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Pink Papulonodular Eruption on the Trunk and Arms
Pink Papulonodular Eruption on the Trunk and Arms
THE DIAGNOSIS: Sarcoidlike Reaction
Sarcoidlike reaction (SLR) is a rare cutaneous immune-related adverse event characterized by a multisystem granulomatous reaction indistinguishable from sarcoidosis but temporally associated with a trigger.1 Drug-induced SLR typically involves the mediastinal or hilar lymph nodes, with frequent involvement of the lungs and skin; cutaneous manifestations typically encompass erythematous papulonodular eruptions on the trunk and extremities.1-3 Sarcoidosis predominantly affects middle-aged women of African American or Scandinavian descent; genetic predisposition likely is a contributing factor.4 Unlike sarcoidosis, SLR is linked to various triggers such as medication or malignancy.
Immune checkpoint inhibitors (ICIs), particularly anti–PD-1 agents, have been linked to SLR through overexpression of proinflammatory cytokines, resulting in excessive T-helper 1 cell and macrophage activation and granulomatous eruption; notably, cutaneous immune-related adverse events often are correlated with greater treatment efficacy.5,6 Overall, anticancer therapy–induced SLR is most commonly reported in patients receiving ICIs for melanoma but it also has been described with ICI therapy for other cancers and with chemotherapy for melanoma. 1,3 Although most cases demonstrate both cutaneous and extracutaneous involvement, approximately 13 reported cases have been exclusively cutaneous.1 Recognition of SLR is important because misdiagnosis as true sarcoidosis may prompt unnecessary testing or therapy; furthermore, distinction from tumor progression is critical.3 The lesions can mimic other granulomatous or inflammatory dermatoses, posing a diagnostic challenge.
On histopathology, SLR typically demonstrates well-formed, noncaseating dermal granulomas composed of epithelioid histiocytes and Langhans or foreign-body giant cells, a sparse lymphocytic rim, and few plasma cells.2,4 Immunohistochemistry shows CD68-positive histiocytes predominating within the granulomas. Asteroid and Schaumann bodies occasionally are present.7 Special stains will be negative for microorganisms. Sarcoidosis manifests essentially identically from both a clinical and histopathologic perspective (Figure 1). Temporal association with an offending agent and symptomatic resolution following drug cessation remain the most reliable features for distinguishing SLR from sarcoidosis.7
Tuberculoid leprosy is a chronic infectious disease caused by Mycobacterium leprae (found most commonly in tropical regions) and manifesting as localized hypopigmented macules or papules with raised erythematous margins.8 Histopathologically, lesions show well-formed granulomas composed of epithelioid histiocytes and Langhans giant cells without necrosis, surrounded by a prominent lymphocytic rim (Figure 2).9 Rarely, focal caseous necrosis occurs, particularly in involved nerves.10 Hallmark features include enlarged cutaneous nerves surrounded by dermal granulomas and absence of bacilli on special stains; eccrine glands are infrequently involved.9 Standard treatment is 6 months of combination therapy with dapsone and rifampin.
Generalized granuloma annulare is an inflammatory dermatosis manifesting as diffuse erythematous annular papules, classically on the trunk and extremities.11 It predominantly affects individuals in their fifth and sixth decades of life and may be drug induced.2 Histopathology may reveal palisaded granulomas with central necrobiotic collagen, intercalating histiocytes, and interstitial mucin (Figure 3).2 Pathology also may show interstitial histiocytes and lymphocytes intercalating between collagen bundles with increased mucin but absent palisading or necrobiosis or a mixed pattern.2,12 Alcian blue or colloidal iron stains highlight mucin to help distinguish from other granulomatous processes. Multinucleated giant cells are rare. The nonnecrobiotic histologic pattern can mimic sarcoidosis, necessitating clinical correlation for correct diagnosis.13 Certain cases show genetic predisposition, such as HLA-B35, with a relapsing course often requiring combined systemic immunosuppression and phototherapy.14
Granulomatosis with polyangiitis is a systemic vasculitis that classically manifests as palpable purpura on the lower extremities, often with ulceration. Localized erythematous papules on the extensor surfaces may occur less commonly.15 Pathogenesis involves antineutrophil cytoplasmic antibodies inducing neutrophil degranulation, release of reactive oxygen species and proinflammatory cytokines, and subsequent endothelial damage.15 Histopathology shows necrotizing granulomatous inflammation and necrotizing vasculitis of small and medium vessels with nuclear debris.15 Poorly formed granulomas containing abundant neutrophils and mixed perivascular inflammatory infiltrates may be seen with or without vasculitis (Figure 4). Systemic features commonly include chronic rhinosinusitis, pauci-immune glomerulonephritis, and pulmonary nodules.15 Pharmacotherapy includes glucocorticoids combined with a glucocorticoid-sparing agent.
