Mixed Topics

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative malignancies originating from T, B, or natural killer (NK) lymphocytes.¹ Compared to Hodgkin lymphomas, NHLs exhibit a broader clinical spectrum and have a poorer prognosis and frequent extranodal involvement, with the skin being the second most frequent extranodal site.² Primary cutaneous lymphomas (PCLs) are NHLs that are first evident on the skin without evidence of extracutaneous disease at diagnosis. They include a heterogeneous group of cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas. Among CTCLs, mycosis fungoides (MF) is the most prevalent subtype, generally following an indolent course. Cutaneous B-cell lymphomas primarily include follicle center lymphoma and diffuse large B-cell lymphoma.^3,4

The clinical behavior and incidence of PCLs vary dramatically between children and adults, suggesting underlying biologic, immunologic, and genetic differences.^5,6 However, there is a notable lack of comparative studies in the literature addressing these variations, limiting a comprehensive understanding of PCLs and hindering the development of tailored therapeutic strategies. The main objective of this study was to evaluate the different clinical characteristics, subtypes, treatment options, and prognosis in PCLs between pediatric and adult populations.^7,8

Methods

This retrospective observational study included pediatric (aged ≤18 years at diagnosis) and adult (aged >18 years at diagnosis) patients with a clinical and histopathologic diagnosis of PCL who were diagnosed and treated at either of 2 tertiary institutions (Dr. Manuel Gea Gonzalez General Hospital or the National Institute of Pediatrics, both in Mexico City, Mexico) between January 1, 1999, and December 31, 2019. The data analysis included demographic and clinical characteristics, type of PCL (according to World Health Organization [WHO]/European Organisation for Research and Treatment of Cancer [EORTC]) classification,^3,4 treatment administered, and outcome. Disease remission was defined as remittance of clinical PCL manifestations for 3 months or more. Disease control was defined as stable clinical manifestations with no change in PCL stage following treatment initiation. Disease progression was defined as worsening clinical manifestations with an increase in PCL stage and/or development of systemic lymphoma. Beyond similarities and differences across age groups, we also analyzed differences by sex. χ² and Mann-Whitney U tests were used to assess differences between groups. Statistical significance was set at P≤.05. Institutional approval was obtained from both tertiary centers.

Results

Our analysis included a total of 158 patients: 54 (34.2%) were children and 104 (65.8%) were adults. Eighty-eight (55.7%) patients were male (eTable 1). The mean (SD) age at diagnosis was 9.5 (1.9) years in children and 49.7 (18) years in adults. Regarding differences between age groups, adult patients had a similar sex distribution, while in children, the majority of patients were male (37/54 [68.5%]; P=.01).

Overall, the most frequent diagnosis was MF, which occurred in 119 (75.3%) patients, and the most common lesions were erythematous plaques, noted in 95 (60.1%) patients. The lower extremities were the most affected body sites, impacting 127 (80.4%) patients, and the most common treatment was phototherapy, used to treat 110 (69.6%) patients. Reported outcomes included disease control in 45 (28.5%) patients and progression in 36 (22.8%) patients; 50 (31.6%) patients were lost to follow-up. Only 15 (9.5%) patients experienced disease remission, and 12 (7.6%) died.

The mean (SD) time between the onset of symptoms and diagnosis was shorter in children than in adults (18.1 [12.6] months vs 66.2 [34.9] months; P<.001). Regarding involved body sites, the head and neck more frequently affected children than adults (40 [74.1%] vs 33 [31.7%]; P<.001), while the upper extremities were more frequently involved in adults than in children (67 [64.4%] vs 45 [83.3%]; P<.001).

There were significant differences in the morphology of lesions and diagnoses. Children most frequently had hypopigmented plaques (25 [46.3%]) and macules (24 [44.4%])(P<.001) associated with MF, and scars (7 [13.0%]), blisters (6 [11.1%]), and edema (8 [14.8%])(P<.001) associated with positive Epstein-Barr virus (EBV) infection. Adults presented more frequently with hyperpigmented macules (19 [18.3%]) and plaques (37 [35.6%]), erythematous plaques (71 [68.3%]), atrophy (36 [34.6%]), and tumors (32 [30.8%])(P<.001). Adults were more often asymptomatic (86.5% vs 38.8%; P<.001).

Subtypes of PCL differed by age group (eTable 2), with MF being more frequent in adults (87 [83.6%] vs 32 [59.2%]; P<.001), while chronic active positive EBV infection (CAEBVI) manifesting as lymphoproliferative disease (LPD) was exclusive to male children (9 [16.6%])(P<.001). Accordingly, we found variations in systemic treatments used: monoclonal antibodies (mAb), thalidomide, intravenous immunoglobulin (IVIg), and hematopoietic stem cell transplantation (HSCT) were used exclusively for treating children (all P<.001). Outcomes were distributed similarly by age group.

The type of PCL, clinical manifestations, and treatment also varied by sex (eTables 2 and 3). Only males had CAEBVI and presented with edema (8 [9.1%] vs 0%; P<.01). Males also had tumors (23 [26.1%] vs 9 [12.9%]; P=.03) and lesions affecting the head and neck (52 [59.1%] vs 21 [30.0%]; P<.001) more frequently than females. Males were more likely than females to report pain (28 [31.8%] vs 13 [18.6%]; P=.05) and receive systemic treatment with thalidomide (11 [12.5%] vs 1 [1.4%]; P<.001) and IVIg (6 [6.8%] vs 0%; P=.02). Only females were diagnosed with primary cutaneous anaplastic large cell lymphoma (PC-ALCL)(4 [5.7%] vs 0%; P=.03) and had genital involvement (4 [5.7%] vs 0%; P=.03). Females were more likely to be asymptomatic (57 [81.4%] vs 54 [61.4%]; P<.001) or report pruritus (46 [65.7%] vs 44 [50%]; P<.001) and receive local treatment with phototherapy (58 [82.9%] vs 52 [59.1%]; P<.001) compared to males. Although distribution of outcomes was similar by sex, we found males were more frequently lost to follow-up (38 [43.2%] vs 12 [17.1%]; P<.001).

We further searched for differences in clinical manifestations according to the PCL subtype in each age group. The most frequent lesions in 32 children with MF were hypopigmented macules (21 [65.6%]; P<.001)(Figure 1). Three of 5 (60%) children with extranodal NK/T-cell lymphoma, nasal type (ENKTCL), had nodules (P=.002). Of 9 children with CAEBVI, 8 (88.9%) had edema (P<.001), ulcers (P<.001), erythematous plaques (P=.007), and hypopigmented plaques (P=.008); 5 (55.6%) children presented with scars (P<.001) and atrophy (P<.001); and 4 (44.4%) children had blisters (P=.005)(Figure 2). The 2 children with EBV-positive mucocutaneous ulcer (EBV-MCU) had crusts (P=.002) and blisters (P=.01).

Of 87 adults with MF, 54 (62%) had scaly lesions (P=.006)(Figure 3). Of 3 adult patients with PC-ALCL, 2 (66.7%) had crusts (P=.04) and ulcers (P=.05). Two of 3 (66.7%) adults with lymphomatoid papulosis (LyP) had erythematous papules (P<.001). All 4 adult patients with ENKTCL (P=.008) and all 5 patients with primary cutaneous diffuse large B-cell lymphoma, leg-type, had tumors (P<.001).

Finally, we found no differences in outcomes according to types of PCL overall or by age group; however, when categorized by sex, we found males with EBV-MCU more frequently had disease progression than females with EBV-MCU (P=.04).

Comment

Primary cutaneous lymphomas were similarly distributed among males and females (55.6% vs 44.3%, respectively). This slight male predominance was similar to other reports in the literature: one US study reported a male-to-female incidence rate ratio of 1.72, indicating a significantly higher incidence in males (P<.001).⁶ Similar trends have been observed in other geographic regions, with reported male-to-female ratios of 1.56 in Greece and 1.35 in Argentina.^9,10 These findings suggest that PCLs are slightly more prevalent in males across different populations; however, when we stratified by age, pediatric cases of PCL were significantly more frequent in males than in females (68.5% vs. 31.4%; P=.01).

Our analysis revealed that the time to diagnosis was significantly longer in adults than in children (66.2 months vs 18.1 months) for all PCLs (P<.001). The most common type of PCL in both age groups was MF, with a notably higher prevalence in adults than in children (87 [83.7%] vs 32 [59.2%]). The prolonged course of MF in adults, often taking years to progress from early to advanced stages (47.0-52.7 months) may contribute to delayed diagnosis.^8,11,12 Additionally, classic lesions of MF (erythematous scaly plaques) may resemble other common dermatologic conditions, further complicating early recognition and treatment in adults more than in children.^11,12 Conversely, more aggressive and rapidly progressing PCL subtypes, including CAEBVI and ENKTCL-NT, were more frequent in children and would likely be diagnosed more promptly because of the acute onset and fast evolution of signs and symptoms.¹³

Mycosis fungoides is the most common CTCL, followed by CD30+ T-cell disorders such as LyP and PC-ALCL.¹⁴ While MF was the predominant subtype in both age groups, similar to previous reports,^6,7 pediatric patients in our study exhibited distinctive features, such as hypopigmented macules and plaques. Hypopigmented lesions may suggest an underlying immunologic mechanism unique to younger patients, specifically children, in contrast to the hyperpigmented or violaceous lesions predominating in adults.⁷ The hypopigmented variant of MF has been reported to be more prevalent in children, similar to our data, accounting for 54.5% of all pediatric MF cases. These hypopigmented lesions typically manifest at an early stage and follow an indolent course.^15,16 Jung et al⁸ conducted a systematic review of children with MF and reported a mean age at diagnosis of 12.2 years, whereas in our cohort, the mean age was 9.5 years. These findings highlight the different clinical manifestations of MF in children, which may aid in early recognition and diagnosis.

In adults, MF most commonly manifested as hyperpigmented macules and plaques, erythematous plaques, atrophic lesions, and tumors. In this population, MF remained the most frequently diagnosed PCL subtype, followed by PC-ALCL.

