Article

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by uncontrolled hyperglycemia. Over the past few decades, its prevalence has steadily increased, now affecting approximately 10% of adults worldwide and ranking among the top 10 leading causes of death globally.¹ The pathophysiology of T2DM involves persistent hyperglycemia that drives insulin resistance and a progressive decline in insulin production from the pancreas.² Medical management of this condition aims to reduce blood glucose levels or enhance insulin production and sensitivity. Aside from lifestyle modifications, metformin is considered the first-line treatment for glycemic control according to the 2023 American Association of Clinical Endocrinology’s T2DM management algorithm.³ These updated guidelines stratify adjunct treatments by individualized glycemic targets and patient needs. For patients who are overweight or obese, glucagonlike peptide 1 (GLP-1) and dual GLP-1/ gastric inhibitory polypeptide (GIP) agonists are the preferred adjunct or second-line treatments.³

In this review, we highlight the dermatologic adverse effects and potential therapeutic benefits of metformin as well as GLP-1 and GLP-1/GIP agonists.

METFORMIN

Metformin is a biguanide agent used as a first-line treatment for T2DM because of its ability to reduce hepatic glucose production and increase peripheral tissue glucose uptake.⁴ In addition to its effects on glucose, metformin has been shown to have anti-inflammatory properties via inhibition of the nuclear factor κB and mammalian target of rapamycin (mTOR) pathways, leading to decreased production of cytokines associated with T helper (Th) 1 and Th17 cell responses, such as IL-17, interferon gamma (IFN-γ), and tumor necrosis factor α (TNF-α).^5-7 These findings have spurred interest among clinicians in the potential use of metformin for inflammatory conditions, including dermatologic diseases such as psoriasis and hidradenitis suppurativa (HS).⁸

Adverse Effects

Metformin is administered orally and generally is well tolerated. The most common adverse effects include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain.⁹ While cutaneous adverse effects are rare, multiple dermatologic adverse reactions to metformin have been reported,^10,11 including leukocytoclastic vasculitis,^11-13 fixed drug eruptions,^14-17 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,¹⁸ and photosensitivity reactions.¹⁹ Leukocytoclastic vasculitis and DRESS syndrome typically develop within the first month following metformin initiation, while fixed drug eruption and photosensitivity reactions have more variable timing, occurring weeks to years after treatment initiation.^12-19

Dermatologic Implications

Acanthosis Nigricans—Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvety skin thickening, typically in intertriginous areas such as the back of the neck, axillae, and groin.²⁰ It commonly is associated with insulin resistance and obesity.^21-23 Treatments for AN primarily center around insulin sensitivity and weight loss,^24,25 with some benefit observed from the use of keratolytic agents.^26,27 Metformin may have utility in treating AN through its effects on insulin sensitivity and glycemic control. Multiple case reports have noted marked improvements in AN in patients with and without obesity with the addition of metformin to their existing treatment regimens in doses ranging from 500 mg to 1700 mg daily.^28-30 However, an unblinded randomized controlled trial (RCT) comparing the efficacy of metformin (500 mg 3 times daily) with rosiglitazone (4 mg/d), another T2DM medication, on AN neck lesions in patients who were overweight and obese found no significant effects in lesion severity and only modest improvements in skin texture in both groups at 12 weeks following treatment initiation.³¹ Another RCT comparing metformin (500 mg twice daily) with a twice-daily capsule containing α-lipoic acid, biotin, chromium polynicotinate, and zinc sulfate, showed significant (P<.001) improvements in AN neck lesions in both groups after 12 weeks.³² According to Sung et al,⁸ longer duration of therapy (>6 months), higher doses (1700–2000 mg), and lower baseline weight were associated with higher efficacy of metformin for treatment of AN. Overall, the use of metformin as an adjunct treatment for AN, particularly in patients with underlying hyperglycemia, is supported in the literature, but further studies are needed to clarify dosing, duration of therapy, and patient populations that will benefit most from adding metformin to their treatment regimens.

Hirsutism—Hirsutism, which is characterized by excessive hair growth in androgen-dependent areas, can be challenging to treat. Metformin has been shown to reduce circulating insulin, luteinizing hormone, androstenedione, and testosterone, thus improving underlying hyperandrogenism, particularly in patients with polycystic ovary syndrome (PCOS).^33-35 Although single studies evaluating the efficacy of metformin for treatment of hirsutism in patients with PCOS have shown potential benefits,^36-38 meta-analyses showed no significant effects of metformin compared to placebo or oral contraceptives and decreased benefits compared to spironolactone and flutamide.³⁹ Given these findings showing that metformin was no more effective than placebo or other treatments, the current Endocrine Society guidelines recommend against the use of metformin for hirsutism.^39,40 There may be a role for metformin as an adjuvant therapy in certain populations (eg, patients with comorbid T2DM), although further studies stratifying risk factors such as body mass index and age are needed.⁴¹

Hidradenitis Suppurativa—Hidradenitis suppurativa is a follicular occlusive disease characterized by recurrent inflamed nodules leading to chronic dermal abscesses, fibrosis, and sinus tract formation primarily in intertriginous areas such as the axillae and groin.⁴² Medical management depends on disease severity but usually involves antibiotic treatment with adjunct therapies such as oral contraceptives, antiandrogenic medications (eg, spironolactone), biologic medications, and metformin.⁴² Preclinical and clinical data suggest that metformin can impact HS through metabolic and immunomodulatory mechanisms.^5,42 Like many chronic inflammatory disorders, HS is associated with metabolic syndrome.^43,44 A study evaluating insulin secretion after oral glucose tolerance testing showed increased insulin levels in patients with HS compared to controls (P=.02), with 60% (6/10) of patients with HS meeting criteria for insulin resistance. In addition, serum insulin levels in insulin-resistant patients with HS correlated with increased lesional skin mTOR gene expression at 30 (r=.80) and 60 (r=1.00) minutes, and mTOR was found to be upregulated in lesional and extralesional skin in patients with HS compared to healthy controls (P<.01).45 Insulin activates mTOR signaling, which mediates cell growth and survival, among other processes.⁴⁶ Thus, metformin’s ability to increase insulin sensitivity and inhibit mTOR signaling could be beneficial in the setting of HS. Additionally, insulin and insulinlike growth factor 1 (IGF-1) increase androgen signaling, a process that has been implicated in HS.⁴⁷

Metformin also may impact HS through its effects on testosterone and other hormones.⁴⁸ A study evaluating peripheral blood mononuclear cells in patients with HS showed reduced IL-17, IFN-γ, TNF-α, and IL-6 levels in patients who were taking metformin (dose not reported) for longer than 6 months compared to patients who were not on metformin. Further analysis of ex vivo HS lesions cultured with metformin showed decreased IL-17, IFN-γ, TNF-α, and IL-8 expression in tissue, suggesting an antiinflammatory role of metformin in HS.⁵

Although there are no known RCTs assessing the efficacy of metformin in HS, existing clinical data are supportive of the use of metformin for refractory HS.⁴⁹ Following a case report describing a patient with T2DM and stable HS while on metformin,⁵⁰ several cohort studies have assessed the efficacy of metformin for the treatment of HS. A prospective study evaluating the efficacy of metformin monotherapy (starting dose of 500 mg/d, titrated to 500 mg 3 times daily) in patients with and without T2DM with HS refractory to other therapies found clinical improvement in 72% (18/25) of patients using the Sartorius Hidradenitis Suppurativa Score, improving from a mean (SD) score of 34.40 (12.46) to 26.76 (11.22) at 12 weeks (P=.0055,) and 22.39 (11.30) at 24 weeks (P=.0001). Additionally, 64% (16/25) of patients showed improved quality of life as evaluated by the Dermatology Life Quality Index (DLQI), which decreased from a mean (SD) score of 15.00 (4.96) to 10.08 (5.96)(P=.0017) at 12 weeks and 7.65 (7.12)(P=.000009) at 24 weeks on treatment.⁴⁸ In a retrospective study of 53 patients with HS taking metformin started at 500 mg daily and increased to 500 mg twice daily after 2 weeks (when tolerated), 68% (36/53) showed some clinical response, with 19% (7/36) of those patients having achieved complete response to metformin monotherapy (defined as no active HS).⁵¹ Similarly, a retrospective study of pediatric patients with HS evaluating metformin (doses ranging from 500-2000 mg daily) as an adjunct therapy described a subset of patients with decreased frequency of HS flares with metformin.⁵² These studies emphasize the safety profile of metformin and support its current use as an adjunctive therapy for HS.

Acne Vulgaris—Acne vulgaris (AV) is a chronic inflammatory disorder affecting the pilosebaceous follicles.¹¹ Similar to HS, AV has metabolic and hormonal influences that can be targeted by metformin.⁵³ In AV, androgens lead to increased sebum production by binding to androgen receptors on sebocytes, which in turn attracts Cutibacterium acnes and promotes hyperkeratinization, inducing inflammation.⁵⁴ Thus, the antiandrogenic effects of metformin may be beneficial for treatment of AV. Additionally, sebocytes express receptors for insulin and IGF-1, which can increase the size and number of sebocytes, as well as promote lipogenesis and inflammatory response, influencing sebum production.⁵⁴ Serum levels for IGF-1 have been observed to be increased in patients with AV⁵⁵ and reduced by metformin.⁵⁶ A recent meta-analysis assessing the efficacy of metformin on AV indicated that 87% (13/15) of studies noted disease improvement on metformin, with 47% (7/15) of studies showing statistically significant (P<0.05) decreases in acne severity.57 Although most studies showed improvement, 47% (7/15) did not find significant differences between metformin and other interventions, indicating the availability of comparable treatment options. Overall, there has been a positive association between metformin use and acne improvement.⁵⁷ However, it is important to note that most studies have focused on females with PCOS,⁵⁷ and the main benefits of metformin in acne might be seen when managing comorbid conditions, particularly those associated with metabolic dysregulation and insulin resistance. Further studies are needed to determine the generalizability of prior results.

Psoriasis—Psoriasis is a chronic autoinflammatory disease characterized by epidermal hyperplasia with multiple cutaneous manifestations and potential for multiorgan involvement. Comorbid conditions include psoriatic arthritis, metabolic syndrome, and cardiovascular disease.⁵⁸ Current treatment options depend on several factors (eg, disease severity, location of cutaneous lesions, comorbidities) and include topical, systemic, and phototherapy options, many of which target the immune system.^58,59 A meta-analysis of 3 RCTs showed that metformin (500 mg/d or 1000 mg/d) was associated with significantly improved Psoriasis Area and Severity Index (PASI) 75% reductions (odds ratio [OR], 22.02; 95% CI, 2.12-228.49; P=.01) and 75% reductions in erythema, scaling, and induration (OR, 9.12; 95% CI, 2.13-39.02; P=.003) compared to placebo.⁶⁰ In addition, an RCT evaluating the efficacy of metformin (1000 mg/d) or pioglitazone (30 mg/d) for 12 weeks in patients with psoriasis with metabolic syndrome found significant improvements in PASI75 (P=.001) and erythema, scaling, and induration (P=.016) scores as well as in Physician Global Assessment scores (P=.012) compared to placebo and no differences compared to pioglitazone.⁶¹ While current psoriasis management guidelines do not include metformin, its use may be worth consideration as an adjunct therapy in patients with psoriasis and comorbidities such as T2DM and metabolic syndrome.⁵⁹ Metformin’s potential benefits in psoriasis may lie outside its metabolic influences and occur secondary to its immunomodulatory effects, including targeting of the Th17 axis or cytokine-specific pathways such as TNF-α, which are known to be involved in psoriasis pathogenesis.⁵⁸

Central Centrifugal Cicatricial Alopecia—Central centrifugal cicatricial alopecia (CCCA) is a form of scarring alopecia characterized by chronic inflammation leading to permanent loss of hair follicles on the crown of the scalp.⁶² Current treatments include topical and intralesional corticosteroids, as well as oral antibiotics. In addition, therapies including the antimalarial hydroxychloroquine and immunosuppressants mycophenolate and cyclosporine are used in refractory disease.^63,64 A case report described 2 patients with hair regrowth after 4 and 6 months of treatment with topical metformin 10% compounded in a proprietary transdermal vehicle.⁶⁵ The authors speculated that metformin’s effects on CCCA could be attributed to its known agonistic effects on the adenosine monophosphate-activated protein kinase (AMPK) pathway with subsequent reduction in inflammation-induced fibrosis.^65,66 Microarray⁶⁷ and proteomic⁶⁸ analysis have shown that AMPK is known to be downregulated in CCCA , making it an interesting therapeutic target in this disease. A recent retrospective case series demonstrated that 67% (8/12) of patients with refractory CCCA had symptomatic improvement, and 50% (6/12) showed hair regrowth after 6 months of low-dose (500 mg/d) oral metformin treatment.⁶² In addition, metformin therapy showed antifibrotic and anti-inflammatory effects when comparing scalp biopsies before and after treatment. Results showed decreased expression of fibrosisrelated genes (matrix metalloproteinase 7, collagen type IV á 1 chain), and gene set variation analysis showing reduced Th17 (P=.04) and increased AMPK signaling (P=.02) gene set expression.⁶² These findings are consistent with previous studies describing the upregulation of AMPK66 and downregulation of Th176 following metformin treatment. The immunomodulatory effects of metformin could be attributed to AMPK-mediated mTOR and NF-κB downregulation,⁶² although more studies are needed to understand these mechanisms and further explore the use of metformin in CCCA.

Skin Cancer—Metformin also has been evaluated in the setting of skin malignancies, including melanoma, squamous cell carcinoma, and basal cell carcinoma. Preclinical data suggest that metformin decreases cell viability in tumors through interactions with pathways involved in proinflammatory and prosurvival mechanisms such as NF-κB and mTOR.^69,70 Additionally, given metformin’s inhibitory effects on oxidative phosphorylation, it has been postulated that it could be used to overcome treatment resistance driven by metabolic reprogramming.^71,72 Most studies related to metformin and skin malignancies are still in preclinical stages; however, a meta-analysis of RCTs and cohort studies did not find significant associations between metformin use and skin cancer risk, although data trended toward a modest reduction in skin cancer among metformin users.⁷³ A retrospective cohort study of melanoma in patients with T2DM taking metformin (250-2000 mg/d) found that the 5-year incidence of recurrence was lower in the metformin cohort compared to nonusers (43.8% vs 58.2%, respectively)(P=.002), and overall survival rates trended upward in the higher body mass index (>30) and melanoma stages 1 and 2 groups but did not reach statistical significance.⁷⁴ In addition, a whole population casecontrol study in Iceland reported that metformin use at least 2 years before first-time basal cell carcinoma diagnosis was associated with a lower risk for disease (adjusted OR, 0.71; 95% CI, 0.61-0.83) with no significant dose-dependent differences; there were no notable effects on squamous cell carcinoma risk.⁷⁵ Further preclinical and clinical data are needed to elucidate metformin’s effects on skin malignancies.

GLP-1 AND DUAL GLP-1/GIP AGONISTS

Glucagonlike peptide 1 and dual GLP-1/GIP agonists are emerging classes of medications currently approved as adjunct and second-line therapies for T2DM, particularly in patients who are overweight or obese as well as in those who are at risk for hypoglycemia.³ Currently approved GLP-1 agonists for T2DM include semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, while tirzepatide is the only approved dual GLP-1/GIP agonist. Activating GLP-1 and GIP receptors stimulates insulin secretion and decreases glucagon production by the pancreas, thereby reducing blood glucose levels. Additionally, some of these medications are approved for obesity given their effects in delayed gastric emptying and increased satiety, among other factors.

Over the past few years, multiple case reports have described the associations between GLP-1 agonist use and improvement of dermatologic conditions, particularly those associated with T2DM and obesity, including HS and psoriasis.^76,77 The mechanisms through which this occurs are not fully elucidated, although basic science and clinical studies have shown that GLP-1 agonists have immunomodulatory effects by reducing proinflammatory cytokines and altering immune cell populations.^77-80 The numerous ongoing clinical trials and research studies will help further elucidate their benefits in other disease settings.⁸¹

Adverse Reactions

Most GLP-1 and GLP-1/GIP agonists are administered subcutaneously, and the most commonly reported cutaneous adverse effects are injection site reactions.⁸² Anaphylactic reactions to these medications also have been reported, although it is unclear if these were specific to the active ingredients or to injection excipients.^83,84 A review of 33 cases of cutaneous reactions to GLP-1 agonists reported 11 (33%) dermal hypersensitivity reactions occurring as early as 4 weeks and as late as 3 years after treatment initiation. It also described 10 (30%) cases of eosinophilic panniculitis that developed within 3 weeks to 5 months of GLP-1 treatment, 3 (9%) cases of bullous pemphigoid that occurred within the first 2 months, 2 (6%) morbilliform drug eruptions that occurred within 5 weeks, 2 (6%) cases of angioedema that occurred 15 minutes to 2 weeks after treatment initiation, and 7 (21%) other isolated cutaneous reactions. Extended-release exenatide had the most reported reactions followed by liraglutide and subcutaneous semaglutide.⁸⁵

In a different study, semaglutide use was most commonly associated with injection site reactions followed by alopecia, especially with oral administration. Unique cases of angioedema (2 days after injection), cutaneous hypersensitivity (within 10 months on treatment), bullous pemphigoid (within 2 months on treatment), eosinophilic fasciitis (within 2 weeks on treatment), and leukocytoclastic vasculitis (unclear timing), most of which resolved after discontinuation, also were reported.⁸⁶ A recent case report linked semaglutide (0.5 mg/wk) to a case of drug-induced systemic lupus erythematosus that developed within 3 months of treatment initiation and described systemic lupus erythematosus–like symptoms in a subset of patients using this medication, namely females older than 60 years, within the first month of treatment.⁸⁷ Hyperhidrosis was listed as a common adverse event in exenatide clinical trials, and various cases of panniculitis with exenatide use have been reported.^82,88 Alopecia, mainly attributed to accelerated telogen effluvium secondary to rapid weight loss, also has been reported, although hair loss is not officially listed as an adverse effect of GLP-1 agonists, and reports are highly variable.⁸⁹ Also secondary to weight loss, facial changes including sunken eyes, development of wrinkles, sagging jowls around the neck and jaw, and a hollowed appearance, among others, are recognized as undesirable adverse effects.⁹⁰ Mansour et al⁹⁰ described the potential challenges and considerations to these rising concerns associated with GLP1-agonist use.

