Stacey Pilkington, DO

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.