There were notable differences in symptom presentation between age groups and sexes. Adults were more often asymptomatic, and males reported pain more frequently.

When analyzing PCL subtypes in our study, we found that CAEBVI was exclusive to children, specifically males. The updated WHO/EORTC classification contains a new section on EBV-positive LPD in childhood, including hydroa vacciniforme–like LPD and hypersensitivity reactions to mosquito bites.⁴ Both are cutaneous manifestations of CAEBVI with a risk for progression to systemic EBV-positive T-cell or NK-cell lymphoma. These disorders mainly affect children and adolescents from Asia or Indigenous populations from Mexico and Central and South America.^3,4,17 Cases in both female and male patients have been reported, without a clear sex predominance; however, mutations in the Src homology 2 domain containing 1A (SH2D1A) gene recently have been shown to cause X-linked lymphoproliferative disease, which is associated with predilection for EBV infection and subsequent EBV-positive LPD, including CAEBVI.^18,19 Thus, it is possible some of the children with CAEBVI in our study may have an underlying X-linked lymphoproliferative disease, accounting for the male predominance.

Similarly, ENKTCL-NT tended to occur more in children than in adults in our study. Both CAEBVI-LPD and ENKTCL-NT are aggressive lymphomas with a suboptimal prognosis. Although treatment with immunomodulatory agents may lead to temporary remission in most cases, disease progression has been reported in larger cohorts, emphasizing the need for long-term follow-up and more aggressive treatments in severe cases of CAEBVI.^13,17 Treatment options for EBV-positive LPD include mAb such as rituximab, IVIg, HSCT, antiviral agents, interferons α and γ, and corticosteroids.²⁰

Treatment approaches were notably different between children and adults (P<.0001). Monoclonal antibodies, immunomodulatory agents such as thalidomide, IVIg, and HSCT were exclusively used in pediatric patients, reflecting the presence of CAEBVI and ENKTCL-NT (P<.0001). Additionally, edema, blisters, and scars were observed more frequently in children, likely due to the clinical manifestations of these EBV-related disorders.

A recent review of systemic NHL highlighted various age-related differences in clinical presentation, biology, and outcomes.¹³ In general, children tend to present with more aggressive subtypes and achieve better outcomes compared to adults.¹³ These differences may be attributed to variations in tumor biology, immune responses, and/or the benefits of early and intensive interventions in pediatric populations. These findings resonate with our results, as pediatric PCL patients received more aggressive treatments—including mAb, thalidomide, IVIg, and HSCT—likely due to the higher frequency of CAEBVI/ENKTCL-NT; however, we were unable to properly assess treatment outcomes, as many patients, both adults and children, were lost to follow-up.

Overall, our findings and comparisons with existing studies highlight the need for age-specific research and management approaches for PCL. The distinct clinical and biological profiles across age groups highlight opportunities for personalized therapies and further investigation into the molecular drivers of these differences to optimize outcomes for pediatric and adult patients.

When analyzing differences by sex, we found that CAEBVI was diagnosed exclusively in male children, who correspondingly exhibited clinical features such as edema and tumors, with lesions predominantly located on the head and neck. This also influenced treatment approach, as these patients were more likely to receive thalidomide and IVIg. In contrast, PC-ALCL was observed only in female patients, a finding that deviates from previously reported epidemiology.¹⁴ Females with PC-ALCL were more likely to have genital involvement and be asymptomatic, which could suggest a sex-related bias in disease recognition and seeking health care.

Recognizing distinctive clinical manifestations across different diagnoses and age groups can aid health care providers in early identification and accurate diagnosis of PCL. Our findings revealed several notable differences: adults with MF more frequently had scaly lesions, those with PC-ALCL had crusts and ulcers, and those with LyP had erythematous papules. All adults with ENKTCL and primary cutaneous diffuse large B-cell lymphoma, leg-type, presented with tumors. While children with MF had an increased frequency of hypopigmented macules, those with ENKTCL more frequently developed nodules, and children with EBV-MCU often had crusts and ulcers. As has already been mentioned, children with CAEBVI displayed a broad range of lesions, including edema, ulcers, erythematous and hypopigmented plaques, atrophy, blisters, and scars.

Our study was limited by the retrospective design and missing data from one-third of patients, which prevented outcome comparison. We also lacked molecular profiling of patients, which could help refine therapeutic strategies for PCL.¹³ Finally, as both centers included are reference institutions, results may be biased and overestimated and could differ from the rest of the population.

Conclusion

This comparative study of PCL highlighted age-related differences in clinical presentation, diagnostic distribution, and treatment patterns, including a higher prevalence among male children than female children. Adult patients with PCL had a notably longer time to diagnosis than children. The most common type of PCL identified in both age groups and sex categories was MF, but hypopigmented lesions predominated in children with this condition. Epstein-Barr virus–associated PCL occurred almost exclusively in children and manifested with nodules, edema, blisters, and scars. In terms of treatment, children received more aggressive and advanced therapies, including mAb, thalidomide, IVIg, and HSCT. Further prospective research is needed to establish variations in clinical manifestations, diagnoses, treatments, and outcomes.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative malignancies originating from T, B, or natural killer (NK) lymphocytes.¹ Compared to Hodgkin lymphomas, NHLs exhibit a broader clinical spectrum and have a poorer prognosis and frequent extranodal involvement, with the skin being the second most frequent extranodal site.² Primary cutaneous lymphomas (PCLs) are NHLs that are first evident on the skin without evidence of extracutaneous disease at diagnosis. They include a heterogeneous group of cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas. Among CTCLs, mycosis fungoides (MF) is the most prevalent subtype, generally following an indolent course. Cutaneous B-cell lymphomas primarily include follicle center lymphoma and diffuse large B-cell lymphoma.^3,4

The clinical behavior and incidence of PCLs vary dramatically between children and adults, suggesting underlying biologic, immunologic, and genetic differences.^5,6 However, there is a notable lack of comparative studies in the literature addressing these variations, limiting a comprehensive understanding of PCLs and hindering the development of tailored therapeutic strategies. The main objective of this study was to evaluate the different clinical characteristics, subtypes, treatment options, and prognosis in PCLs between pediatric and adult populations.^7,8

Methods

This retrospective observational study included pediatric (aged ≤18 years at diagnosis) and adult (aged >18 years at diagnosis) patients with a clinical and histopathologic diagnosis of PCL who were diagnosed and treated at either of 2 tertiary institutions (Dr. Manuel Gea Gonzalez General Hospital or the National Institute of Pediatrics, both in Mexico City, Mexico) between January 1, 1999, and December 31, 2019. The data analysis included demographic and clinical characteristics, type of PCL (according to World Health Organization [WHO]/European Organisation for Research and Treatment of Cancer [EORTC]) classification,^3,4 treatment administered, and outcome. Disease remission was defined as remittance of clinical PCL manifestations for 3 months or more. Disease control was defined as stable clinical manifestations with no change in PCL stage following treatment initiation. Disease progression was defined as worsening clinical manifestations with an increase in PCL stage and/or development of systemic lymphoma. Beyond similarities and differences across age groups, we also analyzed differences by sex. χ² and Mann-Whitney U tests were used to assess differences between groups. Statistical significance was set at P≤.05. Institutional approval was obtained from both tertiary centers.

Results

Our analysis included a total of 158 patients: 54 (34.2%) were children and 104 (65.8%) were adults. Eighty-eight (55.7%) patients were male (eTable 1). The mean (SD) age at diagnosis was 9.5 (1.9) years in children and 49.7 (18) years in adults. Regarding differences between age groups, adult patients had a similar sex distribution, while in children, the majority of patients were male (37/54 [68.5%]; P=.01).

Overall, the most frequent diagnosis was MF, which occurred in 119 (75.3%) patients, and the most common lesions were erythematous plaques, noted in 95 (60.1%) patients. The lower extremities were the most affected body sites, impacting 127 (80.4%) patients, and the most common treatment was phototherapy, used to treat 110 (69.6%) patients. Reported outcomes included disease control in 45 (28.5%) patients and progression in 36 (22.8%) patients; 50 (31.6%) patients were lost to follow-up. Only 15 (9.5%) patients experienced disease remission, and 12 (7.6%) died.

The mean (SD) time between the onset of symptoms and diagnosis was shorter in children than in adults (18.1 [12.6] months vs 66.2 [34.9] months; P<.001). Regarding involved body sites, the head and neck more frequently affected children than adults (40 [74.1%] vs 33 [31.7%]; P<.001), while the upper extremities were more frequently involved in adults than in children (67 [64.4%] vs 45 [83.3%]; P<.001).

There were significant differences in the morphology of lesions and diagnoses. Children most frequently had hypopigmented plaques (25 [46.3%]) and macules (24 [44.4%])(P<.001) associated with MF, and scars (7 [13.0%]), blisters (6 [11.1%]), and edema (8 [14.8%])(P<.001) associated with positive Epstein-Barr virus (EBV) infection. Adults presented more frequently with hyperpigmented macules (19 [18.3%]) and plaques (37 [35.6%]), erythematous plaques (71 [68.3%]), atrophy (36 [34.6%]), and tumors (32 [30.8%])(P<.001). Adults were more often asymptomatic (86.5% vs 38.8%; P<.001).

Subtypes of PCL differed by age group (eTable 2), with MF being more frequent in adults (87 [83.6%] vs 32 [59.2%]; P<.001), while chronic active positive EBV infection (CAEBVI) manifesting as lymphoproliferative disease (LPD) was exclusive to male children (9 [16.6%])(P<.001). Accordingly, we found variations in systemic treatments used: monoclonal antibodies (mAb), thalidomide, intravenous immunoglobulin (IVIg), and hematopoietic stem cell transplantation (HSCT) were used exclusively for treating children (all P<.001). Outcomes were distributed similarly by age group.