Dermatologic Implications

Hidradenitis Suppurativa—Weight loss commonly is recommended as a lifestyle modification in the management of HS. Multiple reports have described clinical improvement of HS following weight loss with other medical interventions, such as dietary measures and bariatric surgery.^91-94 Thus, it has been postulated that medically supported weight loss with GLP-1 agonists can help improve HS⁹⁵; however, the data on the effectiveness of GLP-1 agonists on HS are still scarce and mostly have been reported in individual patients. One case report described a patient with improvements in their recalcitrant HS and DLQI score following weight loss on liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d).⁷⁶ In addition, a recent case report described improvements in HS and DLQI score following concomitant tirzepatide (initial dose of 2.5 mg/0.5 mL weekly, titrated to 7.5 mg/0.5 mL weekly) and infliximab treatment.⁹⁶ The off-label use of these medications for HS is debated, and further studies regarding the benefits of GLP-1 agonists on HS still are needed.

Psoriasis—Similarly, several case reports have commented on the effects of GLP-1 agonists on psoriasis.^97,98 An early study found GLP-1 receptors were expressed in psoriasis plaques but not in healthy skin and discussed that this could be due to immune infiltration in the plaques, providing a potential rationale for using anti-inflammatory GLP-1 agonists for psoriasis.⁹⁹ Two prospective cohort studies observed improvements in PASI and DLQI scores in patients with psoriasis and T2DM after liraglutide treatment and noted important changes in immune cell populations.^80,100 A recent RCT also found improvements in DLQI and PASI scores (P<.05) in patients with T2DM following liraglutide (1.8 mg/d) treatment, along with overall decreases in inflammatory cytokines, such as IL-23, IL-17, and TNF-α.⁷⁷ However, another RCT in patients with obesity did not observe significant improvements in PASI and DLQI scores compared to placebo after 8 weeks of liraglutide (initial dose of 0.6 mg/d, titrated to 1.8 mg/d) treatment. ⁹⁹ Although these results could have been influenced by the short length of treatment compared to other studies, which observed participants for more than 10 weeks, they highlight the need for tailored studies considering the different comorbidities to identify patients who could benefit the most from these therapies.

Alopecia—Although some studies have reported increased rates of alopecia following GLP-1 agonist treatment, others have speculated about the potential role of these medications in treating hair loss through improved insulin sensitivity and scalp blood flow.^86,89 For example, a case report described a patient with improvement in androgenetic alopecia within 6 months of tirzepatide monotherapy at 2.5 mg weekly for the first 3 months followed by an increased dose of 5 mg weekly.¹⁰¹ The authors described the role of insulin in increasing dihydrotestosterone levels, which leads to miniaturization of the dermal papilla of hair follicles and argued that improvement of insulin resistance could benefit hair loss. Further studies can help elucidate the role of these medications on alopecia.

FINAL THOUGHTS

Standard T2DM treatments including metformin and GLP-1 and GLP-1/GIP agonists exhibit metabolic, immunologic, and hormonal effects that should be explored in other disease contexts. We reviewed the current data on T2DM medications in dermatologic conditions to highlight the need for additional studies to better understand the role that these medications play across diverse patient populations. Type 2 diabetes mellitus is a common comorbidity in dermatology patients, and understanding the multifactorial effects of these medications can help optimize treatment strategies, especially in patients with coexisting dermatologic and metabolic diseases.

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

The advent of social media has revolutionized the way patients access and consume health information. While this increased access has its merits, it also has given rise to the proliferation of medical myths, which have considerable effects on patient-physician interactions.¹ Myths are prevalent across all fields of health care, ranging from misconceptions about disease etiology and prevention to the efficacy and safety of treatments. This influx of misinformation can derail the clinical encounter, shifting the focus from evidence-based medicine to myth-busting.² The COVID-19 pandemic exacerbated this issue, as widespread lockdowns and social distancing measures limited access to in-person medical consultations, prompting patients to increasingly turn to online sources for health information that often were unreliable, thereby bypassing professional medical advice.³ Herein, we highlight the challenges and implications of common dermatology myths and provide strategies for effectively debunking these myths to enhance patient care.

Common Dermatology Myths

In dermatology, where visible and often distressing conditions such as acne and hair loss are common, the impact of myths on patient perceptions and treatment outcomes can be particularly profound. Patients often arrive for consultations with preconceived notions that are not grounded in scientific evidence. Common dermatologic myths include eczema and the efficacy of topical corticosteroids, the causes and treatment of hair loss, and risk factors associated with skin cancer.

Eczema and Topical Corticosteroids—Topical corticosteroids for eczema are safe and effective, but nonadherence due to phobias stemming from misinformation online can impede treatment.⁴ Myths such as red skin syndrome and topical corticosteroid addiction are prevalent. Red skin syndrome refers to claims that prolonged use of topical corticosteroids causes severe redness and burning of the skin and worsening eczema symptoms upon withdrawal. Topical corticosteroid addiction suggests that patients become dependent on corticosteroids, requiring higher doses over time to maintain efficacy. These misconceptions contribute to fear and avoidance of prescribed treatments.

Eczema myths often divert focus from its true etiology as a genetic inflammatory skin disease, suggesting instead that it is caused by leaky gut or food intolerances.⁴ Risks such as skin thinning and stunted growth often are exaggerated on social media and other nonmedical platforms, though these adverse effects rarely are seen when topical corticosteroids are used appropriately under medical supervision. Misinformation often is linked to companies promoting unregulated consultations, tests, or supposedly natural treatments, including herbal remedies that may surreptitiously contain corticosteroids without clear labeling. This fosters distrust of US Food and Drug Administration– approved and dermatologist-prescribed treatments, as patients may cite concerns based on experiences with or claims about unapproved products.⁴

Sunscreen and Skin Cancer—In 2018, the American Academy of Dermatology prioritized skin cancer prevention due to suboptimal public adoption of photoprotection measures.⁵ However, the proliferation of misinformation regarding sunscreen and its potential to cause skin cancer is a more pressing issue. Myths range from claims that sunscreen is ineffective to warnings that it is dangerous, with some social media influencers even suggesting that sunscreen causes skin cancer due to toxic ingredients.⁶ Oxybenzone, typically found in chemical sunscreens, has been criticized by some advocacy groups and social media influencers as a potential hormone disruptor (ie, a chemical that could interfere with hormone production).⁷ However, no conclusive evidence has shown that oxybenzone is harmful to humans. Consumer concerns often are based on animal studies in which rats are fed oxybenzone, but mathematical modeling has indicated it would take 277 years of sunscreen use by humans to match the doses used in these studies.⁸ The false association between sunscreen use and skin cancer is based on flawed studies that found higher rates of skin cancer—including melanoma—in sunscreen users compared to those who did not use sunscreen. However, those using sunscreen also were more likely to travel to sunnier climates and engage in sunbathing, and it may have been this increased sun exposure that elevated their risk for skin cancer.⁷ It is imperative that the dermatology community counteract this type of misinformation with evidence-based advice.

Hair Loss—Some patients believe that hair loss is caused by wearing hats, frequent shampooing, or even stress in a way that oversimplifies complex physiological processes. Biotin, which commonly is added to supplements for hair, skin, and nails, has been linked to potential risks, such as interference with laboratory testing and false-positive or false-negative results in critical medical tests, which can lead to misdiagnosis or inappropriate treatment.⁹ Biotin interference can result in falsely low troponin readings, which are critical in diagnosing acute myocardial infarction. Tests for other hormones such as cortisol and parathyroid hormone also are affected, potentially impacting the evaluation and management of endocrine disorders. The US Food and Drug Administration has issued warnings for patients on this topic, emphasizing the importance of informing health care providers about any biotin supplementation prior to laboratory testing. Despite its popularity, there is no substantial scientific evidence to suggest that biotin supplementation promotes hair growth in anyone other than those with deficiency, which is quite rare.⁹

Myths and the Patient-Physician Relationship

The proliferation of medical myths and misinformation affects the dynamic between patients and dermatologists in several ways. Research across various medical fields has demonstrated that misinformation can substantially impact patient behavior and treatment adherence. Like many other specialists, dermatologists often spend considerable time during consultations with patients debunking myths and correcting misconceptions, which can detract from discussing more critical aspects of the patient’s condition and treatment plan and lead to frustration and anxiety among patients. It also can be challenging for physicians to have these conversations without alienating patients, who may distrust medical recommendations and believe that natural or alternative treatments are superior. This can lead to noncompliance with prescribed treatments, and patients may instead opt to try unproven remedies they encounter online, ultimately resulting in poorer health outcomes.

Strategies to Debunk Myths

By implementing the following strategies, dermatologists can combat the spread of myths, foster trust among patients, and promote adherence to evidence-based treatments:

• Provide educational outreach. Preemptively address myths by giving patients accurate and accessible resources. Including a dedicated section on your clinic’s website with articles, frequently asked questions, videos, and links to reputable sources can be effective. Sharing patient testimonials and before-and-after photographs to demonstrate the success of evidence-based treatments also is recommended, as real-life stories can be powerful tools in dispelling myths.
• Practice effective communication. Involve patients in the decision-making process by discussing their treatment goals, preferences, and concerns. It is important to present all options clearly, including the potential benefits and adverse effects. Discuss the expected outcomes and timelines, and be transparent about the limitations of certain treatment—honesty helps build trust and sets realistic expectations.
• Conduct structured consultations. Ensure that consultations with patients follow a structured format—history, physical examination, and discussion—to help keep the focus on evidence-based practice.
• Leverage technology. Guide patients toward reliable digital patient education tools to empower them with accurate information. Hosting live sessions on social media platforms during which patients can ask questions and receive evidence-based answers also can be beneficial.

Final Thoughts

In summary, the rise of medical myths poses a considerable challenge to dermatologic practice. By understanding the sources and impacts of these myths and employing strategies to dispel them, dermatologists can better navigate the complexities of modern patient interactions and ensure that care remains grounded in scientific evidence.

The advent of social media has revolutionized the way patients access and consume health information. While this increased access has its merits, it also has given rise to the proliferation of medical myths, which have considerable effects on patient-physician interactions.¹ Myths are prevalent across all fields of health care, ranging from misconceptions about disease etiology and prevention to the efficacy and safety of treatments. This influx of misinformation can derail the clinical encounter, shifting the focus from evidence-based medicine to myth-busting.² The COVID-19 pandemic exacerbated this issue, as widespread lockdowns and social distancing measures limited access to in-person medical consultations, prompting patients to increasingly turn to online sources for health information that often were unreliable, thereby bypassing professional medical advice.³ Herein, we highlight the challenges and implications of common dermatology myths and provide strategies for effectively debunking these myths to enhance patient care.

Common Dermatology Myths

In dermatology, where visible and often distressing conditions such as acne and hair loss are common, the impact of myths on patient perceptions and treatment outcomes can be particularly profound. Patients often arrive for consultations with preconceived notions that are not grounded in scientific evidence. Common dermatologic myths include eczema and the efficacy of topical corticosteroids, the causes and treatment of hair loss, and risk factors associated with skin cancer.

Eczema and Topical Corticosteroids—Topical corticosteroids for eczema are safe and effective, but nonadherence due to phobias stemming from misinformation online can impede treatment.⁴ Myths such as red skin syndrome and topical corticosteroid addiction are prevalent. Red skin syndrome refers to claims that prolonged use of topical corticosteroids causes severe redness and burning of the skin and worsening eczema symptoms upon withdrawal. Topical corticosteroid addiction suggests that patients become dependent on corticosteroids, requiring higher doses over time to maintain efficacy. These misconceptions contribute to fear and avoidance of prescribed treatments.

Eczema myths often divert focus from its true etiology as a genetic inflammatory skin disease, suggesting instead that it is caused by leaky gut or food intolerances.⁴ Risks such as skin thinning and stunted growth often are exaggerated on social media and other nonmedical platforms, though these adverse effects rarely are seen when topical corticosteroids are used appropriately under medical supervision. Misinformation often is linked to companies promoting unregulated consultations, tests, or supposedly natural treatments, including herbal remedies that may surreptitiously contain corticosteroids without clear labeling. This fosters distrust of US Food and Drug Administration– approved and dermatologist-prescribed treatments, as patients may cite concerns based on experiences with or claims about unapproved products.⁴

Sunscreen and Skin Cancer—In 2018, the American Academy of Dermatology prioritized skin cancer prevention due to suboptimal public adoption of photoprotection measures.⁵ However, the proliferation of misinformation regarding sunscreen and its potential to cause skin cancer is a more pressing issue. Myths range from claims that sunscreen is ineffective to warnings that it is dangerous, with some social media influencers even suggesting that sunscreen causes skin cancer due to toxic ingredients.⁶ Oxybenzone, typically found in chemical sunscreens, has been criticized by some advocacy groups and social media influencers as a potential hormone disruptor (ie, a chemical that could interfere with hormone production).⁷ However, no conclusive evidence has shown that oxybenzone is harmful to humans. Consumer concerns often are based on animal studies in which rats are fed oxybenzone, but mathematical modeling has indicated it would take 277 years of sunscreen use by humans to match the doses used in these studies.⁸ The false association between sunscreen use and skin cancer is based on flawed studies that found higher rates of skin cancer—including melanoma—in sunscreen users compared to those who did not use sunscreen. However, those using sunscreen also were more likely to travel to sunnier climates and engage in sunbathing, and it may have been this increased sun exposure that elevated their risk for skin cancer.⁷ It is imperative that the dermatology community counteract this type of misinformation with evidence-based advice.

Hair Loss—Some patients believe that hair loss is caused by wearing hats, frequent shampooing, or even stress in a way that oversimplifies complex physiological processes. Biotin, which commonly is added to supplements for hair, skin, and nails, has been linked to potential risks, such as interference with laboratory testing and false-positive or false-negative results in critical medical tests, which can lead to misdiagnosis or inappropriate treatment.⁹ Biotin interference can result in falsely low troponin readings, which are critical in diagnosing acute myocardial infarction. Tests for other hormones such as cortisol and parathyroid hormone also are affected, potentially impacting the evaluation and management of endocrine disorders. The US Food and Drug Administration has issued warnings for patients on this topic, emphasizing the importance of informing health care providers about any biotin supplementation prior to laboratory testing. Despite its popularity, there is no substantial scientific evidence to suggest that biotin supplementation promotes hair growth in anyone other than those with deficiency, which is quite rare.⁹

Myths and the Patient-Physician Relationship

The proliferation of medical myths and misinformation affects the dynamic between patients and dermatologists in several ways. Research across various medical fields has demonstrated that misinformation can substantially impact patient behavior and treatment adherence. Like many other specialists, dermatologists often spend considerable time during consultations with patients debunking myths and correcting misconceptions, which can detract from discussing more critical aspects of the patient’s condition and treatment plan and lead to frustration and anxiety among patients. It also can be challenging for physicians to have these conversations without alienating patients, who may distrust medical recommendations and believe that natural or alternative treatments are superior. This can lead to noncompliance with prescribed treatments, and patients may instead opt to try unproven remedies they encounter online, ultimately resulting in poorer health outcomes.

Strategies to Debunk Myths

By implementing the following strategies, dermatologists can combat the spread of myths, foster trust among patients, and promote adherence to evidence-based treatments:

• Provide educational outreach. Preemptively address myths by giving patients accurate and accessible resources. Including a dedicated section on your clinic’s website with articles, frequently asked questions, videos, and links to reputable sources can be effective. Sharing patient testimonials and before-and-after photographs to demonstrate the success of evidence-based treatments also is recommended, as real-life stories can be powerful tools in dispelling myths.
• Practice effective communication. Involve patients in the decision-making process by discussing their treatment goals, preferences, and concerns. It is important to present all options clearly, including the potential benefits and adverse effects. Discuss the expected outcomes and timelines, and be transparent about the limitations of certain treatment—honesty helps build trust and sets realistic expectations.
• Conduct structured consultations. Ensure that consultations with patients follow a structured format—history, physical examination, and discussion—to help keep the focus on evidence-based practice.
• Leverage technology. Guide patients toward reliable digital patient education tools to empower them with accurate information. Hosting live sessions on social media platforms during which patients can ask questions and receive evidence-based answers also can be beneficial.

Final Thoughts

In summary, the rise of medical myths poses a considerable challenge to dermatologic practice. By understanding the sources and impacts of these myths and employing strategies to dispel them, dermatologists can better navigate the complexities of modern patient interactions and ensure that care remains grounded in scientific evidence.

The advent of social media has revolutionized the way patients access and consume health information. While this increased access has its merits, it also has given rise to the proliferation of medical myths, which have considerable effects on patient-physician interactions.¹ Myths are prevalent across all fields of health care, ranging from misconceptions about disease etiology and prevention to the efficacy and safety of treatments. This influx of misinformation can derail the clinical encounter, shifting the focus from evidence-based medicine to myth-busting.² The COVID-19 pandemic exacerbated this issue, as widespread lockdowns and social distancing measures limited access to in-person medical consultations, prompting patients to increasingly turn to online sources for health information that often were unreliable, thereby bypassing professional medical advice.³ Herein, we highlight the challenges and implications of common dermatology myths and provide strategies for effectively debunking these myths to enhance patient care.

Common Dermatology Myths

In dermatology, where visible and often distressing conditions such as acne and hair loss are common, the impact of myths on patient perceptions and treatment outcomes can be particularly profound. Patients often arrive for consultations with preconceived notions that are not grounded in scientific evidence. Common dermatologic myths include eczema and the efficacy of topical corticosteroids, the causes and treatment of hair loss, and risk factors associated with skin cancer.

Eczema and Topical Corticosteroids—Topical corticosteroids for eczema are safe and effective, but nonadherence due to phobias stemming from misinformation online can impede treatment.⁴ Myths such as red skin syndrome and topical corticosteroid addiction are prevalent. Red skin syndrome refers to claims that prolonged use of topical corticosteroids causes severe redness and burning of the skin and worsening eczema symptoms upon withdrawal. Topical corticosteroid addiction suggests that patients become dependent on corticosteroids, requiring higher doses over time to maintain efficacy. These misconceptions contribute to fear and avoidance of prescribed treatments.

