BRIEF REPORT
Necrobiosis Lipoidica With Elastophagocytosis on an Unusual Location Shang-Ian Tee, MRCP, Qi Ping Chen, MRCP, MSc, and Yen Loo Lim, FRCP
Abstract: Necrobiosis lipoidica (NL) is a granulomatous disease of collagen degeneration classically affecting the lower extremities. Elastophagocytosis is a histological finding, whereby multinucleate macrophages demonstrate phagocytosis of elastic fibers commonly associated with sun-damaged skin. Elastophagocytosis is not typically described in NL. The authors present a patient who presented with reddish-yellow plaques on both his forearms. Skin biopsy revealed extensive palisaded granulomas consistent with NL and features of elastophagocytosis in the upper dermis. The unusual site of presentation is a diagnostic pitfall, further complicated by the histological features of elastophagocytosis, for which the differential diagnosis of actinic granuloma needs to be considered. This case highlights the importance of clinicopathological correlation to arrive at a definitive diagnosis in situations where unexpected features on physical examination and histology may confound the clinical picture. Key Words: necrobiosis lipoidica, elastophagocytosis, diabetes mellitus (Am J Dermatopathol 2014;36:741–743)
INTRODUCTION Necrobiosis lipoidica (NL) is a noninfective granulomatous skin disease of collagen degeneration. The pathogenesis is unknown but may be related to either immune-mediated or hypoxia-induced vasculopathy,1,2 or primary collagen disease with secondary inflammation.3 The average age of onset is 30–40 years, although it can occur in any age group, including children.4 It has a female to male ratio of 3:1. There is a clear association with diabetes mellitus; up to 75% of patients with NL have or will develop diabetes mellitus, although only ;0.3% of diabetic patients develop NL.5 Clinically, it is characterized by violaceous to red-brown plaques with palpable peripheral rims and yellow-brown atrophic centers with telangiectasia. Ulceration may or may not occur. NL is typically distributed over the lower extremities, especially the anterior shins. However, there are rare reports of NL on other sites, such as the upper extremities, trunk, face, scalp, and genitalis.5,6 In a number of these cases affecting unusual sites, From the National Skin Centre, Singapore. The authors declare no conflicts of interest. Reprints: Shang-Ian Tee, MRCP, National Skin Centre, 1 Mandalay Road, Singapore 308205, Singapore (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 9, September 2014
patients also report preceding or concurrent lesions on the lower extremities. Histology of NL shows a palisaded necrobiotic granulomatous dermatitis with “layered” tiers of granulomatous inflammation aligned parallel to the skin surface involving the entire dermis and extending down to the subcutaneous fat septae, often with perivascular plasma cells. Actinic granuloma (AG) is another uncommon granulomatous disease that occurs predominantly in middle-aged women. Its pathogenesis is not understood, but may involve a cell-mediated response precipitated by actinic damage.7 As with NL, an association with diabetes mellitus is also noted.8 AG presents as asymptomatic annular plaques, predominantly on chronically sun-exposed sites. The histology shows nonpalisading granulomas, elastosis, and elastophagocytosis (phagocytosis of elastic fibers by multinucleate giant cells).9 AG was previously thought to be a form of granuloma annulare that presents on sun-damaged skin, on the basis of shared clinical and histopathological features.10 However, it is seldom described in association with NL. We report a patient presenting with isolated reddishyellow plaques on his forearms, clinically and histologically consistent with NL, but with additional histological features of actinic damage and elastophagocytosis, resembling what is seen in AG.
