A woman with diabetes and a sore on her leg

Necrobiosis lipoidica (NL) is an indolent, chronic, granulomatous, cutaneous disorder. Although it is most commonly seen in those with insulin-dependent diabetes mellitus, it has also been described in patients with other conditions, such as sarcoidosis, inflammatory bowel disease, and rheumatoid...

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Necrobiosis lipoidica (NL) is an indolent, chronic, granulomatous, cutaneous disorder. Although it is most commonly seen in those with insulin-dependent diabetes mellitus, it has also been described in patients with other conditions, such as sarcoidosis, inflammatory bowel disease, and rheumatoid arthritis, and also in otherwise healthy individuals.¹ It has a strong predominance in women, with a 3:1 ratio of women to men. 

The condition is rare, even in individuals with type 1 diabetes, in whom incidence ranges from 0.3% to 1.2%.^1,2 Development of NL precedes the diagnosis of diabetes mellitus in approximately 14% of patients and is found simultaneously in 24%, but more commonly develops well after the diagnosis of diabetes mellitus has been established, accounting for 62% of cases.³ 

Typically, NL lesions begin as painless, small, red-brown papules on the shins, unilaterally or bilaterally, which enlarge over time, evolving into one or more variably sized plaques.⁴ Although the shins are most commonly affected, lesions may occur anywhere, especially on the arms, back, and (peculiarly) within the periorbital areas.⁴ The increased incidence on the shins may be a result of the Koebner phenomenon¹—induction of skin lesions following minor trauma. Eventually the color of the plaques evolves to a yellow-brown, although active lesions maintain a persistently violaceous rim. As a result of collagen degeneration, the central areas of the plaques are often atrophic and appear waxy; telangiectasia can be visible through the atrophic dermis. Approximately 30% of patients will develop ulcers, most frequently as a result of localized trauma. Although NL itself is usually asymptomatic, ulcerative NL may be painful and very difficult to manage. In rare cases, an area within a plaque of NL may degenerate into a squamous cell carcinoma.⁵ 

The diagnosis of NL can typically be made by clinical inspection alone. If necessary, a biopsy will confirm the diagnosis; however, NL is poor to heal, and a biopsy should only be done if the diagnosis is in question. Histologic changes of NL consist of palisading granulomas, aligned parallel to the skin surface and extending deep into the subcutaneous tissue. Degeneration of collagen fibers (necrobiosis) is noted within the granulomas. A diffuse perivascular infiltrate is often present, consisting mostly of lymphocytes and plasma cells, although eosinophils may also be present.⁴ 

The pathogenesis of NL remains unknown. Although, there are several theories, each has both supportive and contradictory data. Some investigators propose NL to be a result of the same microangiopathic changes that cause diabetic nephropathy and retinopathy. However, a large retrospective study found no correlation between nephropathy, retinopathy, and the development of NL; although those who developed NL did have a higher glycated hemoglobin level (8.7% vs 8.3%; P = .0065).2 Celiac disease has been found to be more prevalent among individuals with type 1 diabetes and with NL than in those without (1% vs 3.4%; P = .0035), which lends credence to the theory that the pathogenesis could be an autoimmune phenomenon.² Further supporting an immune mechanism is the finding of immune complexes in the vascular walls of vessels in the deep dermis of lesions of NL. However, it is debated whether these immune complexes cause the collagen degeneration or occur as a result of the collagen degeneration.^3,4 Thus far, the pathogenesis is speculative at best. 

The differential diagnosis of NL includes conditions such as granuloma annulare (GA), sarcoidosis, necrobiotic xanthogranuloma (NXG), and diabetic dermopathy. Although the clinical appearance of a GA lesion may be somewhat similar, the distribution is not; GA is more common over joints, especially on the hands and elbows, but lesions may be found over ankles as well. Sarcoidosis is the great imitator, but its lesions usually do not have telangiectasias, which are classically seen in NL. NXG is a rare, chronic granulomatous disorder with predilection for the periorbital area; however, the yellowish hew of lesions is more suggestive of a xanthomatous process. Although diabetic dermopathy is atrophic and present on the shins, it is usually hyperpigmented and lacks telangiectasia.⁴ 

If the diagnosis is still in doubt, histologic findings on biopsy will differentiate these various conditions. A biopsy of GA will uniquely demonstrate mucin deposition within the granulomas.^4,6 Sarcoidosis lacks the necrobiosis seen in GA, NL, and NXG. Histology of NXG reveals cholesterol clefts, which are absent in the other conditions, and no granulomas or necrobiosis are seen histologically with diabetic dermopathy. 

Given the rarity of NL, there are no randomized controlled trials to determine the optimal therapy. Only case reports and case series exist to support the various treatment regimens, which include lifestyle modifications to minimize trauma, optimizing glucose control, and several medications. Corticosteroids, administered topically or intralesionally, are the most common initial medicinal intervention. However, care should be taken to minimize the risk of further atrophy. Topical tretinoin may be a good alternative, as it promotes collagen formation and angiogenesis.^1,7 Intravenous immunoglobulin, topical immune modulators, and systemic methylprednisone have shown some efficacy for recalcitrant, ulcerative NL. Unfortunately, recurrence is common when these agents are discontinued, and retreatment often yields disappointing results.⁷ 

Psoralen with ultraviolet A phototherapy reduces inflammation at the dermal-subepidermal junction, which may improve the granulomatous inflammation of NL but has no effect on atrophic areas.^2,7 Systemic immune modulators, such as methotrexate, mycophenolate mofetil, and cyclosporine, have anecdotally improved NL; however, numerous side effects can occur with these medications and, despite treatment success, recurrence rates are disappointingly high upon cessation of treatment.^1,2,7 If a squamous cell carcinoma develops, surgical removal is indicated; however, this may be complicated by Koebnerization of NL, or by causing ulcerative NL; at times, a split thickness skin graft may be beneficial.^1,5 

In our case, the diagnosis was made on the classic clinical findings: bilateral plaques on the anterior shins of an individual with type 1 diabetes and an ulcer following minimal trauma. The ulcer was treated with intralesional triamcinolone acetate and a 5-week taper of prednisone; wound care consisted of petroleum-impregnated gauze and a light pressure dressing. Her fluctuating blood sugar levels, associated with the steroid taper, were managed by her primary care provider. This treatment regimen managed to heal the ulcer but had little effect on the established plaque of NL. She was educated about the risk associated with minimal trauma and the high recurrence rate of the ulcer. 

Merrick D. Kozak, BA, is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.

References

1. 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.
2. Hammer E, Lilienthal E, Hofer SE, et al. Risk factors for necrobiosis lipoidica in type 1 diabetes mellitus. Diabet Med. 2016 Apr 21. doi: 10.1111/dme.13138. [Epub ahead of print]
3. Sibbald C, Reid S, Alavi A. Necrobiosis lipoidica. Dermatol Clin. 2015;33:343-360.
4. Reisenauer A, White KP, Korcheva V, White CR. Non-infectious granulomas. In: Bolognia J, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:93-94.
5. Lim C, Tschuchnigg M, Lim J. Squamous cell carcinoma arising in an area of long-standing necrobiosis lipoidica. J Cutan Pathol. 2006;33:581-583.
6. Rupley KA, Riahi RR, Hooper DO. Granuloma annulare and necrobiosis lipoidica with sequential occurrence in a patient: report and review of literature. Dermatol Pract Concept. 2015;5:29-34.
7. Feily A, Mehraban S. Treatment modalities of necrobiosis lipoidica: a concise systematic review. Dermatol Reports. 2015;7:5749.