually in the setting of exposure to cold.² This phenomenon usually appears as erythematous or violaceous macules and papules on acral skin, particularly on the dorsum and sides of the fingers and toes, with edema, vesiculation, and ulceration in more severe cases. Initially, it is pruritic and painful at times.

With COVID toes, there often is a delayed presentation of perniolike lesions after the onset of other COVID-19 symptoms, such as fever, cough, headache, and sore throat.^2,3 It has been described more often in younger patients and those with milder disease. However, because our patients had no known exposure to SARS-CoV-2 or other associated symptoms, our suspicion was low.

The 4 patients we evaluated—aged 4 to 12 years and in their usual good health—had blanchable erythema of the palmar fingers, palmar eminences of both hands, and plantar surfaces of both feet (Figure). There was no swelling or tenderness, and the lesions had no violaceous coloration, vesiculation, or ulceration. There was no associated pruritus or pain. One patient reported rough texture and mild peeling of the hands.

Upon further inquiry, the patients reported a history of extended time spent in home swimming pools, including holding on to the edge of the pool, due to limitation of activities because of COVID restrictions. One parent noted that the pool that caused the rash had a rough nonslip surface, whereas other pools that the children used, which had a smoother surface, caused no problems.

The morphology of symmetric blanching erythema in areas of pressure and friction, in the absence of a notable medical history, signs, or symptoms, was consistent with a diagnosis of pool palms, which has been described in the medical literature.^4-9 Pool palms can affect the palms and soles, which are subject to substantial friction, especially when a person is getting in and out of the pool. There is a general consensus that pool palms is a frictional dermatitis affecting children because the greater fragility of their skin is exacerbated by immersion in water.^4-9

Pool palms and feet is benign. Only supportive care, with cessation of swimming and application of emollients, is necessary.

Apart from COVID-19, other conditions to consider in a patient with erythematous lesions of the palms and soles include eczematous dermatitis; neutrophilic eccrine hidradenitis; and, if lesions are vesicular, hand-foot-and-mouth disease. Juvenile plantar dermatosis, which is thought to be due to moisture with occlusion in shoes, also might be considered but is distinguished by more scales and fissures that can be painful.

Location of the lesions is a critical variable. The patients we evaluated had lesions primarily on palmar and plantar surfaces where contact with pool surfaces was greatest, such as at bony prominences, which supported a diagnosis of frictional dermatitis, such as pool palms and feet. A thorough history and physical examination are helpful in determining the diagnosis.

Practical Implications

It is important to consider and recognize this localized pressure phenomenon of pool palms and feet, thus obviating an unnecessary workup or therapeutic interventions. Specifically, a finding of erythematous asymptomatic macules, with or without scaling, on bony prominences of the palms and soles is more consistent with pool palms and feet.

Pernio and COVID toes both present as erythematous to violaceous papules and macules, with edema, vesiculation, and ulceration in severe cases, often on the dorsum and sides of fingers and toes; typically the conditions are pruritic and painful at times.

Explaining the diagnosis of pool palms and feet and sharing one’s experience with similar cases might help alleviate parental fear and anxiety during the COVID-19 pandemic.

Pediatric nail psoriasis is a condition that has not been extensively studied. The prevalence of nail alterations in pediatric patients with psoriasis varies among different studies, ranging from 17% to 39.2%.¹ Nail pitting, onycholysis associated with subungual hyperkeratosis, paronychia, and pachyonychia are the most frequent features of psoriatic nail involvement in children.^2,3 The management of nail psoriasis in children and adolescents is critical due to the quality-of-life impact, from potential functional impairment issues to the obvious cosmetic problems, which can aggravate the psychologic distress and social embarrassment of patients with psoriasis. Despite the emergence of modern potent systemic agents to treat chronic plaque psoriasis, nail psoriasis often is refractory to treatment.⁴ Coupled with the limited on-label options for psoriasis treatment in children, the management of nail psoriasis in this special patient group constitutes an even greater therapeutic challenge. This report aims to summarize the limited existing data on the successful management of nail psoriasis in the pediatric population.

Reviewing the Literature on Nail Psoriasis

We conducted a search of PubMed articles indexed for MEDLINE, Embase, and Scopus using the following Medical Subject Headings key terms: nail psoriasis and children, juvenile, pediatric. Additional articles were identified from the reference lists of the retrieved articles and citations. Our search included reports in the English language published from 2000 to 2019. The selection process included the following 2 steps: screening of the titles and abstracts, followed by evaluation of the selected full-text articles.

Topical Treatments for Nail Psoriasis

Because most systemic antipsoriatic treatments that can be administered in adult patients have not yet been granted an official license for administration in children, topical treatments are considered by many physicians as the preferred first-line therapy for psoriatic nail involvement in pediatric patients.^5,6 However, only scarce data are available in the literature concerning the successful use of local agents in pediatric patients with psoriasis.

The main limitation of local treatments relates mostly to their impaired penetration into the affected area (nails). To optimize drug penetration, some authors suggest the use of potent keratolytic topical preparations to reduce the nail volume and facilitate drug absorption.⁷ A popular suggestion is trimming the onycholytic nail plate followed by 40% urea avulsion to treat subungual hyperkeratosis⁸ or simply the use of occlusive 40% urea in petroleum jelly.⁹ Other approaches include clipping the onycholytic nail over the diseased nail bed or processing the nail plate through grinding or even drilling holes with the use of mechanical burrs or ablative lasers to enhance the penetration of the topical agent.⁷

A frequent approach in pediatric patients is clipping the detached nails combined with daily application of calcipotriene (calcipotriol) and steroids, such as betamethasone dipropionate.^5,8 Reports on the use of regimens with clobetasol propionate ointment 0.05% under occlusion, with or without the concomitant use of calcipotriol solution 0.005%, also are present in the literature but not always with satisfactory results.^10,11 Another successfully administered topical steroid is mometasone furoate cream 0.1%.¹² Although the use of intralesional triamcinolone acetonide also has demonstrated encouraging outcomes in isolated reports,¹³ associated adverse events, such as pain and hematomas, can result in tolerability issues for pediatric patients.⁷

Piraccini et al¹⁴ described the case of an 8-year-old patient with pustular nail psoriasis who showed improvement within 3 to 6 months of treatment with topical calcipotriol 5 μg/g as monotherapy applied to the nail and periungual tissues twice daily. Another approach, described by Diluvio et al,¹⁵ is the use of tazarotene gel 0.05% applied once daily to the affected nail plates, nail folds, and periungual skin without occlusion. In a 6-year-old patient with isolated nail psoriasis, this treatment regimen demonstrated notable improvement within 8 weeks.¹⁵

Systemic Treatments for Nail Psoriasis

Data on the successful administration of systemic agents in pediatric patients also are extremely scarce. Due to the lack of clinical trials, everyday practice is mostly based on isolated case series and case reports.

Methotrexate—Lee¹¹ described the case of an 11-year-old girl with severe, symptomatic, 20-nail psoriatic onychodystrophy who showed a complete response to oral methotrexate 5 mg/wk after topical clobetasol propionate and calcipotriol failed. Improvement was seen as early as 4 weeks after therapy initiation, and complete resolution of the lesions was documented after 9 and 13 months of methotrexate therapy for the fingers and toes, respectively.¹¹ The successful use of methotrexate in the improvement of psoriatic nail dystrophy in a pediatric patient also was documented by Teran et al.¹⁶ In this case, a 9-year-old girl with erythrodermic psoriasis, psoriatic arthritis, and severe onychodystrophy showed notable amelioration of all psoriatic manifestations, including the nail findings, with systemic methotrexate therapy (dose not specified).¹⁶ Notably, the authors reported that the improvement of onychodystrophy occurred with considerable delay compared to the other psoriatic lesions,¹⁶ indicating the already-known refractoriness of nail psoriasis to the various therapeutic attempts.^9-15

Acitretin—Another agent that has been linked with partial improvement of acrodermatitis continua of Hallopeau (ACH)–associated onychodystrophy is acitretin. In a case series of 15 pediatric patients with pustular psoriasis, a 5-year-old boy with severe nail involvement presented with partial amelioration of nail changes with acitretin within the first 6 weeks of treatment using the following regimen: initial dosage of 0.8 mg/kg/d for 6 weeks, followed by 0.3 mg/kg/d for 4 weeks.¹⁷

Biologics—The emerging use of biologics in pediatric psoriasis also has brought important advances in the successful management of nail psoriasis in children and adolescents.^18-21 Wells et al¹⁸ presented the case of an 8-year-old girl with nail psoriasis, psoriatic arthritis, and plaque psoriasis who showed complete resolution of all psoriatic manifestations, including nail involvement, within 3 months of treatment with secukinumab 150 mg subcutaneously every 4 weeks. Prior failed treatments included various systemic agents (ie, subcutaneous methotrexate 20 mg/m², etanercept 0.8 mg/kg weekly, adalimumab 40 mg every 2 weeks) as well as topical agents (ie, urea, tazarotene, corticosteroids) and intralesional triamcinolone.¹⁸

Infliximab also has been successfully used for pediatric nail psoriasis. Watabe et al¹⁹ presented the case of an 8-year-old girl with psoriatic onychodystrophy in addition to psoriatic onycho-pachydermo-periostitis. Prior therapy with adalimumab 20 mg every other week combined with methotrexate 10 mg weekly failed. She experienced notable amelioration of the nail dystrophy within 3 months of using a combination of infliximab and methotrexate (infliximab 5 mg/kg intravenously on weeks 0, 2, and 6, and every 8 weeks thereafter; methotrexate 10 mg/wk).¹⁹

Cases in which infliximab has resulted in rapid yet only transient restoration of psoriatic onychodystrophy also are present in the literature. Pereira et al²⁰ reported that a 3-year-old patient with severe 20-digit onychodystrophy in addition to pustular psoriasis had complete resolution of nail lesions within 2 weeks of treatment with infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 7 weeks thereafter), which was sustained over the course of 1 year. The therapy had to be discontinued because of exacerbation of the cutaneous symptoms; thereafter, etanercept was initiated. Although the patient noted major improvement of all skin lesions under etanercept, only moderate amelioration of the psoriatic nail lesions was demonstrated.²⁰

Dini et al²¹ described a 9-year-old girl with severe ACH-associated psoriatic onychodystrophy who showed complete clearance of all lesions within 8 weeks of treatment with adalimumab (initially 80 mg, followed by 40 mg after 1 week and then 40 mg every other week). Prior treatment with potent topical corticosteroids, cyclosporine (3 mg/kg/d for 6 months), and etanercept (0.4 mg/kg twice weekly for 3 months) was ineffective.²¹

Phototherapy—Other systemic agents with reported satisfactory outcomes in the treatment of psoriatic onychodystrophy include thalidomide combined with UVB phototherapy. Kiszewski et al²² described a 2-year-old patient with ACH and severe 19-digit onychodystrophy. Prior failed therapies included occluded clobetasol ointment 0.05%, occluded pimecrolimus 0.1%, and systemic methotrexate, while systemic acitretin (0.8 mg⁄kg⁄d) resulted in elevated cholesterol levels and therefore had to be interrupted. Improvement was seen 2 months after the initiation of a combined broadband UVB and thalidomide (50 mg⁄d) treatment, with no documented relapses after discontinuation of therapy.²²

Narrowband UVB (311 nm) also has been used as monotherapy for ACH-associated onychodystrophy, as demonstrated by Bordignon et al.²³ They reported a 9-year-old patient who showed partial improvement of isolated onychodystrophy of the fourth nail plate of the left hand after 36 sessions of narrowband UVB using a 311-nm filtering handpiece with a square spot size of 19×19 mm.²³

Conclusion

Nail psoriasis constitutes a type of psoriasis that is not only refractory to most treatments but is accompanied by substantial psychological and occasionally functional burden for the affected individuals.²⁴ Data concerning therapeutic options in the pediatric population are extremely limited, and therefore the everyday practice often involves administration of off-label medications, which can constitute a dilemma for many physicians, especially for safety.¹⁰ We suggest a simple therapeutic algorithm for the management of pediatric nail psoriasis based on the summarized data that are currently available in the literature. This algorithm is shown in the eFigure.

As progressively more agents—especially biologics—receive approval for use in plaque psoriasis in pediatric patients,²⁵ it is expected that gradually more real-life data on their side efficacy for plaque psoriasis of the nails in children also will come to light. Furthermore, their on-label use in pediatric psoriasis patients will facilitate further relevant clinical trials to this target group so that the potential of these medications in the management of nail psoriasis can be fully explored.

Pediatric nail psoriasis is a condition that has not been extensively studied. The prevalence of nail alterations in pediatric patients with psoriasis varies among different studies, ranging from 17% to 39.2%.¹ Nail pitting, onycholysis associated with subungual hyperkeratosis, paronychia, and pachyonychia are the most frequent features of psoriatic nail involvement in children.^2,3 The management of nail psoriasis in children and adolescents is critical due to the quality-of-life impact, from potential functional impairment issues to the obvious cosmetic problems, which can aggravate the psychologic distress and social embarrassment of patients with psoriasis. Despite the emergence of modern potent systemic agents to treat chronic plaque psoriasis, nail psoriasis often is refractory to treatment.⁴ Coupled with the limited on-label options for psoriasis treatment in children, the management of nail psoriasis in this special patient group constitutes an even greater therapeutic challenge. This report aims to summarize the limited existing data on the successful management of nail psoriasis in the pediatric population.

Reviewing the Literature on Nail Psoriasis

We conducted a search of PubMed articles indexed for MEDLINE, Embase, and Scopus using the following Medical Subject Headings key terms: nail psoriasis and children, juvenile, pediatric. Additional articles were identified from the reference lists of the retrieved articles and citations. Our search included reports in the English language published from 2000 to 2019. The selection process included the following 2 steps: screening of the titles and abstracts, followed by evaluation of the selected full-text articles.

Topical Treatments for Nail Psoriasis

Because most systemic antipsoriatic treatments that can be administered in adult patients have not yet been granted an official license for administration in children, topical treatments are considered by many physicians as the preferred first-line therapy for psoriatic nail involvement in pediatric patients.^5,6 However, only scarce data are available in the literature concerning the successful use of local agents in pediatric patients with psoriasis.