CASE REPORT Our patient is an 84-year-old Chinese man who presented with an erythematous slightly pruritic plaque on his right forearm for a few months. Apart from a history of application of an antiseptic medicament, there was no precedent injury. The patient has a long history of type 2 diabetes mellitus complicated by diabetic nephropathy, as well as hypertension, hyperlipidemia, and bullous pemphigoid. His bullous pemphigoid is well controlled with low-dose prednisolone (7.5 mg/d). Physical examination revealed a large erythematous yellowish plaque with indurated borders, almost encircling his right forearm (Fig. 1). The patient was treated as for cellulitis with oral ciprofloxacin without improvement. A similar but smaller plaque developed on his left forearm 2 months later. A skin biopsy specimen was taken from the raised border of the right forearm plaque. Histopathological examination revealed a diffuse dermal granulomatous infiltrate comprising several zones of necrobiosis, more prominent at the upper half, but also present towards the dermal-subcuticular junction (Fig. 2A). Bands of lymphocytes, plasma cells, histiocytes, and Langhans-type giant cells surround the zones of necrobiosis forming horizontal palisades (Fig. 2B). Notably, some giant cells appear to engulf elastic fibers (Fig. 2C). Verhoeff Van Gieson stain demonstrated a reduction of elastic fibers within the infiltrate (Fig. 3). Dermal mucin was not www.amjdermatopathology.com |
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Am J Dermatopathol Volume 36, Number 9, September 2014
Tee et al
FIGURE 1. The patient presents with a large erythematous yellowish plaque with sharp borders spanning both the volar and dorsal aspects of the forearm.
increased (Fig. 4) while infective stains for fungal and mycobacterial organisms were negative. Direct immunofluorescence was also negative for IgM, IgG, IgA, and C3. The clinical and histological findings were consistent with NL with actinic elastolytic damage. The patient was treated with topical mometasone furoate 0.1% cream twice daily with improvement.
DISCUSSION Our case highlights the diagnostic challenges that one may face when the lesions of NL occur on an unusual site and when there is concomitant presence of elastophagocytosis. The typical location of NL is the pretibial region; its presentation at other anatomical sites is much less common.3 Features inconsistent with the diagnoses of cellulitis and contact dermatitis, which were originally considered in our patient, include the sharp demarcation of the indurated
plaques, as well as the erythematous and yellowish color of the plaques. AG may be included as a possible diagnosis for our patient because the lesions are often localized to the sunexposed areas of the body, and elastolytic granulomas with elastophagocytosis are the features seen. However, plaques of AG tend to be smaller and show significant central atrophy and hypopigmentation, neither of which were observed in our patient. Furthermore, the elastophagocytosis noted in this case is not prominent and confined to a few giant cells in the superficial dermis. Finally, the presence of palisading granulomas with necrobiosis supports NL rather than AG. Cases previously reported as atypical NL or Miescher granuloma of the face, occurring on the face and neck, might be entities similar to our case of NL with actinic damage.11 Necrobiotic xanthogranuloma, which presents as erythematous violaceous plaques and nodules mostly involving the periorbital region, may be considered as another possible differential diagnosis. The histological hallmark of foamy histiocytes, cholesterol clefts, and Touton giant cells is, however, absent in our case and thus makes this diagnosis unlikely.12 Finally, granuloma annulare, a common cause of necrobiotic palisading granulomas, was excluded on the basis of inconsistent clinical morphology and lack of mucinous deposits in the histology. The therapy of NL remains challenging. First-line treatment involves the use of topical, intralesional, or systemic corticosteroids.13 An alternative strategy is directed at increasing fibrinolysis or decreasing platelet aggregation and thromboxane A 2 synthesis to decrease microangiopathy and vascular thrombosis.14–16 Other therapeutic options include niacinamide, antimalarials, tumor necrosis factor–a inhibitors (etanercept, infliximab), cyclosporine, mycophenolate mofetil, thalidomide, and phototherapy with either topical PUVA or UVA1. 17,18 Finally, surgery might be necessary for lesions with severe ulcerations that are refractory to medical treatment.19,20
FIGURE 2. A, Histology shows extensive palisaded necrobiotic granulomas at all levels of the dermis, orientated parallel to the surface (hematoxylin and eosin, original magnification ·40). B, The granulomas show a central zone of collagen and elastin degeneration with a surrounding infiltrate of histiocytes and Langhans giant cells (hematoxylin and eosin, original magnification ·100). C, High power view of a Langhans-type giant cell, which appears to contain elastic fibers (hematoxylin and eosin, original magnification ·400).