- Mazumder A, Mehrmal S, Chaudhry S. Immunotherapy-induced exclusively cutaneous sarcoid-like reaction. BMJ Case Rep. 2023;16:E252766. doi:10.1136/bcr-2022-252766
- Shah N, Shah M, Drucker AM, et al. Granulomatous cutaneous drug eruptions: a systematic review. Am J Clin Dermatol. 2021;22:39-53. doi:10.1007/s40257-020-00566-4
- Nykaza I, Murciano-Goroff YR, Desilets A, et al. Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors. Oncologist. 2025;30:oyaf017. doi:10.1093/oncolo /oyaf017
- Tana C, Donatiello I, Caputo A, et al. Clinical features, histopathology and differential diagnosis of sarcoidosis. Cells. 2021;11:59. doi:10.3390/cells11010059
- Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19:345-361. doi:10.1007/s40257-017-0336-3
- Diaz-Perez JA, Beveridge MG, Victor TA, et al. Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer. J Cutan Pathol. 2018;45:434-438. doi:10.1111/cup.13133
- Chopra A, Nautiyal A, Kalkanis A, et al. Drug-induced sarcoidosis-like reactions. Chest. 2018;154:664-677. doi:10.1016 /j.chest.2018.03.056
- Froes LAR Jr, Sotto MN, Trindade MAB. Leprosy: clinical and immunopathological characteristics. An Bras Dermatol. 2022;97:338-347. doi:10.1016/j.abd.2021.08.006
- Magaña M, Vargas Bornacini MF, Landeta-Sa AP, et al. Lucio phenomenon: a review. Am J Dermatopathol. 2025;47:1-8. doi:10.1097 /DAD.0000000000002833
- Jayalakshmy PS, Prasad PH, Kamala VV, et al. Segmental necrotizing granulomatous neuritis: a rare manifestation of Hansen disease-report of 2 cases. Case Rep Dermatol Med. 2012;2012:758093. doi:10.1155/2012/758093
- Lee JH, Cho S. Resolution of refractory generalized granuloma annulare after treatment with alitretinoin. JAAD Case Rep. 2022;24:38-41. doi:10.1016/j.jdcr.2022.04.006
- Yun JH, Lee JY, Kim MK, et al. Clinical and pathological features of generalized granuloma annulare with their correlation: a retrospective multicenter study in Korea. Ann Dermatol. 2009; 21:113-119. doi:10.5021/ad.2009.21.2.113
- Cohen PR, Carlos CA. Granuloma annulare mimicking sarcoidosis: report of patient with localized granuloma annulare whose skin lesions show 3 clinical morphologies and 2 histology patterns. Am J Dermatopathol. 2015;37:547-550. doi:10.1097/DAD.0000000000000125
- Rankin BD, Haber RM. Familial granuloma annulare: first report of occurrence in a father and daughter and updated review of the literature. JAAD Case Rep. 2021;17:61-64. doi:10.1016 /j.jdcr.2021.09.023
- Rout P, Garlapati P, Qurie A. Granulomatosis with polyangiitis. StatPearls (Internet). Updated August 31, 2024. Accessed May 4, 2026. https://www.ncbi.nlm.nih.gov/books/NBK557827/
THE DIAGNOSIS: Sarcoidlike Reaction
Sarcoidlike reaction (SLR) is a rare cutaneous immune-related adverse event characterized by a multisystem granulomatous reaction indistinguishable from sarcoidosis but temporally associated with a trigger.1 Drug-induced SLR typically involves the mediastinal or hilar lymph nodes, with frequent involvement of the lungs and skin; cutaneous manifestations typically encompass erythematous papulonodular eruptions on the trunk and extremities.1-3 Sarcoidosis predominantly affects middle-aged women of African American or Scandinavian descent; genetic predisposition likely is a contributing factor.4 Unlike sarcoidosis, SLR is linked to various triggers such as medication or malignancy.