The type of PCL, clinical manifestations, and treatment also varied by sex (eTables 2 and 3). Only males had CAEBVI and presented with edema (8 [9.1%] vs 0%; P<.01). Males also had tumors (23 [26.1%] vs 9 [12.9%]; P=.03) and lesions affecting the head and neck (52 [59.1%] vs 21 [30.0%]; P<.001) more frequently than females. Males were more likely than females to report pain (28 [31.8%] vs 13 [18.6%]; P=.05) and receive systemic treatment with thalidomide (11 [12.5%] vs 1 [1.4%]; P<.001) and IVIg (6 [6.8%] vs 0%; P=.02). Only females were diagnosed with primary cutaneous anaplastic large cell lymphoma (PC-ALCL)(4 [5.7%] vs 0%; P=.03) and had genital involvement (4 [5.7%] vs 0%; P=.03). Females were more likely to be asymptomatic (57 [81.4%] vs 54 [61.4%]; P<.001) or report pruritus (46 [65.7%] vs 44 [50%]; P<.001) and receive local treatment with phototherapy (58 [82.9%] vs 52 [59.1%]; P<.001) compared to males. Although distribution of outcomes was similar by sex, we found males were more frequently lost to follow-up (38 [43.2%] vs 12 [17.1%]; P<.001).

We further searched for differences in clinical manifestations according to the PCL subtype in each age group. The most frequent lesions in 32 children with MF were hypopigmented macules (21 [65.6%]; P<.001)(Figure 1). Three of 5 (60%) children with extranodal NK/T-cell lymphoma, nasal type (ENKTCL), had nodules (P=.002). Of 9 children with CAEBVI, 8 (88.9%) had edema (P<.001), ulcers (P<.001), erythematous plaques (P=.007), and hypopigmented plaques (P=.008); 5 (55.6%) children presented with scars (P<.001) and atrophy (P<.001); and 4 (44.4%) children had blisters (P=.005)(Figure 2). The 2 children with EBV-positive mucocutaneous ulcer (EBV-MCU) had crusts (P=.002) and blisters (P=.01).

Of 87 adults with MF, 54 (62%) had scaly lesions (P=.006)(Figure 3). Of 3 adult patients with PC-ALCL, 2 (66.7%) had crusts (P=.04) and ulcers (P=.05). Two of 3 (66.7%) adults with lymphomatoid papulosis (LyP) had erythematous papules (P<.001). All 4 adult patients with ENKTCL (P=.008) and all 5 patients with primary cutaneous diffuse large B-cell lymphoma, leg-type, had tumors (P<.001).

Finally, we found no differences in outcomes according to types of PCL overall or by age group; however, when categorized by sex, we found males with EBV-MCU more frequently had disease progression than females with EBV-MCU (P=.04).

Comment

Primary cutaneous lymphomas were similarly distributed among males and females (55.6% vs 44.3%, respectively). This slight male predominance was similar to other reports in the literature: one US study reported a male-to-female incidence rate ratio of 1.72, indicating a significantly higher incidence in males (P<.001).⁶ Similar trends have been observed in other geographic regions, with reported male-to-female ratios of 1.56 in Greece and 1.35 in Argentina.^9,10 These findings suggest that PCLs are slightly more prevalent in males across different populations; however, when we stratified by age, pediatric cases of PCL were significantly more frequent in males than in females (68.5% vs. 31.4%; P=.01).

Our analysis revealed that the time to diagnosis was significantly longer in adults than in children (66.2 months vs 18.1 months) for all PCLs (P<.001). The most common type of PCL in both age groups was MF, with a notably higher prevalence in adults than in children (87 [83.7%] vs 32 [59.2%]). The prolonged course of MF in adults, often taking years to progress from early to advanced stages (47.0-52.7 months) may contribute to delayed diagnosis.^8,11,12 Additionally, classic lesions of MF (erythematous scaly plaques) may resemble other common dermatologic conditions, further complicating early recognition and treatment in adults more than in children.^11,12 Conversely, more aggressive and rapidly progressing PCL subtypes, including CAEBVI and ENKTCL-NT, were more frequent in children and would likely be diagnosed more promptly because of the acute onset and fast evolution of signs and symptoms.¹³

Mycosis fungoides is the most common CTCL, followed by CD30+ T-cell disorders such as LyP and PC-ALCL.¹⁴ While MF was the predominant subtype in both age groups, similar to previous reports,^6,7 pediatric patients in our study exhibited distinctive features, such as hypopigmented macules and plaques. Hypopigmented lesions may suggest an underlying immunologic mechanism unique to younger patients, specifically children, in contrast to the hyperpigmented or violaceous lesions predominating in adults.⁷ The hypopigmented variant of MF has been reported to be more prevalent in children, similar to our data, accounting for 54.5% of all pediatric MF cases. These hypopigmented lesions typically manifest at an early stage and follow an indolent course.^15,16 Jung et al⁸ conducted a systematic review of children with MF and reported a mean age at diagnosis of 12.2 years, whereas in our cohort, the mean age was 9.5 years. These findings highlight the different clinical manifestations of MF in children, which may aid in early recognition and diagnosis.

In adults, MF most commonly manifested as hyperpigmented macules and plaques, erythematous plaques, atrophic lesions, and tumors. In this population, MF remained the most frequently diagnosed PCL subtype, followed by PC-ALCL.

There were notable differences in symptom presentation between age groups and sexes. Adults were more often asymptomatic, and males reported pain more frequently.

When analyzing PCL subtypes in our study, we found that CAEBVI was exclusive to children, specifically males. The updated WHO/EORTC classification contains a new section on EBV-positive LPD in childhood, including hydroa vacciniforme–like LPD and hypersensitivity reactions to mosquito bites.⁴ Both are cutaneous manifestations of CAEBVI with a risk for progression to systemic EBV-positive T-cell or NK-cell lymphoma. These disorders mainly affect children and adolescents from Asia or Indigenous populations from Mexico and Central and South America.^3,4,17 Cases in both female and male patients have been reported, without a clear sex predominance; however, mutations in the Src homology 2 domain containing 1A (SH2D1A) gene recently have been shown to cause X-linked lymphoproliferative disease, which is associated with predilection for EBV infection and subsequent EBV-positive LPD, including CAEBVI.^18,19 Thus, it is possible some of the children with CAEBVI in our study may have an underlying X-linked lymphoproliferative disease, accounting for the male predominance.

Similarly, ENKTCL-NT tended to occur more in children than in adults in our study. Both CAEBVI-LPD and ENKTCL-NT are aggressive lymphomas with a suboptimal prognosis. Although treatment with immunomodulatory agents may lead to temporary remission in most cases, disease progression has been reported in larger cohorts, emphasizing the need for long-term follow-up and more aggressive treatments in severe cases of CAEBVI.^13,17 Treatment options for EBV-positive LPD include mAb such as rituximab, IVIg, HSCT, antiviral agents, interferons α and γ, and corticosteroids.²⁰

Treatment approaches were notably different between children and adults (P<.0001). Monoclonal antibodies, immunomodulatory agents such as thalidomide, IVIg, and HSCT were exclusively used in pediatric patients, reflecting the presence of CAEBVI and ENKTCL-NT (P<.0001). Additionally, edema, blisters, and scars were observed more frequently in children, likely due to the clinical manifestations of these EBV-related disorders.

A recent review of systemic NHL highlighted various age-related differences in clinical presentation, biology, and outcomes.¹³ In general, children tend to present with more aggressive subtypes and achieve better outcomes compared to adults.¹³ These differences may be attributed to variations in tumor biology, immune responses, and/or the benefits of early and intensive interventions in pediatric populations. These findings resonate with our results, as pediatric PCL patients received more aggressive treatments—including mAb, thalidomide, IVIg, and HSCT—likely due to the higher frequency of CAEBVI/ENKTCL-NT; however, we were unable to properly assess treatment outcomes, as many patients, both adults and children, were lost to follow-up.

Overall, our findings and comparisons with existing studies highlight the need for age-specific research and management approaches for PCL. The distinct clinical and biological profiles across age groups highlight opportunities for personalized therapies and further investigation into the molecular drivers of these differences to optimize outcomes for pediatric and adult patients.

When analyzing differences by sex, we found that CAEBVI was diagnosed exclusively in male children, who correspondingly exhibited clinical features such as edema and tumors, with lesions predominantly located on the head and neck. This also influenced treatment approach, as these patients were more likely to receive thalidomide and IVIg. In contrast, PC-ALCL was observed only in female patients, a finding that deviates from previously reported epidemiology.¹⁴ Females with PC-ALCL were more likely to have genital involvement and be asymptomatic, which could suggest a sex-related bias in disease recognition and seeking health care.

Recognizing distinctive clinical manifestations across different diagnoses and age groups can aid health care providers in early identification and accurate diagnosis of PCL. Our findings revealed several notable differences: adults with MF more frequently had scaly lesions, those with PC-ALCL had crusts and ulcers, and those with LyP had erythematous papules. All adults with ENKTCL and primary cutaneous diffuse large B-cell lymphoma, leg-type, presented with tumors. While children with MF had an increased frequency of hypopigmented macules, those with ENKTCL more frequently developed nodules, and children with EBV-MCU often had crusts and ulcers. As has already been mentioned, children with CAEBVI displayed a broad range of lesions, including edema, ulcers, erythematous and hypopigmented plaques, atrophy, blisters, and scars.

Our study was limited by the retrospective design and missing data from one-third of patients, which prevented outcome comparison. We also lacked molecular profiling of patients, which could help refine therapeutic strategies for PCL.¹³ Finally, as both centers included are reference institutions, results may be biased and overestimated and could differ from the rest of the population.