Eczema myths often divert focus from its true etiology as a genetic inflammatory skin disease, suggesting instead that it is caused by leaky gut or food intolerances.⁴ Risks such as skin thinning and stunted growth often are exaggerated on social media and other nonmedical platforms, though these adverse effects rarely are seen when topical corticosteroids are used appropriately under medical supervision. Misinformation often is linked to companies promoting unregulated consultations, tests, or supposedly natural treatments, including herbal remedies that may surreptitiously contain corticosteroids without clear labeling. This fosters distrust of US Food and Drug Administration– approved and dermatologist-prescribed treatments, as patients may cite concerns based on experiences with or claims about unapproved products.⁴

Sunscreen and Skin Cancer—In 2018, the American Academy of Dermatology prioritized skin cancer prevention due to suboptimal public adoption of photoprotection measures.⁵ However, the proliferation of misinformation regarding sunscreen and its potential to cause skin cancer is a more pressing issue. Myths range from claims that sunscreen is ineffective to warnings that it is dangerous, with some social media influencers even suggesting that sunscreen causes skin cancer due to toxic ingredients.⁶ Oxybenzone, typically found in chemical sunscreens, has been criticized by some advocacy groups and social media influencers as a potential hormone disruptor (ie, a chemical that could interfere with hormone production).⁷ However, no conclusive evidence has shown that oxybenzone is harmful to humans. Consumer concerns often are based on animal studies in which rats are fed oxybenzone, but mathematical modeling has indicated it would take 277 years of sunscreen use by humans to match the doses used in these studies.⁸ The false association between sunscreen use and skin cancer is based on flawed studies that found higher rates of skin cancer—including melanoma—in sunscreen users compared to those who did not use sunscreen. However, those using sunscreen also were more likely to travel to sunnier climates and engage in sunbathing, and it may have been this increased sun exposure that elevated their risk for skin cancer.⁷ It is imperative that the dermatology community counteract this type of misinformation with evidence-based advice.

Hair Loss—Some patients believe that hair loss is caused by wearing hats, frequent shampooing, or even stress in a way that oversimplifies complex physiological processes. Biotin, which commonly is added to supplements for hair, skin, and nails, has been linked to potential risks, such as interference with laboratory testing and false-positive or false-negative results in critical medical tests, which can lead to misdiagnosis or inappropriate treatment.⁹ Biotin interference can result in falsely low troponin readings, which are critical in diagnosing acute myocardial infarction. Tests for other hormones such as cortisol and parathyroid hormone also are affected, potentially impacting the evaluation and management of endocrine disorders. The US Food and Drug Administration has issued warnings for patients on this topic, emphasizing the importance of informing health care providers about any biotin supplementation prior to laboratory testing. Despite its popularity, there is no substantial scientific evidence to suggest that biotin supplementation promotes hair growth in anyone other than those with deficiency, which is quite rare.⁹

Myths and the Patient-Physician Relationship

The proliferation of medical myths and misinformation affects the dynamic between patients and dermatologists in several ways. Research across various medical fields has demonstrated that misinformation can substantially impact patient behavior and treatment adherence. Like many other specialists, dermatologists often spend considerable time during consultations with patients debunking myths and correcting misconceptions, which can detract from discussing more critical aspects of the patient’s condition and treatment plan and lead to frustration and anxiety among patients. It also can be challenging for physicians to have these conversations without alienating patients, who may distrust medical recommendations and believe that natural or alternative treatments are superior. This can lead to noncompliance with prescribed treatments, and patients may instead opt to try unproven remedies they encounter online, ultimately resulting in poorer health outcomes.

Strategies to Debunk Myths

By implementing the following strategies, dermatologists can combat the spread of myths, foster trust among patients, and promote adherence to evidence-based treatments:

• Provide educational outreach. Preemptively address myths by giving patients accurate and accessible resources. Including a dedicated section on your clinic’s website with articles, frequently asked questions, videos, and links to reputable sources can be effective. Sharing patient testimonials and before-and-after photographs to demonstrate the success of evidence-based treatments also is recommended, as real-life stories can be powerful tools in dispelling myths.
• Practice effective communication. Involve patients in the decision-making process by discussing their treatment goals, preferences, and concerns. It is important to present all options clearly, including the potential benefits and adverse effects. Discuss the expected outcomes and timelines, and be transparent about the limitations of certain treatment—honesty helps build trust and sets realistic expectations.
• Conduct structured consultations. Ensure that consultations with patients follow a structured format—history, physical examination, and discussion—to help keep the focus on evidence-based practice.
• Leverage technology. Guide patients toward reliable digital patient education tools to empower them with accurate information. Hosting live sessions on social media platforms during which patients can ask questions and receive evidence-based answers also can be beneficial.

Final Thoughts

In summary, the rise of medical myths poses a considerable challenge to dermatologic practice. By understanding the sources and impacts of these myths and employing strategies to dispel them, dermatologists can better navigate the complexities of modern patient interactions and ensure that care remains grounded in scientific evidence.

The year was 2023, and I was on my way to the American Academy of Dermatology meeting in New Orleans, Louisiana. “Geaux Tigers!” I exclaimed to a stranger as she walked by in her purple and gold shoes and scrubs. We chatted for a minute or two about Louisiana State University (LSU) football, then went our separate ways. Later that day, in the hands-on wound closures workshop, I was surprised to see my new acquaintance step up to the podium to lecture, then make rounds across the room to instruct residents. I didn’t know it at the time, but those purple and gold shoes sparked a conversation with a fellowship program director who would become one of my most valued mentors.

I didn’t set out to find a mentor that day—I simply was excited to connect with a fellow Tigers fan. But mentorship often finds us unexpectedly, and that encounter serves as a reminder that mentorship doesn’t always start in a formal setting. Sometimes it begins with a quick conversation in the right place at the right time. This story is one of many experiences that taught me valuable lessons about mentorship—its importance, how it can grow naturally, and the impact it can have.

Residency is a pivotal time in a physician’s life, filled with rapid learning, complex challenges, and new professional relationships. Amidst the long hours and heavy responsibilities, mentorship stands out as a support system for guiding residents toward professional and personal growth. Herein, I share more about my experiences with mentorship in residency, the lessons I have learned, and how they can serve as guidance for residents.

The Value of Mentorship

Mentorship in residency has been shown to have a major impact on career satisfaction, clinical confidence, and professional development.¹ A good mentor offers more than just advice—he or she can provide a model of professionalism and skills that resonates with the mentee’s own aspirations. Mentorship can help residents refine their clinical skills, navigate the complexities of patient care, engage in research, and connect with professionals in their field.²

Mentorship can be sought intentionally or arise naturally from shared interests and connections. Some residents reach out to potential mentors directly through emails, set up one-on-one meetings, or shadow them to gain firsthand experience. Others find mentorship simply by putting themselves in situations that foster these connections, such as attending conferences or lectures. Both approaches can lead to impactful relationships that shape a resident’s career and personal growth.

For residents involved in research, an effective faculty research mentor is particularly impactful. Studies show that residents who work with knowledgeable research mentors are more likely to experience success and productivity in their research efforts.³ Research mentors can provide essential guidance—from helping formulate research questions to navigating the complexities of publishing—which makes them invaluable in a resident’s academic development.

If you have interests in specific areas not heavily emphasized within your residency program (eg, transplantation dermatology, hair restoration, cutaneous lymphoma), consider checking within your broader medical community for specialists. Many dermatologists and other specialists welcome the opportunity to mentor residents who express a sincere interest in learning. By reaching out to these professionals, you not only expand your clinical knowledge but also gain access to niche areas of dermatology that can shape and refine your future practice. Often, these experiences lead to invaluable mentorships that may otherwise be unavailable within your immediate training environment.

Networking Through Professional Society Rotational and Mentorship Programs

The Women’s Dermatologic Society (https://www.womensderm.org/), the American Society for Dermatologic Surgery (https://www.asds.net/), and the American Society for Laser Medicine and Surgery (https://www.aslms.org/) all provide excellent formalized mentorship or preceptorship programs. Check their websites for application requirements and timelines. Participating in these programs is a great way to network with experts in dermatology, providing a structured way to interact with physicians who share your interests. Whether you are interested in medical dermatology, surgery, pediatrics, dermatopathology, or cosmetics, there are many mentors who greatly enjoy sharing their knowledge and experience with residents. Oftentimes, these programs include stipends to assist with costs that are awarded as accolades that can enhance your curriculum vitae. Engaging in these recognized preceptorship programs often builds lasting connections and ensures that both mentor and mentee have a vested interest in the relationship’s success.

Making Connections at Conferences and Maximizing Hands-on Learning

Professional conferences offer valuable opportunities to connect with mentors, whether you are proactively seeking mentorship or simply allowing connections to happen naturally. Conferences such as those of the American Academy of Dermatology and American Society for Dermatologic Surgery publish educational booklets and schedules online prior to the event, giving you a chance to explore both topics and speaker names ahead of time. This can be an excellent opportunity to create a day-by-day game plan, identifying sessions and lectures of interest as well as specific authors or experts you might like to meet. Planning in advance makes it easier to engage with leaders in the field, introduce yourself, and make meaningful connections.

Oftentimes, these society meetings offer hands-on courses, which are a great way to meet mentors and learn from direct instruction. Instructors for these courses often are leaders in dermatology who are passionate about teaching. With small group sizes, hands-on courses offer both technical skill-building opportunities and a chance to connect personally with instructors. Take a moment to introduce yourself and engage in a quick conversation, and if you feel it is appropriate, follow up with an email after the conference. This helps keep the connection alive beyond the event and may open doors for future mentorship opportunities.

Away Rotations

For residents looking to build specialized skills and connect with mentors outside their own program—especially those considering fellowship—away rotations can be a great tool. Though it may require using vacation time, an away rotation offers immersive learning in a particular area while providing opportunities to observe new mentors and establish relationships within a desired subspecialty or program. By simply reaching out and expressing interest, residents can connect with physicians who may become lasting mentors and advocates.

Building a Mentor-Mentee Relationship

A meaningful mentor-mentee relationship requires time, effort, and effective communication, with clear expectations around mentorship goals, time commitments, and how both parties envision the relationship evolving.⁴ Ideally, mentees should feel comfortable sharing their goals with mentors and asking for feedback. In the right context, a simple and effective practice is to send your mentor a brief update on your progress every few months. This could be a quick email sharing your latest projects, ideas, and/or achievements. By regularly checking in, you show your mentor that you are committed to growing from their guidance and respect their time.

The Lasting Impact of Mentorship

The effects of mentorship in residency extend well beyond the training years, as mentors often become lifelong guides and professional advocates for their mentees.⁵ Residency often is the last time a resident trains under the direct supervision of an attending physician, making it a unique and formative period. After graduation, many new physicians find the transition to independent practice challenging, and the “real world” can be a shock. Having a mentor during this time, or maintaining connections with mentors from residency, can be invaluable. Mentors can offer advice, act as sounding boards, and remind new graduates of the importance of being lifelong learners. These relationships help ease the transition into practice, instilling a commitment to continuous improvement and professional growth. For me, a conversation about LSU football at the AAD meeting in New Orleans exemplifies how mentorship can begin in the most unexpected ways. That casual exchange led to an away rotation, a fellowship interview, connections at national meetings, and the start of what I hope will be a lifelong friendship.

The year was 2023, and I was on my way to the American Academy of Dermatology meeting in New Orleans, Louisiana. “Geaux Tigers!” I exclaimed to a stranger as she walked by in her purple and gold shoes and scrubs. We chatted for a minute or two about Louisiana State University (LSU) football, then went our separate ways. Later that day, in the hands-on wound closures workshop, I was surprised to see my new acquaintance step up to the podium to lecture, then make rounds across the room to instruct residents. I didn’t know it at the time, but those purple and gold shoes sparked a conversation with a fellowship program director who would become one of my most valued mentors.

I didn’t set out to find a mentor that day—I simply was excited to connect with a fellow Tigers fan. But mentorship often finds us unexpectedly, and that encounter serves as a reminder that mentorship doesn’t always start in a formal setting. Sometimes it begins with a quick conversation in the right place at the right time. This story is one of many experiences that taught me valuable lessons about mentorship—its importance, how it can grow naturally, and the impact it can have.

Residency is a pivotal time in a physician’s life, filled with rapid learning, complex challenges, and new professional relationships. Amidst the long hours and heavy responsibilities, mentorship stands out as a support system for guiding residents toward professional and personal growth. Herein, I share more about my experiences with mentorship in residency, the lessons I have learned, and how they can serve as guidance for residents.

The Value of Mentorship

Mentorship in residency has been shown to have a major impact on career satisfaction, clinical confidence, and professional development.¹ A good mentor offers more than just advice—he or she can provide a model of professionalism and skills that resonates with the mentee’s own aspirations. Mentorship can help residents refine their clinical skills, navigate the complexities of patient care, engage in research, and connect with professionals in their field.²

Mentorship can be sought intentionally or arise naturally from shared interests and connections. Some residents reach out to potential mentors directly through emails, set up one-on-one meetings, or shadow them to gain firsthand experience. Others find mentorship simply by putting themselves in situations that foster these connections, such as attending conferences or lectures. Both approaches can lead to impactful relationships that shape a resident’s career and personal growth.

For residents involved in research, an effective faculty research mentor is particularly impactful. Studies show that residents who work with knowledgeable research mentors are more likely to experience success and productivity in their research efforts.³ Research mentors can provide essential guidance—from helping formulate research questions to navigating the complexities of publishing—which makes them invaluable in a resident’s academic development.

If you have interests in specific areas not heavily emphasized within your residency program (eg, transplantation dermatology, hair restoration, cutaneous lymphoma), consider checking within your broader medical community for specialists. Many dermatologists and other specialists welcome the opportunity to mentor residents who express a sincere interest in learning. By reaching out to these professionals, you not only expand your clinical knowledge but also gain access to niche areas of dermatology that can shape and refine your future practice. Often, these experiences lead to invaluable mentorships that may otherwise be unavailable within your immediate training environment.

Networking Through Professional Society Rotational and Mentorship Programs

The Women’s Dermatologic Society (https://www.womensderm.org/), the American Society for Dermatologic Surgery (https://www.asds.net/), and the American Society for Laser Medicine and Surgery (https://www.aslms.org/) all provide excellent formalized mentorship or preceptorship programs. Check their websites for application requirements and timelines. Participating in these programs is a great way to network with experts in dermatology, providing a structured way to interact with physicians who share your interests. Whether you are interested in medical dermatology, surgery, pediatrics, dermatopathology, or cosmetics, there are many mentors who greatly enjoy sharing their knowledge and experience with residents. Oftentimes, these programs include stipends to assist with costs that are awarded as accolades that can enhance your curriculum vitae. Engaging in these recognized preceptorship programs often builds lasting connections and ensures that both mentor and mentee have a vested interest in the relationship’s success.

Making Connections at Conferences and Maximizing Hands-on Learning

Professional conferences offer valuable opportunities to connect with mentors, whether you are proactively seeking mentorship or simply allowing connections to happen naturally. Conferences such as those of the American Academy of Dermatology and American Society for Dermatologic Surgery publish educational booklets and schedules online prior to the event, giving you a chance to explore both topics and speaker names ahead of time. This can be an excellent opportunity to create a day-by-day game plan, identifying sessions and lectures of interest as well as specific authors or experts you might like to meet. Planning in advance makes it easier to engage with leaders in the field, introduce yourself, and make meaningful connections.

Oftentimes, these society meetings offer hands-on courses, which are a great way to meet mentors and learn from direct instruction. Instructors for these courses often are leaders in dermatology who are passionate about teaching. With small group sizes, hands-on courses offer both technical skill-building opportunities and a chance to connect personally with instructors. Take a moment to introduce yourself and engage in a quick conversation, and if you feel it is appropriate, follow up with an email after the conference. This helps keep the connection alive beyond the event and may open doors for future mentorship opportunities.

Away Rotations

For residents looking to build specialized skills and connect with mentors outside their own program—especially those considering fellowship—away rotations can be a great tool. Though it may require using vacation time, an away rotation offers immersive learning in a particular area while providing opportunities to observe new mentors and establish relationships within a desired subspecialty or program. By simply reaching out and expressing interest, residents can connect with physicians who may become lasting mentors and advocates.

Building a Mentor-Mentee Relationship

A meaningful mentor-mentee relationship requires time, effort, and effective communication, with clear expectations around mentorship goals, time commitments, and how both parties envision the relationship evolving.⁴ Ideally, mentees should feel comfortable sharing their goals with mentors and asking for feedback. In the right context, a simple and effective practice is to send your mentor a brief update on your progress every few months. This could be a quick email sharing your latest projects, ideas, and/or achievements. By regularly checking in, you show your mentor that you are committed to growing from their guidance and respect their time.

The Lasting Impact of Mentorship

The effects of mentorship in residency extend well beyond the training years, as mentors often become lifelong guides and professional advocates for their mentees.⁵ Residency often is the last time a resident trains under the direct supervision of an attending physician, making it a unique and formative period. After graduation, many new physicians find the transition to independent practice challenging, and the “real world” can be a shock. Having a mentor during this time, or maintaining connections with mentors from residency, can be invaluable. Mentors can offer advice, act as sounding boards, and remind new graduates of the importance of being lifelong learners. These relationships help ease the transition into practice, instilling a commitment to continuous improvement and professional growth. For me, a conversation about LSU football at the AAD meeting in New Orleans exemplifies how mentorship can begin in the most unexpected ways. That casual exchange led to an away rotation, a fellowship interview, connections at national meetings, and the start of what I hope will be a lifelong friendship.

The year was 2023, and I was on my way to the American Academy of Dermatology meeting in New Orleans, Louisiana. “Geaux Tigers!” I exclaimed to a stranger as she walked by in her purple and gold shoes and scrubs. We chatted for a minute or two about Louisiana State University (LSU) football, then went our separate ways. Later that day, in the hands-on wound closures workshop, I was surprised to see my new acquaintance step up to the podium to lecture, then make rounds across the room to instruct residents. I didn’t know it at the time, but those purple and gold shoes sparked a conversation with a fellowship program director who would become one of my most valued mentors.

I didn’t set out to find a mentor that day—I simply was excited to connect with a fellow Tigers fan. But mentorship often finds us unexpectedly, and that encounter serves as a reminder that mentorship doesn’t always start in a formal setting. Sometimes it begins with a quick conversation in the right place at the right time. This story is one of many experiences that taught me valuable lessons about mentorship—its importance, how it can grow naturally, and the impact it can have.

Residency is a pivotal time in a physician’s life, filled with rapid learning, complex challenges, and new professional relationships. Amidst the long hours and heavy responsibilities, mentorship stands out as a support system for guiding residents toward professional and personal growth. Herein, I share more about my experiences with mentorship in residency, the lessons I have learned, and how they can serve as guidance for residents.