Immune checkpoint inhibitors (ICIs), particularly anti–PD-1 agents, have been linked to SLR through overexpression of proinflammatory cytokines, resulting in excessive T-helper 1 cell and macrophage activation and granulomatous eruption; notably, cutaneous immune-related adverse events often are correlated with greater treatment efficacy.5,6 Overall, anticancer therapy–induced SLR is most commonly reported in patients receiving ICIs for melanoma but it also has been described with ICI therapy for other cancers and with chemotherapy for melanoma. 1,3 Although most cases demonstrate both cutaneous and extracutaneous involvement, approximately 13 reported cases have been exclusively cutaneous.1 Recognition of SLR is important because misdiagnosis as true sarcoidosis may prompt unnecessary testing or therapy; furthermore, distinction from tumor progression is critical.3 The lesions can mimic other granulomatous or inflammatory dermatoses, posing a diagnostic challenge.
On histopathology, SLR typically demonstrates well-formed, noncaseating dermal granulomas composed of epithelioid histiocytes and Langhans or foreign-body giant cells, a sparse lymphocytic rim, and few plasma cells.2,4 Immunohistochemistry shows CD68-positive histiocytes predominating within the granulomas. Asteroid and Schaumann bodies occasionally are present.7 Special stains will be negative for microorganisms. Sarcoidosis manifests essentially identically from both a clinical and histopathologic perspective (Figure 1). Temporal association with an offending agent and symptomatic resolution following drug cessation remain the most reliable features for distinguishing SLR from sarcoidosis.7
Tuberculoid leprosy is a chronic infectious disease caused by Mycobacterium leprae (found most commonly in tropical regions) and manifesting as localized hypopigmented macules or papules with raised erythematous margins.8 Histopathologically, lesions show well-formed granulomas composed of epithelioid histiocytes and Langhans giant cells without necrosis, surrounded by a prominent lymphocytic rim (Figure 2).9 Rarely, focal caseous necrosis occurs, particularly in involved nerves.10 Hallmark features include enlarged cutaneous nerves surrounded by dermal granulomas and absence of bacilli on special stains; eccrine glands are infrequently involved.9 Standard treatment is 6 months of combination therapy with dapsone and rifampin.
Generalized granuloma annulare is an inflammatory dermatosis manifesting as diffuse erythematous annular papules, classically on the trunk and extremities.11 It predominantly affects individuals in their fifth and sixth decades of life and may be drug induced.2 Histopathology may reveal palisaded granulomas with central necrobiotic collagen, intercalating histiocytes, and interstitial mucin (Figure 3).2 Pathology also may show interstitial histiocytes and lymphocytes intercalating between collagen bundles with increased mucin but absent palisading or necrobiosis or a mixed pattern.2,12 Alcian blue or colloidal iron stains highlight mucin to help distinguish from other granulomatous processes. Multinucleated giant cells are rare. The nonnecrobiotic histologic pattern can mimic sarcoidosis, necessitating clinical correlation for correct diagnosis.13 Certain cases show genetic predisposition, such as HLA-B35, with a relapsing course often requiring combined systemic immunosuppression and phototherapy.14
Granulomatosis with polyangiitis is a systemic vasculitis that classically manifests as palpable purpura on the lower extremities, often with ulceration. Localized erythematous papules on the extensor surfaces may occur less commonly.15 Pathogenesis involves antineutrophil cytoplasmic antibodies inducing neutrophil degranulation, release of reactive oxygen species and proinflammatory cytokines, and subsequent endothelial damage.15 Histopathology shows necrotizing granulomatous inflammation and necrotizing vasculitis of small and medium vessels with nuclear debris.15 Poorly formed granulomas containing abundant neutrophils and mixed perivascular inflammatory infiltrates may be seen with or without vasculitis (Figure 4). Systemic features commonly include chronic rhinosinusitis, pauci-immune glomerulonephritis, and pulmonary nodules.15 Pharmacotherapy includes glucocorticoids combined with a glucocorticoid-sparing agent.
THE DIAGNOSIS: Sarcoidlike Reaction
Sarcoidlike reaction (SLR) is a rare cutaneous immune-related adverse event characterized by a multisystem granulomatous reaction indistinguishable from sarcoidosis but temporally associated with a trigger.1 Drug-induced SLR typically involves the mediastinal or hilar lymph nodes, with frequent involvement of the lungs and skin; cutaneous manifestations typically encompass erythematous papulonodular eruptions on the trunk and extremities.1-3 Sarcoidosis predominantly affects middle-aged women of African American or Scandinavian descent; genetic predisposition likely is a contributing factor.4 Unlike sarcoidosis, SLR is linked to various triggers such as medication or malignancy.