The main limitation of local treatments relates mostly to their impaired penetration into the affected area (nails). To optimize drug penetration, some authors suggest the use of potent keratolytic topical preparations to reduce the nail volume and facilitate drug absorption.⁷ A popular suggestion is trimming the onycholytic nail plate followed by 40% urea avulsion to treat subungual hyperkeratosis⁸ or simply the use of occlusive 40% urea in petroleum jelly.⁹ Other approaches include clipping the onycholytic nail over the diseased nail bed or processing the nail plate through grinding or even drilling holes with the use of mechanical burrs or ablative lasers to enhance the penetration of the topical agent.⁷

A frequent approach in pediatric patients is clipping the detached nails combined with daily application of calcipotriene (calcipotriol) and steroids, such as betamethasone dipropionate.^5,8 Reports on the use of regimens with clobetasol propionate ointment 0.05% under occlusion, with or without the concomitant use of calcipotriol solution 0.005%, also are present in the literature but not always with satisfactory results.^10,11 Another successfully administered topical steroid is mometasone furoate cream 0.1%.¹² Although the use of intralesional triamcinolone acetonide also has demonstrated encouraging outcomes in isolated reports,¹³ associated adverse events, such as pain and hematomas, can result in tolerability issues for pediatric patients.⁷

Piraccini et al¹⁴ described the case of an 8-year-old patient with pustular nail psoriasis who showed improvement within 3 to 6 months of treatment with topical calcipotriol 5 μg/g as monotherapy applied to the nail and periungual tissues twice daily. Another approach, described by Diluvio et al,¹⁵ is the use of tazarotene gel 0.05% applied once daily to the affected nail plates, nail folds, and periungual skin without occlusion. In a 6-year-old patient with isolated nail psoriasis, this treatment regimen demonstrated notable improvement within 8 weeks.¹⁵

Systemic Treatments for Nail Psoriasis

Data on the successful administration of systemic agents in pediatric patients also are extremely scarce. Due to the lack of clinical trials, everyday practice is mostly based on isolated case series and case reports.

Methotrexate—Lee¹¹ described the case of an 11-year-old girl with severe, symptomatic, 20-nail psoriatic onychodystrophy who showed a complete response to oral methotrexate 5 mg/wk after topical clobetasol propionate and calcipotriol failed. Improvement was seen as early as 4 weeks after therapy initiation, and complete resolution of the lesions was documented after 9 and 13 months of methotrexate therapy for the fingers and toes, respectively.¹¹ The successful use of methotrexate in the improvement of psoriatic nail dystrophy in a pediatric patient also was documented by Teran et al.¹⁶ In this case, a 9-year-old girl with erythrodermic psoriasis, psoriatic arthritis, and severe onychodystrophy showed notable amelioration of all psoriatic manifestations, including the nail findings, with systemic methotrexate therapy (dose not specified).¹⁶ Notably, the authors reported that the improvement of onychodystrophy occurred with considerable delay compared to the other psoriatic lesions,¹⁶ indicating the already-known refractoriness of nail psoriasis to the various therapeutic attempts.^9-15

Acitretin—Another agent that has been linked with partial improvement of acrodermatitis continua of Hallopeau (ACH)–associated onychodystrophy is acitretin. In a case series of 15 pediatric patients with pustular psoriasis, a 5-year-old boy with severe nail involvement presented with partial amelioration of nail changes with acitretin within the first 6 weeks of treatment using the following regimen: initial dosage of 0.8 mg/kg/d for 6 weeks, followed by 0.3 mg/kg/d for 4 weeks.¹⁷

Biologics—The emerging use of biologics in pediatric psoriasis also has brought important advances in the successful management of nail psoriasis in children and adolescents.^18-21 Wells et al¹⁸ presented the case of an 8-year-old girl with nail psoriasis, psoriatic arthritis, and plaque psoriasis who showed complete resolution of all psoriatic manifestations, including nail involvement, within 3 months of treatment with secukinumab 150 mg subcutaneously every 4 weeks. Prior failed treatments included various systemic agents (ie, subcutaneous methotrexate 20 mg/m², etanercept 0.8 mg/kg weekly, adalimumab 40 mg every 2 weeks) as well as topical agents (ie, urea, tazarotene, corticosteroids) and intralesional triamcinolone.¹⁸

Infliximab also has been successfully used for pediatric nail psoriasis. Watabe et al¹⁹ presented the case of an 8-year-old girl with psoriatic onychodystrophy in addition to psoriatic onycho-pachydermo-periostitis. Prior therapy with adalimumab 20 mg every other week combined with methotrexate 10 mg weekly failed. She experienced notable amelioration of the nail dystrophy within 3 months of using a combination of infliximab and methotrexate (infliximab 5 mg/kg intravenously on weeks 0, 2, and 6, and every 8 weeks thereafter; methotrexate 10 mg/wk).¹⁹

Cases in which infliximab has resulted in rapid yet only transient restoration of psoriatic onychodystrophy also are present in the literature. Pereira et al²⁰ reported that a 3-year-old patient with severe 20-digit onychodystrophy in addition to pustular psoriasis had complete resolution of nail lesions within 2 weeks of treatment with infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 7 weeks thereafter), which was sustained over the course of 1 year. The therapy had to be discontinued because of exacerbation of the cutaneous symptoms; thereafter, etanercept was initiated. Although the patient noted major improvement of all skin lesions under etanercept, only moderate amelioration of the psoriatic nail lesions was demonstrated.²⁰

Dini et al²¹ described a 9-year-old girl with severe ACH-associated psoriatic onychodystrophy who showed complete clearance of all lesions within 8 weeks of treatment with adalimumab (initially 80 mg, followed by 40 mg after 1 week and then 40 mg every other week). Prior treatment with potent topical corticosteroids, cyclosporine (3 mg/kg/d for 6 months), and etanercept (0.4 mg/kg twice weekly for 3 months) was ineffective.²¹

Phototherapy—Other systemic agents with reported satisfactory outcomes in the treatment of psoriatic onychodystrophy include thalidomide combined with UVB phototherapy. Kiszewski et al²² described a 2-year-old patient with ACH and severe 19-digit onychodystrophy. Prior failed therapies included occluded clobetasol ointment 0.05%, occluded pimecrolimus 0.1%, and systemic methotrexate, while systemic acitretin (0.8 mg⁄kg⁄d) resulted in elevated cholesterol levels and therefore had to be interrupted. Improvement was seen 2 months after the initiation of a combined broadband UVB and thalidomide (50 mg⁄d) treatment, with no documented relapses after discontinuation of therapy.²²

Narrowband UVB (311 nm) also has been used as monotherapy for ACH-associated onychodystrophy, as demonstrated by Bordignon et al.²³ They reported a 9-year-old patient who showed partial improvement of isolated onychodystrophy of the fourth nail plate of the left hand after 36 sessions of narrowband UVB using a 311-nm filtering handpiece with a square spot size of 19×19 mm.²³

Conclusion

Nail psoriasis constitutes a type of psoriasis that is not only refractory to most treatments but is accompanied by substantial psychological and occasionally functional burden for the affected individuals.²⁴ Data concerning therapeutic options in the pediatric population are extremely limited, and therefore the everyday practice often involves administration of off-label medications, which can constitute a dilemma for many physicians, especially for safety.¹⁰ We suggest a simple therapeutic algorithm for the management of pediatric nail psoriasis based on the summarized data that are currently available in the literature. This algorithm is shown in the eFigure.

As progressively more agents—especially biologics—receive approval for use in plaque psoriasis in pediatric patients,²⁵ it is expected that gradually more real-life data on their side efficacy for plaque psoriasis of the nails in children also will come to light. Furthermore, their on-label use in pediatric psoriasis patients will facilitate further relevant clinical trials to this target group so that the potential of these medications in the management of nail psoriasis can be fully explored.

Pediatric nail psoriasis is a condition that has not been extensively studied. The prevalence of nail alterations in pediatric patients with psoriasis varies among different studies, ranging from 17% to 39.2%.¹ Nail pitting, onycholysis associated with subungual hyperkeratosis, paronychia, and pachyonychia are the most frequent features of psoriatic nail involvement in children.^2,3 The management of nail psoriasis in children and adolescents is critical due to the quality-of-life impact, from potential functional impairment issues to the obvious cosmetic problems, which can aggravate the psychologic distress and social embarrassment of patients with psoriasis. Despite the emergence of modern potent systemic agents to treat chronic plaque psoriasis, nail psoriasis often is refractory to treatment.⁴ Coupled with the limited on-label options for psoriasis treatment in children, the management of nail psoriasis in this special patient group constitutes an even greater therapeutic challenge. This report aims to summarize the limited existing data on the successful management of nail psoriasis in the pediatric population.

Reviewing the Literature on Nail Psoriasis

We conducted a search of PubMed articles indexed for MEDLINE, Embase, and Scopus using the following Medical Subject Headings key terms: nail psoriasis and children, juvenile, pediatric. Additional articles were identified from the reference lists of the retrieved articles and citations. Our search included reports in the English language published from 2000 to 2019. The selection process included the following 2 steps: screening of the titles and abstracts, followed by evaluation of the selected full-text articles.

Topical Treatments for Nail Psoriasis

Because most systemic antipsoriatic treatments that can be administered in adult patients have not yet been granted an official license for administration in children, topical treatments are considered by many physicians as the preferred first-line therapy for psoriatic nail involvement in pediatric patients.^5,6 However, only scarce data are available in the literature concerning the successful use of local agents in pediatric patients with psoriasis.

The main limitation of local treatments relates mostly to their impaired penetration into the affected area (nails). To optimize drug penetration, some authors suggest the use of potent keratolytic topical preparations to reduce the nail volume and facilitate drug absorption.⁷ A popular suggestion is trimming the onycholytic nail plate followed by 40% urea avulsion to treat subungual hyperkeratosis⁸ or simply the use of occlusive 40% urea in petroleum jelly.⁹ Other approaches include clipping the onycholytic nail over the diseased nail bed or processing the nail plate through grinding or even drilling holes with the use of mechanical burrs or ablative lasers to enhance the penetration of the topical agent.⁷

A frequent approach in pediatric patients is clipping the detached nails combined with daily application of calcipotriene (calcipotriol) and steroids, such as betamethasone dipropionate.^5,8 Reports on the use of regimens with clobetasol propionate ointment 0.05% under occlusion, with or without the concomitant use of calcipotriol solution 0.005%, also are present in the literature but not always with satisfactory results.^10,11 Another successfully administered topical steroid is mometasone furoate cream 0.1%.¹² Although the use of intralesional triamcinolone acetonide also has demonstrated encouraging outcomes in isolated reports,¹³ associated adverse events, such as pain and hematomas, can result in tolerability issues for pediatric patients.⁷

Piraccini et al¹⁴ described the case of an 8-year-old patient with pustular nail psoriasis who showed improvement within 3 to 6 months of treatment with topical calcipotriol 5 μg/g as monotherapy applied to the nail and periungual tissues twice daily. Another approach, described by Diluvio et al,¹⁵ is the use of tazarotene gel 0.05% applied once daily to the affected nail plates, nail folds, and periungual skin without occlusion. In a 6-year-old patient with isolated nail psoriasis, this treatment regimen demonstrated notable improvement within 8 weeks.¹⁵

Systemic Treatments for Nail Psoriasis

Data on the successful administration of systemic agents in pediatric patients also are extremely scarce. Due to the lack of clinical trials, everyday practice is mostly based on isolated case series and case reports.

Methotrexate—Lee¹¹ described the case of an 11-year-old girl with severe, symptomatic, 20-nail psoriatic onychodystrophy who showed a complete response to oral methotrexate 5 mg/wk after topical clobetasol propionate and calcipotriol failed. Improvement was seen as early as 4 weeks after therapy initiation, and complete resolution of the lesions was documented after 9 and 13 months of methotrexate therapy for the fingers and toes, respectively.¹¹ The successful use of methotrexate in the improvement of psoriatic nail dystrophy in a pediatric patient also was documented by Teran et al.¹⁶ In this case, a 9-year-old girl with erythrodermic psoriasis, psoriatic arthritis, and severe onychodystrophy showed notable amelioration of all psoriatic manifestations, including the nail findings, with systemic methotrexate therapy (dose not specified).¹⁶ Notably, the authors reported that the improvement of onychodystrophy occurred with considerable delay compared to the other psoriatic lesions,¹⁶ indicating the already-known refractoriness of nail psoriasis to the various therapeutic attempts.^9-15

Acitretin—Another agent that has been linked with partial improvement of acrodermatitis continua of Hallopeau (ACH)–associated onychodystrophy is acitretin. In a case series of 15 pediatric patients with pustular psoriasis, a 5-year-old boy with severe nail involvement presented with partial amelioration of nail changes with acitretin within the first 6 weeks of treatment using the following regimen: initial dosage of 0.8 mg/kg/d for 6 weeks, followed by 0.3 mg/kg/d for 4 weeks.¹⁷

Biologics—The emerging use of biologics in pediatric psoriasis also has brought important advances in the successful management of nail psoriasis in children and adolescents.^18-21 Wells et al¹⁸ presented the case of an 8-year-old girl with nail psoriasis, psoriatic arthritis, and plaque psoriasis who showed complete resolution of all psoriatic manifestations, including nail involvement, within 3 months of treatment with secukinumab 150 mg subcutaneously every 4 weeks. Prior failed treatments included various systemic agents (ie, subcutaneous methotrexate 20 mg/m², etanercept 0.8 mg/kg weekly, adalimumab 40 mg every 2 weeks) as well as topical agents (ie, urea, tazarotene, corticosteroids) and intralesional triamcinolone.¹⁸

Infliximab also has been successfully used for pediatric nail psoriasis. Watabe et al¹⁹ presented the case of an 8-year-old girl with psoriatic onychodystrophy in addition to psoriatic onycho-pachydermo-periostitis. Prior therapy with adalimumab 20 mg every other week combined with methotrexate 10 mg weekly failed. She experienced notable amelioration of the nail dystrophy within 3 months of using a combination of infliximab and methotrexate (infliximab 5 mg/kg intravenously on weeks 0, 2, and 6, and every 8 weeks thereafter; methotrexate 10 mg/wk).¹⁹

Cases in which infliximab has resulted in rapid yet only transient restoration of psoriatic onychodystrophy also are present in the literature. Pereira et al²⁰ reported that a 3-year-old patient with severe 20-digit onychodystrophy in addition to pustular psoriasis had complete resolution of nail lesions within 2 weeks of treatment with infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 7 weeks thereafter), which was sustained over the course of 1 year. The therapy had to be discontinued because of exacerbation of the cutaneous symptoms; thereafter, etanercept was initiated. Although the patient noted major improvement of all skin lesions under etanercept, only moderate amelioration of the psoriatic nail lesions was demonstrated.²⁰

Dini et al²¹ described a 9-year-old girl with severe ACH-associated psoriatic onychodystrophy who showed complete clearance of all lesions within 8 weeks of treatment with adalimumab (initially 80 mg, followed by 40 mg after 1 week and then 40 mg every other week). Prior treatment with potent topical corticosteroids, cyclosporine (3 mg/kg/d for 6 months), and etanercept (0.4 mg/kg twice weekly for 3 months) was ineffective.²¹

Phototherapy—Other systemic agents with reported satisfactory outcomes in the treatment of psoriatic onychodystrophy include thalidomide combined with UVB phototherapy. Kiszewski et al²² described a 2-year-old patient with ACH and severe 19-digit onychodystrophy. Prior failed therapies included occluded clobetasol ointment 0.05%, occluded pimecrolimus 0.1%, and systemic methotrexate, while systemic acitretin (0.8 mg⁄kg⁄d) resulted in elevated cholesterol levels and therefore had to be interrupted. Improvement was seen 2 months after the initiation of a combined broadband UVB and thalidomide (50 mg⁄d) treatment, with no documented relapses after discontinuation of therapy.²²

Narrowband UVB (311 nm) also has been used as monotherapy for ACH-associated onychodystrophy, as demonstrated by Bordignon et al.²³ They reported a 9-year-old patient who showed partial improvement of isolated onychodystrophy of the fourth nail plate of the left hand after 36 sessions of narrowband UVB using a 311-nm filtering handpiece with a square spot size of 19×19 mm.²³

Conclusion

Nail psoriasis constitutes a type of psoriasis that is not only refractory to most treatments but is accompanied by substantial psychological and occasionally functional burden for the affected individuals.²⁴ Data concerning therapeutic options in the pediatric population are extremely limited, and therefore the everyday practice often involves administration of off-label medications, which can constitute a dilemma for many physicians, especially for safety.¹⁰ We suggest a simple therapeutic algorithm for the management of pediatric nail psoriasis based on the summarized data that are currently available in the literature. This algorithm is shown in the eFigure.

