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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.
Enlarging Pigmented Lesion on the Thigh
The Diagnosis: Localized Cutaneous Argyria
The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.
Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.1 Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.2 Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.3
Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.1 Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.3 Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.4
Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).3,5,6
Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.7
Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.8
Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.3
Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.3,8
Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.
- Ondrasik RM, Jordan P, Sriharan A. A clinical mimicker of melanoma with distinctive histopathology: topical silver nitrate exposure. J Cutan Pathol. 2020;47:1205-1210.
- Gill P, Richards K, Cho WC, et al. Localized cutaneous argyria: review of a rare clinical mimicker of melanocytic lesions. Ann Diagn Pathol. 2021;54:151776.
- Molina-Ruiz AM, Cerroni L, Kutzner H, et al. Cutaneous deposits. Am J Dermatopathol. 2014;36:1-48.
- Lee J, Korgavkar K, DiMarco C, et al. Localized argyria with pseudoochronosis. J Cutan Pathol. 2020;47:671-674.
- El Sharouni MA, Aivazian K, Witkamp AJ, et al. Association of histologic regression with a favorable outcome in patients with stage 1 and stage 2 cutaneous melanoma. JAMA Dermatol. 2021;157:166-173.
- Staser K, Chen D, Solus J, et al. Extensive tumoral melanosis associated with ipilimumab-treated melanoma. Br J Dermatol. 2016;175:391-393.
- Sugianto JZ, Ralston JS, Metcalf JS, et al. Blue nevus and “malignant blue nevus”: a concise review. Semin Diagn Pathol. 2016;33:219-224.
- Wang RF, Ko D, Friedman BJ, et al. Disorders of hyperpigmentation. part I. pathogenesis and clinical features of common pigmentary disorders. J Am Acad Dermatol. 2023;88:271-288.
The Diagnosis: Localized Cutaneous Argyria
The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.
Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.1 Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.2 Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.3
Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.1 Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.3 Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.4
Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).3,5,6
Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.7
Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.8
Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.3
Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.3,8
Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.
The Diagnosis: Localized Cutaneous Argyria
The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.
Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.1 Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.2 Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.3
Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.1 Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.3 Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.4
Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).3,5,6
Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.7
Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.8
Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.3
Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.3,8
Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.
- Ondrasik RM, Jordan P, Sriharan A. A clinical mimicker of melanoma with distinctive histopathology: topical silver nitrate exposure. J Cutan Pathol. 2020;47:1205-1210.
- Gill P, Richards K, Cho WC, et al. Localized cutaneous argyria: review of a rare clinical mimicker of melanocytic lesions. Ann Diagn Pathol. 2021;54:151776.
- Molina-Ruiz AM, Cerroni L, Kutzner H, et al. Cutaneous deposits. Am J Dermatopathol. 2014;36:1-48.
- Lee J, Korgavkar K, DiMarco C, et al. Localized argyria with pseudoochronosis. J Cutan Pathol. 2020;47:671-674.
- El Sharouni MA, Aivazian K, Witkamp AJ, et al. Association of histologic regression with a favorable outcome in patients with stage 1 and stage 2 cutaneous melanoma. JAMA Dermatol. 2021;157:166-173.
- Staser K, Chen D, Solus J, et al. Extensive tumoral melanosis associated with ipilimumab-treated melanoma. Br J Dermatol. 2016;175:391-393.
- Sugianto JZ, Ralston JS, Metcalf JS, et al. Blue nevus and “malignant blue nevus”: a concise review. Semin Diagn Pathol. 2016;33:219-224.
- Wang RF, Ko D, Friedman BJ, et al. Disorders of hyperpigmentation. part I. pathogenesis and clinical features of common pigmentary disorders. J Am Acad Dermatol. 2023;88:271-288.
- Ondrasik RM, Jordan P, Sriharan A. A clinical mimicker of melanoma with distinctive histopathology: topical silver nitrate exposure. J Cutan Pathol. 2020;47:1205-1210.
- Gill P, Richards K, Cho WC, et al. Localized cutaneous argyria: review of a rare clinical mimicker of melanocytic lesions. Ann Diagn Pathol. 2021;54:151776.
- Molina-Ruiz AM, Cerroni L, Kutzner H, et al. Cutaneous deposits. Am J Dermatopathol. 2014;36:1-48.
- Lee J, Korgavkar K, DiMarco C, et al. Localized argyria with pseudoochronosis. J Cutan Pathol. 2020;47:671-674.
- El Sharouni MA, Aivazian K, Witkamp AJ, et al. Association of histologic regression with a favorable outcome in patients with stage 1 and stage 2 cutaneous melanoma. JAMA Dermatol. 2021;157:166-173.
- Staser K, Chen D, Solus J, et al. Extensive tumoral melanosis associated with ipilimumab-treated melanoma. Br J Dermatol. 2016;175:391-393.
- Sugianto JZ, Ralston JS, Metcalf JS, et al. Blue nevus and “malignant blue nevus”: a concise review. Semin Diagn Pathol. 2016;33:219-224.
- Wang RF, Ko D, Friedman BJ, et al. Disorders of hyperpigmentation. part I. pathogenesis and clinical features of common pigmentary disorders. J Am Acad Dermatol. 2023;88:271-288.
An 80-year-old man presented with a pigmented lesion on the left lateral thigh near the knee that had been gradually enlarging over several weeks (top [inset]). He underwent a left knee replacement surgery for advanced osteoarthritis many months prior that was complicated by postoperative Staphylococcus aureus infection with sinus tract formation that was persistent for 6 months and treated with a topical medication. A pigmented lesion developed near the opening of the sinus tract. His medical history was remarkable for extensive actinic damage as well as multiple actinic keratoses treated with cryotherapy but no history of melanoma. An excisional biopsy was performed (top and bottom).