Immune checkpoint inhibitors (ICIs), particularly anti–PD-1 agents, have been linked to SLR through overexpression of proinflammatory cytokines, resulting in excessive T-helper 1 cell and macrophage activation and granulomatous eruption; notably, cutaneous immune-related adverse events often are correlated with greater treatment efficacy.5,6 Overall, anticancer therapy–induced SLR is most commonly reported in patients receiving ICIs for melanoma but it also has been described with ICI therapy for other cancers and with chemotherapy for melanoma. 1,3 Although most cases demonstrate both cutaneous and extracutaneous involvement, approximately 13 reported cases have been exclusively cutaneous.1 Recognition of SLR is important because misdiagnosis as true sarcoidosis may prompt unnecessary testing or therapy; furthermore, distinction from tumor progression is critical.3 The lesions can mimic other granulomatous or inflammatory dermatoses, posing a diagnostic challenge.
On histopathology, SLR typically demonstrates well-formed, noncaseating dermal granulomas composed of epithelioid histiocytes and Langhans or foreign-body giant cells, a sparse lymphocytic rim, and few plasma cells.2,4 Immunohistochemistry shows CD68-positive histiocytes predominating within the granulomas. Asteroid and Schaumann bodies occasionally are present.7 Special stains will be negative for microorganisms. Sarcoidosis manifests essentially identically from both a clinical and histopathologic perspective (Figure 1). Temporal association with an offending agent and symptomatic resolution following drug cessation remain the most reliable features for distinguishing SLR from sarcoidosis.7
Tuberculoid leprosy is a chronic infectious disease caused by Mycobacterium leprae (found most commonly in tropical regions) and manifesting as localized hypopigmented macules or papules with raised erythematous margins.8 Histopathologically, lesions show well-formed granulomas composed of epithelioid histiocytes and Langhans giant cells without necrosis, surrounded by a prominent lymphocytic rim (Figure 2).9 Rarely, focal caseous necrosis occurs, particularly in involved nerves.10 Hallmark features include enlarged cutaneous nerves surrounded by dermal granulomas and absence of bacilli on special stains; eccrine glands are infrequently involved.9 Standard treatment is 6 months of combination therapy with dapsone and rifampin.
Generalized granuloma annulare is an inflammatory dermatosis manifesting as diffuse erythematous annular papules, classically on the trunk and extremities.11 It predominantly affects individuals in their fifth and sixth decades of life and may be drug induced.2 Histopathology may reveal palisaded granulomas with central necrobiotic collagen, intercalating histiocytes, and interstitial mucin (Figure 3).2 Pathology also may show interstitial histiocytes and lymphocytes intercalating between collagen bundles with increased mucin but absent palisading or necrobiosis or a mixed pattern.2,12 Alcian blue or colloidal iron stains highlight mucin to help distinguish from other granulomatous processes. Multinucleated giant cells are rare. The nonnecrobiotic histologic pattern can mimic sarcoidosis, necessitating clinical correlation for correct diagnosis.13 Certain cases show genetic predisposition, such as HLA-B35, with a relapsing course often requiring combined systemic immunosuppression and phototherapy.14
Granulomatosis with polyangiitis is a systemic vasculitis that classically manifests as palpable purpura on the lower extremities, often with ulceration. Localized erythematous papules on the extensor surfaces may occur less commonly.15 Pathogenesis involves antineutrophil cytoplasmic antibodies inducing neutrophil degranulation, release of reactive oxygen species and proinflammatory cytokines, and subsequent endothelial damage.15 Histopathology shows necrotizing granulomatous inflammation and necrotizing vasculitis of small and medium vessels with nuclear debris.15 Poorly formed granulomas containing abundant neutrophils and mixed perivascular inflammatory infiltrates may be seen with or without vasculitis (Figure 4). Systemic features commonly include chronic rhinosinusitis, pauci-immune glomerulonephritis, and pulmonary nodules.15 Pharmacotherapy includes glucocorticoids combined with a glucocorticoid-sparing agent.