As progressively more agents—especially biologics—receive approval for use in plaque psoriasis in pediatric patients,²⁵ it is expected that gradually more real-life data on their side efficacy for plaque psoriasis of the nails in children also will come to light. Furthermore, their on-label use in pediatric psoriasis patients will facilitate further relevant clinical trials to this target group so that the potential of these medications in the management of nail psoriasis can be fully explored.

Annular erythemas of infancy (AEIs) are rare benign skin eruptions characterized by annular or circinate, erythematous patches and plaques that arise in patients younger than 1 year.¹ Annular erythemas of infancy originally were described by Peterson and Jarratt² in 1981. Relatively few cases of AEIs have been reported in the literature (eTable).^2-15

Case Report

An 11-month-old girl presented to dermatology for a rash characterized by annular erythematous patches and plaques on the back, arms, and legs (Figure 1). Three months prior, the rash was more diffuse, monomorphic, and papular. Based on physical examination, the differential diagnosis included a gyrate erythema such as erythema annulare centrifugum (EAC), neonatal lupus, a viral exanthem, leukemia cutis, and AEI. A skin punch biopsy was performed.

Histologically, the biopsy revealed a superficial to mid dermal, tight, coat sleeve–like, perivascular lymphohistiocytic infiltrate admixed with rare neutrophils in eosinophils within the dermis (Figure 2A). The infiltrate also contained numerous large mononuclear cells with enlarged nuclei, fine loose chromatin, rare nucleoli, and a thin rim of cytoplasm (Figure 2B). There were associated apoptotic bodies with karyorrhectic debris. Immunohistochemistry exhibited enlarged cells that were strong staining with CD3 and CD4, which was consistent with reactive helper T cells (Figure 3). A myeloperoxidase stain highlighted few neutrophils. Stains for terminal deoxynucleotidyl transferase, CD1a, CD117, and CD34 were negative. These findings along with the clinical presentation yielded a diagnosis of AEI with reactive helper T cells.

Comment

Clinical Presentation of AEIs—Annular erythemas of infancy are rare benign skin eruptions that develop in the first few months of life.^1,16 Few cases have been reported (eTable). Clinically, AEIs are characterized by annular or circinate, erythematous patches and plaques. They can occur on the face, trunk, and extremities, and they completely resolve by 1 year of age in most cases. One case was reported to persist in a patient from birth until 15 years of age.⁹ It is thought that AEIs may occur as a hypersensitivity reaction to an unrecognized antigen.

Histopathology—Histologically, AEIs demonstrate a superficial and deep, perivascular, inflammatory infiltrate in the dermis composed of small lymphocytes, some neutrophils, and eosinophils.¹⁶ Less common variants of AEI include eosinophilic annular erythema, characterized by a diffuse dermal infiltrate of eosinophils and some lymphocytes, and neutrophilic figurate erythema of infancy, characterized by a dermal infiltrate with neutrophils and leukocytoclasis without vasculitis.¹

Our patient’s skin rash was unusual in that the biopsy demonstrated few neutrophils, rare eosinophils, and larger mononuclear cells consistent with reactive helper T lymphocytes. Although these cells may raise concern for an atypical lymphoid infiltrate, recognition of areas with more conventional histopathology of AEIs can facilitate the correct diagnosis.

Differential Diagnosis—The main considerations in the differential diagnosis for AEIs include the following: EAC, familial annular erythema, erythema gyratum atrophicans transiens neonatale, erythema chronicum migrans, urticaria, tinea corporis, neonatal lupus erythematosus, viral exanthems, and leukemia cutis.¹⁶

Erythema annulare centrifugum typically begins in middle age and follows a course of 2 or more years.² It occurs in association with an underlying infection or neoplasm, and it can develop on the trunk and proximal extremities. Morphologically, EAC can present with arcuate or polycyclic lesions with trailing scale. Histologically, a skin biopsy shows a tight, coat sleeve–like, perivascular, lymphohistiocytic infiltrate in the dermis, with variable epidermal spongiosis and parakeratosis.¹⁶ Our patient’s biopsy did show a tight perivascular infiltrate, raising suspicion for EAC. However, the eruption occurred in infancy, and she had no clinical evidence of infection or neoplasm.

Familial annular erythemas can arise within a few days after birth and can present on any part of the body, including the tongue.² Individual lesions can persist for 4 to 5 days and can accompany congenital malformations. Morphologically, they can present as papules that slowly enlarge to form arcuate lesions with central hyperpigmentation. Histologically, there can be a mild, perivascular, lymphocytic infiltrate in the dermis.¹⁶ Our patient’s lesions showed no scale or pigmentation and occurred without a family history or associated malformations.

Erythema gyratum atrophicans transiens neonatale also can arise in the first few days of life and can affect the trunk, neck, and lips.¹⁶ Morphologically, the skin lesions can present as arcuate erythematous patches (3–20 mm) with raised borders and central atrophy. Histologically, there is epidermal atrophy with a dermal perivascular mononuclear cell infiltrate with edema. Our patient’s clinical presentation was not classic for this condition, and the lesions showed no atrophy.

Erythema chronicum migrans can arise in children, often with a history of an arthropod bite.¹³ Morphologically, lesions can evolve over weeks to months and rarely are multiple. Erythema chronicum migrans most commonly occurs in the United States in association with Lyme disease from infection with Borrelia burgdorferi. Histologically, erythema chronicum migrans shows a superficial and deep, perivascular lymphocytic infiltrate in the dermis with plasma cells and eosinophils. A silver stain can demonstrate dermal spirochetes. Our patient had no history of an arthropod bite. A Warthin-Starry stain performed on the biopsy was negative for spirochetes, and serologies for Lyme disease were negative.

Urticaria is rare in neonates and can occur on any part of the body.² Morphologically, the skin lesions can present as arcuate, erythematous, and polycyclic plaques that wax and wane. Histologically, there is dermal edema with a mild, perivascular and interstitial, mixed inflammatory infiltrate.¹⁶ Our patient’s biopsy did not reveal notable edema, and the perivascular infiltrate was coat sleeve–like with few neutrophils and eosinophils. The patient did not respond to initial treatment with antihistamines, making urticaria less likely.

Tinea corporis is rare in neonates and can occur on any part of the body.¹³ Morphologically, it can present as scaly annular lesions that are fixed and more persistent. Histologically, there are fungal hyphae and/or yeast in the stratum corneum with spongiotic dermatitis and parakeratosis. Our patient’s lesions were not scaly, and the biopsy demonstrated minimal spongiosis. A periodic acid–Schiff special stain was negative for fungal microorganisms.

Neonatal lupus erythematosus can arise at birth or during the first few weeks of life.¹⁶ Morphologically, the skin lesions occur on the scalp, forehead, or neck in a periorbital or malar distribution. They can present as erythematous, annular, scaly patches and plaques. Transplacental transmission of material autoantibodies has been implicated in the etiology, and a complication is infantile heart block. Histologically, a skin biopsy typically shows interface/lichenoid dermatitis. However, our patient’s biopsy did not demonstrate interface changes, and serologically she was negative for autoantibodies.

Viral exanthems are skin eruptions that accompany underlying viral infections.¹⁷ Morphologically, patients can present with an erythematous maculopapular rash, sometimes with vesicular, petechial, and urticarial lesions. Laboratory confirmation is made by virus-specific serologies. Histologically, viral exanthems can show a superficial, perivascular, lymphocytic infiltrate in the dermis, with reactive T cells and epidermal spongiosis. Our patient was afebrile and had no known sick contacts. A cytomegalovirus immunohistochemical study on the biopsy was negative, and an Epstein-Barr encoding region in situ hybridization study was negative.

Leukemia cutis is the infiltration of the skin by leukemic cells, most often in conjunction with systemic leukemia.¹⁸ In infants and children, the most common leukemia is B-cell acute lymphoblastic leukemia. Morphologically, the skin lesions are characterized by single or multiple violaceous papules, nodules, and plaques. Histologically, there is a perivascular to interstitial infiltrate of atypical mononuclear cells in the dermis and sometimes subcutis. The leukemic cells demonstrate enlarged nuclei with coarse chromatin and prominent nucleoli. Increased mitotic activity may be seen with karyorrhectic debris. Immunohistochemically, the tumor cells can be positive for myeloperoxidase, CD43, CD68, CD34, and CD117.¹⁸ Although our patient’s biopsy demonstrated mononuclear cells with karyorrhexis, the cells did not have striking atypia and were negative for blast markers. A recent complete blood cell count on the patient was normal.

Conclusion

We report an unusual case of AEI with mononuclear cells consistent with helper T cells. One must keep these cells in mind when evaluating a biopsy of AEI, as they are benign and not suggestive of an atypical lymphoid infiltrate or leukemia cutis. This will prevent misdiagnosis and ensure that the patient receives appropriate management.

Annular erythemas of infancy (AEIs) are rare benign skin eruptions characterized by annular or circinate, erythematous patches and plaques that arise in patients younger than 1 year.¹ Annular erythemas of infancy originally were described by Peterson and Jarratt² in 1981. Relatively few cases of AEIs have been reported in the literature (eTable).^2-15

Case Report

An 11-month-old girl presented to dermatology for a rash characterized by annular erythematous patches and plaques on the back, arms, and legs (Figure 1). Three months prior, the rash was more diffuse, monomorphic, and papular. Based on physical examination, the differential diagnosis included a gyrate erythema such as erythema annulare centrifugum (EAC), neonatal lupus, a viral exanthem, leukemia cutis, and AEI. A skin punch biopsy was performed.

Histologically, the biopsy revealed a superficial to mid dermal, tight, coat sleeve–like, perivascular lymphohistiocytic infiltrate admixed with rare neutrophils in eosinophils within the dermis (Figure 2A). The infiltrate also contained numerous large mononuclear cells with enlarged nuclei, fine loose chromatin, rare nucleoli, and a thin rim of cytoplasm (Figure 2B). There were associated apoptotic bodies with karyorrhectic debris. Immunohistochemistry exhibited enlarged cells that were strong staining with CD3 and CD4, which was consistent with reactive helper T cells (Figure 3). A myeloperoxidase stain highlighted few neutrophils. Stains for terminal deoxynucleotidyl transferase, CD1a, CD117, and CD34 were negative. These findings along with the clinical presentation yielded a diagnosis of AEI with reactive helper T cells.

Comment

Clinical Presentation of AEIs—Annular erythemas of infancy are rare benign skin eruptions that develop in the first few months of life.^1,16 Few cases have been reported (eTable). Clinically, AEIs are characterized by annular or circinate, erythematous patches and plaques. They can occur on the face, trunk, and extremities, and they completely resolve by 1 year of age in most cases. One case was reported to persist in a patient from birth until 15 years of age.⁹ It is thought that AEIs may occur as a hypersensitivity reaction to an unrecognized antigen.

Histopathology—Histologically, AEIs demonstrate a superficial and deep, perivascular, inflammatory infiltrate in the dermis composed of small lymphocytes, some neutrophils, and eosinophils.¹⁶ Less common variants of AEI include eosinophilic annular erythema, characterized by a diffuse dermal infiltrate of eosinophils and some lymphocytes, and neutrophilic figurate erythema of infancy, characterized by a dermal infiltrate with neutrophils and leukocytoclasis without vasculitis.¹

Our patient’s skin rash was unusual in that the biopsy demonstrated few neutrophils, rare eosinophils, and larger mononuclear cells consistent with reactive helper T lymphocytes. Although these cells may raise concern for an atypical lymphoid infiltrate, recognition of areas with more conventional histopathology of AEIs can facilitate the correct diagnosis.

Differential Diagnosis—The main considerations in the differential diagnosis for AEIs include the following: EAC, familial annular erythema, erythema gyratum atrophicans transiens neonatale, erythema chronicum migrans, urticaria, tinea corporis, neonatal lupus erythematosus, viral exanthems, and leukemia cutis.¹⁶

Erythema annulare centrifugum typically begins in middle age and follows a course of 2 or more years.² It occurs in association with an underlying infection or neoplasm, and it can develop on the trunk and proximal extremities. Morphologically, EAC can present with arcuate or polycyclic lesions with trailing scale. Histologically, a skin biopsy shows a tight, coat sleeve–like, perivascular, lymphohistiocytic infiltrate in the dermis, with variable epidermal spongiosis and parakeratosis.¹⁶ Our patient’s biopsy did show a tight perivascular infiltrate, raising suspicion for EAC. However, the eruption occurred in infancy, and she had no clinical evidence of infection or neoplasm.

Familial annular erythemas can arise within a few days after birth and can present on any part of the body, including the tongue.² Individual lesions can persist for 4 to 5 days and can accompany congenital malformations. Morphologically, they can present as papules that slowly enlarge to form arcuate lesions with central hyperpigmentation. Histologically, there can be a mild, perivascular, lymphocytic infiltrate in the dermis.¹⁶ Our patient’s lesions showed no scale or pigmentation and occurred without a family history or associated malformations.

Erythema gyratum atrophicans transiens neonatale also can arise in the first few days of life and can affect the trunk, neck, and lips.¹⁶ Morphologically, the skin lesions can present as arcuate erythematous patches (3–20 mm) with raised borders and central atrophy. Histologically, there is epidermal atrophy with a dermal perivascular mononuclear cell infiltrate with edema. Our patient’s clinical presentation was not classic for this condition, and the lesions showed no atrophy.

Erythema chronicum migrans can arise in children, often with a history of an arthropod bite.¹³ Morphologically, lesions can evolve over weeks to months and rarely are multiple. Erythema chronicum migrans most commonly occurs in the United States in association with Lyme disease from infection with Borrelia burgdorferi. Histologically, erythema chronicum migrans shows a superficial and deep, perivascular lymphocytic infiltrate in the dermis with plasma cells and eosinophils. A silver stain can demonstrate dermal spirochetes. Our patient had no history of an arthropod bite. A Warthin-Starry stain performed on the biopsy was negative for spirochetes, and serologies for Lyme disease were negative.

Urticaria is rare in neonates and can occur on any part of the body.² Morphologically, the skin lesions can present as arcuate, erythematous, and polycyclic plaques that wax and wane. Histologically, there is dermal edema with a mild, perivascular and interstitial, mixed inflammatory infiltrate.¹⁶ Our patient’s biopsy did not reveal notable edema, and the perivascular infiltrate was coat sleeve–like with few neutrophils and eosinophils. The patient did not respond to initial treatment with antihistamines, making urticaria less likely.