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| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 9, September 2014
Necrobiosis Lipoidica With Elastophagocytosis
can be challenging, and careful clinicopathological correlation is needed. REFERENCES
FIGURE 3. Elastic fibers are present within the areas of necrobiosis but not in the granulomatous infiltrate itself (Verhoeff Van Gieson stain).
FIGURE 4. Mucinous deposits are not detected within the granulomatous infiltrates (Alcian blue stain).
CONCLUSIONS We present an unusual case of NL localized to the forearms with elastophagocytosis as the histological feature of actinic damage. Distinction between other similar entities
2014 Lippincott Williams & Wilkins
1. Quimby SR, Muller SA, Schroeter AL. The cutaneous immunopathology of necrobiosis lipoidica diabeticorum. Arch Dermatol. 1988;124: 1364–1371. 2. Boateng B, Hiller D, Albrecht HP, et al. Kutane Mikrozirkulation bei prätibialer Nekrobiosis lipoidica. Vergleichende Laser-Doppler Fluxmetrie und Sauerstoffpartialdruckmessungen bei Patienten und Hautgesunden. Hautarzt. 1993;44:581–586. 3. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991; 25:735–748. 4. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol. 1966;93:272–281. 5. Peyrí J, Moreno A, Marcoval J. Necrobiosis lipoidica. Semin Cutan Med Surg. 2007;26:87–89. 6. Kavanagh GM, Novelli M, Hartog M, et al. Necrobiosis lipoidica— involvement of atypical sites. Clin Exp Dermatol. 1993;18:543–544. 7. McGrae JD Jr. Actinic granuloma. A clinical, histopathologic, and immunocytochemical study. Arch Dermatol. 1986;122:43–47. 8. Limas C. The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis. Histopathology. 2004;44:277–282. 9. O’Brien JP. Actinic granuloma. An annular connective tissue disorder affecting sun- and heat-damaged (elastotic) skin. Arch Dermatol. 1975; 111:460–466. 10. Ragaz A, Ackerman AB. Is actinic granuloma a specific condition? Am J Dermatopathol. 1979;1:43–50. 11. Weedon D. The granulomatous reaction pattern. In: Weedon’s Skin Pathology. 3rd ed. Edinburgh, United Kingdom: Churchill Livingstone; 2010:190. 12. Spicknall KE, Mehregan DA. Necrobiotic xanthogranuloma. Int J Dermatol. 2009;48:1–10. 13. Erfurt-Berge C, Seitz AT, Rehse C, et al. Update on clinical and laboratory features in necrobiosis lipoidica: a retrospective multicentre study of 52 patients. Eur J Dermatol. 2012;22:770–775. 14. Beck H, Bjerring P, Rasmussen I, et al. Treatment of necrobiosis lipoidica with low-dose acetylsalicylic acid. Acta Derm Venereol. 1985;65: 230–234. 15. Statham B, Finlay AY, Marks R. A randomized double blind comparison of an aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica. Acta Derm Venereol. 1981;61:270–271. 16. Wilkin JK. Perilesional heparin injections for necrobiosis lipoidica. J Am Acad Dermatol. 1983;8:904. 17. Reid SD, Ladizinski B, Lee K, et al. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol. 2013;69:783–791. 18. Beattie PE, Dawe RS, Ibbotson SH, et al. UVA1 phototherapy for treatment of necrobiosis lipoidica. Clin Exp Dermatol. 2006;31:235–238. 19. Brauns B, Schön MP, Zutt M. Ulcerative necrobiosis lipoidica successfully treated by vacuum-assisted closure therapy. Eur J Dermatol. 2011; 21:791–792. 20. Elmholdt TR, Sørensen HB, Fogh K. A severe case of ulcerating necrobiosis lipoidica. Acta Derm Venereol. 2008;88:177–178.