Conclusion

This comparative study of PCL highlighted age-related differences in clinical presentation, diagnostic distribution, and treatment patterns, including a higher prevalence among male children than female children. Adult patients with PCL had a notably longer time to diagnosis than children. The most common type of PCL identified in both age groups and sex categories was MF, but hypopigmented lesions predominated in children with this condition. Epstein-Barr virus–associated PCL occurred almost exclusively in children and manifested with nodules, edema, blisters, and scars. In terms of treatment, children received more aggressive and advanced therapies, including mAb, thalidomide, IVIg, and HSCT. Further prospective research is needed to establish variations in clinical manifestations, diagnoses, treatments, and outcomes.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative malignancies originating from T, B, or natural killer (NK) lymphocytes.¹ Compared to Hodgkin lymphomas, NHLs exhibit a broader clinical spectrum and have a poorer prognosis and frequent extranodal involvement, with the skin being the second most frequent extranodal site.² Primary cutaneous lymphomas (PCLs) are NHLs that are first evident on the skin without evidence of extracutaneous disease at diagnosis. They include a heterogeneous group of cutaneous T-cell lymphomas (CTCLs) and cutaneous B-cell lymphomas. Among CTCLs, mycosis fungoides (MF) is the most prevalent subtype, generally following an indolent course. Cutaneous B-cell lymphomas primarily include follicle center lymphoma and diffuse large B-cell lymphoma.^3,4

The clinical behavior and incidence of PCLs vary dramatically between children and adults, suggesting underlying biologic, immunologic, and genetic differences.^5,6 However, there is a notable lack of comparative studies in the literature addressing these variations, limiting a comprehensive understanding of PCLs and hindering the development of tailored therapeutic strategies. The main objective of this study was to evaluate the different clinical characteristics, subtypes, treatment options, and prognosis in PCLs between pediatric and adult populations.^7,8

Methods

This retrospective observational study included pediatric (aged ≤18 years at diagnosis) and adult (aged >18 years at diagnosis) patients with a clinical and histopathologic diagnosis of PCL who were diagnosed and treated at either of 2 tertiary institutions (Dr. Manuel Gea Gonzalez General Hospital or the National Institute of Pediatrics, both in Mexico City, Mexico) between January 1, 1999, and December 31, 2019. The data analysis included demographic and clinical characteristics, type of PCL (according to World Health Organization [WHO]/European Organisation for Research and Treatment of Cancer [EORTC]) classification,^3,4 treatment administered, and outcome. Disease remission was defined as remittance of clinical PCL manifestations for 3 months or more. Disease control was defined as stable clinical manifestations with no change in PCL stage following treatment initiation. Disease progression was defined as worsening clinical manifestations with an increase in PCL stage and/or development of systemic lymphoma. Beyond similarities and differences across age groups, we also analyzed differences by sex. χ² and Mann-Whitney U tests were used to assess differences between groups. Statistical significance was set at P≤.05. Institutional approval was obtained from both tertiary centers.

Results

Our analysis included a total of 158 patients: 54 (34.2%) were children and 104 (65.8%) were adults. Eighty-eight (55.7%) patients were male (eTable 1). The mean (SD) age at diagnosis was 9.5 (1.9) years in children and 49.7 (18) years in adults. Regarding differences between age groups, adult patients had a similar sex distribution, while in children, the majority of patients were male (37/54 [68.5%]; P=.01).

Overall, the most frequent diagnosis was MF, which occurred in 119 (75.3%) patients, and the most common lesions were erythematous plaques, noted in 95 (60.1%) patients. The lower extremities were the most affected body sites, impacting 127 (80.4%) patients, and the most common treatment was phototherapy, used to treat 110 (69.6%) patients. Reported outcomes included disease control in 45 (28.5%) patients and progression in 36 (22.8%) patients; 50 (31.6%) patients were lost to follow-up. Only 15 (9.5%) patients experienced disease remission, and 12 (7.6%) died.

The mean (SD) time between the onset of symptoms and diagnosis was shorter in children than in adults (18.1 [12.6] months vs 66.2 [34.9] months; P<.001). Regarding involved body sites, the head and neck more frequently affected children than adults (40 [74.1%] vs 33 [31.7%]; P<.001), while the upper extremities were more frequently involved in adults than in children (67 [64.4%] vs 45 [83.3%]; P<.001).

There were significant differences in the morphology of lesions and diagnoses. Children most frequently had hypopigmented plaques (25 [46.3%]) and macules (24 [44.4%])(P<.001) associated with MF, and scars (7 [13.0%]), blisters (6 [11.1%]), and edema (8 [14.8%])(P<.001) associated with positive Epstein-Barr virus (EBV) infection. Adults presented more frequently with hyperpigmented macules (19 [18.3%]) and plaques (37 [35.6%]), erythematous plaques (71 [68.3%]), atrophy (36 [34.6%]), and tumors (32 [30.8%])(P<.001). Adults were more often asymptomatic (86.5% vs 38.8%; P<.001).

Subtypes of PCL differed by age group (eTable 2), with MF being more frequent in adults (87 [83.6%] vs 32 [59.2%]; P<.001), while chronic active positive EBV infection (CAEBVI) manifesting as lymphoproliferative disease (LPD) was exclusive to male children (9 [16.6%])(P<.001). Accordingly, we found variations in systemic treatments used: monoclonal antibodies (mAb), thalidomide, intravenous immunoglobulin (IVIg), and hematopoietic stem cell transplantation (HSCT) were used exclusively for treating children (all P<.001). Outcomes were distributed similarly by age group.

The type of PCL, clinical manifestations, and treatment also varied by sex (eTables 2 and 3). Only males had CAEBVI and presented with edema (8 [9.1%] vs 0%; P<.01). Males also had tumors (23 [26.1%] vs 9 [12.9%]; P=.03) and lesions affecting the head and neck (52 [59.1%] vs 21 [30.0%]; P<.001) more frequently than females. Males were more likely than females to report pain (28 [31.8%] vs 13 [18.6%]; P=.05) and receive systemic treatment with thalidomide (11 [12.5%] vs 1 [1.4%]; P<.001) and IVIg (6 [6.8%] vs 0%; P=.02). Only females were diagnosed with primary cutaneous anaplastic large cell lymphoma (PC-ALCL)(4 [5.7%] vs 0%; P=.03) and had genital involvement (4 [5.7%] vs 0%; P=.03). Females were more likely to be asymptomatic (57 [81.4%] vs 54 [61.4%]; P<.001) or report pruritus (46 [65.7%] vs 44 [50%]; P<.001) and receive local treatment with phototherapy (58 [82.9%] vs 52 [59.1%]; P<.001) compared to males. Although distribution of outcomes was similar by sex, we found males were more frequently lost to follow-up (38 [43.2%] vs 12 [17.1%]; P<.001).

We further searched for differences in clinical manifestations according to the PCL subtype in each age group. The most frequent lesions in 32 children with MF were hypopigmented macules (21 [65.6%]; P<.001)(Figure 1). Three of 5 (60%) children with extranodal NK/T-cell lymphoma, nasal type (ENKTCL), had nodules (P=.002). Of 9 children with CAEBVI, 8 (88.9%) had edema (P<.001), ulcers (P<.001), erythematous plaques (P=.007), and hypopigmented plaques (P=.008); 5 (55.6%) children presented with scars (P<.001) and atrophy (P<.001); and 4 (44.4%) children had blisters (P=.005)(Figure 2). The 2 children with EBV-positive mucocutaneous ulcer (EBV-MCU) had crusts (P=.002) and blisters (P=.01).

Of 87 adults with MF, 54 (62%) had scaly lesions (P=.006)(Figure 3). Of 3 adult patients with PC-ALCL, 2 (66.7%) had crusts (P=.04) and ulcers (P=.05). Two of 3 (66.7%) adults with lymphomatoid papulosis (LyP) had erythematous papules (P<.001). All 4 adult patients with ENKTCL (P=.008) and all 5 patients with primary cutaneous diffuse large B-cell lymphoma, leg-type, had tumors (P<.001).

Finally, we found no differences in outcomes according to types of PCL overall or by age group; however, when categorized by sex, we found males with EBV-MCU more frequently had disease progression than females with EBV-MCU (P=.04).

Comment

Primary cutaneous lymphomas were similarly distributed among males and females (55.6% vs 44.3%, respectively). This slight male predominance was similar to other reports in the literature: one US study reported a male-to-female incidence rate ratio of 1.72, indicating a significantly higher incidence in males (P<.001).⁶ Similar trends have been observed in other geographic regions, with reported male-to-female ratios of 1.56 in Greece and 1.35 in Argentina.^9,10 These findings suggest that PCLs are slightly more prevalent in males across different populations; however, when we stratified by age, pediatric cases of PCL were significantly more frequent in males than in females (68.5% vs. 31.4%; P=.01).

Our analysis revealed that the time to diagnosis was significantly longer in adults than in children (66.2 months vs 18.1 months) for all PCLs (P<.001). The most common type of PCL in both age groups was MF, with a notably higher prevalence in adults than in children (87 [83.7%] vs 32 [59.2%]). The prolonged course of MF in adults, often taking years to progress from early to advanced stages (47.0-52.7 months) may contribute to delayed diagnosis.^8,11,12 Additionally, classic lesions of MF (erythematous scaly plaques) may resemble other common dermatologic conditions, further complicating early recognition and treatment in adults more than in children.^11,12 Conversely, more aggressive and rapidly progressing PCL subtypes, including CAEBVI and ENKTCL-NT, were more frequent in children and would likely be diagnosed more promptly because of the acute onset and fast evolution of signs and symptoms.¹³

Mycosis fungoides is the most common CTCL, followed by CD30+ T-cell disorders such as LyP and PC-ALCL.¹⁴ While MF was the predominant subtype in both age groups, similar to previous reports,^6,7 pediatric patients in our study exhibited distinctive features, such as hypopigmented macules and plaques. Hypopigmented lesions may suggest an underlying immunologic mechanism unique to younger patients, specifically children, in contrast to the hyperpigmented or violaceous lesions predominating in adults.⁷ The hypopigmented variant of MF has been reported to be more prevalent in children, similar to our data, accounting for 54.5% of all pediatric MF cases. These hypopigmented lesions typically manifest at an early stage and follow an indolent course.^15,16 Jung et al⁸ conducted a systematic review of children with MF and reported a mean age at diagnosis of 12.2 years, whereas in our cohort, the mean age was 9.5 years. These findings highlight the different clinical manifestations of MF in children, which may aid in early recognition and diagnosis.