The Value of Mentorship

Mentorship in residency has been shown to have a major impact on career satisfaction, clinical confidence, and professional development.¹ A good mentor offers more than just advice—he or she can provide a model of professionalism and skills that resonates with the mentee’s own aspirations. Mentorship can help residents refine their clinical skills, navigate the complexities of patient care, engage in research, and connect with professionals in their field.²

Mentorship can be sought intentionally or arise naturally from shared interests and connections. Some residents reach out to potential mentors directly through emails, set up one-on-one meetings, or shadow them to gain firsthand experience. Others find mentorship simply by putting themselves in situations that foster these connections, such as attending conferences or lectures. Both approaches can lead to impactful relationships that shape a resident’s career and personal growth.

For residents involved in research, an effective faculty research mentor is particularly impactful. Studies show that residents who work with knowledgeable research mentors are more likely to experience success and productivity in their research efforts.³ Research mentors can provide essential guidance—from helping formulate research questions to navigating the complexities of publishing—which makes them invaluable in a resident’s academic development.

If you have interests in specific areas not heavily emphasized within your residency program (eg, transplantation dermatology, hair restoration, cutaneous lymphoma), consider checking within your broader medical community for specialists. Many dermatologists and other specialists welcome the opportunity to mentor residents who express a sincere interest in learning. By reaching out to these professionals, you not only expand your clinical knowledge but also gain access to niche areas of dermatology that can shape and refine your future practice. Often, these experiences lead to invaluable mentorships that may otherwise be unavailable within your immediate training environment.

Networking Through Professional Society Rotational and Mentorship Programs

The Women’s Dermatologic Society (https://www.womensderm.org/), the American Society for Dermatologic Surgery (https://www.asds.net/), and the American Society for Laser Medicine and Surgery (https://www.aslms.org/) all provide excellent formalized mentorship or preceptorship programs. Check their websites for application requirements and timelines. Participating in these programs is a great way to network with experts in dermatology, providing a structured way to interact with physicians who share your interests. Whether you are interested in medical dermatology, surgery, pediatrics, dermatopathology, or cosmetics, there are many mentors who greatly enjoy sharing their knowledge and experience with residents. Oftentimes, these programs include stipends to assist with costs that are awarded as accolades that can enhance your curriculum vitae. Engaging in these recognized preceptorship programs often builds lasting connections and ensures that both mentor and mentee have a vested interest in the relationship’s success.

Making Connections at Conferences and Maximizing Hands-on Learning

Professional conferences offer valuable opportunities to connect with mentors, whether you are proactively seeking mentorship or simply allowing connections to happen naturally. Conferences such as those of the American Academy of Dermatology and American Society for Dermatologic Surgery publish educational booklets and schedules online prior to the event, giving you a chance to explore both topics and speaker names ahead of time. This can be an excellent opportunity to create a day-by-day game plan, identifying sessions and lectures of interest as well as specific authors or experts you might like to meet. Planning in advance makes it easier to engage with leaders in the field, introduce yourself, and make meaningful connections.

Oftentimes, these society meetings offer hands-on courses, which are a great way to meet mentors and learn from direct instruction. Instructors for these courses often are leaders in dermatology who are passionate about teaching. With small group sizes, hands-on courses offer both technical skill-building opportunities and a chance to connect personally with instructors. Take a moment to introduce yourself and engage in a quick conversation, and if you feel it is appropriate, follow up with an email after the conference. This helps keep the connection alive beyond the event and may open doors for future mentorship opportunities.

Away Rotations

For residents looking to build specialized skills and connect with mentors outside their own program—especially those considering fellowship—away rotations can be a great tool. Though it may require using vacation time, an away rotation offers immersive learning in a particular area while providing opportunities to observe new mentors and establish relationships within a desired subspecialty or program. By simply reaching out and expressing interest, residents can connect with physicians who may become lasting mentors and advocates.

Building a Mentor-Mentee Relationship

A meaningful mentor-mentee relationship requires time, effort, and effective communication, with clear expectations around mentorship goals, time commitments, and how both parties envision the relationship evolving.⁴ Ideally, mentees should feel comfortable sharing their goals with mentors and asking for feedback. In the right context, a simple and effective practice is to send your mentor a brief update on your progress every few months. This could be a quick email sharing your latest projects, ideas, and/or achievements. By regularly checking in, you show your mentor that you are committed to growing from their guidance and respect their time.

The Lasting Impact of Mentorship

The effects of mentorship in residency extend well beyond the training years, as mentors often become lifelong guides and professional advocates for their mentees.⁵ Residency often is the last time a resident trains under the direct supervision of an attending physician, making it a unique and formative period. After graduation, many new physicians find the transition to independent practice challenging, and the “real world” can be a shock. Having a mentor during this time, or maintaining connections with mentors from residency, can be invaluable. Mentors can offer advice, act as sounding boards, and remind new graduates of the importance of being lifelong learners. These relationships help ease the transition into practice, instilling a commitment to continuous improvement and professional growth. For me, a conversation about LSU football at the AAD meeting in New Orleans exemplifies how mentorship can begin in the most unexpected ways. That casual exchange led to an away rotation, a fellowship interview, connections at national meetings, and the start of what I hope will be a lifelong friendship.

THE DIAGNOSIS: Hidradenocarcinoma

Both the original and recurrent lesions were interpreted as a chondroid syringoma, a benign adnexal tumor; however, the third biopsy of the lesion revealed a low-grade adnexal neoplasm with irregular nests of variably sized epithelial cells demonstrating mild nuclear atypia and low mitotic activity. Given the multiple recurrences, accelerated growth, and more aggressive histologic findings, the patient was referred to our clinic for surgical management.

We elected to perform modified Mohs micrographic surgery (MMS) with permanent tissue sections to enable the application of immunohistochemical stains to fully characterize the tumor. Histopathology showed a poorly circumscribed infiltrative dermal neoplasm composed of basaloid cells with a solid and cystic growth pattern in a background of hyalinized, fibrotic stroma (Figure, A and B). There were focal clear cell and squamous features as well as focal ductal differentiation (Figure, C and D). No obvious papillary structures were noted. The tumor cells were positive for D2-40, and staining for CD31 failed to reveal lymphovascular invasion. Based on the infiltrative features in conjunction with the findings from the prior biopsies, a diagnosis of hidradenocarcinoma (HAC) was made. Deep and peripheral margins were cleared after 2 stages of MMS.

Initially described in 1954, HAC is an exceedingly rare adnexal tumor of apocrine and eccrine derivation.¹ Historically, nomenclature for this entity has varied in the literature, including synonyms such as malignant nodular hidradenoma, malignant acrospiroma, solid-cystic adenocarcinoma, and malignant clear cell myoepithelioma.^2,3 Approximately 6% of all malignant eccrine tumors worldwide are HACs, which account for only 1 in 13,000 dermatopathology specimens.¹ These tumors may transform from clear cell hidradenomas (their benign counterparts) but more commonly arise de novo. Compared to benign hidradenomas, HACs are poorly circumscribed with infiltrative growth patterns on histopathology and may exhibit nuclear pleomorphism, prominent mitotic activity, necrosis, and perineural or vascular invasion.²

Clinically, HAC manifests as a 1- to 5-cm, solitary, firm, intradermal pink or violaceous nodule with possible ulceration.^2,4 The nodule often is asymptomatic but may be tender, as in our patient. There seems to be no clear anatomic site of predilection, with approximately 42% of HACs localized to the head and neck and the remainder occurring on the trunk, arms, and legs.^3,5-7 Females and males are affected equally, and lesions tend to arise in the seventh decade of life.⁷

Reports in the literature suggest that HAC is a very aggressive tumor with a generally poor prognosis.¹ Several studies have found that up to half of tumors locally recur despite aggressive surgical management, and metastasis occurs in 20% to 60% of patients.^3,8 However, a large study of US Surveillance, Epidemiology, and End Results data investigating the clinicopathologic characteristics of 289 patients with HAC revealed a more favorable prognosis.⁷ Mean overall survival and cancer-specific survival were greater than 13 years, and 10-year overall survival and cancer-specific survival rates were 60.2% and 90.5%, respectively.

Traditionally used to treat keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, complete margin assessment with MMS is increasingly being utilized in the management of other cutaneous malignancies, including adnexal tumors.⁸ Due to its rarity, there remains no standard optimal treatment approach for HAC. One small retrospective study of 10 patients with HAC treated with MMS demonstrated favorable outcomes with no cases of recurrence, metastasis, or diseaserelated mortality in a mean 7-year follow-up period.⁹

Whole-body positron emission tomography/computed tomography performed in our patient approximately 1 month after MMS revealed mildly hypermetabolic left inguinal lymph nodes, which were thought to be reactive, and a question of small hypermetabolic foci in the liver. Follow-up computed tomography of the abdomen subsequently was performed and was negative for hepatic metastases. The patient will be monitored closely for local recurrence; however, the clearance of the tumor with MMS, which allowed complete margin assessment, is encouraging and supports MMS as superior to traditional surgical excision in the treatment of HAC. At his most recent examination 17 months after Mohs surgery, the patient remained tumor free.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare malignant tumor originating in the sweat glands that can occur on the first toe but most commonly arises on the fingers. While both HAC and ADPA can manifest with an infiltrative growth pattern and cytologic atypia, ADPA classically reveals a well-circumscribed multinodular tumor in the dermis comprised of solid and cystic proliferation as well as papillary projections. In addition, ADPA has been described as having back-to-back glandular and ductal structures.¹⁰ Giant cell tumor of the tendon sheath is a benign fibrohistiocytic tumor that also typically manifests on the fingers but rarely can occur on the foot, including the first toe.^11,12 This tumor is more common in women and most frequently affects individuals aged 30 to 50 years.¹² Microscopically, giant cell tumor of the tendon sheath is characterized by a proliferation of osteoclastlike giant cells, epithelioid histiocytelike cells, mononuclear cells, and xanthomatous cells among collagenous bands.¹¹

Osteosarcoma is an uncommon tumor of osteoidproducing cells that usually arises in the metaphysis of long bones and manifests as a tender subcutaneous mass. It has a bimodal age distribution, peaking in adolescents and adults older than 65 years.¹³ While very rare, osteosarcoma has been reported to occur in the bones of the feet, including the phalanges.¹⁴ Given the recurrent nature of our patient’s tumor, metastasis should always be considered; however, in his case, full-body imaging was negative for additional malignancy.

THE DIAGNOSIS: Hidradenocarcinoma

Both the original and recurrent lesions were interpreted as a chondroid syringoma, a benign adnexal tumor; however, the third biopsy of the lesion revealed a low-grade adnexal neoplasm with irregular nests of variably sized epithelial cells demonstrating mild nuclear atypia and low mitotic activity. Given the multiple recurrences, accelerated growth, and more aggressive histologic findings, the patient was referred to our clinic for surgical management.

We elected to perform modified Mohs micrographic surgery (MMS) with permanent tissue sections to enable the application of immunohistochemical stains to fully characterize the tumor. Histopathology showed a poorly circumscribed infiltrative dermal neoplasm composed of basaloid cells with a solid and cystic growth pattern in a background of hyalinized, fibrotic stroma (Figure, A and B). There were focal clear cell and squamous features as well as focal ductal differentiation (Figure, C and D). No obvious papillary structures were noted. The tumor cells were positive for D2-40, and staining for CD31 failed to reveal lymphovascular invasion. Based on the infiltrative features in conjunction with the findings from the prior biopsies, a diagnosis of hidradenocarcinoma (HAC) was made. Deep and peripheral margins were cleared after 2 stages of MMS.

Initially described in 1954, HAC is an exceedingly rare adnexal tumor of apocrine and eccrine derivation.¹ Historically, nomenclature for this entity has varied in the literature, including synonyms such as malignant nodular hidradenoma, malignant acrospiroma, solid-cystic adenocarcinoma, and malignant clear cell myoepithelioma.^2,3 Approximately 6% of all malignant eccrine tumors worldwide are HACs, which account for only 1 in 13,000 dermatopathology specimens.¹ These tumors may transform from clear cell hidradenomas (their benign counterparts) but more commonly arise de novo. Compared to benign hidradenomas, HACs are poorly circumscribed with infiltrative growth patterns on histopathology and may exhibit nuclear pleomorphism, prominent mitotic activity, necrosis, and perineural or vascular invasion.²

Clinically, HAC manifests as a 1- to 5-cm, solitary, firm, intradermal pink or violaceous nodule with possible ulceration.^2,4 The nodule often is asymptomatic but may be tender, as in our patient. There seems to be no clear anatomic site of predilection, with approximately 42% of HACs localized to the head and neck and the remainder occurring on the trunk, arms, and legs.^3,5-7 Females and males are affected equally, and lesions tend to arise in the seventh decade of life.⁷

Reports in the literature suggest that HAC is a very aggressive tumor with a generally poor prognosis.¹ Several studies have found that up to half of tumors locally recur despite aggressive surgical management, and metastasis occurs in 20% to 60% of patients.^3,8 However, a large study of US Surveillance, Epidemiology, and End Results data investigating the clinicopathologic characteristics of 289 patients with HAC revealed a more favorable prognosis.⁷ Mean overall survival and cancer-specific survival were greater than 13 years, and 10-year overall survival and cancer-specific survival rates were 60.2% and 90.5%, respectively.

Traditionally used to treat keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, complete margin assessment with MMS is increasingly being utilized in the management of other cutaneous malignancies, including adnexal tumors.⁸ Due to its rarity, there remains no standard optimal treatment approach for HAC. One small retrospective study of 10 patients with HAC treated with MMS demonstrated favorable outcomes with no cases of recurrence, metastasis, or diseaserelated mortality in a mean 7-year follow-up period.⁹

Whole-body positron emission tomography/computed tomography performed in our patient approximately 1 month after MMS revealed mildly hypermetabolic left inguinal lymph nodes, which were thought to be reactive, and a question of small hypermetabolic foci in the liver. Follow-up computed tomography of the abdomen subsequently was performed and was negative for hepatic metastases. The patient will be monitored closely for local recurrence; however, the clearance of the tumor with MMS, which allowed complete margin assessment, is encouraging and supports MMS as superior to traditional surgical excision in the treatment of HAC. At his most recent examination 17 months after Mohs surgery, the patient remained tumor free.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare malignant tumor originating in the sweat glands that can occur on the first toe but most commonly arises on the fingers. While both HAC and ADPA can manifest with an infiltrative growth pattern and cytologic atypia, ADPA classically reveals a well-circumscribed multinodular tumor in the dermis comprised of solid and cystic proliferation as well as papillary projections. In addition, ADPA has been described as having back-to-back glandular and ductal structures.¹⁰ Giant cell tumor of the tendon sheath is a benign fibrohistiocytic tumor that also typically manifests on the fingers but rarely can occur on the foot, including the first toe.^11,12 This tumor is more common in women and most frequently affects individuals aged 30 to 50 years.¹² Microscopically, giant cell tumor of the tendon sheath is characterized by a proliferation of osteoclastlike giant cells, epithelioid histiocytelike cells, mononuclear cells, and xanthomatous cells among collagenous bands.¹¹

Osteosarcoma is an uncommon tumor of osteoidproducing cells that usually arises in the metaphysis of long bones and manifests as a tender subcutaneous mass. It has a bimodal age distribution, peaking in adolescents and adults older than 65 years.¹³ While very rare, osteosarcoma has been reported to occur in the bones of the feet, including the phalanges.¹⁴ Given the recurrent nature of our patient’s tumor, metastasis should always be considered; however, in his case, full-body imaging was negative for additional malignancy.

THE DIAGNOSIS: Hidradenocarcinoma

Both the original and recurrent lesions were interpreted as a chondroid syringoma, a benign adnexal tumor; however, the third biopsy of the lesion revealed a low-grade adnexal neoplasm with irregular nests of variably sized epithelial cells demonstrating mild nuclear atypia and low mitotic activity. Given the multiple recurrences, accelerated growth, and more aggressive histologic findings, the patient was referred to our clinic for surgical management.

We elected to perform modified Mohs micrographic surgery (MMS) with permanent tissue sections to enable the application of immunohistochemical stains to fully characterize the tumor. Histopathology showed a poorly circumscribed infiltrative dermal neoplasm composed of basaloid cells with a solid and cystic growth pattern in a background of hyalinized, fibrotic stroma (Figure, A and B). There were focal clear cell and squamous features as well as focal ductal differentiation (Figure, C and D). No obvious papillary structures were noted. The tumor cells were positive for D2-40, and staining for CD31 failed to reveal lymphovascular invasion. Based on the infiltrative features in conjunction with the findings from the prior biopsies, a diagnosis of hidradenocarcinoma (HAC) was made. Deep and peripheral margins were cleared after 2 stages of MMS.

Initially described in 1954, HAC is an exceedingly rare adnexal tumor of apocrine and eccrine derivation.¹ Historically, nomenclature for this entity has varied in the literature, including synonyms such as malignant nodular hidradenoma, malignant acrospiroma, solid-cystic adenocarcinoma, and malignant clear cell myoepithelioma.^2,3 Approximately 6% of all malignant eccrine tumors worldwide are HACs, which account for only 1 in 13,000 dermatopathology specimens.¹ These tumors may transform from clear cell hidradenomas (their benign counterparts) but more commonly arise de novo. Compared to benign hidradenomas, HACs are poorly circumscribed with infiltrative growth patterns on histopathology and may exhibit nuclear pleomorphism, prominent mitotic activity, necrosis, and perineural or vascular invasion.²

Clinically, HAC manifests as a 1- to 5-cm, solitary, firm, intradermal pink or violaceous nodule with possible ulceration.^2,4 The nodule often is asymptomatic but may be tender, as in our patient. There seems to be no clear anatomic site of predilection, with approximately 42% of HACs localized to the head and neck and the remainder occurring on the trunk, arms, and legs.^3,5-7 Females and males are affected equally, and lesions tend to arise in the seventh decade of life.⁷

Reports in the literature suggest that HAC is a very aggressive tumor with a generally poor prognosis.¹ Several studies have found that up to half of tumors locally recur despite aggressive surgical management, and metastasis occurs in 20% to 60% of patients.^3,8 However, a large study of US Surveillance, Epidemiology, and End Results data investigating the clinicopathologic characteristics of 289 patients with HAC revealed a more favorable prognosis.⁷ Mean overall survival and cancer-specific survival were greater than 13 years, and 10-year overall survival and cancer-specific survival rates were 60.2% and 90.5%, respectively.