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Necrobiosis Lipoidica With Elastophagocytosis on an Unusual Location Shang-Ian Tee, MRCP, Qi Ping Chen, MRCP, MSc, and Yen Loo Lim, FRCP
Abstract: Necrobiosis lipoidica (NL) is a granulomatous disease of collagen degeneration classically affecting the lower extremities. Elastophagocytosis is a histological finding, whereby multinucleate macrophages demonstrate phagocytosis of elastic fibers commonly associated with sun-damaged skin. Elastophagocytosis is not typically described in NL. The authors present a patient who presented with reddish-yellow plaques on both his forearms. Skin biopsy revealed extensive palisaded granulomas consistent with NL and features of elastophagocytosis in the upper dermis. The unusual site of presentation is a diagnostic pitfall, further complicated by the histological features of elastophagocytosis, for which the differential diagnosis of actinic granuloma needs to be considered. This case highlights the importance of clinicopathological correlation to arrive at a definitive diagnosis in situations where unexpected features on physical examination and histology may confound the clinical picture. Key Words: necrobiosis lipoidica, elastophagocytosis, diabetes mellitus (Am J Dermatopathol 2014;36:741–743)
INTRODUCTION Necrobiosis lipoidica (NL) is a noninfective granulomatous skin disease of collagen degeneration. The pathogenesis is unknown but may be related to either immune-mediated or hypoxia-induced vasculopathy,1,2 or primary collagen disease with secondary inflammation.3 The average age of onset is 30–40 years, although it can occur in any age group, including children.4 It has a female to male ratio of 3:1. There is a clear association with diabetes mellitus; up to 75% of patients with NL have or will develop diabetes mellitus, although only ;0.3% of diabetic patients develop NL.5 Clinically, it is characterized by violaceous to red-brown plaques with palpable peripheral rims and yellow-brown atrophic centers with telangiectasia. Ulceration may or may not occur. NL is typically distributed over the lower extremities, especially the anterior shins. However, there are rare reports of NL on other sites, such as the upper extremities, trunk, face, scalp, and genitalis.5,6 In a number of these cases affecting unusual sites, From the National Skin Centre, Singapore. The authors declare no conflicts of interest. Reprints: Shang-Ian Tee, MRCP, National Skin Centre, 1 Mandalay Road, Singapore 308205, Singapore (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 9, September 2014
patients also report preceding or concurrent lesions on the lower extremities. Histology of NL shows a palisaded necrobiotic granulomatous dermatitis with “layered” tiers of granulomatous inflammation aligned parallel to the skin surface involving the entire dermis and extending down to the subcutaneous fat septae, often with perivascular plasma cells. Actinic granuloma (AG) is another uncommon granulomatous disease that occurs predominantly in middle-aged women. Its pathogenesis is not understood, but may involve a cell-mediated response precipitated by actinic damage.7 As with NL, an association with diabetes mellitus is also noted.8 AG presents as asymptomatic annular plaques, predominantly on chronically sun-exposed sites. The histology shows nonpalisading granulomas, elastosis, and elastophagocytosis (phagocytosis of elastic fibers by multinucleate giant cells).9 AG was previously thought to be a form of granuloma annulare that presents on sun-damaged skin, on the basis of shared clinical and histopathological features.10 However, it is seldom described in association with NL. We report a patient presenting with isolated reddishyellow plaques on his forearms, clinically and histologically consistent with NL, but with additional histological features of actinic damage and elastophagocytosis, resembling what is seen in AG.