In adults, MF most commonly manifested as hyperpigmented macules and plaques, erythematous plaques, atrophic lesions, and tumors. In this population, MF remained the most frequently diagnosed PCL subtype, followed by PC-ALCL.

There were notable differences in symptom presentation between age groups and sexes. Adults were more often asymptomatic, and males reported pain more frequently.

When analyzing PCL subtypes in our study, we found that CAEBVI was exclusive to children, specifically males. The updated WHO/EORTC classification contains a new section on EBV-positive LPD in childhood, including hydroa vacciniforme–like LPD and hypersensitivity reactions to mosquito bites.⁴ Both are cutaneous manifestations of CAEBVI with a risk for progression to systemic EBV-positive T-cell or NK-cell lymphoma. These disorders mainly affect children and adolescents from Asia or Indigenous populations from Mexico and Central and South America.^3,4,17 Cases in both female and male patients have been reported, without a clear sex predominance; however, mutations in the Src homology 2 domain containing 1A (SH2D1A) gene recently have been shown to cause X-linked lymphoproliferative disease, which is associated with predilection for EBV infection and subsequent EBV-positive LPD, including CAEBVI.^18,19 Thus, it is possible some of the children with CAEBVI in our study may have an underlying X-linked lymphoproliferative disease, accounting for the male predominance.

Similarly, ENKTCL-NT tended to occur more in children than in adults in our study. Both CAEBVI-LPD and ENKTCL-NT are aggressive lymphomas with a suboptimal prognosis. Although treatment with immunomodulatory agents may lead to temporary remission in most cases, disease progression has been reported in larger cohorts, emphasizing the need for long-term follow-up and more aggressive treatments in severe cases of CAEBVI.^13,17 Treatment options for EBV-positive LPD include mAb such as rituximab, IVIg, HSCT, antiviral agents, interferons α and γ, and corticosteroids.²⁰

Treatment approaches were notably different between children and adults (P<.0001). Monoclonal antibodies, immunomodulatory agents such as thalidomide, IVIg, and HSCT were exclusively used in pediatric patients, reflecting the presence of CAEBVI and ENKTCL-NT (P<.0001). Additionally, edema, blisters, and scars were observed more frequently in children, likely due to the clinical manifestations of these EBV-related disorders.

A recent review of systemic NHL highlighted various age-related differences in clinical presentation, biology, and outcomes.¹³ In general, children tend to present with more aggressive subtypes and achieve better outcomes compared to adults.¹³ These differences may be attributed to variations in tumor biology, immune responses, and/or the benefits of early and intensive interventions in pediatric populations. These findings resonate with our results, as pediatric PCL patients received more aggressive treatments—including mAb, thalidomide, IVIg, and HSCT—likely due to the higher frequency of CAEBVI/ENKTCL-NT; however, we were unable to properly assess treatment outcomes, as many patients, both adults and children, were lost to follow-up.

Overall, our findings and comparisons with existing studies highlight the need for age-specific research and management approaches for PCL. The distinct clinical and biological profiles across age groups highlight opportunities for personalized therapies and further investigation into the molecular drivers of these differences to optimize outcomes for pediatric and adult patients.

When analyzing differences by sex, we found that CAEBVI was diagnosed exclusively in male children, who correspondingly exhibited clinical features such as edema and tumors, with lesions predominantly located on the head and neck. This also influenced treatment approach, as these patients were more likely to receive thalidomide and IVIg. In contrast, PC-ALCL was observed only in female patients, a finding that deviates from previously reported epidemiology.¹⁴ Females with PC-ALCL were more likely to have genital involvement and be asymptomatic, which could suggest a sex-related bias in disease recognition and seeking health care.

Recognizing distinctive clinical manifestations across different diagnoses and age groups can aid health care providers in early identification and accurate diagnosis of PCL. Our findings revealed several notable differences: adults with MF more frequently had scaly lesions, those with PC-ALCL had crusts and ulcers, and those with LyP had erythematous papules. All adults with ENKTCL and primary cutaneous diffuse large B-cell lymphoma, leg-type, presented with tumors. While children with MF had an increased frequency of hypopigmented macules, those with ENKTCL more frequently developed nodules, and children with EBV-MCU often had crusts and ulcers. As has already been mentioned, children with CAEBVI displayed a broad range of lesions, including edema, ulcers, erythematous and hypopigmented plaques, atrophy, blisters, and scars.

Our study was limited by the retrospective design and missing data from one-third of patients, which prevented outcome comparison. We also lacked molecular profiling of patients, which could help refine therapeutic strategies for PCL.¹³ Finally, as both centers included are reference institutions, results may be biased and overestimated and could differ from the rest of the population.

Conclusion

This comparative study of PCL highlighted age-related differences in clinical presentation, diagnostic distribution, and treatment patterns, including a higher prevalence among male children than female children. Adult patients with PCL had a notably longer time to diagnosis than children. The most common type of PCL identified in both age groups and sex categories was MF, but hypopigmented lesions predominated in children with this condition. Epstein-Barr virus–associated PCL occurred almost exclusively in children and manifested with nodules, edema, blisters, and scars. In terms of treatment, children received more aggressive and advanced therapies, including mAb, thalidomide, IVIg, and HSCT. Further prospective research is needed to establish variations in clinical manifestations, diagnoses, treatments, and outcomes.

Practice Gap

Accurate biopsy site identification prior to Mohs micrographic surgery (MMS) can be challenging, particularly on the scalp, where excellent healing, field cancerization, prior procedures, large surface area, and hair density may complicate localization. Accurate site identification is further hindered when patients are unable to recall the biopsy location, when the biopsy and MMS are performed by different clinicians, or when photographic documentation is absent. Scalp lesions pose an additional challenge because even high-quality photographs may fail to capture subtle landmarks that are obscured by hair.

Wrong-site surgery was the most common serious error reported in a survey of 150 dermatologists, accounting for 19.0% of these errors.¹ Research has shown that dermatologists may misidentify biopsy sites in up to 17.6% of cases, and patients (eg, if a patient goes to a dermatologic surgeon and is asked to identify the biopsy site for the surgeon) in up to 25.5% (N=278).² Additionally, a survey of Mohs surgeons revealed that 14.0% of 42 malpractice cases were due to wrong-site surgery.³ A Delphi consensus study assessing possible preventive interventions found that the best way to document the site is with a photograph in association with landmarks and diagrams.⁴

The Technique

The hair-cut sign is a simple and effective technique for identifying biopsy sites on the scalp. Hair at the biopsy site typically is cut during biopsy; as the surrounding hair grows, the resulting short tuft serves as an anatomic marker that can persist for weeks to months to facilitate accurate site localization by the Mohs surgeon (Figure). This noninvasive, equipment-free method may be particularly useful when documentation or photography is limited. To maximize its effectiveness, clinical staff should avoid trimming the area before physician verification of the site. The technique is most effective in patients with longer hair and when the interval between biopsy and surgery is less than 3 months, as hair regrowth may reduce contrast with the surrounding scalp.

Practice Implications

Accurate biopsy site identification is a critical component of patient safety in dermatologic surgery, particularly on the scalp, where traditional localization strategies may be unreliable. The hair-cut sign is a simple, reliable, no-cost, and reproducible adjunct to photography, anatomic documentation, and patient verification that may improve site localization and help reduce the risk for wrong-site surgery in select patients to complement standard practices. Incorporating the hair-cut sign into routine scalp surgery workflow represents a low-burden intervention that may improve accuracy when other documentation is limited.

Practice Gap

Accurate biopsy site identification prior to Mohs micrographic surgery (MMS) can be challenging, particularly on the scalp, where excellent healing, field cancerization, prior procedures, large surface area, and hair density may complicate localization. Accurate site identification is further hindered when patients are unable to recall the biopsy location, when the biopsy and MMS are performed by different clinicians, or when photographic documentation is absent. Scalp lesions pose an additional challenge because even high-quality photographs may fail to capture subtle landmarks that are obscured by hair.

Wrong-site surgery was the most common serious error reported in a survey of 150 dermatologists, accounting for 19.0% of these errors.¹ Research has shown that dermatologists may misidentify biopsy sites in up to 17.6% of cases, and patients (eg, if a patient goes to a dermatologic surgeon and is asked to identify the biopsy site for the surgeon) in up to 25.5% (N=278).² Additionally, a survey of Mohs surgeons revealed that 14.0% of 42 malpractice cases were due to wrong-site surgery.³ A Delphi consensus study assessing possible preventive interventions found that the best way to document the site is with a photograph in association with landmarks and diagrams.⁴

The Technique

The hair-cut sign is a simple and effective technique for identifying biopsy sites on the scalp. Hair at the biopsy site typically is cut during biopsy; as the surrounding hair grows, the resulting short tuft serves as an anatomic marker that can persist for weeks to months to facilitate accurate site localization by the Mohs surgeon (Figure). This noninvasive, equipment-free method may be particularly useful when documentation or photography is limited. To maximize its effectiveness, clinical staff should avoid trimming the area before physician verification of the site. The technique is most effective in patients with longer hair and when the interval between biopsy and surgery is less than 3 months, as hair regrowth may reduce contrast with the surrounding scalp.

Practice Implications

Accurate biopsy site identification is a critical component of patient safety in dermatologic surgery, particularly on the scalp, where traditional localization strategies may be unreliable. The hair-cut sign is a simple, reliable, no-cost, and reproducible adjunct to photography, anatomic documentation, and patient verification that may improve site localization and help reduce the risk for wrong-site surgery in select patients to complement standard practices. Incorporating the hair-cut sign into routine scalp surgery workflow represents a low-burden intervention that may improve accuracy when other documentation is limited.

Practice Gap

Accurate biopsy site identification prior to Mohs micrographic surgery (MMS) can be challenging, particularly on the scalp, where excellent healing, field cancerization, prior procedures, large surface area, and hair density may complicate localization. Accurate site identification is further hindered when patients are unable to recall the biopsy location, when the biopsy and MMS are performed by different clinicians, or when photographic documentation is absent. Scalp lesions pose an additional challenge because even high-quality photographs may fail to capture subtle landmarks that are obscured by hair.