Traditionally used to treat keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, complete margin assessment with MMS is increasingly being utilized in the management of other cutaneous malignancies, including adnexal tumors.⁸ Due to its rarity, there remains no standard optimal treatment approach for HAC. One small retrospective study of 10 patients with HAC treated with MMS demonstrated favorable outcomes with no cases of recurrence, metastasis, or diseaserelated mortality in a mean 7-year follow-up period.⁹

Whole-body positron emission tomography/computed tomography performed in our patient approximately 1 month after MMS revealed mildly hypermetabolic left inguinal lymph nodes, which were thought to be reactive, and a question of small hypermetabolic foci in the liver. Follow-up computed tomography of the abdomen subsequently was performed and was negative for hepatic metastases. The patient will be monitored closely for local recurrence; however, the clearance of the tumor with MMS, which allowed complete margin assessment, is encouraging and supports MMS as superior to traditional surgical excision in the treatment of HAC. At his most recent examination 17 months after Mohs surgery, the patient remained tumor free.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare malignant tumor originating in the sweat glands that can occur on the first toe but most commonly arises on the fingers. While both HAC and ADPA can manifest with an infiltrative growth pattern and cytologic atypia, ADPA classically reveals a well-circumscribed multinodular tumor in the dermis comprised of solid and cystic proliferation as well as papillary projections. In addition, ADPA has been described as having back-to-back glandular and ductal structures.¹⁰ Giant cell tumor of the tendon sheath is a benign fibrohistiocytic tumor that also typically manifests on the fingers but rarely can occur on the foot, including the first toe.^11,12 This tumor is more common in women and most frequently affects individuals aged 30 to 50 years.¹² Microscopically, giant cell tumor of the tendon sheath is characterized by a proliferation of osteoclastlike giant cells, epithelioid histiocytelike cells, mononuclear cells, and xanthomatous cells among collagenous bands.¹¹

Osteosarcoma is an uncommon tumor of osteoidproducing cells that usually arises in the metaphysis of long bones and manifests as a tender subcutaneous mass. It has a bimodal age distribution, peaking in adolescents and adults older than 65 years.¹³ While very rare, osteosarcoma has been reported to occur in the bones of the feet, including the phalanges.¹⁴ Given the recurrent nature of our patient’s tumor, metastasis should always be considered; however, in his case, full-body imaging was negative for additional malignancy.

Prior to the COVID-19 pandemic, health care systems had been increasingly focused on expanding care delivery through clinical video telehealth (CVT) services.^1-3 These modalities offer clinicians and patients opportunities to interact without needing face-to-face visits. CVT services offer significant advantages to patients who encounter challenges accessing traditional face-to-face services, including those living in rural or underserved areas, individuals with mobility limitations, and those with difficulty attending appointments due to work or caregiving commitments.⁴ The COVID-19 pandemic accelerated the expansion of CVT services to mitigate the spread of the virus.¹

Despite its evident advantages, widespread adoption of CVT has encountered resistance.² Physicians have frequently expressed concerns about the reliability and functionality of CVT platforms for scheduled encounters and frustration with inadequate training.^4-6 Additionally, there is a lack trust in the technology, as physicians are unfamiliar with reimbursement or workload capture associated with CVT. Physicians have concerns that telecommunication may diminish the intangible aspects of the “art of medicine.”⁴ As a result, the implementation of telehealth services has been inconsistent, with successful adoption limited to specific medical and surgical specialties.⁴ Only recently have entire departments within major health care systems expressed interest in providing comprehensive CVT services in response to the challenges posed by the COVID-19 pandemic.⁴

The Veterans Health Administration (VHA) of the US Department of Veterans Affairs (VA) provides an appropriate setting for assessing clinician perceptions of telehealth services. Since 2003, the VHA has significantly expanded CVT services to eligible veterans and has used the VA Video Connect (VVC) platform since 2018.^7-10 Through VVC, VA staff and clinicians may schedule video visits with patients, meet with patients through virtual face-to-face interaction, and share relevant laboratory results and imaging through screen sharing. Prior research has shown increased accessibility to care through VVC. For example, a single-site study demonstrated that VVC implementation for delivering psychotherapies significantly increased CVT encounters from 15% to 85% among veterans with anxiety and/or depression.¹¹

The VA New Mexico Healthcare System (VANMHCS) serves a high volume of veterans living in remote and rural regions and significantly increased its use of CVT during the COVID-19 pandemic to reduce in-person visits. Expectedly, this was met with a variety of challenges. Herein, we sought to assess physician perspectives, concerns, and attitudes toward VVC via semistructured interviews. Our hypothesis was that VA physicians may feel uncomfortable with video encounters but recognize the growing importance of such practices providing specialty care to veterans in rural areas.

METHODS

A semistructured interview protocol was created following discussions with physicians from the VANMHCS Medicine Service. Questions were constructed to assess the following domains: overarching views of video telehealth, perceptions of various applications for conducting VVC encounters, and barriers to the broad implementation of video telehealth. A qualitative investigation specialist aided with question development. Two pilot interviews were conducted prior to performing the interviews with the recruited participants to evaluate the quality and delivery of questions.

All VANMHCS physicians who provided outpatient care within the Department of Medicine and had completed ≥ 1 VVC encounter were eligible to participate. Invitations were disseminated via email, and follow-up emails to encourage participation were sent periodically for 2 months following the initial request. Union approval was obtained to interview employees for a research study. In total, 64 physicians were invited and 13 (20%) chose to participate. As the study did not involve assessing medical interventions among patients, a waiver of informed consent was granted by the VANMHCS Institutional Review Board. Physicians who participated in this study were informed that their responses would be used for reporting purposes and could be rescinded at any time.

Data Analysis

Semistructured interviews were conducted by a single interviewer and recorded using Microsoft Teams. The interviews took place between February 2021 and December 2021 and lasted 5 to 15 minutes, with a mean duration of 9 minutes. Verbal informed consent was obtained from all participants before the interviews. Interviewees were encouraged to expand on their responses to structured questions by recounting past experiences with VVC. Recorded audio was additionally transcribed via Microsoft Teams, and the research team reviewed the transcriptions to ensure accuracy.

The tracking and coding of responses to interview questions were conducted using Microsoft Excel. Initially, 5 transcripts were reviewed and responses were assessed by 2 study team members through open coding. All team members examined the 5 coded transcripts to identify differences and reach a consensus for any discrepancies. Based on recommendations from all team members regarding nuanced excerpts of transcripts, 1 study team member coded the remaining interviews. Thematic analysis was subsequently conducted according to the method described by Braun and Clarke.¹² Themes were developed both deductively and inductively by reviewing the direct responses to interview questions and identifying emerging patterns of data, respectively. Indicative quotes representing each theme were carefully chosen for reporting.

RESULTS

Thirteen interviews were conducted and 9 participants (69%) were female. Participating physicians included 3 internal medicine/primary care physicians (23%), 2 nephrologists (15%), and 1 (8%) from cardiology, endocrinology, hematology, infectious diseases, palliative care, critical care, pulmonology, and sleep medicine. Years of post training experience among physicians ranged from 1 to 9 years (n = 5, 38%), 10 to 19 years (n = 3, 23%), and . 20 years (n = 5, 38%). Seven participants (54%) had conducted ≥ 5 VVC visits, with 1 physician completing > 50 video visits (Table).

Using open coding and a deductive approach to thematic analysis, 5 themes were identified: (1) VVC software and internet connection issues affected implementation; (2) patient technological literacy affected veteran and physician comfort with VVC; (3) integration of supportive measures was desired; (4) CVT services may increasingly be used to enhance access to care; and (5) in-person encounters afforded unique advantages over CVT. Illustrative quotes from physicians that reflect these themes can be found in the Appendix.

Theme 1: VVC software and internet connection issues affected its implementation. Most participants expressed concern about the technical challenges with VVC. Interviewees cited inconsistencies for both patients and physicians receiving emails with links to join VVC visits, which should be generated when appointments are scheduled. Some physicians were unaware of scheduled VVC visits until the day of the appointment and only received the link via email. Such issues appeared to occur regardless whether the physicians or support staff scheduled the encounter. Poor video and audio quality was also cited as significant barriers to successful VVC visits and were often not resolvable through troubleshooting efforts by physicians, patients, or support personnel. Given the limited time allotted to each patient encounter, such issues could significantly impact the physician’s ability to remain on schedule. Moreover, connectivity problems led to significant lapses, delays in audio and video transmission, and complete disconnections from the VVC encounter. This was a significant concern for participants, given the rural nature of New Mexico and the large geographical gaps in internet service throughout the state.

Theme 2: Patient technological literacy affected veteran and physician comfort with VVC. Successful VVC appointments require high-speed Internet and compatible hardware. Physicians indicated that some patients reported difficulties with critical steps in the process, such as logging into the VVC platform or ensuring their microphones and cameras were active. Physicians also expressed concern about older veterans’ ability to utilize electronic devices, noting they may generally be less technology savvy. Additionally, physicians reported that despite offering the option of a virtual visit, many veterans preferred in-person visits, regardless of the drive time required. This appeared related to a fear of using the technology, which led veterans to believe that virtual visits do not provide the same quality of care as in-person visits.

Theme 3: Integration of supportive measures is desired. Interviewees felt that integrated VVC technical assistance and technology literacy education were imperative. First, training the patient or the patient’s caregiver on how to complete a VVC encounter using the preferred device and the VVC platform would be beneficial. Second, education to inform physicians about common troubleshooting issues could help streamline VVC encounters. Third, managing a VVC encounter similarly to standard in-person visits could allow for better patient and physician experience. For example, physicians suggested that a medical assistant or a nurse triage the patient, take vital signs, and set them up in a room, potentially at a regional VA community based outpatient clinic. Such efforts would also allow patients to receive specialty care in remote areas where only primary care is generally offered. Support staff could assist with technological issues, such as setting up the VVC encounter and addressing potential problems before the physician joins the encounter, thereby preventing delays in patient care. Finally, physicians felt that designating a day solely for CVT visits would help prevent disruption in care with in-person visits.

Theme 4: CVT services may increasingly be used to enhance access to care. Physicians felt that VVC would help patients encountering obstacles in accessing conventional in person services, including patients in rural and underserved areas, with disabilities, or with scheduling challenges.4 Patients with chronic conditions might drive the use of virtual visits, as many of these patients are already accustomed to remote medical monitoring. Data from devices such as scales and continuous glucose monitors can be easily reviewed during VVC visits. Second, video encounters facilitate closer monitoring that some patients might otherwise skip due to significant travel barriers, especially in a rural state like New Mexico. Lastly, VVC may be more efficient than in person visits as they eliminate the need for lengthy parking, checking in, and checking out processes. Thus, if technological issues are resolved, a typical physician’s day in the clinic may be more efficient with virtual visits.

Theme 5: In-person encounters afforded unique advantages over CVT. Some physicians felt in-person visits still offer unique advantages. They opined that the selection of appropriate candidates for CVT is critical. Patients requiring a physical examination should be scheduled for in person visits. For example, patients with advanced chronic kidney disease who require accurate volume status assessment or patients who have recently undergone surgery and need detailed wound inspection should be seen in the clinic. In-person visits may also be preferable for patients with recurrent admissions, or those whose condition is difficult to assess; accurate assessments of such patients may help prevent readmissions. Finally, many patients are more comfortable and satisfied with in-person visits, which are perceived as a more standard or traditional process. Respondents noted that some patients felt physicians may not focus as much attention during a VVC visit as they do during in-person visits. There were also concerns that some patients feel more motivation to come to in-person visits, as they see the VA as a place to interact with other veterans and staff with whom they are familiar and comfortable.

DISCUSSION

VANMHCS physicians, which serves veterans across an expansive territory ranging from Southern Colorado to West Texas. About 4.6 million veterans reside in rural regions, constituting roughly 25% of the total veteran population, a pattern mirrored in New Mexico.¹³ Medicine Service physicians agreed on a number of themes: VVC user-interface issues may affect its use and effectiveness, technological literacy was important for both patients and health care staff, technical support staff roles before and during VVC visits should be standardized, CVT is likely to increase health care delivery, and in-person encounters are preferred for many patients.

This is the first study to qualitatively evaluate a diverse group of physicians at a VA medical center incorporating CVT services across specialties. A few related qualitative studies have been conducted external to VHA, generally evaluating clinicians within a single specialty. Kalicki and colleagues surveyed 16 physicians working at a large home-based primary care program in New York City between April and June 2020 to identify and explore barriers to telehealth among homebound older adults. Similarly to our study, physicians noted that many patients required assistance (family members or caregivers) with the visit, either due to technological literacy issues or medical conditions like dementia.¹⁴

Heyer and colleagues surveyed 29 oncologists at an urban academic center prior to the COVID-19 pandemic. Similar to our observations, the oncologists said telemedicine helped eliminate travel as a barrier to health care. Heyer and colleagues noted difficulty for oncologists in performing virtual physical examinations, despite training. This group did note the benefits when being selective as to which clinical issues they would handle virtually vs in person.¹⁵

Budhwani and colleagues reported that mental health professionals in an academic setting cited difficulty establishing therapeutic relationships via telehealth and felt that this affected quality of care.¹⁶ While this was not a topic during our interviews, it is reasonable to question how potentially missed nonverbal cues may impact patient assessments.

Notably, technological issues were common among all reviewed studies. These ranged from internet connectivity issues to necessary electronic devices. As mentioned, these barriers are more prevalent in rural states like New Mexico.

Limitations

All participants in this study were Medicine Service physicians of a single VA health care system, which may limit generalizability. Many of our respondents were female (69%), compared with 39.2% of active internal medicine physicians and therefore may not be representative.¹⁷ Nearly one-half of our participants only completed 1 to 4 VVC encounters, which may have contributed to the emergence of a common theme regarding technological issues. Physicians with more experience with CVT services may be more skilled at troubleshooting technological issues that arise during visits.

CONCLUSIONS

Our study, conducted with VANMHCS physicians, illuminated 5 key themes influencing the use and implementation of video encounters: technological issues, technological literacy, a desire for integrated support measures, perceived future growth of video telehealth, and the unique advantages of in-person visits. Addressing technological barriers and providing more extensive training may streamline CVT use. However, it is vital to recognize the unique benefits of in-person visits and consider the benefits of each modality along with patient preferences when selecting the best care venue. As health care evolves, better understanding and acting upon these themes will optimize telehealth services, particularly in rural areas. Future research should involve patients and other health care team members to further explore strategies for effective CVT service integration.

Appendix

Prior to the COVID-19 pandemic, health care systems had been increasingly focused on expanding care delivery through clinical video telehealth (CVT) services.^1-3 These modalities offer clinicians and patients opportunities to interact without needing face-to-face visits. CVT services offer significant advantages to patients who encounter challenges accessing traditional face-to-face services, including those living in rural or underserved areas, individuals with mobility limitations, and those with difficulty attending appointments due to work or caregiving commitments.⁴ The COVID-19 pandemic accelerated the expansion of CVT services to mitigate the spread of the virus.¹

Despite its evident advantages, widespread adoption of CVT has encountered resistance.² Physicians have frequently expressed concerns about the reliability and functionality of CVT platforms for scheduled encounters and frustration with inadequate training.^4-6 Additionally, there is a lack trust in the technology, as physicians are unfamiliar with reimbursement or workload capture associated with CVT. Physicians have concerns that telecommunication may diminish the intangible aspects of the “art of medicine.”⁴ As a result, the implementation of telehealth services has been inconsistent, with successful adoption limited to specific medical and surgical specialties.⁴ Only recently have entire departments within major health care systems expressed interest in providing comprehensive CVT services in response to the challenges posed by the COVID-19 pandemic.⁴

The Veterans Health Administration (VHA) of the US Department of Veterans Affairs (VA) provides an appropriate setting for assessing clinician perceptions of telehealth services. Since 2003, the VHA has significantly expanded CVT services to eligible veterans and has used the VA Video Connect (VVC) platform since 2018.^7-10 Through VVC, VA staff and clinicians may schedule video visits with patients, meet with patients through virtual face-to-face interaction, and share relevant laboratory results and imaging through screen sharing. Prior research has shown increased accessibility to care through VVC. For example, a single-site study demonstrated that VVC implementation for delivering psychotherapies significantly increased CVT encounters from 15% to 85% among veterans with anxiety and/or depression.¹¹

The VA New Mexico Healthcare System (VANMHCS) serves a high volume of veterans living in remote and rural regions and significantly increased its use of CVT during the COVID-19 pandemic to reduce in-person visits. Expectedly, this was met with a variety of challenges. Herein, we sought to assess physician perspectives, concerns, and attitudes toward VVC via semistructured interviews. Our hypothesis was that VA physicians may feel uncomfortable with video encounters but recognize the growing importance of such practices providing specialty care to veterans in rural areas.

METHODS

A semistructured interview protocol was created following discussions with physicians from the VANMHCS Medicine Service. Questions were constructed to assess the following domains: overarching views of video telehealth, perceptions of various applications for conducting VVC encounters, and barriers to the broad implementation of video telehealth. A qualitative investigation specialist aided with question development. Two pilot interviews were conducted prior to performing the interviews with the recruited participants to evaluate the quality and delivery of questions.

All VANMHCS physicians who provided outpatient care within the Department of Medicine and had completed ≥ 1 VVC encounter were eligible to participate. Invitations were disseminated via email, and follow-up emails to encourage participation were sent periodically for 2 months following the initial request. Union approval was obtained to interview employees for a research study. In total, 64 physicians were invited and 13 (20%) chose to participate. As the study did not involve assessing medical interventions among patients, a waiver of informed consent was granted by the VANMHCS Institutional Review Board. Physicians who participated in this study were informed that their responses would be used for reporting purposes and could be rescinded at any time.

Data Analysis

Semistructured interviews were conducted by a single interviewer and recorded using Microsoft Teams. The interviews took place between February 2021 and December 2021 and lasted 5 to 15 minutes, with a mean duration of 9 minutes. Verbal informed consent was obtained from all participants before the interviews. Interviewees were encouraged to expand on their responses to structured questions by recounting past experiences with VVC. Recorded audio was additionally transcribed via Microsoft Teams, and the research team reviewed the transcriptions to ensure accuracy.