- Mazumder A, Mehrmal S, Chaudhry S. Immunotherapy-induced exclusively cutaneous sarcoid-like reaction. BMJ Case Rep. 2023;16:E252766. doi:10.1136/bcr-2022-252766
- Shah N, Shah M, Drucker AM, et al. Granulomatous cutaneous drug eruptions: a systematic review. Am J Clin Dermatol. 2021;22:39-53. doi:10.1007/s40257-020-00566-4
- Nykaza I, Murciano-Goroff YR, Desilets A, et al. Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors. Oncologist. 2025;30:oyaf017. doi:10.1093/oncolo /oyaf017
- Tana C, Donatiello I, Caputo A, et al. Clinical features, histopathology and differential diagnosis of sarcoidosis. Cells. 2021;11:59. doi:10.3390/cells11010059
- Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19:345-361. doi:10.1007/s40257-017-0336-3
- Diaz-Perez JA, Beveridge MG, Victor TA, et al. Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer. J Cutan Pathol. 2018;45:434-438. doi:10.1111/cup.13133
- Chopra A, Nautiyal A, Kalkanis A, et al. Drug-induced sarcoidosis-like reactions. Chest. 2018;154:664-677. doi:10.1016 /j.chest.2018.03.056
- Froes LAR Jr, Sotto MN, Trindade MAB. Leprosy: clinical and immunopathological characteristics. An Bras Dermatol. 2022;97:338-347. doi:10.1016/j.abd.2021.08.006
- Magaña M, Vargas Bornacini MF, Landeta-Sa AP, et al. Lucio phenomenon: a review. Am J Dermatopathol. 2025;47:1-8. doi:10.1097 /DAD.0000000000002833
- Jayalakshmy PS, Prasad PH, Kamala VV, et al. Segmental necrotizing granulomatous neuritis: a rare manifestation of Hansen disease-report of 2 cases. Case Rep Dermatol Med. 2012;2012:758093. doi:10.1155/2012/758093
- Lee JH, Cho S. Resolution of refractory generalized granuloma annulare after treatment with alitretinoin. JAAD Case Rep. 2022;24:38-41. doi:10.1016/j.jdcr.2022.04.006
- Yun JH, Lee JY, Kim MK, et al. Clinical and pathological features of generalized granuloma annulare with their correlation: a retrospective multicenter study in Korea. Ann Dermatol. 2009; 21:113-119. doi:10.5021/ad.2009.21.2.113
- Cohen PR, Carlos CA. Granuloma annulare mimicking sarcoidosis: report of patient with localized granuloma annulare whose skin lesions show 3 clinical morphologies and 2 histology patterns. Am J Dermatopathol. 2015;37:547-550. doi:10.1097/DAD.0000000000000125
- Rankin BD, Haber RM. Familial granuloma annulare: first report of occurrence in a father and daughter and updated review of the literature. JAAD Case Rep. 2021;17:61-64. doi:10.1016 /j.jdcr.2021.09.023
- Rout P, Garlapati P, Qurie A. Granulomatosis with polyangiitis. StatPearls (Internet). Updated August 31, 2024. Accessed May 4, 2026. https://www.ncbi.nlm.nih.gov/books/NBK557827/
- Mazumder A, Mehrmal S, Chaudhry S. Immunotherapy-induced exclusively cutaneous sarcoid-like reaction. BMJ Case Rep. 2023;16:E252766. doi:10.1136/bcr-2022-252766
- Shah N, Shah M, Drucker AM, et al. Granulomatous cutaneous drug eruptions: a systematic review. Am J Clin Dermatol. 2021;22:39-53. doi:10.1007/s40257-020-00566-4
- Nykaza I, Murciano-Goroff YR, Desilets A, et al. Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors. Oncologist. 2025;30:oyaf017. doi:10.1093/oncolo /oyaf017
- Tana C, Donatiello I, Caputo A, et al. Clinical features, histopathology and differential diagnosis of sarcoidosis. Cells. 2021;11:59. doi:10.3390/cells11010059
- Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19:345-361. doi:10.1007/s40257-017-0336-3
- Diaz-Perez JA, Beveridge MG, Victor TA, et al. Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer. J Cutan Pathol. 2018;45:434-438. doi:10.1111/cup.13133
- Chopra A, Nautiyal A, Kalkanis A, et al. Drug-induced sarcoidosis-like reactions. Chest. 2018;154:664-677. doi:10.1016 /j.chest.2018.03.056
- Froes LAR Jr, Sotto MN, Trindade MAB. Leprosy: clinical and immunopathological characteristics. An Bras Dermatol. 2022;97:338-347. doi:10.1016/j.abd.2021.08.006
- Magaña M, Vargas Bornacini MF, Landeta-Sa AP, et al. Lucio phenomenon: a review. Am J Dermatopathol. 2025;47:1-8. doi:10.1097 /DAD.0000000000002833
- Jayalakshmy PS, Prasad PH, Kamala VV, et al. Segmental necrotizing granulomatous neuritis: a rare manifestation of Hansen disease-report of 2 cases. Case Rep Dermatol Med. 2012;2012:758093. doi:10.1155/2012/758093
- Lee JH, Cho S. Resolution of refractory generalized granuloma annulare after treatment with alitretinoin. JAAD Case Rep. 2022;24:38-41. doi:10.1016/j.jdcr.2022.04.006