Tinea corporis is rare in neonates and can occur on any part of the body.¹³ Morphologically, it can present as scaly annular lesions that are fixed and more persistent. Histologically, there are fungal hyphae and/or yeast in the stratum corneum with spongiotic dermatitis and parakeratosis. Our patient’s lesions were not scaly, and the biopsy demonstrated minimal spongiosis. A periodic acid–Schiff special stain was negative for fungal microorganisms.

Neonatal lupus erythematosus can arise at birth or during the first few weeks of life.¹⁶ Morphologically, the skin lesions occur on the scalp, forehead, or neck in a periorbital or malar distribution. They can present as erythematous, annular, scaly patches and plaques. Transplacental transmission of material autoantibodies has been implicated in the etiology, and a complication is infantile heart block. Histologically, a skin biopsy typically shows interface/lichenoid dermatitis. However, our patient’s biopsy did not demonstrate interface changes, and serologically she was negative for autoantibodies.

Viral exanthems are skin eruptions that accompany underlying viral infections.¹⁷ Morphologically, patients can present with an erythematous maculopapular rash, sometimes with vesicular, petechial, and urticarial lesions. Laboratory confirmation is made by virus-specific serologies. Histologically, viral exanthems can show a superficial, perivascular, lymphocytic infiltrate in the dermis, with reactive T cells and epidermal spongiosis. Our patient was afebrile and had no known sick contacts. A cytomegalovirus immunohistochemical study on the biopsy was negative, and an Epstein-Barr encoding region in situ hybridization study was negative.

Leukemia cutis is the infiltration of the skin by leukemic cells, most often in conjunction with systemic leukemia.¹⁸ In infants and children, the most common leukemia is B-cell acute lymphoblastic leukemia. Morphologically, the skin lesions are characterized by single or multiple violaceous papules, nodules, and plaques. Histologically, there is a perivascular to interstitial infiltrate of atypical mononuclear cells in the dermis and sometimes subcutis. The leukemic cells demonstrate enlarged nuclei with coarse chromatin and prominent nucleoli. Increased mitotic activity may be seen with karyorrhectic debris. Immunohistochemically, the tumor cells can be positive for myeloperoxidase, CD43, CD68, CD34, and CD117.¹⁸ Although our patient’s biopsy demonstrated mononuclear cells with karyorrhexis, the cells did not have striking atypia and were negative for blast markers. A recent complete blood cell count on the patient was normal.

Conclusion

We report an unusual case of AEI with mononuclear cells consistent with helper T cells. One must keep these cells in mind when evaluating a biopsy of AEI, as they are benign and not suggestive of an atypical lymphoid infiltrate or leukemia cutis. This will prevent misdiagnosis and ensure that the patient receives appropriate management.

Annular erythemas of infancy (AEIs) are rare benign skin eruptions characterized by annular or circinate, erythematous patches and plaques that arise in patients younger than 1 year.¹ Annular erythemas of infancy originally were described by Peterson and Jarratt² in 1981. Relatively few cases of AEIs have been reported in the literature (eTable).^2-15

Case Report

An 11-month-old girl presented to dermatology for a rash characterized by annular erythematous patches and plaques on the back, arms, and legs (Figure 1). Three months prior, the rash was more diffuse, monomorphic, and papular. Based on physical examination, the differential diagnosis included a gyrate erythema such as erythema annulare centrifugum (EAC), neonatal lupus, a viral exanthem, leukemia cutis, and AEI. A skin punch biopsy was performed.

Histologically, the biopsy revealed a superficial to mid dermal, tight, coat sleeve–like, perivascular lymphohistiocytic infiltrate admixed with rare neutrophils in eosinophils within the dermis (Figure 2A). The infiltrate also contained numerous large mononuclear cells with enlarged nuclei, fine loose chromatin, rare nucleoli, and a thin rim of cytoplasm (Figure 2B). There were associated apoptotic bodies with karyorrhectic debris. Immunohistochemistry exhibited enlarged cells that were strong staining with CD3 and CD4, which was consistent with reactive helper T cells (Figure 3). A myeloperoxidase stain highlighted few neutrophils. Stains for terminal deoxynucleotidyl transferase, CD1a, CD117, and CD34 were negative. These findings along with the clinical presentation yielded a diagnosis of AEI with reactive helper T cells.

Comment

Clinical Presentation of AEIs—Annular erythemas of infancy are rare benign skin eruptions that develop in the first few months of life.^1,16 Few cases have been reported (eTable). Clinically, AEIs are characterized by annular or circinate, erythematous patches and plaques. They can occur on the face, trunk, and extremities, and they completely resolve by 1 year of age in most cases. One case was reported to persist in a patient from birth until 15 years of age.⁹ It is thought that AEIs may occur as a hypersensitivity reaction to an unrecognized antigen.

Histopathology—Histologically, AEIs demonstrate a superficial and deep, perivascular, inflammatory infiltrate in the dermis composed of small lymphocytes, some neutrophils, and eosinophils.¹⁶ Less common variants of AEI include eosinophilic annular erythema, characterized by a diffuse dermal infiltrate of eosinophils and some lymphocytes, and neutrophilic figurate erythema of infancy, characterized by a dermal infiltrate with neutrophils and leukocytoclasis without vasculitis.¹

Our patient’s skin rash was unusual in that the biopsy demonstrated few neutrophils, rare eosinophils, and larger mononuclear cells consistent with reactive helper T lymphocytes. Although these cells may raise concern for an atypical lymphoid infiltrate, recognition of areas with more conventional histopathology of AEIs can facilitate the correct diagnosis.

Differential Diagnosis—The main considerations in the differential diagnosis for AEIs include the following: EAC, familial annular erythema, erythema gyratum atrophicans transiens neonatale, erythema chronicum migrans, urticaria, tinea corporis, neonatal lupus erythematosus, viral exanthems, and leukemia cutis.¹⁶

Erythema annulare centrifugum typically begins in middle age and follows a course of 2 or more years.² It occurs in association with an underlying infection or neoplasm, and it can develop on the trunk and proximal extremities. Morphologically, EAC can present with arcuate or polycyclic lesions with trailing scale. Histologically, a skin biopsy shows a tight, coat sleeve–like, perivascular, lymphohistiocytic infiltrate in the dermis, with variable epidermal spongiosis and parakeratosis.¹⁶ Our patient’s biopsy did show a tight perivascular infiltrate, raising suspicion for EAC. However, the eruption occurred in infancy, and she had no clinical evidence of infection or neoplasm.

Familial annular erythemas can arise within a few days after birth and can present on any part of the body, including the tongue.² Individual lesions can persist for 4 to 5 days and can accompany congenital malformations. Morphologically, they can present as papules that slowly enlarge to form arcuate lesions with central hyperpigmentation. Histologically, there can be a mild, perivascular, lymphocytic infiltrate in the dermis.¹⁶ Our patient’s lesions showed no scale or pigmentation and occurred without a family history or associated malformations.

Erythema gyratum atrophicans transiens neonatale also can arise in the first few days of life and can affect the trunk, neck, and lips.¹⁶ Morphologically, the skin lesions can present as arcuate erythematous patches (3–20 mm) with raised borders and central atrophy. Histologically, there is epidermal atrophy with a dermal perivascular mononuclear cell infiltrate with edema. Our patient’s clinical presentation was not classic for this condition, and the lesions showed no atrophy.

Erythema chronicum migrans can arise in children, often with a history of an arthropod bite.¹³ Morphologically, lesions can evolve over weeks to months and rarely are multiple. Erythema chronicum migrans most commonly occurs in the United States in association with Lyme disease from infection with Borrelia burgdorferi. Histologically, erythema chronicum migrans shows a superficial and deep, perivascular lymphocytic infiltrate in the dermis with plasma cells and eosinophils. A silver stain can demonstrate dermal spirochetes. Our patient had no history of an arthropod bite. A Warthin-Starry stain performed on the biopsy was negative for spirochetes, and serologies for Lyme disease were negative.

Urticaria is rare in neonates and can occur on any part of the body.² Morphologically, the skin lesions can present as arcuate, erythematous, and polycyclic plaques that wax and wane. Histologically, there is dermal edema with a mild, perivascular and interstitial, mixed inflammatory infiltrate.¹⁶ Our patient’s biopsy did not reveal notable edema, and the perivascular infiltrate was coat sleeve–like with few neutrophils and eosinophils. The patient did not respond to initial treatment with antihistamines, making urticaria less likely.

Tinea corporis is rare in neonates and can occur on any part of the body.¹³ Morphologically, it can present as scaly annular lesions that are fixed and more persistent. Histologically, there are fungal hyphae and/or yeast in the stratum corneum with spongiotic dermatitis and parakeratosis. Our patient’s lesions were not scaly, and the biopsy demonstrated minimal spongiosis. A periodic acid–Schiff special stain was negative for fungal microorganisms.

Neonatal lupus erythematosus can arise at birth or during the first few weeks of life.¹⁶ Morphologically, the skin lesions occur on the scalp, forehead, or neck in a periorbital or malar distribution. They can present as erythematous, annular, scaly patches and plaques. Transplacental transmission of material autoantibodies has been implicated in the etiology, and a complication is infantile heart block. Histologically, a skin biopsy typically shows interface/lichenoid dermatitis. However, our patient’s biopsy did not demonstrate interface changes, and serologically she was negative for autoantibodies.

Viral exanthems are skin eruptions that accompany underlying viral infections.¹⁷ Morphologically, patients can present with an erythematous maculopapular rash, sometimes with vesicular, petechial, and urticarial lesions. Laboratory confirmation is made by virus-specific serologies. Histologically, viral exanthems can show a superficial, perivascular, lymphocytic infiltrate in the dermis, with reactive T cells and epidermal spongiosis. Our patient was afebrile and had no known sick contacts. A cytomegalovirus immunohistochemical study on the biopsy was negative, and an Epstein-Barr encoding region in situ hybridization study was negative.

Leukemia cutis is the infiltration of the skin by leukemic cells, most often in conjunction with systemic leukemia.¹⁸ In infants and children, the most common leukemia is B-cell acute lymphoblastic leukemia. Morphologically, the skin lesions are characterized by single or multiple violaceous papules, nodules, and plaques. Histologically, there is a perivascular to interstitial infiltrate of atypical mononuclear cells in the dermis and sometimes subcutis. The leukemic cells demonstrate enlarged nuclei with coarse chromatin and prominent nucleoli. Increased mitotic activity may be seen with karyorrhectic debris. Immunohistochemically, the tumor cells can be positive for myeloperoxidase, CD43, CD68, CD34, and CD117.¹⁸ Although our patient’s biopsy demonstrated mononuclear cells with karyorrhexis, the cells did not have striking atypia and were negative for blast markers. A recent complete blood cell count on the patient was normal.

Conclusion

We report an unusual case of AEI with mononuclear cells consistent with helper T cells. One must keep these cells in mind when evaluating a biopsy of AEI, as they are benign and not suggestive of an atypical lymphoid infiltrate or leukemia cutis. This will prevent misdiagnosis and ensure that the patient receives appropriate management.

Exostosis is a type of benign bone tumor in which trabecular (spongy) bone overgrows its normal border in a nodular pattern. ^1,2 Histologically, it usually is surrounded by a fibrocartilaginous cap. ³ It is most commonly found on the lateral or medial aspect of the foot and is thought to be caused by trauma, either physical pressure or infection. ⁴ When this lesion is found under the nail bed, it is termed subungual exostosis ( Dupuytren exostosis ) . ³ Sequelae of a subungual exostosis include nail dystrophy and lifting of the nail away from the toe, in addition to infection and possible loss of the toenail (onycholysis). There are only 2 genetic conditions related to exostosis: hereditary multiple exostosis and multiple exostoses-mental retardation syndrome.

An exostosis may appear to be a wart on first inspection. It may present similar to osteochondromas, and the only way to get a true diagnosis is by biopsy of the lesion. The treatment for an exostosis is surgery. The surgeon must remove the lesion at the base of the bone from which it grows to prevent recurrence of the lesion.⁵

Because exostosis may cause nail bed disruption, the differential diagnosis may include nail deformities, such as traumatic onycholysis, onychogryphosis, verrucae, subungual infection, or nail trauma.^6,7

Case Report

A 7-year-old boy presented with changes of the right great toenail over the last 4 months. The patient noted that the affected nail was discolored, dystrophic, painful, and thickened. He did not recall prior trauma to the affected nail, and his mother stated that the lesion was growing and becoming more painful with a throbbing sensation at times. He described the pain as stabbing, which was exacerbated while walking and playing sports. Neither the patient nor his family had ever had any similar condition. He was not taking any medications, only a daily multivitamin. He had a history of eczematous dermatitis and keratosis pilaris without any other medical illnesses. He had a family history of psoriasis; however, no prior instances of exostosis had been reported. He had no medication allergies.

A full-body cutaneous and nail examination showed a well-developed, well-nourished boy who was in no acute distress. A firm, subungual, pink, pearly,hyperkeratotic nodule was appreciated on the right great toe (Figure 1). The lesion was tender to palpation. The rest of the examination and review of systems were normal.

From the clinical findings, a differential diagnosis of glomus tumor, hemangioma, and infection was considered. Periodic acid–Schiff stain was negative, which ruled out fungal infection. Nail avulsion and a shave biopsy were performed under general anesthesia. There was an exostosis arising from the dorsal aspect of the great toe measuring approximately 5 mm in width at the base and approximately 1 mm in height, which endorsed a diagnosis of distal phalanx subungual exostosis. A postsurgery radiograph (Figure 2) showed residual bone below the level of shave removal at the nail bed.

Comment

Exostosis is most commonly found on the lateral or medial aspect of the hallux (great toe) in patients younger than 18 years.⁸ Diagnosis often is obvious, even without a radiograph or biopsy, because the exostosis comes out from under the tip of the nail. Our case was interesting because the patient was a child, and the exostosis did not lift the nail or extrude from the distal tip of the nail bed. Evidence suggests that a greater-than-expected genetic influence contributes to an exostosis, though further investigation is needed to determine all of the causes and risk factors for subungual bony exostosis. Timely diagnosis and treatment are essential to the prevention of sequelae of the disease, such as toe infection or chronic pain.

Exostosis is a type of benign bone tumor in which trabecular (spongy) bone overgrows its normal border in a nodular pattern. ^1,2 Histologically, it usually is surrounded by a fibrocartilaginous cap. ³ It is most commonly found on the lateral or medial aspect of the foot and is thought to be caused by trauma, either physical pressure or infection. ⁴ When this lesion is found under the nail bed, it is termed subungual exostosis ( Dupuytren exostosis ) . ³ Sequelae of a subungual exostosis include nail dystrophy and lifting of the nail away from the toe, in addition to infection and possible loss of the toenail (onycholysis). There are only 2 genetic conditions related to exostosis: hereditary multiple exostosis and multiple exostoses-mental retardation syndrome.