CASE REPORT Our patient is an 84-year-old Chinese man who presented with an erythematous slightly pruritic plaque on his right forearm for a few months. Apart from a history of application of an antiseptic medicament, there was no precedent injury. The patient has a long history of type 2 diabetes mellitus complicated by diabetic nephropathy, as well as hypertension, hyperlipidemia, and bullous pemphigoid. His bullous pemphigoid is well controlled with low-dose prednisolone (7.5 mg/d). Physical examination revealed a large erythematous yellowish plaque with indurated borders, almost encircling his right forearm (Fig. 1). The patient was treated as for cellulitis with oral ciprofloxacin without improvement. A similar but smaller plaque developed on his left forearm 2 months later. A skin biopsy specimen was taken from the raised border of the right forearm plaque. Histopathological examination revealed a diffuse dermal granulomatous infiltrate comprising several zones of necrobiosis, more prominent at the upper half, but also present towards the dermal-subcuticular junction (Fig. 2A). Bands of lymphocytes, plasma cells, histiocytes, and Langhans-type giant cells surround the zones of necrobiosis forming horizontal palisades (Fig. 2B). Notably, some giant cells appear to engulf elastic fibers (Fig. 2C). Verhoeff Van Gieson stain demonstrated a reduction of elastic fibers within the infiltrate (Fig. 3). Dermal mucin was not www.amjdermatopathology.com |
741
Am J Dermatopathol Volume 36, Number 9, September 2014
Tee et al
FIGURE 1. The patient presents with a large erythematous yellowish plaque with sharp borders spanning both the volar and dorsal aspects of the forearm.
increased (Fig. 4) while infective stains for fungal and mycobacterial organisms were negative. Direct immunofluorescence was also negative for IgM, IgG, IgA, and C3. The clinical and histological findings were consistent with NL with actinic elastolytic damage. The patient was treated with topical mometasone furoate 0.1% cream twice daily with improvement.
DISCUSSION Our case highlights the diagnostic challenges that one may face when the lesions of NL occur on an unusual site and when there is concomitant presence of elastophagocytosis. The typical location of NL is the pretibial region; its presentation at other anatomical sites is much less common.3 Features inconsistent with the diagnoses of cellulitis and contact dermatitis, which were originally considered in our patient, include the sharp demarcation of the indurated
plaques, as well as the erythematous and yellowish color of the plaques. AG may be included as a possible diagnosis for our patient because the lesions are often localized to the sunexposed areas of the body, and elastolytic granulomas with elastophagocytosis are the features seen. However, plaques of AG tend to be smaller and show significant central atrophy and hypopigmentation, neither of which were observed in our patient. Furthermore, the elastophagocytosis noted in this case is not prominent and confined to a few giant cells in the superficial dermis. Finally, the presence of palisading granulomas with necrobiosis supports NL rather than AG. Cases previously reported as atypical NL or Miescher granuloma of the face, occurring on the face and neck, might be entities similar to our case of NL with actinic damage.11 Necrobiotic xanthogranuloma, which presents as erythematous violaceous plaques and nodules mostly involving the periorbital region, may be considered as another possible differential diagnosis. The histological hallmark of foamy histiocytes, cholesterol clefts, and Touton giant cells is, however, absent in our case and thus makes this diagnosis unlikely.12 Finally, granuloma annulare, a common cause of necrobiotic palisading granulomas, was excluded on the basis of inconsistent clinical morphology and lack of mucinous deposits in the histology. The therapy of NL remains challenging. First-line treatment involves the use of topical, intralesional, or systemic corticosteroids.13 An alternative strategy is directed at increasing fibrinolysis or decreasing platelet aggregation and thromboxane A 2 synthesis to decrease microangiopathy and vascular thrombosis.14–16 Other therapeutic options include niacinamide, antimalarials, tumor necrosis factor–a inhibitors (etanercept, infliximab), cyclosporine, mycophenolate mofetil, thalidomide, and phototherapy with either topical PUVA or UVA1. 17,18 Finally, surgery might be necessary for lesions with severe ulcerations that are refractory to medical treatment.19,20
FIGURE 2. A, Histology shows extensive palisaded necrobiotic granulomas at all levels of the dermis, orientated parallel to the surface (hematoxylin and eosin, original magnification ·40). B, The granulomas show a central zone of collagen and elastin degeneration with a surrounding infiltrate of histiocytes and Langhans giant cells (hematoxylin and eosin, original magnification ·100). C, High power view of a Langhans-type giant cell, which appears to contain elastic fibers (hematoxylin and eosin, original magnification ·400).