- Yun JH, Lee JY, Kim MK, et al. Clinical and pathological features of generalized granuloma annulare with their correlation: a retrospective multicenter study in Korea. Ann Dermatol. 2009; 21:113-119. doi:10.5021/ad.2009.21.2.113
- Cohen PR, Carlos CA. Granuloma annulare mimicking sarcoidosis: report of patient with localized granuloma annulare whose skin lesions show 3 clinical morphologies and 2 histology patterns. Am J Dermatopathol. 2015;37:547-550. doi:10.1097/DAD.0000000000000125
- Rankin BD, Haber RM. Familial granuloma annulare: first report of occurrence in a father and daughter and updated review of the literature. JAAD Case Rep. 2021;17:61-64. doi:10.1016 /j.jdcr.2021.09.023
- Rout P, Garlapati P, Qurie A. Granulomatosis with polyangiitis. StatPearls (Internet). Updated August 31, 2024. Accessed May 4, 2026. https://www.ncbi.nlm.nih.gov/books/NBK557827/
Pink Papulonodular Eruption on the Trunk and Arms
Pink Papulonodular Eruption on the Trunk and Arms
A 47-year-old man with a history of chronic kidney disease and bilateral clear cell renal cell carcinoma who was undergoing treatment with adjuvant pembrolizumab presented to the dermatology department with a scattered papulonodular eruption of several weeks’ duration. Physical examination revealed pink papules and nodules with coalescing erythema over the trunk and upper extremities, most pronounced on the right elbow (bottom [inset]). A 4-mm punch biopsy demonstrated dermal granulomatous inflammation. Special stains were negative for microorganisms. Computed tomography of the chest revealed a new subpleural nodule and new hilar lymphadenopathy.
Combined Treatment of Disfiguring Facial Angiofibromas in Tuberous Sclerosis Complex With Surgical Debulking and Topical Sirolimus
Practice Gap
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder resulting in loss-of-function mutations in the TSC1 and TSC2 genes. These mutations lead to constitutive activation of the mitogenic mTOR pathway and release of lymphangiogenic growth factors, causing the formation of hamartomatous tumors throughout multiple organ systems.1 Facial angiofibromas (FAs) are a common cutaneous manifestation of TSC, affecting up to 80% of patients worldwide.2 Aesthetic disfigurement, vision obstruction, and breathing impairment often are associated with FAs. They frequently arise in children with TSC and impose a psychosocial burden that can affect the patient’s overall quality of life.
Cutaneous stigmata of TSC pose a significant therapeutic challenge. Topical sirolimus has become a first-line treatment of FAs by inhibiting the mitogenic mTOR pathway1; however, thicker, more extensive lesions are less responsive to topical therapy. The entire dermis is involved in TSC, and topical sirolimus alone often is ineffective for large fibrous FAs.3 Likewise, oral mTOR inhibition has shown only 25% to 50% improvement in FAs and has potential side effects that can limit patients’ tolerance and compliance.4
The Technique
A 46-year-old man with TSC was referred to dermatology for treatment of numerous facial papules and plaques that had been present since childhood and were consistent with FAs (Figure 1A). The lesions were tender, impaired the patient’s breathing, and caused emotional distress. Dermabrasion was attempted 20 years prior with minimal improvement and subsequent progression of the FAs. Other stigmata of TSC were present, including cutaneous hypopigmented macules and shagreen patches as well as seizures and renal angiomyolipomas. Due to multiorgan involvement, the patient was started on once-daily oral everolimus 2.5 mg; however, the FAs were progressive despite the systemic mTOR inhibition. Furthermore, it was presumed that topical sirolimus monotherapy would be ineffective due to thickness and extent of FAs; therefore, we proposed a novel treatment approach combining initial surgical debulking with subsequent longitudinal use of topical sirolimus to reduce the risk of recurrence.
Local anesthesia with lidocaine 1% and epinephrine 1:100,000 was administered. Larger FAs were removed at the base with a sterile surgical blade. Nasal recontouring subsequently was performed using a combination of shave biopsy and curettage. Extensive electrocautery was performed for hemostasis and destruction of residual FAs. Figure 1B shows the immediate postoperative result.