An exostosis may appear to be a wart on first inspection. It may present similar to osteochondromas, and the only way to get a true diagnosis is by biopsy of the lesion. The treatment for an exostosis is surgery. The surgeon must remove the lesion at the base of the bone from which it grows to prevent recurrence of the lesion.⁵

Because exostosis may cause nail bed disruption, the differential diagnosis may include nail deformities, such as traumatic onycholysis, onychogryphosis, verrucae, subungual infection, or nail trauma.^6,7

Case Report

A 7-year-old boy presented with changes of the right great toenail over the last 4 months. The patient noted that the affected nail was discolored, dystrophic, painful, and thickened. He did not recall prior trauma to the affected nail, and his mother stated that the lesion was growing and becoming more painful with a throbbing sensation at times. He described the pain as stabbing, which was exacerbated while walking and playing sports. Neither the patient nor his family had ever had any similar condition. He was not taking any medications, only a daily multivitamin. He had a history of eczematous dermatitis and keratosis pilaris without any other medical illnesses. He had a family history of psoriasis; however, no prior instances of exostosis had been reported. He had no medication allergies.

A full-body cutaneous and nail examination showed a well-developed, well-nourished boy who was in no acute distress. A firm, subungual, pink, pearly,hyperkeratotic nodule was appreciated on the right great toe (Figure 1). The lesion was tender to palpation. The rest of the examination and review of systems were normal.

From the clinical findings, a differential diagnosis of glomus tumor, hemangioma, and infection was considered. Periodic acid–Schiff stain was negative, which ruled out fungal infection. Nail avulsion and a shave biopsy were performed under general anesthesia. There was an exostosis arising from the dorsal aspect of the great toe measuring approximately 5 mm in width at the base and approximately 1 mm in height, which endorsed a diagnosis of distal phalanx subungual exostosis. A postsurgery radiograph (Figure 2) showed residual bone below the level of shave removal at the nail bed.

Comment

Exostosis is most commonly found on the lateral or medial aspect of the hallux (great toe) in patients younger than 18 years.⁸ Diagnosis often is obvious, even without a radiograph or biopsy, because the exostosis comes out from under the tip of the nail. Our case was interesting because the patient was a child, and the exostosis did not lift the nail or extrude from the distal tip of the nail bed. Evidence suggests that a greater-than-expected genetic influence contributes to an exostosis, though further investigation is needed to determine all of the causes and risk factors for subungual bony exostosis. Timely diagnosis and treatment are essential to the prevention of sequelae of the disease, such as toe infection or chronic pain.

Exostosis is a type of benign bone tumor in which trabecular (spongy) bone overgrows its normal border in a nodular pattern. ^1,2 Histologically, it usually is surrounded by a fibrocartilaginous cap. ³ It is most commonly found on the lateral or medial aspect of the foot and is thought to be caused by trauma, either physical pressure or infection. ⁴ When this lesion is found under the nail bed, it is termed subungual exostosis ( Dupuytren exostosis ) . ³ Sequelae of a subungual exostosis include nail dystrophy and lifting of the nail away from the toe, in addition to infection and possible loss of the toenail (onycholysis). There are only 2 genetic conditions related to exostosis: hereditary multiple exostosis and multiple exostoses-mental retardation syndrome.

An exostosis may appear to be a wart on first inspection. It may present similar to osteochondromas, and the only way to get a true diagnosis is by biopsy of the lesion. The treatment for an exostosis is surgery. The surgeon must remove the lesion at the base of the bone from which it grows to prevent recurrence of the lesion.⁵

Because exostosis may cause nail bed disruption, the differential diagnosis may include nail deformities, such as traumatic onycholysis, onychogryphosis, verrucae, subungual infection, or nail trauma.^6,7

Case Report

A 7-year-old boy presented with changes of the right great toenail over the last 4 months. The patient noted that the affected nail was discolored, dystrophic, painful, and thickened. He did not recall prior trauma to the affected nail, and his mother stated that the lesion was growing and becoming more painful with a throbbing sensation at times. He described the pain as stabbing, which was exacerbated while walking and playing sports. Neither the patient nor his family had ever had any similar condition. He was not taking any medications, only a daily multivitamin. He had a history of eczematous dermatitis and keratosis pilaris without any other medical illnesses. He had a family history of psoriasis; however, no prior instances of exostosis had been reported. He had no medication allergies.

A full-body cutaneous and nail examination showed a well-developed, well-nourished boy who was in no acute distress. A firm, subungual, pink, pearly,hyperkeratotic nodule was appreciated on the right great toe (Figure 1). The lesion was tender to palpation. The rest of the examination and review of systems were normal.

From the clinical findings, a differential diagnosis of glomus tumor, hemangioma, and infection was considered. Periodic acid–Schiff stain was negative, which ruled out fungal infection. Nail avulsion and a shave biopsy were performed under general anesthesia. There was an exostosis arising from the dorsal aspect of the great toe measuring approximately 5 mm in width at the base and approximately 1 mm in height, which endorsed a diagnosis of distal phalanx subungual exostosis. A postsurgery radiograph (Figure 2) showed residual bone below the level of shave removal at the nail bed.

Comment

Exostosis is most commonly found on the lateral or medial aspect of the hallux (great toe) in patients younger than 18 years.⁸ Diagnosis often is obvious, even without a radiograph or biopsy, because the exostosis comes out from under the tip of the nail. Our case was interesting because the patient was a child, and the exostosis did not lift the nail or extrude from the distal tip of the nail bed. Evidence suggests that a greater-than-expected genetic influence contributes to an exostosis, though further investigation is needed to determine all of the causes and risk factors for subungual bony exostosis. Timely diagnosis and treatment are essential to the prevention of sequelae of the disease, such as toe infection or chronic pain.

To the Editor:

Photodynamic therapy (PDT) is a US Food and Drug Administration–approved treatment for actinic keratosis (AK). It also commonly is administered off label for basal cell carcinoma, Bowen disease, photoaging, and acne vulgaris and is being investigated for other applications.^1,2 In the context of treating AK, the mechanism employed in PDT most commonly involves the application of exogenous aminolevulinic acid (ALA), which is metabolized to the endogenous photosensitizer protoporphyrin IX (PpIX) in skin cells by enzymes in the heme biosynthetic pathway.³ The preferential uptake of ALA and conversion to PpIX is due to the altered and increased permeability of abnormal keratin layers of aging, sun-damaged cells, and skin tumors. Selectivity of ALA also occurs due to the preferential intracellular accumulation of PpIX in proliferating, relatively iron–deficient, precancerous and cancerous cells. The therapeutic effect is achieved with light exposure to blue light wavelength at 417 nm and corresponds to the excitation peak of PpIX,⁴ which activates PpIX and forms reactive oxygen species in the presence of oxygen that ultimately cause cell necrosis and apoptosis.⁵ Because it takes approximately 24 hours for PpIX to be completely metabolized from the skin, patients are counseled to avoid sun or artificial light exposure in the first 24 hours post-PDT, regardless of the indication, to avoid a severe phototoxic reaction.^3,6,7 Although it is normal and desirable for patients to experience some form of a phototoxic reaction, which may include erythema, edema, crusting, vesiculation, or erosion in most patients, these types of reactions most often are secondary to the intended exposure and incidental natural or artificial light exposures.⁶ We report a case of a severe phototoxic reaction in which a patient experienced painful erythema and purulence on the left side of the chin after being within an arm’s length of a flame in a fireplace following PDT treatment.

A 59-year-old man presented to our dermatology clinic for his second of 3 PDT sessions to treat AKs on the face. He had a history of a basal cell carcinoma on the left nasolabial fold that previously was treated with Mohs micrographic surgery and melanoma on the left ear that was previously treated with excision. The patient received the initial PDT session 1 month prior and experienced a mild reaction with minimal redness and peeling that resolved in 4 to 5 days. For the second treatment, per standard protocol at our clinic, ALA was applied to the face, after which the patient incubated for 1 hour prior to blue light exposure (mean [SD] peak output of 417 [5] nm for 1000 seconds and 10 J/cm²).

After blue light exposure, broad-spectrum sunscreen (sun protection factor 47) was applied to our patient’s face, and he wore a wide-brimmed hat upon leaving the clinic and walking to his car. Similar to the first PDT session 1 month prior, he experienced minimal pain immediately after treatment. Once home and approximately 4 to 5 hours after PDT, he tended to a fire using his left hand and leaned into the fireplace with the left side of his face, which was within an arm’s length of the flames. Although his skin did not come in direct contact with the flames, the brief 2- to 3-minute exposure to the flame’s light and heat produced an immediate intense burning pain that the patient likened to the pain of blue light exposure. Within 24 hours, he developed a severe inflammatory reaction that included erythema, edema, desquamation, and pustules on the left side of the chin and cheek that produced a purulent discharge (Figure). The purulence resolved the next day; however, the other clinical manifestations persisted for 1 week. Despite the discomfort and symptoms, our patient did not seek medical attention and instead managed his symptoms conservatively with cold compresses. Although he noticed an overall subjective improvement in the appearance of his face after this second treatment, he received a third treatment with PDT approximately 1 month later, which resulted in a response that was similar to his first visit.

Photodynamic therapy is an increasingly accepted treatment modality for a plethora of benign and malignant dermatologic conditions. Although blue and red light are the most common light sources utilized with PDT because their wavelengths (404–420 nm and 635 nm, respectively) correspond to the excitation peaks of photosensitizers, alternative light sources increasingly are being explored. There is increasing interest in utilizing infrared (IR) light sources (700–1,000,000 nm) to penetrate deeper into the skin in the treatment of precancerous and cancerous lesions. Exposure to IR radiation is known to raise skin temperature via inside-out dermal water absorption and is thought to be useful in PDT-ALA by promoting ALA penetration and its conversion to PpIX.⁸ In a randomized controlled trial by Giehl et al,⁹ visible light plus water-filtered IR-A light was shown to produce considerably less pain in ALA-PDT compared to placebo, though efficacy was not statistically affected. There are burgeoning trials examining the role of IR in treating dermatologic conditions such as acne, but research is still needed on ALA-PDT activated by IR radiation to target AKs.

Although the PDT side-effect profile of phototoxicity, dyspigmentation, and hypersensitivity is well documented, phototoxicity secondary to flame exposure is rare. In our patient, the synergistic effect of light and heat produced an exuberant phototoxic reaction. As the applications for PDT continue to broaden, this case may represent the importance of addressing additional precautions, such as avoiding open flames in the house or while camping, in the PDT aftercare instructions to maximize patient safety.

To the Editor:

Photodynamic therapy (PDT) is a US Food and Drug Administration–approved treatment for actinic keratosis (AK). It also commonly is administered off label for basal cell carcinoma, Bowen disease, photoaging, and acne vulgaris and is being investigated for other applications.^1,2 In the context of treating AK, the mechanism employed in PDT most commonly involves the application of exogenous aminolevulinic acid (ALA), which is metabolized to the endogenous photosensitizer protoporphyrin IX (PpIX) in skin cells by enzymes in the heme biosynthetic pathway.³ The preferential uptake of ALA and conversion to PpIX is due to the altered and increased permeability of abnormal keratin layers of aging, sun-damaged cells, and skin tumors. Selectivity of ALA also occurs due to the preferential intracellular accumulation of PpIX in proliferating, relatively iron–deficient, precancerous and cancerous cells. The therapeutic effect is achieved with light exposure to blue light wavelength at 417 nm and corresponds to the excitation peak of PpIX,⁴ which activates PpIX and forms reactive oxygen species in the presence of oxygen that ultimately cause cell necrosis and apoptosis.⁵ Because it takes approximately 24 hours for PpIX to be completely metabolized from the skin, patients are counseled to avoid sun or artificial light exposure in the first 24 hours post-PDT, regardless of the indication, to avoid a severe phototoxic reaction.^3,6,7 Although it is normal and desirable for patients to experience some form of a phototoxic reaction, which may include erythema, edema, crusting, vesiculation, or erosion in most patients, these types of reactions most often are secondary to the intended exposure and incidental natural or artificial light exposures.⁶ We report a case of a severe phototoxic reaction in which a patient experienced painful erythema and purulence on the left side of the chin after being within an arm’s length of a flame in a fireplace following PDT treatment.

A 59-year-old man presented to our dermatology clinic for his second of 3 PDT sessions to treat AKs on the face. He had a history of a basal cell carcinoma on the left nasolabial fold that previously was treated with Mohs micrographic surgery and melanoma on the left ear that was previously treated with excision. The patient received the initial PDT session 1 month prior and experienced a mild reaction with minimal redness and peeling that resolved in 4 to 5 days. For the second treatment, per standard protocol at our clinic, ALA was applied to the face, after which the patient incubated for 1 hour prior to blue light exposure (mean [SD] peak output of 417 [5] nm for 1000 seconds and 10 J/cm²).

After blue light exposure, broad-spectrum sunscreen (sun protection factor 47) was applied to our patient’s face, and he wore a wide-brimmed hat upon leaving the clinic and walking to his car. Similar to the first PDT session 1 month prior, he experienced minimal pain immediately after treatment. Once home and approximately 4 to 5 hours after PDT, he tended to a fire using his left hand and leaned into the fireplace with the left side of his face, which was within an arm’s length of the flames. Although his skin did not come in direct contact with the flames, the brief 2- to 3-minute exposure to the flame’s light and heat produced an immediate intense burning pain that the patient likened to the pain of blue light exposure. Within 24 hours, he developed a severe inflammatory reaction that included erythema, edema, desquamation, and pustules on the left side of the chin and cheek that produced a purulent discharge (Figure). The purulence resolved the next day; however, the other clinical manifestations persisted for 1 week. Despite the discomfort and symptoms, our patient did not seek medical attention and instead managed his symptoms conservatively with cold compresses. Although he noticed an overall subjective improvement in the appearance of his face after this second treatment, he received a third treatment with PDT approximately 1 month later, which resulted in a response that was similar to his first visit.

Photodynamic therapy is an increasingly accepted treatment modality for a plethora of benign and malignant dermatologic conditions. Although blue and red light are the most common light sources utilized with PDT because their wavelengths (404–420 nm and 635 nm, respectively) correspond to the excitation peaks of photosensitizers, alternative light sources increasingly are being explored. There is increasing interest in utilizing infrared (IR) light sources (700–1,000,000 nm) to penetrate deeper into the skin in the treatment of precancerous and cancerous lesions. Exposure to IR radiation is known to raise skin temperature via inside-out dermal water absorption and is thought to be useful in PDT-ALA by promoting ALA penetration and its conversion to PpIX.⁸ In a randomized controlled trial by Giehl et al,⁹ visible light plus water-filtered IR-A light was shown to produce considerably less pain in ALA-PDT compared to placebo, though efficacy was not statistically affected. There are burgeoning trials examining the role of IR in treating dermatologic conditions such as acne, but research is still needed on ALA-PDT activated by IR radiation to target AKs.

Although the PDT side-effect profile of phototoxicity, dyspigmentation, and hypersensitivity is well documented, phototoxicity secondary to flame exposure is rare. In our patient, the synergistic effect of light and heat produced an exuberant phototoxic reaction. As the applications for PDT continue to broaden, this case may represent the importance of addressing additional precautions, such as avoiding open flames in the house or while camping, in the PDT aftercare instructions to maximize patient safety.