The tracking and coding of responses to interview questions were conducted using Microsoft Excel. Initially, 5 transcripts were reviewed and responses were assessed by 2 study team members through open coding. All team members examined the 5 coded transcripts to identify differences and reach a consensus for any discrepancies. Based on recommendations from all team members regarding nuanced excerpts of transcripts, 1 study team member coded the remaining interviews. Thematic analysis was subsequently conducted according to the method described by Braun and Clarke.¹² Themes were developed both deductively and inductively by reviewing the direct responses to interview questions and identifying emerging patterns of data, respectively. Indicative quotes representing each theme were carefully chosen for reporting.

RESULTS

Thirteen interviews were conducted and 9 participants (69%) were female. Participating physicians included 3 internal medicine/primary care physicians (23%), 2 nephrologists (15%), and 1 (8%) from cardiology, endocrinology, hematology, infectious diseases, palliative care, critical care, pulmonology, and sleep medicine. Years of post training experience among physicians ranged from 1 to 9 years (n = 5, 38%), 10 to 19 years (n = 3, 23%), and . 20 years (n = 5, 38%). Seven participants (54%) had conducted ≥ 5 VVC visits, with 1 physician completing > 50 video visits (Table).

Using open coding and a deductive approach to thematic analysis, 5 themes were identified: (1) VVC software and internet connection issues affected implementation; (2) patient technological literacy affected veteran and physician comfort with VVC; (3) integration of supportive measures was desired; (4) CVT services may increasingly be used to enhance access to care; and (5) in-person encounters afforded unique advantages over CVT. Illustrative quotes from physicians that reflect these themes can be found in the Appendix.

Theme 1: VVC software and internet connection issues affected its implementation. Most participants expressed concern about the technical challenges with VVC. Interviewees cited inconsistencies for both patients and physicians receiving emails with links to join VVC visits, which should be generated when appointments are scheduled. Some physicians were unaware of scheduled VVC visits until the day of the appointment and only received the link via email. Such issues appeared to occur regardless whether the physicians or support staff scheduled the encounter. Poor video and audio quality was also cited as significant barriers to successful VVC visits and were often not resolvable through troubleshooting efforts by physicians, patients, or support personnel. Given the limited time allotted to each patient encounter, such issues could significantly impact the physician’s ability to remain on schedule. Moreover, connectivity problems led to significant lapses, delays in audio and video transmission, and complete disconnections from the VVC encounter. This was a significant concern for participants, given the rural nature of New Mexico and the large geographical gaps in internet service throughout the state.

Theme 2: Patient technological literacy affected veteran and physician comfort with VVC. Successful VVC appointments require high-speed Internet and compatible hardware. Physicians indicated that some patients reported difficulties with critical steps in the process, such as logging into the VVC platform or ensuring their microphones and cameras were active. Physicians also expressed concern about older veterans’ ability to utilize electronic devices, noting they may generally be less technology savvy. Additionally, physicians reported that despite offering the option of a virtual visit, many veterans preferred in-person visits, regardless of the drive time required. This appeared related to a fear of using the technology, which led veterans to believe that virtual visits do not provide the same quality of care as in-person visits.

Theme 3: Integration of supportive measures is desired. Interviewees felt that integrated VVC technical assistance and technology literacy education were imperative. First, training the patient or the patient’s caregiver on how to complete a VVC encounter using the preferred device and the VVC platform would be beneficial. Second, education to inform physicians about common troubleshooting issues could help streamline VVC encounters. Third, managing a VVC encounter similarly to standard in-person visits could allow for better patient and physician experience. For example, physicians suggested that a medical assistant or a nurse triage the patient, take vital signs, and set them up in a room, potentially at a regional VA community based outpatient clinic. Such efforts would also allow patients to receive specialty care in remote areas where only primary care is generally offered. Support staff could assist with technological issues, such as setting up the VVC encounter and addressing potential problems before the physician joins the encounter, thereby preventing delays in patient care. Finally, physicians felt that designating a day solely for CVT visits would help prevent disruption in care with in-person visits.

Theme 4: CVT services may increasingly be used to enhance access to care. Physicians felt that VVC would help patients encountering obstacles in accessing conventional in person services, including patients in rural and underserved areas, with disabilities, or with scheduling challenges.4 Patients with chronic conditions might drive the use of virtual visits, as many of these patients are already accustomed to remote medical monitoring. Data from devices such as scales and continuous glucose monitors can be easily reviewed during VVC visits. Second, video encounters facilitate closer monitoring that some patients might otherwise skip due to significant travel barriers, especially in a rural state like New Mexico. Lastly, VVC may be more efficient than in person visits as they eliminate the need for lengthy parking, checking in, and checking out processes. Thus, if technological issues are resolved, a typical physician’s day in the clinic may be more efficient with virtual visits.

Theme 5: In-person encounters afforded unique advantages over CVT. Some physicians felt in-person visits still offer unique advantages. They opined that the selection of appropriate candidates for CVT is critical. Patients requiring a physical examination should be scheduled for in person visits. For example, patients with advanced chronic kidney disease who require accurate volume status assessment or patients who have recently undergone surgery and need detailed wound inspection should be seen in the clinic. In-person visits may also be preferable for patients with recurrent admissions, or those whose condition is difficult to assess; accurate assessments of such patients may help prevent readmissions. Finally, many patients are more comfortable and satisfied with in-person visits, which are perceived as a more standard or traditional process. Respondents noted that some patients felt physicians may not focus as much attention during a VVC visit as they do during in-person visits. There were also concerns that some patients feel more motivation to come to in-person visits, as they see the VA as a place to interact with other veterans and staff with whom they are familiar and comfortable.

DISCUSSION

VANMHCS physicians, which serves veterans across an expansive territory ranging from Southern Colorado to West Texas. About 4.6 million veterans reside in rural regions, constituting roughly 25% of the total veteran population, a pattern mirrored in New Mexico.¹³ Medicine Service physicians agreed on a number of themes: VVC user-interface issues may affect its use and effectiveness, technological literacy was important for both patients and health care staff, technical support staff roles before and during VVC visits should be standardized, CVT is likely to increase health care delivery, and in-person encounters are preferred for many patients.

This is the first study to qualitatively evaluate a diverse group of physicians at a VA medical center incorporating CVT services across specialties. A few related qualitative studies have been conducted external to VHA, generally evaluating clinicians within a single specialty. Kalicki and colleagues surveyed 16 physicians working at a large home-based primary care program in New York City between April and June 2020 to identify and explore barriers to telehealth among homebound older adults. Similarly to our study, physicians noted that many patients required assistance (family members or caregivers) with the visit, either due to technological literacy issues or medical conditions like dementia.¹⁴

Heyer and colleagues surveyed 29 oncologists at an urban academic center prior to the COVID-19 pandemic. Similar to our observations, the oncologists said telemedicine helped eliminate travel as a barrier to health care. Heyer and colleagues noted difficulty for oncologists in performing virtual physical examinations, despite training. This group did note the benefits when being selective as to which clinical issues they would handle virtually vs in person.¹⁵

Budhwani and colleagues reported that mental health professionals in an academic setting cited difficulty establishing therapeutic relationships via telehealth and felt that this affected quality of care.¹⁶ While this was not a topic during our interviews, it is reasonable to question how potentially missed nonverbal cues may impact patient assessments.

Notably, technological issues were common among all reviewed studies. These ranged from internet connectivity issues to necessary electronic devices. As mentioned, these barriers are more prevalent in rural states like New Mexico.

Limitations

All participants in this study were Medicine Service physicians of a single VA health care system, which may limit generalizability. Many of our respondents were female (69%), compared with 39.2% of active internal medicine physicians and therefore may not be representative.¹⁷ Nearly one-half of our participants only completed 1 to 4 VVC encounters, which may have contributed to the emergence of a common theme regarding technological issues. Physicians with more experience with CVT services may be more skilled at troubleshooting technological issues that arise during visits.

CONCLUSIONS

Our study, conducted with VANMHCS physicians, illuminated 5 key themes influencing the use and implementation of video encounters: technological issues, technological literacy, a desire for integrated support measures, perceived future growth of video telehealth, and the unique advantages of in-person visits. Addressing technological barriers and providing more extensive training may streamline CVT use. However, it is vital to recognize the unique benefits of in-person visits and consider the benefits of each modality along with patient preferences when selecting the best care venue. As health care evolves, better understanding and acting upon these themes will optimize telehealth services, particularly in rural areas. Future research should involve patients and other health care team members to further explore strategies for effective CVT service integration.

Appendix

Prior to the COVID-19 pandemic, health care systems had been increasingly focused on expanding care delivery through clinical video telehealth (CVT) services.^1-3 These modalities offer clinicians and patients opportunities to interact without needing face-to-face visits. CVT services offer significant advantages to patients who encounter challenges accessing traditional face-to-face services, including those living in rural or underserved areas, individuals with mobility limitations, and those with difficulty attending appointments due to work or caregiving commitments.⁴ The COVID-19 pandemic accelerated the expansion of CVT services to mitigate the spread of the virus.¹

Despite its evident advantages, widespread adoption of CVT has encountered resistance.² Physicians have frequently expressed concerns about the reliability and functionality of CVT platforms for scheduled encounters and frustration with inadequate training.^4-6 Additionally, there is a lack trust in the technology, as physicians are unfamiliar with reimbursement or workload capture associated with CVT. Physicians have concerns that telecommunication may diminish the intangible aspects of the “art of medicine.”⁴ As a result, the implementation of telehealth services has been inconsistent, with successful adoption limited to specific medical and surgical specialties.⁴ Only recently have entire departments within major health care systems expressed interest in providing comprehensive CVT services in response to the challenges posed by the COVID-19 pandemic.⁴

The Veterans Health Administration (VHA) of the US Department of Veterans Affairs (VA) provides an appropriate setting for assessing clinician perceptions of telehealth services. Since 2003, the VHA has significantly expanded CVT services to eligible veterans and has used the VA Video Connect (VVC) platform since 2018.^7-10 Through VVC, VA staff and clinicians may schedule video visits with patients, meet with patients through virtual face-to-face interaction, and share relevant laboratory results and imaging through screen sharing. Prior research has shown increased accessibility to care through VVC. For example, a single-site study demonstrated that VVC implementation for delivering psychotherapies significantly increased CVT encounters from 15% to 85% among veterans with anxiety and/or depression.¹¹

The VA New Mexico Healthcare System (VANMHCS) serves a high volume of veterans living in remote and rural regions and significantly increased its use of CVT during the COVID-19 pandemic to reduce in-person visits. Expectedly, this was met with a variety of challenges. Herein, we sought to assess physician perspectives, concerns, and attitudes toward VVC via semistructured interviews. Our hypothesis was that VA physicians may feel uncomfortable with video encounters but recognize the growing importance of such practices providing specialty care to veterans in rural areas.

METHODS

A semistructured interview protocol was created following discussions with physicians from the VANMHCS Medicine Service. Questions were constructed to assess the following domains: overarching views of video telehealth, perceptions of various applications for conducting VVC encounters, and barriers to the broad implementation of video telehealth. A qualitative investigation specialist aided with question development. Two pilot interviews were conducted prior to performing the interviews with the recruited participants to evaluate the quality and delivery of questions.

All VANMHCS physicians who provided outpatient care within the Department of Medicine and had completed ≥ 1 VVC encounter were eligible to participate. Invitations were disseminated via email, and follow-up emails to encourage participation were sent periodically for 2 months following the initial request. Union approval was obtained to interview employees for a research study. In total, 64 physicians were invited and 13 (20%) chose to participate. As the study did not involve assessing medical interventions among patients, a waiver of informed consent was granted by the VANMHCS Institutional Review Board. Physicians who participated in this study were informed that their responses would be used for reporting purposes and could be rescinded at any time.

Data Analysis

Semistructured interviews were conducted by a single interviewer and recorded using Microsoft Teams. The interviews took place between February 2021 and December 2021 and lasted 5 to 15 minutes, with a mean duration of 9 minutes. Verbal informed consent was obtained from all participants before the interviews. Interviewees were encouraged to expand on their responses to structured questions by recounting past experiences with VVC. Recorded audio was additionally transcribed via Microsoft Teams, and the research team reviewed the transcriptions to ensure accuracy.

The tracking and coding of responses to interview questions were conducted using Microsoft Excel. Initially, 5 transcripts were reviewed and responses were assessed by 2 study team members through open coding. All team members examined the 5 coded transcripts to identify differences and reach a consensus for any discrepancies. Based on recommendations from all team members regarding nuanced excerpts of transcripts, 1 study team member coded the remaining interviews. Thematic analysis was subsequently conducted according to the method described by Braun and Clarke.¹² Themes were developed both deductively and inductively by reviewing the direct responses to interview questions and identifying emerging patterns of data, respectively. Indicative quotes representing each theme were carefully chosen for reporting.

RESULTS

Thirteen interviews were conducted and 9 participants (69%) were female. Participating physicians included 3 internal medicine/primary care physicians (23%), 2 nephrologists (15%), and 1 (8%) from cardiology, endocrinology, hematology, infectious diseases, palliative care, critical care, pulmonology, and sleep medicine. Years of post training experience among physicians ranged from 1 to 9 years (n = 5, 38%), 10 to 19 years (n = 3, 23%), and . 20 years (n = 5, 38%). Seven participants (54%) had conducted ≥ 5 VVC visits, with 1 physician completing > 50 video visits (Table).

Using open coding and a deductive approach to thematic analysis, 5 themes were identified: (1) VVC software and internet connection issues affected implementation; (2) patient technological literacy affected veteran and physician comfort with VVC; (3) integration of supportive measures was desired; (4) CVT services may increasingly be used to enhance access to care; and (5) in-person encounters afforded unique advantages over CVT. Illustrative quotes from physicians that reflect these themes can be found in the Appendix.

Theme 1: VVC software and internet connection issues affected its implementation. Most participants expressed concern about the technical challenges with VVC. Interviewees cited inconsistencies for both patients and physicians receiving emails with links to join VVC visits, which should be generated when appointments are scheduled. Some physicians were unaware of scheduled VVC visits until the day of the appointment and only received the link via email. Such issues appeared to occur regardless whether the physicians or support staff scheduled the encounter. Poor video and audio quality was also cited as significant barriers to successful VVC visits and were often not resolvable through troubleshooting efforts by physicians, patients, or support personnel. Given the limited time allotted to each patient encounter, such issues could significantly impact the physician’s ability to remain on schedule. Moreover, connectivity problems led to significant lapses, delays in audio and video transmission, and complete disconnections from the VVC encounter. This was a significant concern for participants, given the rural nature of New Mexico and the large geographical gaps in internet service throughout the state.

Theme 2: Patient technological literacy affected veteran and physician comfort with VVC. Successful VVC appointments require high-speed Internet and compatible hardware. Physicians indicated that some patients reported difficulties with critical steps in the process, such as logging into the VVC platform or ensuring their microphones and cameras were active. Physicians also expressed concern about older veterans’ ability to utilize electronic devices, noting they may generally be less technology savvy. Additionally, physicians reported that despite offering the option of a virtual visit, many veterans preferred in-person visits, regardless of the drive time required. This appeared related to a fear of using the technology, which led veterans to believe that virtual visits do not provide the same quality of care as in-person visits.

Theme 3: Integration of supportive measures is desired. Interviewees felt that integrated VVC technical assistance and technology literacy education were imperative. First, training the patient or the patient’s caregiver on how to complete a VVC encounter using the preferred device and the VVC platform would be beneficial. Second, education to inform physicians about common troubleshooting issues could help streamline VVC encounters. Third, managing a VVC encounter similarly to standard in-person visits could allow for better patient and physician experience. For example, physicians suggested that a medical assistant or a nurse triage the patient, take vital signs, and set them up in a room, potentially at a regional VA community based outpatient clinic. Such efforts would also allow patients to receive specialty care in remote areas where only primary care is generally offered. Support staff could assist with technological issues, such as setting up the VVC encounter and addressing potential problems before the physician joins the encounter, thereby preventing delays in patient care. Finally, physicians felt that designating a day solely for CVT visits would help prevent disruption in care with in-person visits.

Theme 4: CVT services may increasingly be used to enhance access to care. Physicians felt that VVC would help patients encountering obstacles in accessing conventional in person services, including patients in rural and underserved areas, with disabilities, or with scheduling challenges.4 Patients with chronic conditions might drive the use of virtual visits, as many of these patients are already accustomed to remote medical monitoring. Data from devices such as scales and continuous glucose monitors can be easily reviewed during VVC visits. Second, video encounters facilitate closer monitoring that some patients might otherwise skip due to significant travel barriers, especially in a rural state like New Mexico. Lastly, VVC may be more efficient than in person visits as they eliminate the need for lengthy parking, checking in, and checking out processes. Thus, if technological issues are resolved, a typical physician’s day in the clinic may be more efficient with virtual visits.

Theme 5: In-person encounters afforded unique advantages over CVT. Some physicians felt in-person visits still offer unique advantages. They opined that the selection of appropriate candidates for CVT is critical. Patients requiring a physical examination should be scheduled for in person visits. For example, patients with advanced chronic kidney disease who require accurate volume status assessment or patients who have recently undergone surgery and need detailed wound inspection should be seen in the clinic. In-person visits may also be preferable for patients with recurrent admissions, or those whose condition is difficult to assess; accurate assessments of such patients may help prevent readmissions. Finally, many patients are more comfortable and satisfied with in-person visits, which are perceived as a more standard or traditional process. Respondents noted that some patients felt physicians may not focus as much attention during a VVC visit as they do during in-person visits. There were also concerns that some patients feel more motivation to come to in-person visits, as they see the VA as a place to interact with other veterans and staff with whom they are familiar and comfortable.

DISCUSSION

VANMHCS physicians, which serves veterans across an expansive territory ranging from Southern Colorado to West Texas. About 4.6 million veterans reside in rural regions, constituting roughly 25% of the total veteran population, a pattern mirrored in New Mexico.¹³ Medicine Service physicians agreed on a number of themes: VVC user-interface issues may affect its use and effectiveness, technological literacy was important for both patients and health care staff, technical support staff roles before and during VVC visits should be standardized, CVT is likely to increase health care delivery, and in-person encounters are preferred for many patients.