Wrong-site surgery was the most common serious error reported in a survey of 150 dermatologists, accounting for 19.0% of these errors.¹ Research has shown that dermatologists may misidentify biopsy sites in up to 17.6% of cases, and patients (eg, if a patient goes to a dermatologic surgeon and is asked to identify the biopsy site for the surgeon) in up to 25.5% (N=278).² Additionally, a survey of Mohs surgeons revealed that 14.0% of 42 malpractice cases were due to wrong-site surgery.³ A Delphi consensus study assessing possible preventive interventions found that the best way to document the site is with a photograph in association with landmarks and diagrams.⁴

The Technique

The hair-cut sign is a simple and effective technique for identifying biopsy sites on the scalp. Hair at the biopsy site typically is cut during biopsy; as the surrounding hair grows, the resulting short tuft serves as an anatomic marker that can persist for weeks to months to facilitate accurate site localization by the Mohs surgeon (Figure). This noninvasive, equipment-free method may be particularly useful when documentation or photography is limited. To maximize its effectiveness, clinical staff should avoid trimming the area before physician verification of the site. The technique is most effective in patients with longer hair and when the interval between biopsy and surgery is less than 3 months, as hair regrowth may reduce contrast with the surrounding scalp.

Practice Implications

Accurate biopsy site identification is a critical component of patient safety in dermatologic surgery, particularly on the scalp, where traditional localization strategies may be unreliable. The hair-cut sign is a simple, reliable, no-cost, and reproducible adjunct to photography, anatomic documentation, and patient verification that may improve site localization and help reduce the risk for wrong-site surgery in select patients to complement standard practices. Incorporating the hair-cut sign into routine scalp surgery workflow represents a low-burden intervention that may improve accuracy when other documentation is limited.

To the Editor:

Exogenous ochronosis (EO) is a rare dyschromia that affects individuals with darker skin tones and results from the application of skin-lightening topical agents, most commonly those containing hydroquinone. Hydroquinone-induced EO usually is reported outside the United States, mainly in African and South Asian patients,¹ as well as after long-term use of ­high‑concentration hydroquinone. We report a case of stage II EO that developed in a patient in the United States following 6 months' use of hydroquinone cream 2% that was purchased online.

A 75-year-old Black man presented to the dermatology clinic with dark discoloration on the cheeks of 6 months’ duration. He reported that the hyperpigmentation had developed after 6 months of daily use of an over-the-counter (OTC) cream containing 2% hydroquinone, which he purchased online to treat melasma of the bilateral cheeks and temples that had been present for at least a decade. The patient was otherwise healthy and did not take any other daily medications. He was a landscaper by occupation and spent most days outdoors. He reported a history of recurrent blistering sunburns and reported that he applied sunscreen with a sun protection factor of 30 to the face on most days.

Physical examination revealed gray-black, coarsely textured papules and plaques on a background of brown pigmentation involving the malar cheeks. Reticulated, blue-black, caviarlike papules were present within the plaques (Figure 1). Dermoscopy revealed blue-black globules and globularlike structures on a brown background with the absence of follicular openings (Figure 2). A punch biopsy from the left malar cheek revealed banana-shaped, yellow-brown deposits with heavy elastosis in the superficial dermis (Figure 3). The patient was advised to permanently discontinue hydroquinone and was prescribed topical adapalene. He was evaluated for treatment with a fractional erbium-doped yttrium aluminum garnet laser but ultimately elected not to pursue treatment.

Hydroquinone has long been a first-line topical agent for the treatment of skin dyschromia. It generally is regarded as a safe and effective therapy when used under the supervision of a dermatologist. Prolonged use of topical hydroquinone is known to induce paradoxical EO. This acquired dyschromia is characterized by the development of blue-black or gray-blue pigmented patches as well as caviarlike black papules, papulonodules, and skin atrophy in more severe cases.² Most cases are documented in African and South Asian countries, with fewer than 100 cases described in the United States.² Despite the rarity of EO in the United States, concerns regarding the unsupervised use of hydroquinone contributed to regulatory changes. In response to the CARES Act and Over-the-Counter Drug Monograph Reform, the sale of OTC hydroquinone-based products became prohibited in September 2020 in the United States.³ Prior to the CARES Act, an estimated 10 million tubes of OTC hydroquinone were sold, and approximately 330,000 prescriptions were written in 2019.^2,4 Subsequently, its availability was converted to prescription only in the United States.

Exogenous ochronosis occurs in 3 clinical stages: (I) erythema and hyperpigmentation, (II) black colloid milia (caviarlike papules) and atrophy, and (III) papulonodules.¹ Our patient’s case was unusual, as EO is most commonly described after exposure to high concentrations and prolonged hydroquinone treatment. In a global retrospective review of 126 patients of varied racial and ethnic backgrounds with hydroquinone-induced ochronosis, EO was most frequently reported with concentrations exceeding 4%. The median duration of use was 5 years, and only 12 cases (9.5%) of EO were reported with 1 year of use or less, including 4 cases with 3 months or less of use.¹

While large epidemiologic studies from South Africa have reported EO prevalence rates as high as 69% among users of skin-lightening products,⁶ a search of the PubMed, Scopus, and Web of Science databases using the terms exogenous ochronosis and hydroquinone identified only 39 cases in US-based literature between 1983 and 2020.² In a retrospective review of 25 cases of EO in the United States, the average length of product use was 9.2 years, and the shortest duration was 1.5 years.⁷

The pathogenesis of EO is thought to occur due to the inhibitive effect of topical hydroquinone on homogentisic acid oxidase, resulting in the accumulation of homogentisic acid in tissues and ochronotic deposits.^1,5 We suspect that our patient’s occupation as a landscaper and associated chronic sun exposure may have accelerated the development of EO, as UV exposure and inadequate photoprotection have been described as risk factors in the development and severity of EO.⁸ Although the patient reported daily application of sun protection factor 30 sunscreen, the extent of his outdoor occupational exposure may have exceeded the protection afforded.

Treatment of EO is notoriously challenging, and skin changes often are permanent. Of the 25 patients identified in a 10-year retrospective analysis of EO at a single US center, none responded to topical treatment alone.⁷ Among those who underwent procedural interventions, 3 patients treated with microneedling and 3 patients treated with Q-switched Alexandrite laser demonstrated favorable outcomes; however, this was a retrospective chart review, not a controlled trial with predefined treatment arms.⁷ Bellew et al⁹ reported 2 patients with EO who showed progressive lightening in response to Q-switched Alexandrite laser treatments. In this case series, the first patient received 6 treatments at 2-month intervals and the second received 4 treatments at 4-month intervals. Posttreatment biopsies demonstrated decreased dermal pigmentation, and neither patient experienced scarring or textural changes. Méndez Baca et al¹⁰ demonstrated successful lightening of pigmentation in a patient with medium-toned skin following 9 sessions with a fractional nonablative picosecond laser. Ceglio et al¹¹ described a stepwise treatment approach in a patient with dark brown skin with EO, beginning with 12 sessions of a 1064-nm Q-switched Nd:YAG laser that yielded slight improvement, followed by 7 sessions of intense pulsed light therapy with partial response, and ultimately achieving marked improvement after 5 bimonthly sessions of fractional 10,600-nm carbon dioxide laser.

This case highlights the potential for EO to develop even with low-concentration (2%) hydroquinone obtained through unregulated online sources, underscoring the need for dermatologist supervision when hydroquinone is used. Despite the 2020 prohibition of OTC hydroquinone sales in the United States, patients continue to access these products online. Clinicians should maintain a high index of suspicion for EO in patients presenting with paradoxical facial hyperpigmentation and a history of unsupervised hydroquinone use.

To the Editor:

Exogenous ochronosis (EO) is a rare dyschromia that affects individuals with darker skin tones and results from the application of skin-lightening topical agents, most commonly those containing hydroquinone. Hydroquinone-induced EO usually is reported outside the United States, mainly in African and South Asian patients,¹ as well as after long-term use of ­high‑concentration hydroquinone. We report a case of stage II EO that developed in a patient in the United States following 6 months' use of hydroquinone cream 2% that was purchased online.

A 75-year-old Black man presented to the dermatology clinic with dark discoloration on the cheeks of 6 months’ duration. He reported that the hyperpigmentation had developed after 6 months of daily use of an over-the-counter (OTC) cream containing 2% hydroquinone, which he purchased online to treat melasma of the bilateral cheeks and temples that had been present for at least a decade. The patient was otherwise healthy and did not take any other daily medications. He was a landscaper by occupation and spent most days outdoors. He reported a history of recurrent blistering sunburns and reported that he applied sunscreen with a sun protection factor of 30 to the face on most days.

Physical examination revealed gray-black, coarsely textured papules and plaques on a background of brown pigmentation involving the malar cheeks. Reticulated, blue-black, caviarlike papules were present within the plaques (Figure 1). Dermoscopy revealed blue-black globules and globularlike structures on a brown background with the absence of follicular openings (Figure 2). A punch biopsy from the left malar cheek revealed banana-shaped, yellow-brown deposits with heavy elastosis in the superficial dermis (Figure 3). The patient was advised to permanently discontinue hydroquinone and was prescribed topical adapalene. He was evaluated for treatment with a fractional erbium-doped yttrium aluminum garnet laser but ultimately elected not to pursue treatment.

Hydroquinone has long been a first-line topical agent for the treatment of skin dyschromia. It generally is regarded as a safe and effective therapy when used under the supervision of a dermatologist. Prolonged use of topical hydroquinone is known to induce paradoxical EO. This acquired dyschromia is characterized by the development of blue-black or gray-blue pigmented patches as well as caviarlike black papules, papulonodules, and skin atrophy in more severe cases.² Most cases are documented in African and South Asian countries, with fewer than 100 cases described in the United States.² Despite the rarity of EO in the United States, concerns regarding the unsupervised use of hydroquinone contributed to regulatory changes. In response to the CARES Act and Over-the-Counter Drug Monograph Reform, the sale of OTC hydroquinone-based products became prohibited in September 2020 in the United States.³ Prior to the CARES Act, an estimated 10 million tubes of OTC hydroquinone were sold, and approximately 330,000 prescriptions were written in 2019.^2,4 Subsequently, its availability was converted to prescription only in the United States.