To the Editor:

Photodynamic therapy (PDT) is a US Food and Drug Administration–approved treatment for actinic keratosis (AK). It also commonly is administered off label for basal cell carcinoma, Bowen disease, photoaging, and acne vulgaris and is being investigated for other applications.^1,2 In the context of treating AK, the mechanism employed in PDT most commonly involves the application of exogenous aminolevulinic acid (ALA), which is metabolized to the endogenous photosensitizer protoporphyrin IX (PpIX) in skin cells by enzymes in the heme biosynthetic pathway.³ The preferential uptake of ALA and conversion to PpIX is due to the altered and increased permeability of abnormal keratin layers of aging, sun-damaged cells, and skin tumors. Selectivity of ALA also occurs due to the preferential intracellular accumulation of PpIX in proliferating, relatively iron–deficient, precancerous and cancerous cells. The therapeutic effect is achieved with light exposure to blue light wavelength at 417 nm and corresponds to the excitation peak of PpIX,⁴ which activates PpIX and forms reactive oxygen species in the presence of oxygen that ultimately cause cell necrosis and apoptosis.⁵ Because it takes approximately 24 hours for PpIX to be completely metabolized from the skin, patients are counseled to avoid sun or artificial light exposure in the first 24 hours post-PDT, regardless of the indication, to avoid a severe phototoxic reaction.^3,6,7 Although it is normal and desirable for patients to experience some form of a phototoxic reaction, which may include erythema, edema, crusting, vesiculation, or erosion in most patients, these types of reactions most often are secondary to the intended exposure and incidental natural or artificial light exposures.⁶ We report a case of a severe phototoxic reaction in which a patient experienced painful erythema and purulence on the left side of the chin after being within an arm’s length of a flame in a fireplace following PDT treatment.

A 59-year-old man presented to our dermatology clinic for his second of 3 PDT sessions to treat AKs on the face. He had a history of a basal cell carcinoma on the left nasolabial fold that previously was treated with Mohs micrographic surgery and melanoma on the left ear that was previously treated with excision. The patient received the initial PDT session 1 month prior and experienced a mild reaction with minimal redness and peeling that resolved in 4 to 5 days. For the second treatment, per standard protocol at our clinic, ALA was applied to the face, after which the patient incubated for 1 hour prior to blue light exposure (mean [SD] peak output of 417 [5] nm for 1000 seconds and 10 J/cm²).

After blue light exposure, broad-spectrum sunscreen (sun protection factor 47) was applied to our patient’s face, and he wore a wide-brimmed hat upon leaving the clinic and walking to his car. Similar to the first PDT session 1 month prior, he experienced minimal pain immediately after treatment. Once home and approximately 4 to 5 hours after PDT, he tended to a fire using his left hand and leaned into the fireplace with the left side of his face, which was within an arm’s length of the flames. Although his skin did not come in direct contact with the flames, the brief 2- to 3-minute exposure to the flame’s light and heat produced an immediate intense burning pain that the patient likened to the pain of blue light exposure. Within 24 hours, he developed a severe inflammatory reaction that included erythema, edema, desquamation, and pustules on the left side of the chin and cheek that produced a purulent discharge (Figure). The purulence resolved the next day; however, the other clinical manifestations persisted for 1 week. Despite the discomfort and symptoms, our patient did not seek medical attention and instead managed his symptoms conservatively with cold compresses. Although he noticed an overall subjective improvement in the appearance of his face after this second treatment, he received a third treatment with PDT approximately 1 month later, which resulted in a response that was similar to his first visit.

Photodynamic therapy is an increasingly accepted treatment modality for a plethora of benign and malignant dermatologic conditions. Although blue and red light are the most common light sources utilized with PDT because their wavelengths (404–420 nm and 635 nm, respectively) correspond to the excitation peaks of photosensitizers, alternative light sources increasingly are being explored. There is increasing interest in utilizing infrared (IR) light sources (700–1,000,000 nm) to penetrate deeper into the skin in the treatment of precancerous and cancerous lesions. Exposure to IR radiation is known to raise skin temperature via inside-out dermal water absorption and is thought to be useful in PDT-ALA by promoting ALA penetration and its conversion to PpIX.⁸ In a randomized controlled trial by Giehl et al,⁹ visible light plus water-filtered IR-A light was shown to produce considerably less pain in ALA-PDT compared to placebo, though efficacy was not statistically affected. There are burgeoning trials examining the role of IR in treating dermatologic conditions such as acne, but research is still needed on ALA-PDT activated by IR radiation to target AKs.

Although the PDT side-effect profile of phototoxicity, dyspigmentation, and hypersensitivity is well documented, phototoxicity secondary to flame exposure is rare. In our patient, the synergistic effect of light and heat produced an exuberant phototoxic reaction. As the applications for PDT continue to broaden, this case may represent the importance of addressing additional precautions, such as avoiding open flames in the house or while camping, in the PDT aftercare instructions to maximize patient safety.

Pilomatrix carcinoma is a rare adnexal tumor with origin from the germinative matrical cells of the hair follicle. Clinically, it presents as a solitary lesion commonly found in the head and neck region as well as the upper back. The tumors cannot be distinguished by their clinical appearance only and frequently are mistaken for cysts. Histopathologic examination provides the definitive diagnosis in most cases. These carcinomas are aggressive neoplasms with a high probability of local recurrence and distant metastasis. Assessment of the Wnt signaling pathway components such as β-catenin, lymphoid enhancer-binding factor 1 (LEF-1), and caudal-related homeobox transcription factor 2 (CDX-2) potentially can be used for diagnostic purposes and targeted therapy.

We report a rare and unique case of early pilomatrix carcinoma with intralesional melanocytes. We review the molecular pathology and pathogenesis of these carcinomas as well as the significance of early diagnosis.

Case Report

A 73-year-old man with a history of extensive sun exposure presented with a 1-cm, raised, rapidly growing, slightly irregular, purple lesion on the right forearm of 3 months’ duration with tendency to bleed. He did not have a history of skin cancers and was otherwise healthy. Excision was recommended due to the progressive and rapid growth of the lesion.

Histopathologic Findings—Gross examination revealed a 0.9×0.7-cm, raised, slightly irregular lesion located 1 mm away from the closest peripheral margin. Histologically, the lesion was a relatively circumscribed, dermal-based basaloid neoplasm with slightly ill-defined edges involving the superficial and deep dermis (Figure 1A). The neoplasm was formed predominantly of sheets of basaloid cells and small nests of ghost cells, in addition to some squamoid and transitional cells (Figure 1B). The basaloid cells exhibited severe nuclear atypia, pleomorphism, increased nuclear to cytoplasmic ratio (Figure 1C), minimal to moderate amounts of eosinophilic cytoplasm, enlarged nuclei, prominent nucleoli, and coarse chromatin pattern. Abundant mitotic activity and apoptotic bodies were present as well as focal area of central necrosis (Figure 1C). Also, melanophages and a multinucleated giant cell reaction was noted. Elastic trichrome special stain highlighted focal infiltration of the neoplastic cells into the adjacent desmoplastic stroma. Melanin stain was negative for melanin pigment within the neoplasm. Given the presence of severely atypical basaloid cells along with ghost cells indicating matrical differentiation, a diagnosis of pilomatrix carcinoma was rendered.

Immunohistochemistry—The neoplastic cells were diffusely positive for p63, CDX-2 (Figure 2A), β-catenin (Figure 2B), and CD10 (Figure 2C), and focally and weakly positive for cytokeratin (CK) 5, BerEP4 (staining the tumor periphery), androgen receptor, and CK18 (a low-molecular-weight keratin). They were negative for monoclonal carcinoembryonic antigen, epithelial membrane antigen, CK7, CK20, CD34, SOX-10, CD56, synaptophysin, and chromogranin. Cytokeratin 14 was positive in the squamoid cells but negative in the basaloid cells. SOX-10 and melanoma cocktail immunostains demonstrated few intralesional dendritic melanocytes.

Comment

Pilomatrix carcinoma is a rare malignant cutaneous adnexal neoplasm with origin from the germinative matrix of the hair bulb region of hair follicles. Pilomatrix carcinoma was first reported in 1980.^1,2 These tumors are characterized by rapid growth and aggressive behavior. Their benign counterpart, pilomatrixoma, is a slow-growing, dermal or subcutaneous tumor that rarely recurs after complete excision.

As with pilomatrixoma, pilomatrix carcinomas are asymptomatic and present as solitary dermal or subcutaneous masses^3,4 that most commonly are found in the posterior neck, upper back, and preauricular regions of middle-aged or elderly adults with male predominance.⁵ They range in size from 0.5 to 20 cm with a mean of 4 cm that is slightly larger than pilomatrixoma. Pilomatrix carcinomas predominantly are firm tumors with or without cystic components, and they exhibit a high probability of recurrence and have risk for distant metastasis.^6-15

The differential diagnosis includes epidermal cysts, pilomatrixoma, basal cell carcinoma with matrical differentiation, trichoblastoma/trichoblastic carcinoma, and trichilemmal carcinoma. Pilomatrix carcinomas frequently are mistaken for epidermal cysts on clinical examination. Such a distinction can be easily resolved by histopathologic evaluation. The more challenging differential diagnosis is with pilomatrixoma. Histologically, pilomatrixomas consist of a distinct population of cells including basaloid, squamoid, transitional, and shadow cells in variable proportions. The basaloid cells transition to shadow cells in an organized zonal fashion.¹⁶ Compared to pilomatrixomas, pilomatrix carcinomas often show predominance of the basaloid cells; marked cytologic atypia and pleomorphism; numerous mitotic figures; deep infiltrative pattern into subcutaneous fat, fascia, and skeletal muscle; stromal desmoplasia; necrosis; and neurovascular invasion (Tables 1 and 2). Furthermore, the shadow cells tend to form a small nested pattern in pilomatrix carcinoma instead of the flat sheetlike pattern usually observed in pilomatrixoma.¹⁶ Basal cell carcinoma with matrical differentiation can pose a diagnostic challenge in the differential diagnosis; basal cell carcinoma usually exhibits a peripheral palisade of the basaloid cells accompanied by retraction spaces separating the tumor from the stroma. Trichoblastoma/trichoblastic carcinoma with matrical differentiation can be distinguished by its exuberant stroma, prominent primitive hair follicles, and papillary mesenchymal bodies. Trichilemmal carcinomas are recognized by their connection to the overlying epidermis, peripheral palisading, and presence of clear cells, while pilomatrix carcinoma lacks connection to the surface epithelium.

Immunohistochemical stains have little to no role in the differential diagnosis, and morphology is the mainstay in making the diagnosis. Rarely, pilomatrix carcinoma can be confused with poorly differentiated sebaceous carcinoma and poorly differentiated squamous cell carcinoma. Although careful scrutiny of the histologic features may help identify mature sebocytes in sebaceous carcinoma, evidence of keratinization in squamous cell carcinoma and ghost cells in pilomatrix carcinoma, using a panel of immunohistochemical stains can be helpful in reaching the final diagnosis (Table 3).

The development of hair matrix tumors have been known to harbor mutations in exon 3 of the catenin beta-1 gene, CTNNB1, that encodes for β-catenin, a downstream effector in the Wnt signaling pathway responsible for differentiation, proliferation, and adhesion of epithelial stem cells.^17-21 In a study conducted by Kazakov et al,²² DNA was extracted from 86 lesions: 4 were pilomatrixomas and 1 was a pilomatrix carcinoma. A polymerase chain reaction assay revealed 8 pathogenic variants of the β-catenin gene. D32Y (CTNNB1):c.94G>T (p.Asp32Tyr) and G34R (CTNNB1):c.100G>C (p.Gly34Arg) were the mutations present in pilomatrixoma and pilomatrix carcinoma, respectively.²² In addition, there are several proteins that are part of the Wnt pathway in addition to β-catenin—LEF-1 and CDX-2.

Tumminello and Hosler²³ found that pilomatrixomas and pilomatrix carcinomas were positive for CDX-2, β-catenin, and LEF-1 by immunohistochemistry. These downstream molecules in the Wnt signaling pathway could have the potential to be used as diagnostic and prognostic markers.^2,13,15,23

Although the pathogenesis is unclear, there are 2 possible mechanisms by which pilomatrix carcinomas develop. They can either arise as de novo tumors, or it is possible that initial mutations in β-catenin result in the formation of pilomatrixomas at an early age that may undergo malignant transformation in elderly patients over time with additional mutations.²

Our case was strongly and diffusely positive for β-catenin in a nuclear and cytoplasmic pattern and CDX-2 in a nuclear pattern, supporting the role of the Wnt signaling pathway in such tumors. Furthermore, our case demonstrated the presence of few intralesional normal dendritic melanocytes, a rare finding^1,24,25 but not unexpected, as melanocytes normally are present within the hair follicle matrix.

Pilomatrix carcinomas are aggressive tumors with a high risk for local recurrence and tendency for metastasis. In a study of 13 cases of pilomatrix carcinomas, Herrmann et al¹³ found that metastasis was significantly associated with local tumor recurrence (P<.0413). They concluded that the combination of overall high local recurrence and metastatic rates of pilomatrix carcinoma as well as documented tumor-related deaths would warrant continued patient follow-up, especially for recurrent tumors.¹³ Rapid growth of a tumor, either de novo or following several months of stable size, should alert physicians to perform a diagnostic biopsy.

Management options of pilomatrix carcinoma include surgery or radiation with close follow-up. The most widely reported treatment of pilomatrix carcinoma is wide local excision with histologically confirmed clear margins. Mohs micrographic surgery is an excellent treatment option.^2,13-15 Adjuvant radiation therapy may be necessary following excision. Currently there is no consensus on surgical management, and standard excisional margins have not been defined.²⁶ Jones et al² concluded that complete excision with wide margins likely is curative, with decreased rates of recurrence, and better awareness of this carcinoma would lead to appropriate treatment while avoiding unnecessary diagnostic tests.²

Conclusion

We report an exceptionally unique case of early pilomatrix carcinoma with a discussion on the pathogenesis and molecular pathology of hair matrix tumors. A large cohort of patients with longer follow-up periods and better molecular characterization is essential in drawing accurate information about their prognosis, identifying molecular markers that can be used as therapeutic targets, and determining ideal management strategy.

Pilomatrix carcinoma is a rare adnexal tumor with origin from the germinative matrical cells of the hair follicle. Clinically, it presents as a solitary lesion commonly found in the head and neck region as well as the upper back. The tumors cannot be distinguished by their clinical appearance only and frequently are mistaken for cysts. Histopathologic examination provides the definitive diagnosis in most cases. These carcinomas are aggressive neoplasms with a high probability of local recurrence and distant metastasis. Assessment of the Wnt signaling pathway components such as β-catenin, lymphoid enhancer-binding factor 1 (LEF-1), and caudal-related homeobox transcription factor 2 (CDX-2) potentially can be used for diagnostic purposes and targeted therapy.