This is the first study to qualitatively evaluate a diverse group of physicians at a VA medical center incorporating CVT services across specialties. A few related qualitative studies have been conducted external to VHA, generally evaluating clinicians within a single specialty. Kalicki and colleagues surveyed 16 physicians working at a large home-based primary care program in New York City between April and June 2020 to identify and explore barriers to telehealth among homebound older adults. Similarly to our study, physicians noted that many patients required assistance (family members or caregivers) with the visit, either due to technological literacy issues or medical conditions like dementia.¹⁴

Heyer and colleagues surveyed 29 oncologists at an urban academic center prior to the COVID-19 pandemic. Similar to our observations, the oncologists said telemedicine helped eliminate travel as a barrier to health care. Heyer and colleagues noted difficulty for oncologists in performing virtual physical examinations, despite training. This group did note the benefits when being selective as to which clinical issues they would handle virtually vs in person.¹⁵

Budhwani and colleagues reported that mental health professionals in an academic setting cited difficulty establishing therapeutic relationships via telehealth and felt that this affected quality of care.¹⁶ While this was not a topic during our interviews, it is reasonable to question how potentially missed nonverbal cues may impact patient assessments.

Notably, technological issues were common among all reviewed studies. These ranged from internet connectivity issues to necessary electronic devices. As mentioned, these barriers are more prevalent in rural states like New Mexico.

Limitations

All participants in this study were Medicine Service physicians of a single VA health care system, which may limit generalizability. Many of our respondents were female (69%), compared with 39.2% of active internal medicine physicians and therefore may not be representative.¹⁷ Nearly one-half of our participants only completed 1 to 4 VVC encounters, which may have contributed to the emergence of a common theme regarding technological issues. Physicians with more experience with CVT services may be more skilled at troubleshooting technological issues that arise during visits.

CONCLUSIONS

Our study, conducted with VANMHCS physicians, illuminated 5 key themes influencing the use and implementation of video encounters: technological issues, technological literacy, a desire for integrated support measures, perceived future growth of video telehealth, and the unique advantages of in-person visits. Addressing technological barriers and providing more extensive training may streamline CVT use. However, it is vital to recognize the unique benefits of in-person visits and consider the benefits of each modality along with patient preferences when selecting the best care venue. As health care evolves, better understanding and acting upon these themes will optimize telehealth services, particularly in rural areas. Future research should involve patients and other health care team members to further explore strategies for effective CVT service integration.

Appendix

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

There is a direct link between psoriasis and metabolic conditions such as diabetes mellitus and obesity.¹ Exercise of varied intensity in patients with chronic inflammatory and metabolic conditions can help improve quality of life and severity of disease; however, there has not been a clear consensus on the recommended duration and types of exercise that are most advantageous.^1-5 We reviewed the literature to identify physical and mental health impacts of exercise on patients with psoriasis, and we present the recommended duration and types of exercise that are most impactful for these patients.

One indicator of the link between psoriasis and exercise is the level of peroxisome proliferator activated receptor gamma coactivator-1 α (PGC-1α) in muscle cells.² This marker reduces inflammation. When levels are low in muscle cells, an induction occurs that leads to systemic or local inflammation; however, skeletal muscle PGC-1α levels increase following exercise, indicating reduced inflammation.² The level of PGC-1α is measured through muscle biopsy and polymerase chain reaction.⁶ Another indicator of the correlation between exercise and inflammation is lipoprotein-associated phospholipase A2, which is produced by inflammatory cells and has a correlation with cardiovascular disease. Exercise reduces lipoprotein-associated phospholipase A2 levels, and a sedentary lifestyle correlates with increased levels of this marker.³ Lipoprotein-associated phospholipase A2 is measured through an enzyme-linked immunosorbent assay of the blood, with levels around 200 ng/mL considered high.⁷ Patients with psoriasis are 30% less likely to participate in physical activity compared to patients without psoriasis, which can be attributed to psychosocial impairment and other factors. Sedentary lifestyle is associated with new or worsening metabolic disease and prevalence of psoriatic lesions.¹

A metabolic equivalent task score is a classification system that measures the rate of the body’s oxygen uptake for any given activity.⁴ A score of 20.9 or more metabolic equivalent task hours of vigorous exercise per week—equal to 105 minutes of running or 180 minutes of swimming or playing tennis—is linked with a 25% to 30% risk reduction of psoriasis in women.⁴ Therefore, we recommend 30 minutes of exercise 4 to 5 times per week for women. These periods of exercise should consist mainly of activities that will not cause psoriasis flares due to excessive sweating, skin trauma, or prolonged sun exposure.⁵ Walking, yoga, and bike riding all could be good exercise options for those with psoriasis. The National Psoriasis Foundation offers guidance on physical activity in patients with psoriasis or psoriatic arthritis.⁸ Psoriasis has apparent physical and psychosocial impacts on patients that can be prevented and improved through the exercise recommendations presented in this article. Dermatologists should use these recommendations to address psoriasis in their everyday practice.

There is a direct link between psoriasis and metabolic conditions such as diabetes mellitus and obesity.¹ Exercise of varied intensity in patients with chronic inflammatory and metabolic conditions can help improve quality of life and severity of disease; however, there has not been a clear consensus on the recommended duration and types of exercise that are most advantageous.^1-5 We reviewed the literature to identify physical and mental health impacts of exercise on patients with psoriasis, and we present the recommended duration and types of exercise that are most impactful for these patients.

One indicator of the link between psoriasis and exercise is the level of peroxisome proliferator activated receptor gamma coactivator-1 α (PGC-1α) in muscle cells.² This marker reduces inflammation. When levels are low in muscle cells, an induction occurs that leads to systemic or local inflammation; however, skeletal muscle PGC-1α levels increase following exercise, indicating reduced inflammation.² The level of PGC-1α is measured through muscle biopsy and polymerase chain reaction.⁶ Another indicator of the correlation between exercise and inflammation is lipoprotein-associated phospholipase A2, which is produced by inflammatory cells and has a correlation with cardiovascular disease. Exercise reduces lipoprotein-associated phospholipase A2 levels, and a sedentary lifestyle correlates with increased levels of this marker.³ Lipoprotein-associated phospholipase A2 is measured through an enzyme-linked immunosorbent assay of the blood, with levels around 200 ng/mL considered high.⁷ Patients with psoriasis are 30% less likely to participate in physical activity compared to patients without psoriasis, which can be attributed to psychosocial impairment and other factors. Sedentary lifestyle is associated with new or worsening metabolic disease and prevalence of psoriatic lesions.¹

A metabolic equivalent task score is a classification system that measures the rate of the body’s oxygen uptake for any given activity.⁴ A score of 20.9 or more metabolic equivalent task hours of vigorous exercise per week—equal to 105 minutes of running or 180 minutes of swimming or playing tennis—is linked with a 25% to 30% risk reduction of psoriasis in women.⁴ Therefore, we recommend 30 minutes of exercise 4 to 5 times per week for women. These periods of exercise should consist mainly of activities that will not cause psoriasis flares due to excessive sweating, skin trauma, or prolonged sun exposure.⁵ Walking, yoga, and bike riding all could be good exercise options for those with psoriasis. The National Psoriasis Foundation offers guidance on physical activity in patients with psoriasis or psoriatic arthritis.⁸ Psoriasis has apparent physical and psychosocial impacts on patients that can be prevented and improved through the exercise recommendations presented in this article. Dermatologists should use these recommendations to address psoriasis in their everyday practice.

There is a direct link between psoriasis and metabolic conditions such as diabetes mellitus and obesity.¹ Exercise of varied intensity in patients with chronic inflammatory and metabolic conditions can help improve quality of life and severity of disease; however, there has not been a clear consensus on the recommended duration and types of exercise that are most advantageous.^1-5 We reviewed the literature to identify physical and mental health impacts of exercise on patients with psoriasis, and we present the recommended duration and types of exercise that are most impactful for these patients.

One indicator of the link between psoriasis and exercise is the level of peroxisome proliferator activated receptor gamma coactivator-1 α (PGC-1α) in muscle cells.² This marker reduces inflammation. When levels are low in muscle cells, an induction occurs that leads to systemic or local inflammation; however, skeletal muscle PGC-1α levels increase following exercise, indicating reduced inflammation.² The level of PGC-1α is measured through muscle biopsy and polymerase chain reaction.⁶ Another indicator of the correlation between exercise and inflammation is lipoprotein-associated phospholipase A2, which is produced by inflammatory cells and has a correlation with cardiovascular disease. Exercise reduces lipoprotein-associated phospholipase A2 levels, and a sedentary lifestyle correlates with increased levels of this marker.³ Lipoprotein-associated phospholipase A2 is measured through an enzyme-linked immunosorbent assay of the blood, with levels around 200 ng/mL considered high.⁷ Patients with psoriasis are 30% less likely to participate in physical activity compared to patients without psoriasis, which can be attributed to psychosocial impairment and other factors. Sedentary lifestyle is associated with new or worsening metabolic disease and prevalence of psoriatic lesions.¹

A metabolic equivalent task score is a classification system that measures the rate of the body’s oxygen uptake for any given activity.⁴ A score of 20.9 or more metabolic equivalent task hours of vigorous exercise per week—equal to 105 minutes of running or 180 minutes of swimming or playing tennis—is linked with a 25% to 30% risk reduction of psoriasis in women.⁴ Therefore, we recommend 30 minutes of exercise 4 to 5 times per week for women. These periods of exercise should consist mainly of activities that will not cause psoriasis flares due to excessive sweating, skin trauma, or prolonged sun exposure.⁵ Walking, yoga, and bike riding all could be good exercise options for those with psoriasis. The National Psoriasis Foundation offers guidance on physical activity in patients with psoriasis or psoriatic arthritis.⁸ Psoriasis has apparent physical and psychosocial impacts on patients that can be prevented and improved through the exercise recommendations presented in this article. Dermatologists should use these recommendations to address psoriasis in their everyday practice.

Introduction
Large cell neuroendocrine carcinomas (LCNEC) of the lung are sufficiently rare that large trials to establish a standard of care are impractical. Treatment strategies effective for related malignancies, particularly small-cell lung cancer (SCLC), have been commonly applied to LCNEC of the lung, but it is important to recognize the unique features of LCNEC in order to make a diagnosis and to individualize treatment. As current long-term survival in patients with LCNEC of the lung remains poor, participation in clinical trials should be encouraged. Therapies under investigation include those targeted at the delta-like ligand 3 (DLL3), an antigen highly expressed in neuroendocrine (NE) tumors, and Seneca Valley oncolytic viral (SVV) therapy. Early introduction of palliative care should also be offered to optimize quality of life. High-quality data for LCNEC of the lung and novel breakthrough drugs are much needed.

Background
NE tumors can develop from NE cells in almost any organ.¹ After the gastrointestinal tract, the lung is the most common site of NE malignancies. They account for only about 2% of all lung cancers but 25% of NE tumors.² Criteria for differentiating NE tumors from other tumors in the lung were first proposed in 1991.³ In 2022, the World Health Organization described 5 major subtypes of NE lung malignancies.⁴ On a spectrum ranging from best to worst outcome among lung cancers, LCNEC has a significantly more aggressive course compared with typical carcinoids (TC) and atypical carcinoids (AC), approaching that of SCLC, which arguably has the worst outcome (Table).⁵

Table. Comparing NSCLC, SCLC, and LCNEC of the Lung

Similarities exist between LCNEC of the lung and other non-small cell lung cancer (NSCLC) types, but there are more parallels with SCLC. Both are more common in male patients and both are associated with a history of smoking.⁶ They also share a poor prognosis. If diagnosed at an advanced stage, 5-year survival rates for LCNEC of the lung and SCLC have been reported to be as low as 5% to 15%.⁶

The risk of a delay in establishing the correct diagnosis of LCNEC of the lung, even by experienced pathologists, is considerable. The key diagnostic criteria include expression of at least 1 NE marker, such as chromogranin-A or synaptophysin, a high proliferation rate (> 10 mitoses per high-power field), extensive necrosis, and NE morphology features, such as trabeculae and palisading and rosette formations.⁷ However, other lung cancers can also express NE markers and some features might be missed without relatively large tissue specimens.⁷

To improve diagnostic accuracy, additional criteria, such as absence of squamous or adenocarcinoma features or the demonstration of 2 or more NE markers are now being advocated in some reports,⁸ while others have advocated that terms such as “combined NSCLC/SCLC” should not be accepted as a substitute for differentiating and finalizing a diagnosis of LCNEC of the lung.⁷ Excisional or resection biopsies, as opposed to needle biopsies, might be required to obtain an adequate tissue sample to reach a definitive diagnosis.

Illustrating the potential for confusion with other lung cancers, LCNEC of the lung can be characterized by 2 subtypes.⁹ Type 1 is characterized by TP53 and STK11/KEAP1 alternations—similar to adenocarcinomas and squamous cell lung cancers—and it is associated with a higher expression of NE markers, such as ASCL1 and DLL3. Type 2 is typically characterized by inactivation of TP53 and RB1. Ultimately, type I LCNEC of the lung has a mutational pattern similar to NSCLC and type II has a pattern similar to SCLC. While LCNEC is typically located in the periphery of the lung, SCLC is typically centrally located and NSCLC can be found in either location. Complicated further by the fact that a proportion of these tumors have features shared with SCLC and rarer cancers, such as spindle-cell carcinoma and giant cell carcinoma, LCNEC should be considered in the differential diagnosis of any lung cancer with ambiguous features.⁷

For these reasons, a pathology review should be performed at a high-volume center whenever possible. As part of the diagnostic process, molecular testing should be gathered for all patients whether or not it is required to make or confirm the diagnosis. This information will be informative for guiding treatment, particularly second- and third-line interventions. Rather than being unique and definitive, the individual features of LCNEC of the lung—including the genetic, molecular, histologic, and morphologic characteristics—cumulatively support the diagnosis. After establishing a pathological diagnosis, staging of LCNEC of the lung is paramount. In addition, distinctions between the grades of LCNEC of the lung are relative. For example, tumors with a better relative prognosis typically have fewer gene mutations than tumors with a worse relative prognosis, but mutations are generally found in both.

Bronchoscopy with endobronchial ultrasound can be considered for both diagnosis and staging of locally advanced tumors, but a surgical specimen might still be required for a definitive diagnosis. Differentiating local LCNEC, which has been reported in about 25% of cases, from locally advanced and metastatic disease is critical for planning treatment. Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) plays an important role in staging LCNEC of the lung. Unlike TC and AC, for LCNEC of the lung there is a very limited role of somatostatin receptor agonist-based imaging or tetraazacyclododecanetetraacetic acid-DPhel-Tyr3-octreotate (DOTATATE) PET during diagnostic workup.

Therapeutic Strategies
In early stages, resection followed by adjuvant chemotherapy has long been used for LCNEC of the lung. Studies evaluating this approach, such as one that combined cisplatin and etoposide,¹⁰ suggest doublet chemotherapy after surgery offers a benefit in LCNEC of the lung comparable to that seen in SCLC. There is limited support for adjunctive radiotherapy in early-stage LCNEC of the lung,⁵ even if radiotherapy has shown benefit for patients ineligible for surgery.¹¹

In locally advanced and advanced LCNEC (≥ stage III-B) ineligible for resection, chemoradiation has been associated with a survival advantage over chemotherapy alone,¹² but due to the high rates of relapse and limited survival, efforts to move to novel therapies have been expanding for both LCNEC of the lung and SCLC. This includes immunotherapies used before or after chemoradiation. Again, much of the interest in immunotherapies has been derived from studies in SCLC, but several small studies have associated checkpoint inhibitors with substantial antitumor activity in patients with LCNEC.^13,14 There are no large scale prospective trials to determine the optimal treatment in the first line setting for LCNEC of the lung and most data is extrapolated from treatment of ES-SCLC. In a retrospective study, however, comparing survival of palliative chemotherapy with a SCLC versus a NSCLC regimen, the SCLC regimen was favored.¹⁵

Following a pivotal trial of tarlatamab-dlle, that led to an accelerated approval for extensive-stage SCLC in May 2024,¹⁶ this drug has also been evaluated in a small group of patients with LCNEC of the lung. The parallels between LCNEC and SCLC have raised hope that this drug, which is a bispecific T-cell engager (BiTE) that binds to the DLL3 ligand and CD3, may provide benefit in LCNEC of the lung that is commensurate with the benefit seen in SCLC. A recently published LCNEC case study supports this potential.¹⁷ A high-grade NE-carcinoma-specific oncolytic virus called Seneca Valley virus holds promise. Preclinical data suggest encouraging anticancer activity when SVV is combined with immune checkpoint inhibitor therapy.¹⁸ SVV seems to attack cancer cells that express tumor endothelial marker 8 (TEM-8), making it an interesting target in future efforts for screening and tailoring treatment.¹⁹ Human studies are in development.

Due to the high frequency of relapse regardless of frontline therapies, there is also growing interest in maintenance strategies to extend disease control. Maintenance regimens that have been evaluated or are being considered include immunotherapies, even if the optimal sequence of treatment modalities remains unknown. The high rate of relapse also encourages early planning of sequential therapies based on molecular testing. Numerous studies of LCNEC of the lung have now identified activating mutations in targetable pathways, such as P13K/AKT/mTOR, KRAS, and FGFR1.¹⁸ Patients may also harbor a high tumor mutation burden, a characteristic that might favor treatment with immunotherapy. Each mutation is relevant to only a small proportion of patients with LCNEC. However, when all potentially targetable mutations are considered together, the proportion of patients with LCNEC who would benefit from an individualized therapy is substantial, thus supporting trials of individualized therapy, particularly in the second line.

The high rate of relapse with currently available therapies encourages enrollment in clinical trials, particularly among patients who have already failed a first-line strategy. In the United States, studies are enrolling patients with LCNEC of the lung for checkpoint inhibitors with or without combination chemotherapy, novel BiTE therapies, and novel therapies targeting specific activating pathways. Many of these trials offer enrollment to patients with either SCLC or LCNEC.