742
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 9, September 2014
Necrobiosis Lipoidica With Elastophagocytosis
can be challenging, and careful clinicopathological correlation is needed. REFERENCES
FIGURE 3. Elastic fibers are present within the areas of necrobiosis but not in the granulomatous infiltrate itself (Verhoeff Van Gieson stain).
FIGURE 4. Mucinous deposits are not detected within the granulomatous infiltrates (Alcian blue stain).
CONCLUSIONS We present an unusual case of NL localized to the forearms with elastophagocytosis as the histological feature of actinic damage. Distinction between other similar entities
2014 Lippincott Williams & Wilkins
1. Quimby SR, Muller SA, Schroeter AL. The cutaneous immunopathology of necrobiosis lipoidica diabeticorum. Arch Dermatol. 1988;124: 1364–1371. 2. Boateng B, Hiller D, Albrecht HP, et al. Kutane Mikrozirkulation bei prätibialer Nekrobiosis lipoidica. Vergleichende Laser-Doppler Fluxmetrie und Sauerstoffpartialdruckmessungen bei Patienten und Hautgesunden. Hautarzt. 1993;44:581–586. 3. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991; 25:735–748. 4. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol. 1966;93:272–281. 5. Peyrí J, Moreno A, Marcoval J. Necrobiosis lipoidica. Semin Cutan Med Surg. 2007;26:87–89. 6. Kavanagh GM, Novelli M, Hartog M, et al. Necrobiosis lipoidica— involvement of atypical sites. Clin Exp Dermatol. 1993;18:543–544. 7. McGrae JD Jr. Actinic granuloma. A clinical, histopathologic, and immunocytochemical study. Arch Dermatol. 1986;122:43–47. 8. Limas C. The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis. Histopathology. 2004;44:277–282. 9. O’Brien JP. Actinic granuloma. An annular connective tissue disorder affecting sun- and heat-damaged (elastotic) skin. Arch Dermatol. 1975; 111:460–466. 10. Ragaz A, Ackerman AB. Is actinic granuloma a specific condition? Am J Dermatopathol. 1979;1:43–50. 11. Weedon D. The granulomatous reaction pattern. In: Weedon’s Skin Pathology. 3rd ed. Edinburgh, United Kingdom: Churchill Livingstone; 2010:190. 12. Spicknall KE, Mehregan DA. Necrobiotic xanthogranuloma. Int J Dermatol. 2009;48:1–10. 13. Erfurt-Berge C, Seitz AT, Rehse C, et al. Update on clinical and laboratory features in necrobiosis lipoidica: a retrospective multicentre study of 52 patients. Eur J Dermatol. 2012;22:770–775. 14. Beck H, Bjerring P, Rasmussen I, et al. Treatment of necrobiosis lipoidica with low-dose acetylsalicylic acid. Acta Derm Venereol. 1985;65: 230–234. 15. Statham B, Finlay AY, Marks R. A randomized double blind comparison of an aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica. Acta Derm Venereol. 1981;61:270–271. 16. Wilkin JK. Perilesional heparin injections for necrobiosis lipoidica. J Am Acad Dermatol. 1983;8:904. 17. Reid SD, Ladizinski B, Lee K, et al. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol. 2013;69:783–791. 18. Beattie PE, Dawe RS, Ibbotson SH, et al. UVA1 phototherapy for treatment of necrobiosis lipoidica. Clin Exp Dermatol. 2006;31:235–238. 19. Brauns B, Schön MP, Zutt M. Ulcerative necrobiosis lipoidica successfully treated by vacuum-assisted closure therapy. Eur J Dermatol. 2011; 21:791–792. 20. Elmholdt TR, Sørensen HB, Fogh K. A severe case of ulcerating necrobiosis lipoidica. Acta Derm Venereol. 2008;88:177–178.
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![[Necrobiosis lipoidica].](/assets/img/hold.png)