One month postoperatively, the patient stopped the oral everolimus at his oncologist’s recommendation due to abdominal pain and peripheral edema. Once the abraded skin showed evidence of wound healing, the patient was instructed to initiate sirolimus ointment 1% twice daily to reduce the risk of recurrence.1,5,6 At 8-week follow-up, the patient was noted to have cosmetic improvement and resolution of breathing impairment (Figure 2A). He continued to show excellent cosmetic results at 1-year follow-up using topical sirolimus monotherapy (Figure 2B).
Practical Implications
Surgical debulking combined with longitudinal use of sirolimus ointment 1% can achieve an optimal therapeutic response for disfiguring phymatous presentation of FAs in the setting of TSC. We believe it is an effective approach for thick disfiguring FAs that are unlikely to respond to mTOR inhibition alone.
- Wataya-Kaneda M, Nakamura A, Tanaka M, et al. Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2017;153:39‐48.
- Koenig MK, Hebert AA, Roberson J, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Drugs R D. 2012;12:121-126.
- Wataya-Kaneda M, Ohno Y, Fujita Y, et al. Sirolimus gel treatment vs placebo for facial angiofibromas in patients with tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2018;154:781-788.
- Nathan N, Wang JA, Li S, et al. Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J Am Acad Dermatol. 2015;73:802-808.
- Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28:126-133.
- Haemel AK, O’Brian AL, Teng JM. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Arch Dermatol. 2010;146:1538-3652.
Practice Gap
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder resulting in loss-of-function mutations in the TSC1 and TSC2 genes. These mutations lead to constitutive activation of the mitogenic mTOR pathway and release of lymphangiogenic growth factors, causing the formation of hamartomatous tumors throughout multiple organ systems.1 Facial angiofibromas (FAs) are a common cutaneous manifestation of TSC, affecting up to 80% of patients worldwide.2 Aesthetic disfigurement, vision obstruction, and breathing impairment often are associated with FAs. They frequently arise in children with TSC and impose a psychosocial burden that can affect the patient’s overall quality of life.
Cutaneous stigmata of TSC pose a significant therapeutic challenge. Topical sirolimus has become a first-line treatment of FAs by inhibiting the mitogenic mTOR pathway1; however, thicker, more extensive lesions are less responsive to topical therapy. The entire dermis is involved in TSC, and topical sirolimus alone often is ineffective for large fibrous FAs.3 Likewise, oral mTOR inhibition has shown only 25% to 50% improvement in FAs and has potential side effects that can limit patients’ tolerance and compliance.4
The Technique
A 46-year-old man with TSC was referred to dermatology for treatment of numerous facial papules and plaques that had been present since childhood and were consistent with FAs (Figure 1A). The lesions were tender, impaired the patient’s breathing, and caused emotional distress. Dermabrasion was attempted 20 years prior with minimal improvement and subsequent progression of the FAs. Other stigmata of TSC were present, including cutaneous hypopigmented macules and shagreen patches as well as seizures and renal angiomyolipomas. Due to multiorgan involvement, the patient was started on once-daily oral everolimus 2.5 mg; however, the FAs were progressive despite the systemic mTOR inhibition. Furthermore, it was presumed that topical sirolimus monotherapy would be ineffective due to thickness and extent of FAs; therefore, we proposed a novel treatment approach combining initial surgical debulking with subsequent longitudinal use of topical sirolimus to reduce the risk of recurrence.
Local anesthesia with lidocaine 1% and epinephrine 1:100,000 was administered. Larger FAs were removed at the base with a sterile surgical blade. Nasal recontouring subsequently was performed using a combination of shave biopsy and curettage. Extensive electrocautery was performed for hemostasis and destruction of residual FAs. Figure 1B shows the immediate postoperative result.
One month postoperatively, the patient stopped the oral everolimus at his oncologist’s recommendation due to abdominal pain and peripheral edema. Once the abraded skin showed evidence of wound healing, the patient was instructed to initiate sirolimus ointment 1% twice daily to reduce the risk of recurrence.1,5,6 At 8-week follow-up, the patient was noted to have cosmetic improvement and resolution of breathing impairment (Figure 2A). He continued to show excellent cosmetic results at 1-year follow-up using topical sirolimus monotherapy (Figure 2B).
Practical Implications
Surgical debulking combined with longitudinal use of sirolimus ointment 1% can achieve an optimal therapeutic response for disfiguring phymatous presentation of FAs in the setting of TSC. We believe it is an effective approach for thick disfiguring FAs that are unlikely to respond to mTOR inhibition alone.