Due to poor survival, patients with advancing LCNEC of the lung should be considered for palliative care. Although no guideline protocol exists for palliative care, the American Society of Clinical Oncology recommends palliative care for all individuals with advanced cancer based on evidence of improved quality of life and, in some cases, survival.²⁰ 

Summary
LCNEC is an uncommon lung malignancy with a poor prognosis in the advanced stages at which it is most often recognized. The risk of overlooking this cancer in the initial diagnosis emphasizes the need for an adequate index of suspicion and familiarity with its distinguishing characteristics. Treatments of LCNEC of the lung have been largely based on those used for SCLC, but there has been an evolution in the understanding of this disease, which includes a greater appreciation for heterogeneity among driving mutations, a growing interest in maintenance therapies to extend the time to relapse, and trials of a growing array of novel therapies, including immunotherapies and BiTEs. Early intervention with these novel therapies and an emphasis on palliative care is needed because LCNEC has such an aggressive course.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Large cell neuroendocrine carcinomas (LCNEC) of the lung are sufficiently rare that large trials to establish a standard of care are impractical. Treatment strategies effective for related malignancies, particularly small-cell lung cancer (SCLC), have been commonly applied to LCNEC of the lung, but it is important to recognize the unique features of LCNEC in order to make a diagnosis and to individualize treatment. As current long-term survival in patients with LCNEC of the lung remains poor, participation in clinical trials should be encouraged. Therapies under investigation include those targeted at the delta-like ligand 3 (DLL3), an antigen highly expressed in neuroendocrine (NE) tumors, and Seneca Valley oncolytic viral (SVV) therapy. Early introduction of palliative care should also be offered to optimize quality of life. High-quality data for LCNEC of the lung and novel breakthrough drugs are much needed.

Background
NE tumors can develop from NE cells in almost any organ.¹ After the gastrointestinal tract, the lung is the most common site of NE malignancies. They account for only about 2% of all lung cancers but 25% of NE tumors.² Criteria for differentiating NE tumors from other tumors in the lung were first proposed in 1991.³ In 2022, the World Health Organization described 5 major subtypes of NE lung malignancies.⁴ On a spectrum ranging from best to worst outcome among lung cancers, LCNEC has a significantly more aggressive course compared with typical carcinoids (TC) and atypical carcinoids (AC), approaching that of SCLC, which arguably has the worst outcome (Table).⁵

Table. Comparing NSCLC, SCLC, and LCNEC of the Lung

Similarities exist between LCNEC of the lung and other non-small cell lung cancer (NSCLC) types, but there are more parallels with SCLC. Both are more common in male patients and both are associated with a history of smoking.⁶ They also share a poor prognosis. If diagnosed at an advanced stage, 5-year survival rates for LCNEC of the lung and SCLC have been reported to be as low as 5% to 15%.⁶

The risk of a delay in establishing the correct diagnosis of LCNEC of the lung, even by experienced pathologists, is considerable. The key diagnostic criteria include expression of at least 1 NE marker, such as chromogranin-A or synaptophysin, a high proliferation rate (> 10 mitoses per high-power field), extensive necrosis, and NE morphology features, such as trabeculae and palisading and rosette formations.⁷ However, other lung cancers can also express NE markers and some features might be missed without relatively large tissue specimens.⁷

To improve diagnostic accuracy, additional criteria, such as absence of squamous or adenocarcinoma features or the demonstration of 2 or more NE markers are now being advocated in some reports,⁸ while others have advocated that terms such as “combined NSCLC/SCLC” should not be accepted as a substitute for differentiating and finalizing a diagnosis of LCNEC of the lung.⁷ Excisional or resection biopsies, as opposed to needle biopsies, might be required to obtain an adequate tissue sample to reach a definitive diagnosis.

Illustrating the potential for confusion with other lung cancers, LCNEC of the lung can be characterized by 2 subtypes.⁹ Type 1 is characterized by TP53 and STK11/KEAP1 alternations—similar to adenocarcinomas and squamous cell lung cancers—and it is associated with a higher expression of NE markers, such as ASCL1 and DLL3. Type 2 is typically characterized by inactivation of TP53 and RB1. Ultimately, type I LCNEC of the lung has a mutational pattern similar to NSCLC and type II has a pattern similar to SCLC. While LCNEC is typically located in the periphery of the lung, SCLC is typically centrally located and NSCLC can be found in either location. Complicated further by the fact that a proportion of these tumors have features shared with SCLC and rarer cancers, such as spindle-cell carcinoma and giant cell carcinoma, LCNEC should be considered in the differential diagnosis of any lung cancer with ambiguous features.⁷

For these reasons, a pathology review should be performed at a high-volume center whenever possible. As part of the diagnostic process, molecular testing should be gathered for all patients whether or not it is required to make or confirm the diagnosis. This information will be informative for guiding treatment, particularly second- and third-line interventions. Rather than being unique and definitive, the individual features of LCNEC of the lung—including the genetic, molecular, histologic, and morphologic characteristics—cumulatively support the diagnosis. After establishing a pathological diagnosis, staging of LCNEC of the lung is paramount. In addition, distinctions between the grades of LCNEC of the lung are relative. For example, tumors with a better relative prognosis typically have fewer gene mutations than tumors with a worse relative prognosis, but mutations are generally found in both.

Bronchoscopy with endobronchial ultrasound can be considered for both diagnosis and staging of locally advanced tumors, but a surgical specimen might still be required for a definitive diagnosis. Differentiating local LCNEC, which has been reported in about 25% of cases, from locally advanced and metastatic disease is critical for planning treatment. Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) plays an important role in staging LCNEC of the lung. Unlike TC and AC, for LCNEC of the lung there is a very limited role of somatostatin receptor agonist-based imaging or tetraazacyclododecanetetraacetic acid-DPhel-Tyr3-octreotate (DOTATATE) PET during diagnostic workup.

Therapeutic Strategies
In early stages, resection followed by adjuvant chemotherapy has long been used for LCNEC of the lung. Studies evaluating this approach, such as one that combined cisplatin and etoposide,¹⁰ suggest doublet chemotherapy after surgery offers a benefit in LCNEC of the lung comparable to that seen in SCLC. There is limited support for adjunctive radiotherapy in early-stage LCNEC of the lung,⁵ even if radiotherapy has shown benefit for patients ineligible for surgery.¹¹

In locally advanced and advanced LCNEC (≥ stage III-B) ineligible for resection, chemoradiation has been associated with a survival advantage over chemotherapy alone,¹² but due to the high rates of relapse and limited survival, efforts to move to novel therapies have been expanding for both LCNEC of the lung and SCLC. This includes immunotherapies used before or after chemoradiation. Again, much of the interest in immunotherapies has been derived from studies in SCLC, but several small studies have associated checkpoint inhibitors with substantial antitumor activity in patients with LCNEC.^13,14 There are no large scale prospective trials to determine the optimal treatment in the first line setting for LCNEC of the lung and most data is extrapolated from treatment of ES-SCLC. In a retrospective study, however, comparing survival of palliative chemotherapy with a SCLC versus a NSCLC regimen, the SCLC regimen was favored.¹⁵

Following a pivotal trial of tarlatamab-dlle, that led to an accelerated approval for extensive-stage SCLC in May 2024,¹⁶ this drug has also been evaluated in a small group of patients with LCNEC of the lung. The parallels between LCNEC and SCLC have raised hope that this drug, which is a bispecific T-cell engager (BiTE) that binds to the DLL3 ligand and CD3, may provide benefit in LCNEC of the lung that is commensurate with the benefit seen in SCLC. A recently published LCNEC case study supports this potential.¹⁷ A high-grade NE-carcinoma-specific oncolytic virus called Seneca Valley virus holds promise. Preclinical data suggest encouraging anticancer activity when SVV is combined with immune checkpoint inhibitor therapy.¹⁸ SVV seems to attack cancer cells that express tumor endothelial marker 8 (TEM-8), making it an interesting target in future efforts for screening and tailoring treatment.¹⁹ Human studies are in development.

Due to the high frequency of relapse regardless of frontline therapies, there is also growing interest in maintenance strategies to extend disease control. Maintenance regimens that have been evaluated or are being considered include immunotherapies, even if the optimal sequence of treatment modalities remains unknown. The high rate of relapse also encourages early planning of sequential therapies based on molecular testing. Numerous studies of LCNEC of the lung have now identified activating mutations in targetable pathways, such as P13K/AKT/mTOR, KRAS, and FGFR1.¹⁸ Patients may also harbor a high tumor mutation burden, a characteristic that might favor treatment with immunotherapy. Each mutation is relevant to only a small proportion of patients with LCNEC. However, when all potentially targetable mutations are considered together, the proportion of patients with LCNEC who would benefit from an individualized therapy is substantial, thus supporting trials of individualized therapy, particularly in the second line.

The high rate of relapse with currently available therapies encourages enrollment in clinical trials, particularly among patients who have already failed a first-line strategy. In the United States, studies are enrolling patients with LCNEC of the lung for checkpoint inhibitors with or without combination chemotherapy, novel BiTE therapies, and novel therapies targeting specific activating pathways. Many of these trials offer enrollment to patients with either SCLC or LCNEC.

Due to poor survival, patients with advancing LCNEC of the lung should be considered for palliative care. Although no guideline protocol exists for palliative care, the American Society of Clinical Oncology recommends palliative care for all individuals with advanced cancer based on evidence of improved quality of life and, in some cases, survival.²⁰ 

Summary
LCNEC is an uncommon lung malignancy with a poor prognosis in the advanced stages at which it is most often recognized. The risk of overlooking this cancer in the initial diagnosis emphasizes the need for an adequate index of suspicion and familiarity with its distinguishing characteristics. Treatments of LCNEC of the lung have been largely based on those used for SCLC, but there has been an evolution in the understanding of this disease, which includes a greater appreciation for heterogeneity among driving mutations, a growing interest in maintenance therapies to extend the time to relapse, and trials of a growing array of novel therapies, including immunotherapies and BiTEs. Early intervention with these novel therapies and an emphasis on palliative care is needed because LCNEC has such an aggressive course.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Large cell neuroendocrine carcinomas (LCNEC) of the lung are sufficiently rare that large trials to establish a standard of care are impractical. Treatment strategies effective for related malignancies, particularly small-cell lung cancer (SCLC), have been commonly applied to LCNEC of the lung, but it is important to recognize the unique features of LCNEC in order to make a diagnosis and to individualize treatment. As current long-term survival in patients with LCNEC of the lung remains poor, participation in clinical trials should be encouraged. Therapies under investigation include those targeted at the delta-like ligand 3 (DLL3), an antigen highly expressed in neuroendocrine (NE) tumors, and Seneca Valley oncolytic viral (SVV) therapy. Early introduction of palliative care should also be offered to optimize quality of life. High-quality data for LCNEC of the lung and novel breakthrough drugs are much needed.

Background
NE tumors can develop from NE cells in almost any organ.¹ After the gastrointestinal tract, the lung is the most common site of NE malignancies. They account for only about 2% of all lung cancers but 25% of NE tumors.² Criteria for differentiating NE tumors from other tumors in the lung were first proposed in 1991.³ In 2022, the World Health Organization described 5 major subtypes of NE lung malignancies.⁴ On a spectrum ranging from best to worst outcome among lung cancers, LCNEC has a significantly more aggressive course compared with typical carcinoids (TC) and atypical carcinoids (AC), approaching that of SCLC, which arguably has the worst outcome (Table).⁵

Table. Comparing NSCLC, SCLC, and LCNEC of the Lung

Similarities exist between LCNEC of the lung and other non-small cell lung cancer (NSCLC) types, but there are more parallels with SCLC. Both are more common in male patients and both are associated with a history of smoking.⁶ They also share a poor prognosis. If diagnosed at an advanced stage, 5-year survival rates for LCNEC of the lung and SCLC have been reported to be as low as 5% to 15%.⁶

The risk of a delay in establishing the correct diagnosis of LCNEC of the lung, even by experienced pathologists, is considerable. The key diagnostic criteria include expression of at least 1 NE marker, such as chromogranin-A or synaptophysin, a high proliferation rate (> 10 mitoses per high-power field), extensive necrosis, and NE morphology features, such as trabeculae and palisading and rosette formations.⁷ However, other lung cancers can also express NE markers and some features might be missed without relatively large tissue specimens.⁷

To improve diagnostic accuracy, additional criteria, such as absence of squamous or adenocarcinoma features or the demonstration of 2 or more NE markers are now being advocated in some reports,⁸ while others have advocated that terms such as “combined NSCLC/SCLC” should not be accepted as a substitute for differentiating and finalizing a diagnosis of LCNEC of the lung.⁷ Excisional or resection biopsies, as opposed to needle biopsies, might be required to obtain an adequate tissue sample to reach a definitive diagnosis.

Illustrating the potential for confusion with other lung cancers, LCNEC of the lung can be characterized by 2 subtypes.⁹ Type 1 is characterized by TP53 and STK11/KEAP1 alternations—similar to adenocarcinomas and squamous cell lung cancers—and it is associated with a higher expression of NE markers, such as ASCL1 and DLL3. Type 2 is typically characterized by inactivation of TP53 and RB1. Ultimately, type I LCNEC of the lung has a mutational pattern similar to NSCLC and type II has a pattern similar to SCLC. While LCNEC is typically located in the periphery of the lung, SCLC is typically centrally located and NSCLC can be found in either location. Complicated further by the fact that a proportion of these tumors have features shared with SCLC and rarer cancers, such as spindle-cell carcinoma and giant cell carcinoma, LCNEC should be considered in the differential diagnosis of any lung cancer with ambiguous features.⁷

For these reasons, a pathology review should be performed at a high-volume center whenever possible. As part of the diagnostic process, molecular testing should be gathered for all patients whether or not it is required to make or confirm the diagnosis. This information will be informative for guiding treatment, particularly second- and third-line interventions. Rather than being unique and definitive, the individual features of LCNEC of the lung—including the genetic, molecular, histologic, and morphologic characteristics—cumulatively support the diagnosis. After establishing a pathological diagnosis, staging of LCNEC of the lung is paramount. In addition, distinctions between the grades of LCNEC of the lung are relative. For example, tumors with a better relative prognosis typically have fewer gene mutations than tumors with a worse relative prognosis, but mutations are generally found in both.

Bronchoscopy with endobronchial ultrasound can be considered for both diagnosis and staging of locally advanced tumors, but a surgical specimen might still be required for a definitive diagnosis. Differentiating local LCNEC, which has been reported in about 25% of cases, from locally advanced and metastatic disease is critical for planning treatment. Fluorodeoxyglucose F18 (FDG) positron emission tomography (PET) plays an important role in staging LCNEC of the lung. Unlike TC and AC, for LCNEC of the lung there is a very limited role of somatostatin receptor agonist-based imaging or tetraazacyclododecanetetraacetic acid-DPhel-Tyr3-octreotate (DOTATATE) PET during diagnostic workup.

Therapeutic Strategies
In early stages, resection followed by adjuvant chemotherapy has long been used for LCNEC of the lung. Studies evaluating this approach, such as one that combined cisplatin and etoposide,¹⁰ suggest doublet chemotherapy after surgery offers a benefit in LCNEC of the lung comparable to that seen in SCLC. There is limited support for adjunctive radiotherapy in early-stage LCNEC of the lung,⁵ even if radiotherapy has shown benefit for patients ineligible for surgery.¹¹

In locally advanced and advanced LCNEC (≥ stage III-B) ineligible for resection, chemoradiation has been associated with a survival advantage over chemotherapy alone,¹² but due to the high rates of relapse and limited survival, efforts to move to novel therapies have been expanding for both LCNEC of the lung and SCLC. This includes immunotherapies used before or after chemoradiation. Again, much of the interest in immunotherapies has been derived from studies in SCLC, but several small studies have associated checkpoint inhibitors with substantial antitumor activity in patients with LCNEC.^13,14 There are no large scale prospective trials to determine the optimal treatment in the first line setting for LCNEC of the lung and most data is extrapolated from treatment of ES-SCLC. In a retrospective study, however, comparing survival of palliative chemotherapy with a SCLC versus a NSCLC regimen, the SCLC regimen was favored.¹⁵

Following a pivotal trial of tarlatamab-dlle, that led to an accelerated approval for extensive-stage SCLC in May 2024,¹⁶ this drug has also been evaluated in a small group of patients with LCNEC of the lung. The parallels between LCNEC and SCLC have raised hope that this drug, which is a bispecific T-cell engager (BiTE) that binds to the DLL3 ligand and CD3, may provide benefit in LCNEC of the lung that is commensurate with the benefit seen in SCLC. A recently published LCNEC case study supports this potential.¹⁷ A high-grade NE-carcinoma-specific oncolytic virus called Seneca Valley virus holds promise. Preclinical data suggest encouraging anticancer activity when SVV is combined with immune checkpoint inhibitor therapy.¹⁸ SVV seems to attack cancer cells that express tumor endothelial marker 8 (TEM-8), making it an interesting target in future efforts for screening and tailoring treatment.¹⁹ Human studies are in development.

Due to the high frequency of relapse regardless of frontline therapies, there is also growing interest in maintenance strategies to extend disease control. Maintenance regimens that have been evaluated or are being considered include immunotherapies, even if the optimal sequence of treatment modalities remains unknown. The high rate of relapse also encourages early planning of sequential therapies based on molecular testing. Numerous studies of LCNEC of the lung have now identified activating mutations in targetable pathways, such as P13K/AKT/mTOR, KRAS, and FGFR1.¹⁸ Patients may also harbor a high tumor mutation burden, a characteristic that might favor treatment with immunotherapy. Each mutation is relevant to only a small proportion of patients with LCNEC. However, when all potentially targetable mutations are considered together, the proportion of patients with LCNEC who would benefit from an individualized therapy is substantial, thus supporting trials of individualized therapy, particularly in the second line.

The high rate of relapse with currently available therapies encourages enrollment in clinical trials, particularly among patients who have already failed a first-line strategy. In the United States, studies are enrolling patients with LCNEC of the lung for checkpoint inhibitors with or without combination chemotherapy, novel BiTE therapies, and novel therapies targeting specific activating pathways. Many of these trials offer enrollment to patients with either SCLC or LCNEC.

Due to poor survival, patients with advancing LCNEC of the lung should be considered for palliative care. Although no guideline protocol exists for palliative care, the American Society of Clinical Oncology recommends palliative care for all individuals with advanced cancer based on evidence of improved quality of life and, in some cases, survival.²⁰ 

Summary
LCNEC is an uncommon lung malignancy with a poor prognosis in the advanced stages at which it is most often recognized. The risk of overlooking this cancer in the initial diagnosis emphasizes the need for an adequate index of suspicion and familiarity with its distinguishing characteristics. Treatments of LCNEC of the lung have been largely based on those used for SCLC, but there has been an evolution in the understanding of this disease, which includes a greater appreciation for heterogeneity among driving mutations, a growing interest in maintenance therapies to extend the time to relapse, and trials of a growing array of novel therapies, including immunotherapies and BiTEs. Early intervention with these novel therapies and an emphasis on palliative care is needed because LCNEC has such an aggressive course.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.