We report a rare and unique case of early pilomatrix carcinoma with intralesional melanocytes. We review the molecular pathology and pathogenesis of these carcinomas as well as the significance of early diagnosis.

Case Report

A 73-year-old man with a history of extensive sun exposure presented with a 1-cm, raised, rapidly growing, slightly irregular, purple lesion on the right forearm of 3 months’ duration with tendency to bleed. He did not have a history of skin cancers and was otherwise healthy. Excision was recommended due to the progressive and rapid growth of the lesion.

Histopathologic Findings—Gross examination revealed a 0.9×0.7-cm, raised, slightly irregular lesion located 1 mm away from the closest peripheral margin. Histologically, the lesion was a relatively circumscribed, dermal-based basaloid neoplasm with slightly ill-defined edges involving the superficial and deep dermis (Figure 1A). The neoplasm was formed predominantly of sheets of basaloid cells and small nests of ghost cells, in addition to some squamoid and transitional cells (Figure 1B). The basaloid cells exhibited severe nuclear atypia, pleomorphism, increased nuclear to cytoplasmic ratio (Figure 1C), minimal to moderate amounts of eosinophilic cytoplasm, enlarged nuclei, prominent nucleoli, and coarse chromatin pattern. Abundant mitotic activity and apoptotic bodies were present as well as focal area of central necrosis (Figure 1C). Also, melanophages and a multinucleated giant cell reaction was noted. Elastic trichrome special stain highlighted focal infiltration of the neoplastic cells into the adjacent desmoplastic stroma. Melanin stain was negative for melanin pigment within the neoplasm. Given the presence of severely atypical basaloid cells along with ghost cells indicating matrical differentiation, a diagnosis of pilomatrix carcinoma was rendered.

Immunohistochemistry—The neoplastic cells were diffusely positive for p63, CDX-2 (Figure 2A), β-catenin (Figure 2B), and CD10 (Figure 2C), and focally and weakly positive for cytokeratin (CK) 5, BerEP4 (staining the tumor periphery), androgen receptor, and CK18 (a low-molecular-weight keratin). They were negative for monoclonal carcinoembryonic antigen, epithelial membrane antigen, CK7, CK20, CD34, SOX-10, CD56, synaptophysin, and chromogranin. Cytokeratin 14 was positive in the squamoid cells but negative in the basaloid cells. SOX-10 and melanoma cocktail immunostains demonstrated few intralesional dendritic melanocytes.

Comment

Pilomatrix carcinoma is a rare malignant cutaneous adnexal neoplasm with origin from the germinative matrix of the hair bulb region of hair follicles. Pilomatrix carcinoma was first reported in 1980.^1,2 These tumors are characterized by rapid growth and aggressive behavior. Their benign counterpart, pilomatrixoma, is a slow-growing, dermal or subcutaneous tumor that rarely recurs after complete excision.

As with pilomatrixoma, pilomatrix carcinomas are asymptomatic and present as solitary dermal or subcutaneous masses^3,4 that most commonly are found in the posterior neck, upper back, and preauricular regions of middle-aged or elderly adults with male predominance.⁵ They range in size from 0.5 to 20 cm with a mean of 4 cm that is slightly larger than pilomatrixoma. Pilomatrix carcinomas predominantly are firm tumors with or without cystic components, and they exhibit a high probability of recurrence and have risk for distant metastasis.^6-15

The differential diagnosis includes epidermal cysts, pilomatrixoma, basal cell carcinoma with matrical differentiation, trichoblastoma/trichoblastic carcinoma, and trichilemmal carcinoma. Pilomatrix carcinomas frequently are mistaken for epidermal cysts on clinical examination. Such a distinction can be easily resolved by histopathologic evaluation. The more challenging differential diagnosis is with pilomatrixoma. Histologically, pilomatrixomas consist of a distinct population of cells including basaloid, squamoid, transitional, and shadow cells in variable proportions. The basaloid cells transition to shadow cells in an organized zonal fashion.¹⁶ Compared to pilomatrixomas, pilomatrix carcinomas often show predominance of the basaloid cells; marked cytologic atypia and pleomorphism; numerous mitotic figures; deep infiltrative pattern into subcutaneous fat, fascia, and skeletal muscle; stromal desmoplasia; necrosis; and neurovascular invasion (Tables 1 and 2). Furthermore, the shadow cells tend to form a small nested pattern in pilomatrix carcinoma instead of the flat sheetlike pattern usually observed in pilomatrixoma.¹⁶ Basal cell carcinoma with matrical differentiation can pose a diagnostic challenge in the differential diagnosis; basal cell carcinoma usually exhibits a peripheral palisade of the basaloid cells accompanied by retraction spaces separating the tumor from the stroma. Trichoblastoma/trichoblastic carcinoma with matrical differentiation can be distinguished by its exuberant stroma, prominent primitive hair follicles, and papillary mesenchymal bodies. Trichilemmal carcinomas are recognized by their connection to the overlying epidermis, peripheral palisading, and presence of clear cells, while pilomatrix carcinoma lacks connection to the surface epithelium.

Immunohistochemical stains have little to no role in the differential diagnosis, and morphology is the mainstay in making the diagnosis. Rarely, pilomatrix carcinoma can be confused with poorly differentiated sebaceous carcinoma and poorly differentiated squamous cell carcinoma. Although careful scrutiny of the histologic features may help identify mature sebocytes in sebaceous carcinoma, evidence of keratinization in squamous cell carcinoma and ghost cells in pilomatrix carcinoma, using a panel of immunohistochemical stains can be helpful in reaching the final diagnosis (Table 3).

The development of hair matrix tumors have been known to harbor mutations in exon 3 of the catenin beta-1 gene, CTNNB1, that encodes for β-catenin, a downstream effector in the Wnt signaling pathway responsible for differentiation, proliferation, and adhesion of epithelial stem cells.^17-21 In a study conducted by Kazakov et al,²² DNA was extracted from 86 lesions: 4 were pilomatrixomas and 1 was a pilomatrix carcinoma. A polymerase chain reaction assay revealed 8 pathogenic variants of the β-catenin gene. D32Y (CTNNB1):c.94G>T (p.Asp32Tyr) and G34R (CTNNB1):c.100G>C (p.Gly34Arg) were the mutations present in pilomatrixoma and pilomatrix carcinoma, respectively.²² In addition, there are several proteins that are part of the Wnt pathway in addition to β-catenin—LEF-1 and CDX-2.

Tumminello and Hosler²³ found that pilomatrixomas and pilomatrix carcinomas were positive for CDX-2, β-catenin, and LEF-1 by immunohistochemistry. These downstream molecules in the Wnt signaling pathway could have the potential to be used as diagnostic and prognostic markers.^2,13,15,23

Although the pathogenesis is unclear, there are 2 possible mechanisms by which pilomatrix carcinomas develop. They can either arise as de novo tumors, or it is possible that initial mutations in β-catenin result in the formation of pilomatrixomas at an early age that may undergo malignant transformation in elderly patients over time with additional mutations.²

Our case was strongly and diffusely positive for β-catenin in a nuclear and cytoplasmic pattern and CDX-2 in a nuclear pattern, supporting the role of the Wnt signaling pathway in such tumors. Furthermore, our case demonstrated the presence of few intralesional normal dendritic melanocytes, a rare finding^1,24,25 but not unexpected, as melanocytes normally are present within the hair follicle matrix.

Pilomatrix carcinomas are aggressive tumors with a high risk for local recurrence and tendency for metastasis. In a study of 13 cases of pilomatrix carcinomas, Herrmann et al¹³ found that metastasis was significantly associated with local tumor recurrence (P<.0413). They concluded that the combination of overall high local recurrence and metastatic rates of pilomatrix carcinoma as well as documented tumor-related deaths would warrant continued patient follow-up, especially for recurrent tumors.¹³ Rapid growth of a tumor, either de novo or following several months of stable size, should alert physicians to perform a diagnostic biopsy.

Management options of pilomatrix carcinoma include surgery or radiation with close follow-up. The most widely reported treatment of pilomatrix carcinoma is wide local excision with histologically confirmed clear margins. Mohs micrographic surgery is an excellent treatment option.^2,13-15 Adjuvant radiation therapy may be necessary following excision. Currently there is no consensus on surgical management, and standard excisional margins have not been defined.²⁶ Jones et al² concluded that complete excision with wide margins likely is curative, with decreased rates of recurrence, and better awareness of this carcinoma would lead to appropriate treatment while avoiding unnecessary diagnostic tests.²

Conclusion

We report an exceptionally unique case of early pilomatrix carcinoma with a discussion on the pathogenesis and molecular pathology of hair matrix tumors. A large cohort of patients with longer follow-up periods and better molecular characterization is essential in drawing accurate information about their prognosis, identifying molecular markers that can be used as therapeutic targets, and determining ideal management strategy.

Pilomatrix carcinoma is a rare adnexal tumor with origin from the germinative matrical cells of the hair follicle. Clinically, it presents as a solitary lesion commonly found in the head and neck region as well as the upper back. The tumors cannot be distinguished by their clinical appearance only and frequently are mistaken for cysts. Histopathologic examination provides the definitive diagnosis in most cases. These carcinomas are aggressive neoplasms with a high probability of local recurrence and distant metastasis. Assessment of the Wnt signaling pathway components such as β-catenin, lymphoid enhancer-binding factor 1 (LEF-1), and caudal-related homeobox transcription factor 2 (CDX-2) potentially can be used for diagnostic purposes and targeted therapy.

We report a rare and unique case of early pilomatrix carcinoma with intralesional melanocytes. We review the molecular pathology and pathogenesis of these carcinomas as well as the significance of early diagnosis.

Case Report

A 73-year-old man with a history of extensive sun exposure presented with a 1-cm, raised, rapidly growing, slightly irregular, purple lesion on the right forearm of 3 months’ duration with tendency to bleed. He did not have a history of skin cancers and was otherwise healthy. Excision was recommended due to the progressive and rapid growth of the lesion.

Histopathologic Findings—Gross examination revealed a 0.9×0.7-cm, raised, slightly irregular lesion located 1 mm away from the closest peripheral margin. Histologically, the lesion was a relatively circumscribed, dermal-based basaloid neoplasm with slightly ill-defined edges involving the superficial and deep dermis (Figure 1A). The neoplasm was formed predominantly of sheets of basaloid cells and small nests of ghost cells, in addition to some squamoid and transitional cells (Figure 1B). The basaloid cells exhibited severe nuclear atypia, pleomorphism, increased nuclear to cytoplasmic ratio (Figure 1C), minimal to moderate amounts of eosinophilic cytoplasm, enlarged nuclei, prominent nucleoli, and coarse chromatin pattern. Abundant mitotic activity and apoptotic bodies were present as well as focal area of central necrosis (Figure 1C). Also, melanophages and a multinucleated giant cell reaction was noted. Elastic trichrome special stain highlighted focal infiltration of the neoplastic cells into the adjacent desmoplastic stroma. Melanin stain was negative for melanin pigment within the neoplasm. Given the presence of severely atypical basaloid cells along with ghost cells indicating matrical differentiation, a diagnosis of pilomatrix carcinoma was rendered.

Immunohistochemistry—The neoplastic cells were diffusely positive for p63, CDX-2 (Figure 2A), β-catenin (Figure 2B), and CD10 (Figure 2C), and focally and weakly positive for cytokeratin (CK) 5, BerEP4 (staining the tumor periphery), androgen receptor, and CK18 (a low-molecular-weight keratin). They were negative for monoclonal carcinoembryonic antigen, epithelial membrane antigen, CK7, CK20, CD34, SOX-10, CD56, synaptophysin, and chromogranin. Cytokeratin 14 was positive in the squamoid cells but negative in the basaloid cells. SOX-10 and melanoma cocktail immunostains demonstrated few intralesional dendritic melanocytes.

Comment

Pilomatrix carcinoma is a rare malignant cutaneous adnexal neoplasm with origin from the germinative matrix of the hair bulb region of hair follicles. Pilomatrix carcinoma was first reported in 1980.^1,2 These tumors are characterized by rapid growth and aggressive behavior. Their benign counterpart, pilomatrixoma, is a slow-growing, dermal or subcutaneous tumor that rarely recurs after complete excision.

As with pilomatrixoma, pilomatrix carcinomas are asymptomatic and present as solitary dermal or subcutaneous masses^3,4 that most commonly are found in the posterior neck, upper back, and preauricular regions of middle-aged or elderly adults with male predominance.⁵ They range in size from 0.5 to 20 cm with a mean of 4 cm that is slightly larger than pilomatrixoma. Pilomatrix carcinomas predominantly are firm tumors with or without cystic components, and they exhibit a high probability of recurrence and have risk for distant metastasis.^6-15

The differential diagnosis includes epidermal cysts, pilomatrixoma, basal cell carcinoma with matrical differentiation, trichoblastoma/trichoblastic carcinoma, and trichilemmal carcinoma. Pilomatrix carcinomas frequently are mistaken for epidermal cysts on clinical examination. Such a distinction can be easily resolved by histopathologic evaluation. The more challenging differential diagnosis is with pilomatrixoma. Histologically, pilomatrixomas consist of a distinct population of cells including basaloid, squamoid, transitional, and shadow cells in variable proportions. The basaloid cells transition to shadow cells in an organized zonal fashion.¹⁶ Compared to pilomatrixomas, pilomatrix carcinomas often show predominance of the basaloid cells; marked cytologic atypia and pleomorphism; numerous mitotic figures; deep infiltrative pattern into subcutaneous fat, fascia, and skeletal muscle; stromal desmoplasia; necrosis; and neurovascular invasion (Tables 1 and 2). Furthermore, the shadow cells tend to form a small nested pattern in pilomatrix carcinoma instead of the flat sheetlike pattern usually observed in pilomatrixoma.¹⁶ Basal cell carcinoma with matrical differentiation can pose a diagnostic challenge in the differential diagnosis; basal cell carcinoma usually exhibits a peripheral palisade of the basaloid cells accompanied by retraction spaces separating the tumor from the stroma. Trichoblastoma/trichoblastic carcinoma with matrical differentiation can be distinguished by its exuberant stroma, prominent primitive hair follicles, and papillary mesenchymal bodies. Trichilemmal carcinomas are recognized by their connection to the overlying epidermis, peripheral palisading, and presence of clear cells, while pilomatrix carcinoma lacks connection to the surface epithelium.

Immunohistochemical stains have little to no role in the differential diagnosis, and morphology is the mainstay in making the diagnosis. Rarely, pilomatrix carcinoma can be confused with poorly differentiated sebaceous carcinoma and poorly differentiated squamous cell carcinoma. Although careful scrutiny of the histologic features may help identify mature sebocytes in sebaceous carcinoma, evidence of keratinization in squamous cell carcinoma and ghost cells in pilomatrix carcinoma, using a panel of immunohistochemical stains can be helpful in reaching the final diagnosis (Table 3).