Practice Gap
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder resulting in loss-of-function mutations in the TSC1 and TSC2 genes. These mutations lead to constitutive activation of the mitogenic mTOR pathway and release of lymphangiogenic growth factors, causing the formation of hamartomatous tumors throughout multiple organ systems.1 Facial angiofibromas (FAs) are a common cutaneous manifestation of TSC, affecting up to 80% of patients worldwide.2 Aesthetic disfigurement, vision obstruction, and breathing impairment often are associated with FAs. They frequently arise in children with TSC and impose a psychosocial burden that can affect the patient’s overall quality of life.
Cutaneous stigmata of TSC pose a significant therapeutic challenge. Topical sirolimus has become a first-line treatment of FAs by inhibiting the mitogenic mTOR pathway1; however, thicker, more extensive lesions are less responsive to topical therapy. The entire dermis is involved in TSC, and topical sirolimus alone often is ineffective for large fibrous FAs.3 Likewise, oral mTOR inhibition has shown only 25% to 50% improvement in FAs and has potential side effects that can limit patients’ tolerance and compliance.4
The Technique
A 46-year-old man with TSC was referred to dermatology for treatment of numerous facial papules and plaques that had been present since childhood and were consistent with FAs (Figure 1A). The lesions were tender, impaired the patient’s breathing, and caused emotional distress. Dermabrasion was attempted 20 years prior with minimal improvement and subsequent progression of the FAs. Other stigmata of TSC were present, including cutaneous hypopigmented macules and shagreen patches as well as seizures and renal angiomyolipomas. Due to multiorgan involvement, the patient was started on once-daily oral everolimus 2.5 mg; however, the FAs were progressive despite the systemic mTOR inhibition. Furthermore, it was presumed that topical sirolimus monotherapy would be ineffective due to thickness and extent of FAs; therefore, we proposed a novel treatment approach combining initial surgical debulking with subsequent longitudinal use of topical sirolimus to reduce the risk of recurrence.
Local anesthesia with lidocaine 1% and epinephrine 1:100,000 was administered. Larger FAs were removed at the base with a sterile surgical blade. Nasal recontouring subsequently was performed using a combination of shave biopsy and curettage. Extensive electrocautery was performed for hemostasis and destruction of residual FAs. Figure 1B shows the immediate postoperative result.
One month postoperatively, the patient stopped the oral everolimus at his oncologist’s recommendation due to abdominal pain and peripheral edema. Once the abraded skin showed evidence of wound healing, the patient was instructed to initiate sirolimus ointment 1% twice daily to reduce the risk of recurrence.1,5,6 At 8-week follow-up, the patient was noted to have cosmetic improvement and resolution of breathing impairment (Figure 2A). He continued to show excellent cosmetic results at 1-year follow-up using topical sirolimus monotherapy (Figure 2B).
Practical Implications
Surgical debulking combined with longitudinal use of sirolimus ointment 1% can achieve an optimal therapeutic response for disfiguring phymatous presentation of FAs in the setting of TSC. We believe it is an effective approach for thick disfiguring FAs that are unlikely to respond to mTOR inhibition alone.
- Wataya-Kaneda M, Nakamura A, Tanaka M, et al. Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2017;153:39‐48.
- Koenig MK, Hebert AA, Roberson J, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Drugs R D. 2012;12:121-126.
- Wataya-Kaneda M, Ohno Y, Fujita Y, et al. Sirolimus gel treatment vs placebo for facial angiofibromas in patients with tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2018;154:781-788.
- Nathan N, Wang JA, Li S, et al. Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J Am Acad Dermatol. 2015;73:802-808.
- Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28:126-133.
- Haemel AK, O’Brian AL, Teng JM. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Arch Dermatol. 2010;146:1538-3652.
- Wataya-Kaneda M, Nakamura A, Tanaka M, et al. Efficacy and safety of topical sirolimus therapy for facial angiofibromas in the tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2017;153:39‐48.
- Koenig MK, Hebert AA, Roberson J, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Drugs R D. 2012;12:121-126.
- Wataya-Kaneda M, Ohno Y, Fujita Y, et al. Sirolimus gel treatment vs placebo for facial angiofibromas in patients with tuberous sclerosis complex: a randomized clinical trial. JAMA Dermatol. 2018;154:781-788.
- Nathan N, Wang JA, Li S, et al. Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J Am Acad Dermatol. 2015;73:802-808.
- Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014;28:126-133.
- Haemel AK, O’Brian AL, Teng JM. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Arch Dermatol. 2010;146:1538-3652.