Exogenous ochronosis occurs in 3 clinical stages: (I) erythema and hyperpigmentation, (II) black colloid milia (caviarlike papules) and atrophy, and (III) papulonodules.¹ Our patient’s case was unusual, as EO is most commonly described after exposure to high concentrations and prolonged hydroquinone treatment. In a global retrospective review of 126 patients of varied racial and ethnic backgrounds with hydroquinone-induced ochronosis, EO was most frequently reported with concentrations exceeding 4%. The median duration of use was 5 years, and only 12 cases (9.5%) of EO were reported with 1 year of use or less, including 4 cases with 3 months or less of use.¹

While large epidemiologic studies from South Africa have reported EO prevalence rates as high as 69% among users of skin-lightening products,⁶ a search of the PubMed, Scopus, and Web of Science databases using the terms exogenous ochronosis and hydroquinone identified only 39 cases in US-based literature between 1983 and 2020.² In a retrospective review of 25 cases of EO in the United States, the average length of product use was 9.2 years, and the shortest duration was 1.5 years.⁷

The pathogenesis of EO is thought to occur due to the inhibitive effect of topical hydroquinone on homogentisic acid oxidase, resulting in the accumulation of homogentisic acid in tissues and ochronotic deposits.^1,5 We suspect that our patient’s occupation as a landscaper and associated chronic sun exposure may have accelerated the development of EO, as UV exposure and inadequate photoprotection have been described as risk factors in the development and severity of EO.⁸ Although the patient reported daily application of sun protection factor 30 sunscreen, the extent of his outdoor occupational exposure may have exceeded the protection afforded.

Treatment of EO is notoriously challenging, and skin changes often are permanent. Of the 25 patients identified in a 10-year retrospective analysis of EO at a single US center, none responded to topical treatment alone.⁷ Among those who underwent procedural interventions, 3 patients treated with microneedling and 3 patients treated with Q-switched Alexandrite laser demonstrated favorable outcomes; however, this was a retrospective chart review, not a controlled trial with predefined treatment arms.⁷ Bellew et al⁹ reported 2 patients with EO who showed progressive lightening in response to Q-switched Alexandrite laser treatments. In this case series, the first patient received 6 treatments at 2-month intervals and the second received 4 treatments at 4-month intervals. Posttreatment biopsies demonstrated decreased dermal pigmentation, and neither patient experienced scarring or textural changes. Méndez Baca et al¹⁰ demonstrated successful lightening of pigmentation in a patient with medium-toned skin following 9 sessions with a fractional nonablative picosecond laser. Ceglio et al¹¹ described a stepwise treatment approach in a patient with dark brown skin with EO, beginning with 12 sessions of a 1064-nm Q-switched Nd:YAG laser that yielded slight improvement, followed by 7 sessions of intense pulsed light therapy with partial response, and ultimately achieving marked improvement after 5 bimonthly sessions of fractional 10,600-nm carbon dioxide laser.

This case highlights the potential for EO to develop even with low-concentration (2%) hydroquinone obtained through unregulated online sources, underscoring the need for dermatologist supervision when hydroquinone is used. Despite the 2020 prohibition of OTC hydroquinone sales in the United States, patients continue to access these products online. Clinicians should maintain a high index of suspicion for EO in patients presenting with paradoxical facial hyperpigmentation and a history of unsupervised hydroquinone use.

To the Editor:

Exogenous ochronosis (EO) is a rare dyschromia that affects individuals with darker skin tones and results from the application of skin-lightening topical agents, most commonly those containing hydroquinone. Hydroquinone-induced EO usually is reported outside the United States, mainly in African and South Asian patients,¹ as well as after long-term use of ­high‑concentration hydroquinone. We report a case of stage II EO that developed in a patient in the United States following 6 months' use of hydroquinone cream 2% that was purchased online.

A 75-year-old Black man presented to the dermatology clinic with dark discoloration on the cheeks of 6 months’ duration. He reported that the hyperpigmentation had developed after 6 months of daily use of an over-the-counter (OTC) cream containing 2% hydroquinone, which he purchased online to treat melasma of the bilateral cheeks and temples that had been present for at least a decade. The patient was otherwise healthy and did not take any other daily medications. He was a landscaper by occupation and spent most days outdoors. He reported a history of recurrent blistering sunburns and reported that he applied sunscreen with a sun protection factor of 30 to the face on most days.

Physical examination revealed gray-black, coarsely textured papules and plaques on a background of brown pigmentation involving the malar cheeks. Reticulated, blue-black, caviarlike papules were present within the plaques (Figure 1). Dermoscopy revealed blue-black globules and globularlike structures on a brown background with the absence of follicular openings (Figure 2). A punch biopsy from the left malar cheek revealed banana-shaped, yellow-brown deposits with heavy elastosis in the superficial dermis (Figure 3). The patient was advised to permanently discontinue hydroquinone and was prescribed topical adapalene. He was evaluated for treatment with a fractional erbium-doped yttrium aluminum garnet laser but ultimately elected not to pursue treatment.

Hydroquinone has long been a first-line topical agent for the treatment of skin dyschromia. It generally is regarded as a safe and effective therapy when used under the supervision of a dermatologist. Prolonged use of topical hydroquinone is known to induce paradoxical EO. This acquired dyschromia is characterized by the development of blue-black or gray-blue pigmented patches as well as caviarlike black papules, papulonodules, and skin atrophy in more severe cases.² Most cases are documented in African and South Asian countries, with fewer than 100 cases described in the United States.² Despite the rarity of EO in the United States, concerns regarding the unsupervised use of hydroquinone contributed to regulatory changes. In response to the CARES Act and Over-the-Counter Drug Monograph Reform, the sale of OTC hydroquinone-based products became prohibited in September 2020 in the United States.³ Prior to the CARES Act, an estimated 10 million tubes of OTC hydroquinone were sold, and approximately 330,000 prescriptions were written in 2019.^2,4 Subsequently, its availability was converted to prescription only in the United States.

Exogenous ochronosis occurs in 3 clinical stages: (I) erythema and hyperpigmentation, (II) black colloid milia (caviarlike papules) and atrophy, and (III) papulonodules.¹ Our patient’s case was unusual, as EO is most commonly described after exposure to high concentrations and prolonged hydroquinone treatment. In a global retrospective review of 126 patients of varied racial and ethnic backgrounds with hydroquinone-induced ochronosis, EO was most frequently reported with concentrations exceeding 4%. The median duration of use was 5 years, and only 12 cases (9.5%) of EO were reported with 1 year of use or less, including 4 cases with 3 months or less of use.¹

While large epidemiologic studies from South Africa have reported EO prevalence rates as high as 69% among users of skin-lightening products,⁶ a search of the PubMed, Scopus, and Web of Science databases using the terms exogenous ochronosis and hydroquinone identified only 39 cases in US-based literature between 1983 and 2020.² In a retrospective review of 25 cases of EO in the United States, the average length of product use was 9.2 years, and the shortest duration was 1.5 years.⁷

The pathogenesis of EO is thought to occur due to the inhibitive effect of topical hydroquinone on homogentisic acid oxidase, resulting in the accumulation of homogentisic acid in tissues and ochronotic deposits.^1,5 We suspect that our patient’s occupation as a landscaper and associated chronic sun exposure may have accelerated the development of EO, as UV exposure and inadequate photoprotection have been described as risk factors in the development and severity of EO.⁸ Although the patient reported daily application of sun protection factor 30 sunscreen, the extent of his outdoor occupational exposure may have exceeded the protection afforded.

Treatment of EO is notoriously challenging, and skin changes often are permanent. Of the 25 patients identified in a 10-year retrospective analysis of EO at a single US center, none responded to topical treatment alone.⁷ Among those who underwent procedural interventions, 3 patients treated with microneedling and 3 patients treated with Q-switched Alexandrite laser demonstrated favorable outcomes; however, this was a retrospective chart review, not a controlled trial with predefined treatment arms.⁷ Bellew et al⁹ reported 2 patients with EO who showed progressive lightening in response to Q-switched Alexandrite laser treatments. In this case series, the first patient received 6 treatments at 2-month intervals and the second received 4 treatments at 4-month intervals. Posttreatment biopsies demonstrated decreased dermal pigmentation, and neither patient experienced scarring or textural changes. Méndez Baca et al¹⁰ demonstrated successful lightening of pigmentation in a patient with medium-toned skin following 9 sessions with a fractional nonablative picosecond laser. Ceglio et al¹¹ described a stepwise treatment approach in a patient with dark brown skin with EO, beginning with 12 sessions of a 1064-nm Q-switched Nd:YAG laser that yielded slight improvement, followed by 7 sessions of intense pulsed light therapy with partial response, and ultimately achieving marked improvement after 5 bimonthly sessions of fractional 10,600-nm carbon dioxide laser.

This case highlights the potential for EO to develop even with low-concentration (2%) hydroquinone obtained through unregulated online sources, underscoring the need for dermatologist supervision when hydroquinone is used. Despite the 2020 prohibition of OTC hydroquinone sales in the United States, patients continue to access these products online. Clinicians should maintain a high index of suspicion for EO in patients presenting with paradoxical facial hyperpigmentation and a history of unsupervised hydroquinone use.

THE DIAGNOSIS: Dermatofibroma

Histopathologic examination of the shave biopsy revealed fascicles of plump fibroblasts and histiocytes interposed between thick collagen bundles within the dermis, consistent with a diagnosis of dermatofibroma (DF). Dermatofibroma is a common benign skin tumor that classically manifests as brownish or reddish-brown firm papules or nodules that dimple when compressed. While the exact etiology of DF remains uncertain, it is believed to arise from a combined neoplastic and reactive fibroblastic proliferation process in response to stimuli, such as minor trauma or insect bites (as in our patient).¹

On histopathology, the most common findings associated with DF are dermal proliferation of spindle-shaped fibroblasts arranged in a storiform or whorled pattern.² In this patient, fascicles of plump fibroblasts and histiocytes were observed interspersed among thick collagen bundles within the dermis (Figure). Other histologic variants of DF include cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, and epithelioid.