The development of hair matrix tumors have been known to harbor mutations in exon 3 of the catenin beta-1 gene, CTNNB1, that encodes for β-catenin, a downstream effector in the Wnt signaling pathway responsible for differentiation, proliferation, and adhesion of epithelial stem cells.^17-21 In a study conducted by Kazakov et al,²² DNA was extracted from 86 lesions: 4 were pilomatrixomas and 1 was a pilomatrix carcinoma. A polymerase chain reaction assay revealed 8 pathogenic variants of the β-catenin gene. D32Y (CTNNB1):c.94G>T (p.Asp32Tyr) and G34R (CTNNB1):c.100G>C (p.Gly34Arg) were the mutations present in pilomatrixoma and pilomatrix carcinoma, respectively.²² In addition, there are several proteins that are part of the Wnt pathway in addition to β-catenin—LEF-1 and CDX-2.

Tumminello and Hosler²³ found that pilomatrixomas and pilomatrix carcinomas were positive for CDX-2, β-catenin, and LEF-1 by immunohistochemistry. These downstream molecules in the Wnt signaling pathway could have the potential to be used as diagnostic and prognostic markers.^2,13,15,23

Although the pathogenesis is unclear, there are 2 possible mechanisms by which pilomatrix carcinomas develop. They can either arise as de novo tumors, or it is possible that initial mutations in β-catenin result in the formation of pilomatrixomas at an early age that may undergo malignant transformation in elderly patients over time with additional mutations.²

Our case was strongly and diffusely positive for β-catenin in a nuclear and cytoplasmic pattern and CDX-2 in a nuclear pattern, supporting the role of the Wnt signaling pathway in such tumors. Furthermore, our case demonstrated the presence of few intralesional normal dendritic melanocytes, a rare finding^1,24,25 but not unexpected, as melanocytes normally are present within the hair follicle matrix.

Pilomatrix carcinomas are aggressive tumors with a high risk for local recurrence and tendency for metastasis. In a study of 13 cases of pilomatrix carcinomas, Herrmann et al¹³ found that metastasis was significantly associated with local tumor recurrence (P<.0413). They concluded that the combination of overall high local recurrence and metastatic rates of pilomatrix carcinoma as well as documented tumor-related deaths would warrant continued patient follow-up, especially for recurrent tumors.¹³ Rapid growth of a tumor, either de novo or following several months of stable size, should alert physicians to perform a diagnostic biopsy.

Management options of pilomatrix carcinoma include surgery or radiation with close follow-up. The most widely reported treatment of pilomatrix carcinoma is wide local excision with histologically confirmed clear margins. Mohs micrographic surgery is an excellent treatment option.^2,13-15 Adjuvant radiation therapy may be necessary following excision. Currently there is no consensus on surgical management, and standard excisional margins have not been defined.²⁶ Jones et al² concluded that complete excision with wide margins likely is curative, with decreased rates of recurrence, and better awareness of this carcinoma would lead to appropriate treatment while avoiding unnecessary diagnostic tests.²

Conclusion

We report an exceptionally unique case of early pilomatrix carcinoma with a discussion on the pathogenesis and molecular pathology of hair matrix tumors. A large cohort of patients with longer follow-up periods and better molecular characterization is essential in drawing accurate information about their prognosis, identifying molecular markers that can be used as therapeutic targets, and determining ideal management strategy.

The term tanorexia describes compulsive use of a tanning bed, a disorder often identified in White patients. This compulsion is driven by underlying psychological distress that typically correlates with another psychiatric disorder, such as anxiety, body dysmorphic disorder, or an eating disorder. ¹ Severe anorexia combined with excessive indoor tanning led to a notable burden of cutaneous squamous cell carcinomas (SCCs) and keratoacanthomas in one of our patients. We discuss the management and approach to patient care in this difficult situation, which we have coined TANS syndrome (for T anorexia, A norexia, and N onmelanoma s kin cancer).

A Patient With TANS Syndrome

A 35-year-old cachectic woman, who appeared much older than her chronologic age, presented for management of numerous painful bleeding skin lesions. Diffuse, erythematous, tender nodules with central keratotic cores, some several centimeters in diameter, were scattered on the abdomen, chest, and extremities (Figure 1); similar lesions were noted on the neck (Figure 2). Numerous erythematous scaly papules and plaques consistent with actinic keratoses were noted throughout the body.

The patient reported that the cutaneous SCCs presented over the last few years, whereas her eating disorder began in adolescence and persisted despite multiple intensive outpatient and inpatient programs. The patient adamantly refused repeat hospitalization, against repeated suggestions by health care providers and her family. Comorbidities related to her anorexia included severe renal insufficiency, iron deficiency anemia, hypertriglyceridemia, kwashiorkor, and pellagra.

Within the last year, the patient had several biopsies showing SCC, keratoacanthoma type. The largest tumors had been treated by Mohs micrographic surgery, excision, and electrodesiccation or curettage. Adjuvant therapy over the last 2 years consisted of tazarotene cream 0.1%, imiquimod cream 5%, oral nicotinamide 500 mg twice daily, and acitretin 10 to 20 mg daily. Human papillomavirus 9-valent vaccine, recombinant, also had been tried as a chemopreventive and treatment, based on a published report of 2 patients in whom keratinocytic carcinomas decreased after such vaccination.² The dose of acitretin was kept low because of the patient’s severe renal insufficiency and lack of supporting data for its use in this setting. Despite these modalities, our patient continued to develop new cutaneous SCCs.

We considered starting intralesional methotrexate but deferred this course of action, given the patient’s deteriorating renal function. Our plan was to initiate intralesional 5-fluorouracil; however, the patient was admitted to the hospital and subsequently died due to cardiovascular complications of anorexia.

UV Radiation in the Setting of Immune Compromise

Habitual tanning bed use has been recognized as a psychologic addiction.^3,4 After exposure to UV radiation, damaged DNA upregulates pro-opiomelanocortin, which posttranslationally generates β-endorphins to elevate mood.^3,5

Tanning beds deliver a higher dose of UVA radiation than UVB radiation and cause darkening of pigmentation by oxidation of preformed melanin and redistribution of melanosomes.³ UVA radiation (320–400 nm) emitted from a tanning bed is 10- to 15-times higher than the radiation emitted by the midday sun and causes DNA damage through generation of reactive oxygen species. UVA penetrates the dermis; its harmful effect on DNA contributes to the pathogenesis of melanoma.

UVB radiation (290–320 nm) is mainly restricted to the epidermis and is largely responsible for erythema of the skin. UVB specifically causes direct damage to DNA by forming pyrimidine dimers, superficially causing sunburn. Excessive exposure to UVB radiation increases the risk for nonmelanoma skin cancer.⁶

Severe starvation and chronic malnutrition, as seen in anorexia nervosa, also are known to lead to immunosuppression.⁷ Exposure to UV radiation has been shown to impair the function of antigen-presenting cells, cytokines, and suppressor T cells, and is classified as a Group 1 carcinogen by the World Health Organization.^3,8 Combining a compromised immune system in anorexia with DNA damage from frequent indoor tanning provides a dangerous milieu for carcinogenesis.⁸ Without immune surveillance, as occurs with adequate nutrition, treatment of cutaneous SCC is, at best, challenging.

Primary care physicians, dermatologists, psychiatrists, nutritionists, and public health officials should educate high-risk patients to prevent TANS syndrome.

The term tanorexia describes compulsive use of a tanning bed, a disorder often identified in White patients. This compulsion is driven by underlying psychological distress that typically correlates with another psychiatric disorder, such as anxiety, body dysmorphic disorder, or an eating disorder. ¹ Severe anorexia combined with excessive indoor tanning led to a notable burden of cutaneous squamous cell carcinomas (SCCs) and keratoacanthomas in one of our patients. We discuss the management and approach to patient care in this difficult situation, which we have coined TANS syndrome (for T anorexia, A norexia, and N onmelanoma s kin cancer).

A Patient With TANS Syndrome

A 35-year-old cachectic woman, who appeared much older than her chronologic age, presented for management of numerous painful bleeding skin lesions. Diffuse, erythematous, tender nodules with central keratotic cores, some several centimeters in diameter, were scattered on the abdomen, chest, and extremities (Figure 1); similar lesions were noted on the neck (Figure 2). Numerous erythematous scaly papules and plaques consistent with actinic keratoses were noted throughout the body.

The patient reported that the cutaneous SCCs presented over the last few years, whereas her eating disorder began in adolescence and persisted despite multiple intensive outpatient and inpatient programs. The patient adamantly refused repeat hospitalization, against repeated suggestions by health care providers and her family. Comorbidities related to her anorexia included severe renal insufficiency, iron deficiency anemia, hypertriglyceridemia, kwashiorkor, and pellagra.

Within the last year, the patient had several biopsies showing SCC, keratoacanthoma type. The largest tumors had been treated by Mohs micrographic surgery, excision, and electrodesiccation or curettage. Adjuvant therapy over the last 2 years consisted of tazarotene cream 0.1%, imiquimod cream 5%, oral nicotinamide 500 mg twice daily, and acitretin 10 to 20 mg daily. Human papillomavirus 9-valent vaccine, recombinant, also had been tried as a chemopreventive and treatment, based on a published report of 2 patients in whom keratinocytic carcinomas decreased after such vaccination.² The dose of acitretin was kept low because of the patient’s severe renal insufficiency and lack of supporting data for its use in this setting. Despite these modalities, our patient continued to develop new cutaneous SCCs.

We considered starting intralesional methotrexate but deferred this course of action, given the patient’s deteriorating renal function. Our plan was to initiate intralesional 5-fluorouracil; however, the patient was admitted to the hospital and subsequently died due to cardiovascular complications of anorexia.

UV Radiation in the Setting of Immune Compromise

Habitual tanning bed use has been recognized as a psychologic addiction.^3,4 After exposure to UV radiation, damaged DNA upregulates pro-opiomelanocortin, which posttranslationally generates β-endorphins to elevate mood.^3,5

Tanning beds deliver a higher dose of UVA radiation than UVB radiation and cause darkening of pigmentation by oxidation of preformed melanin and redistribution of melanosomes.³ UVA radiation (320–400 nm) emitted from a tanning bed is 10- to 15-times higher than the radiation emitted by the midday sun and causes DNA damage through generation of reactive oxygen species. UVA penetrates the dermis; its harmful effect on DNA contributes to the pathogenesis of melanoma.

UVB radiation (290–320 nm) is mainly restricted to the epidermis and is largely responsible for erythema of the skin. UVB specifically causes direct damage to DNA by forming pyrimidine dimers, superficially causing sunburn. Excessive exposure to UVB radiation increases the risk for nonmelanoma skin cancer.⁶

Severe starvation and chronic malnutrition, as seen in anorexia nervosa, also are known to lead to immunosuppression.⁷ Exposure to UV radiation has been shown to impair the function of antigen-presenting cells, cytokines, and suppressor T cells, and is classified as a Group 1 carcinogen by the World Health Organization.^3,8 Combining a compromised immune system in anorexia with DNA damage from frequent indoor tanning provides a dangerous milieu for carcinogenesis.⁸ Without immune surveillance, as occurs with adequate nutrition, treatment of cutaneous SCC is, at best, challenging.

Primary care physicians, dermatologists, psychiatrists, nutritionists, and public health officials should educate high-risk patients to prevent TANS syndrome.

The term tanorexia describes compulsive use of a tanning bed, a disorder often identified in White patients. This compulsion is driven by underlying psychological distress that typically correlates with another psychiatric disorder, such as anxiety, body dysmorphic disorder, or an eating disorder. ¹ Severe anorexia combined with excessive indoor tanning led to a notable burden of cutaneous squamous cell carcinomas (SCCs) and keratoacanthomas in one of our patients. We discuss the management and approach to patient care in this difficult situation, which we have coined TANS syndrome (for T anorexia, A norexia, and N onmelanoma s kin cancer).

A Patient With TANS Syndrome

A 35-year-old cachectic woman, who appeared much older than her chronologic age, presented for management of numerous painful bleeding skin lesions. Diffuse, erythematous, tender nodules with central keratotic cores, some several centimeters in diameter, were scattered on the abdomen, chest, and extremities (Figure 1); similar lesions were noted on the neck (Figure 2). Numerous erythematous scaly papules and plaques consistent with actinic keratoses were noted throughout the body.

The patient reported that the cutaneous SCCs presented over the last few years, whereas her eating disorder began in adolescence and persisted despite multiple intensive outpatient and inpatient programs. The patient adamantly refused repeat hospitalization, against repeated suggestions by health care providers and her family. Comorbidities related to her anorexia included severe renal insufficiency, iron deficiency anemia, hypertriglyceridemia, kwashiorkor, and pellagra.

Within the last year, the patient had several biopsies showing SCC, keratoacanthoma type. The largest tumors had been treated by Mohs micrographic surgery, excision, and electrodesiccation or curettage. Adjuvant therapy over the last 2 years consisted of tazarotene cream 0.1%, imiquimod cream 5%, oral nicotinamide 500 mg twice daily, and acitretin 10 to 20 mg daily. Human papillomavirus 9-valent vaccine, recombinant, also had been tried as a chemopreventive and treatment, based on a published report of 2 patients in whom keratinocytic carcinomas decreased after such vaccination.² The dose of acitretin was kept low because of the patient’s severe renal insufficiency and lack of supporting data for its use in this setting. Despite these modalities, our patient continued to develop new cutaneous SCCs.

We considered starting intralesional methotrexate but deferred this course of action, given the patient’s deteriorating renal function. Our plan was to initiate intralesional 5-fluorouracil; however, the patient was admitted to the hospital and subsequently died due to cardiovascular complications of anorexia.

UV Radiation in the Setting of Immune Compromise

Habitual tanning bed use has been recognized as a psychologic addiction.^3,4 After exposure to UV radiation, damaged DNA upregulates pro-opiomelanocortin, which posttranslationally generates β-endorphins to elevate mood.^3,5

Tanning beds deliver a higher dose of UVA radiation than UVB radiation and cause darkening of pigmentation by oxidation of preformed melanin and redistribution of melanosomes.³ UVA radiation (320–400 nm) emitted from a tanning bed is 10- to 15-times higher than the radiation emitted by the midday sun and causes DNA damage through generation of reactive oxygen species. UVA penetrates the dermis; its harmful effect on DNA contributes to the pathogenesis of melanoma.

UVB radiation (290–320 nm) is mainly restricted to the epidermis and is largely responsible for erythema of the skin. UVB specifically causes direct damage to DNA by forming pyrimidine dimers, superficially causing sunburn. Excessive exposure to UVB radiation increases the risk for nonmelanoma skin cancer.⁶

Severe starvation and chronic malnutrition, as seen in anorexia nervosa, also are known to lead to immunosuppression.⁷ Exposure to UV radiation has been shown to impair the function of antigen-presenting cells, cytokines, and suppressor T cells, and is classified as a Group 1 carcinogen by the World Health Organization.^3,8 Combining a compromised immune system in anorexia with DNA damage from frequent indoor tanning provides a dangerous milieu for carcinogenesis.⁸ Without immune surveillance, as occurs with adequate nutrition, treatment of cutaneous SCC is, at best, challenging.

Primary care physicians, dermatologists, psychiatrists, nutritionists, and public health officials should educate high-risk patients to prevent TANS syndrome.