On dermatoscopic examination, a pigment network is the most common feature, followed by a white scarlike patch, brown dots and globules, and vascular structures.² Atypical DF variants can manifest with diverse clinical morphologies; one example is giant DF, which exceeds 5 cm and may exhibit an ulcerated or pedunculated appearance, as seen in our case.³ In such cases, a thorough clinical examination coupled with histopathologic analysis becomes paramount for accurate diagnosis.

Most cases of DF do not require intervention unless there are cosmetic concerns or the lesions are symptomatic. Surgical excision is a common and effective treatment method but results in scarring. Intralesional steroid injection and cryotherapy are less aggressive treatment options but have limited efficacy. Lasers, including carbon dioxide and pulsed dye lasers, are infrequently used; however, recurrence is possible with any treatment modality.⁴ Local recurrence is common, occurring in 26% to 50% of cases, particularly in atypical dermatofibroma variants after treatment.⁵ Recurrence is more likely with primary lesions larger than 1 cm.⁵

Several conditions share clinical features with DF, necessitating a thorough differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive, malignant tumor with a propensity for recurrence. It manifests as a slow-growing, red-brown, indurated plaque with irregular nodularity. Immunohistochemical staining can be used to differentiate DF from DFSP, with DF typically expressing factor XIIIa and lacking CD34, whereas DFSP exhibits CD34 positivity and lacks factor XIIIa expression.⁶ Another diagnosis in the differential is fibrosarcoma, a malignant tumor of fibroblasts that manifests as a painless, enlarging, poorly defined mass on the lower extremities. Histopathologic features include atypical fibroblasts and collagen with proliferation of atypical spindle-shaped cells.

Other benign lesions to consider include neurofibroma, which may manifest as a firm nodule but is derived from nerve tissue. Clinically, neurofibromas can be differentiated by their association with neurofibromatosis and softer texture. Cutaneous squamous cell carcinoma also should be considered, as it is a malignant proliferation of cutaneous epithelium that clinically manifests as a hyperkeratotic papule or plaque.⁵

THE DIAGNOSIS: Dermatofibroma

Histopathologic examination of the shave biopsy revealed fascicles of plump fibroblasts and histiocytes interposed between thick collagen bundles within the dermis, consistent with a diagnosis of dermatofibroma (DF). Dermatofibroma is a common benign skin tumor that classically manifests as brownish or reddish-brown firm papules or nodules that dimple when compressed. While the exact etiology of DF remains uncertain, it is believed to arise from a combined neoplastic and reactive fibroblastic proliferation process in response to stimuli, such as minor trauma or insect bites (as in our patient).¹

On histopathology, the most common findings associated with DF are dermal proliferation of spindle-shaped fibroblasts arranged in a storiform or whorled pattern.² In this patient, fascicles of plump fibroblasts and histiocytes were observed interspersed among thick collagen bundles within the dermis (Figure). Other histologic variants of DF include cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, and epithelioid.

On dermatoscopic examination, a pigment network is the most common feature, followed by a white scarlike patch, brown dots and globules, and vascular structures.² Atypical DF variants can manifest with diverse clinical morphologies; one example is giant DF, which exceeds 5 cm and may exhibit an ulcerated or pedunculated appearance, as seen in our case.³ In such cases, a thorough clinical examination coupled with histopathologic analysis becomes paramount for accurate diagnosis.

Most cases of DF do not require intervention unless there are cosmetic concerns or the lesions are symptomatic. Surgical excision is a common and effective treatment method but results in scarring. Intralesional steroid injection and cryotherapy are less aggressive treatment options but have limited efficacy. Lasers, including carbon dioxide and pulsed dye lasers, are infrequently used; however, recurrence is possible with any treatment modality.⁴ Local recurrence is common, occurring in 26% to 50% of cases, particularly in atypical dermatofibroma variants after treatment.⁵ Recurrence is more likely with primary lesions larger than 1 cm.⁵

Several conditions share clinical features with DF, necessitating a thorough differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive, malignant tumor with a propensity for recurrence. It manifests as a slow-growing, red-brown, indurated plaque with irregular nodularity. Immunohistochemical staining can be used to differentiate DF from DFSP, with DF typically expressing factor XIIIa and lacking CD34, whereas DFSP exhibits CD34 positivity and lacks factor XIIIa expression.⁶ Another diagnosis in the differential is fibrosarcoma, a malignant tumor of fibroblasts that manifests as a painless, enlarging, poorly defined mass on the lower extremities. Histopathologic features include atypical fibroblasts and collagen with proliferation of atypical spindle-shaped cells.

Other benign lesions to consider include neurofibroma, which may manifest as a firm nodule but is derived from nerve tissue. Clinically, neurofibromas can be differentiated by their association with neurofibromatosis and softer texture. Cutaneous squamous cell carcinoma also should be considered, as it is a malignant proliferation of cutaneous epithelium that clinically manifests as a hyperkeratotic papule or plaque.⁵

THE DIAGNOSIS: Dermatofibroma

Histopathologic examination of the shave biopsy revealed fascicles of plump fibroblasts and histiocytes interposed between thick collagen bundles within the dermis, consistent with a diagnosis of dermatofibroma (DF). Dermatofibroma is a common benign skin tumor that classically manifests as brownish or reddish-brown firm papules or nodules that dimple when compressed. While the exact etiology of DF remains uncertain, it is believed to arise from a combined neoplastic and reactive fibroblastic proliferation process in response to stimuli, such as minor trauma or insect bites (as in our patient).¹

On histopathology, the most common findings associated with DF are dermal proliferation of spindle-shaped fibroblasts arranged in a storiform or whorled pattern.² In this patient, fascicles of plump fibroblasts and histiocytes were observed interspersed among thick collagen bundles within the dermis (Figure). Other histologic variants of DF include cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, and epithelioid.

On dermatoscopic examination, a pigment network is the most common feature, followed by a white scarlike patch, brown dots and globules, and vascular structures.² Atypical DF variants can manifest with diverse clinical morphologies; one example is giant DF, which exceeds 5 cm and may exhibit an ulcerated or pedunculated appearance, as seen in our case.³ In such cases, a thorough clinical examination coupled with histopathologic analysis becomes paramount for accurate diagnosis.

Most cases of DF do not require intervention unless there are cosmetic concerns or the lesions are symptomatic. Surgical excision is a common and effective treatment method but results in scarring. Intralesional steroid injection and cryotherapy are less aggressive treatment options but have limited efficacy. Lasers, including carbon dioxide and pulsed dye lasers, are infrequently used; however, recurrence is possible with any treatment modality.⁴ Local recurrence is common, occurring in 26% to 50% of cases, particularly in atypical dermatofibroma variants after treatment.⁵ Recurrence is more likely with primary lesions larger than 1 cm.⁵

Several conditions share clinical features with DF, necessitating a thorough differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive, malignant tumor with a propensity for recurrence. It manifests as a slow-growing, red-brown, indurated plaque with irregular nodularity. Immunohistochemical staining can be used to differentiate DF from DFSP, with DF typically expressing factor XIIIa and lacking CD34, whereas DFSP exhibits CD34 positivity and lacks factor XIIIa expression.⁶ Another diagnosis in the differential is fibrosarcoma, a malignant tumor of fibroblasts that manifests as a painless, enlarging, poorly defined mass on the lower extremities. Histopathologic features include atypical fibroblasts and collagen with proliferation of atypical spindle-shaped cells.

Other benign lesions to consider include neurofibroma, which may manifest as a firm nodule but is derived from nerve tissue. Clinically, neurofibromas can be differentiated by their association with neurofibromatosis and softer texture. Cutaneous squamous cell carcinoma also should be considered, as it is a malignant proliferation of cutaneous epithelium that clinically manifests as a hyperkeratotic papule or plaque.⁵

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

A version of this article first appeared on Medscape.com.

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

A version of this article first appeared on Medscape.com.

June 24 (Reuters) - The US military has resumed requiring flu vaccines for some service members in an exception to Defense Secretary Pete Hegseth’s guidance declaring the shots voluntary 2 months ago.

The decision follows a flu outbreak among recruits at Joint Base San Antonio-Lackland in Texas and sharp criticism of the policy from public health experts. More than 220 ‌recruits have been diagnosed with influenza and 4 hospitalized in the outbreak, according to media reports.

Hegseth said in April that the annual flu vaccine would become optional for all US military personnel under the Pentagon’s new vaccine policy. It ‌had previously been mandated and considered critical to troop preparedness.

The Under Secretary for War ‌Personnel and Readiness approved exception requests ‌for the Army, Navy, Air Force, National Security Agency, and Defense Health Agency, according to a statement from chief Pentagon spokesperson Sean Parnell on ‌Wednesday.

“The decisions were based upon thorough risk assessments and are designed to maximize operational readiness, lethality, ‌and force generation, while safeguarding at-risk populations,” Parnell said.

Each department is responsible for implementation, the spokesperson added.

The World Health Organization recommends the flu shot for those aged ≥ 6 months.

Trump administration Health Secretary Robert ‌F. ‌Kennedy Jr., a longtime antivaccine activist, has enacted policies that have decreased the use ‌of inoculations in the US, including dropping its 2025 flu vaccine campaign. Kennedy’s Make America Healthy Again movement has sought to weaken school enrollment mandates around the country.

Flu vaccines from Sanofi, CSL Seqirus, GSK and AstraZeneca are approved ‌in the United States.

(Reporting by Idrees Ali, Mariam Sunny and Mrinalika Roy; Editing by Caroline Humer and Bill Berkrot)

A version of this article first appeared on Medscape.com.