June 2005

3.

4.

5.

Diagnosis:
Necrobiosis Lipoidica Located on the Face

Histopathology:
Two 4 mm punch biopsies where taken from both the superior and inferior aspects of the right temple. The histopathology from both specimens were virtually the same. Figure 3 demonstrates the lesion at lower power. There is a transdermal inflammatory infiltrate, with patchy areas of acellular necrosis (collagenolysis). Figure 4 demonstrates a central area of collagenolysis with a palisaded, granulomatous infiltrate with multinucleated giant cells. Figure 5 shows even higher magnification, further emphasizing the presence of collagenolysis, palisaded granulomas with giant cells, and the presence of plasma cells.

Therapeutic and Clinical Course:
Initially, she used Elidel cream, which was given to her by an outside dermatologist. Although she had some flattening of the lesion, there was not much change noted overall. Surgical excision was considered. However, given the large size and location, this option was not pursued. First-line therapies for necrobiosis lipoidica have included potent topical steroids for early lesions and intralesional corticosteroids into the active borders of older lesions. However, given the significant atrophy already present, as well as the facial location, it was felt caution should be used in chronically using potent topical and intralesional steroids, which were also not felt to be efficacious in past experiences. The literature has published several case reports on potentially successful treatments for necrobiosis lipoidica, including the use of systemic steroids (1), nictotinamide (2), pentoxifylline (3), ticlopidine (4), aspirin, dipyridamole (5), tretinoin (6), chloroquine (7), perilesional heparin (8), cyclosporine (9), mycophenolate mofetil (10), PUVA (11), tacrolimus (12), and infliximab (13). Despite the arsenal of case reports on various successful treatment modalities, none has been uniformly effective. Given our past experience with Thalidomide as an effective means for the treatment of lower extremity necrobiosis lipoidica, as well as the knowledge that the patient was peri-menopausal and her husband had a vasectomy, Thalidomide usage was discussed with the patient. After enrollment in the STEPS program and obtaining a normal baseline EMG and nerve conduction study of bilateral lower extremities, Thalidomide was initiated at 50 mg each night. In order to reduce the potential risk of thrombosis associated with the usage of Thalidomide, especially given the concurrent use of Prempro and her history of tobacco use, aspirin 81 mg daily was also prescribed. The Elidel cream was continued twice daily. Smoking cessation was encouraged.

Discussion:
Necrobiosis lipoidica (NL) is a chronic disorder of collagen degeneration and focal loss of elastic tissue, in which a diffusely palisaded, interstitial, granulomatous, and inflammatory infiltration, along with thickening of blood vessels occurs. More common in females, with a female to male ratio of 3:1, the lesions clinically begin as small red-brown papules, which slowly enlarge into the classically appearing yellow-brown plaques with central telangiectasias, surrounded by elevated, erythematous-violaceous rims. Ultimately, the lesions become atrophic, and painful ulcerations are seen in 35%.

The most common location for the lesions is the pretibial region (14). Although reported in the literature (15), facial NL is extremely rare. Other less common locations include the upper extremities, scalp, and genitalia (16). Rarely, squamous cell carcinoma has been reported to arise in long-standing lesions of NL (17).

Although it has been associated with type-1 more than type-2 diabetes mellitus (14), only 11% of patients with necrobiosis lipoidica, in a recent retrospective study, had diabetes mellitus at the time of presentation. This patient had no history of diabetes mellitus. Moreover, only 0.03% of patients with diabetes have NL (17). Therefore, it has been accepted to drop the "diabeticorum" from the name of the disease.

In NL one histologically sees multinucleated epitheliod histiocytes, which are arranged in a palisaded manner throughout the dermis and into the subcutaneous fat. A superficial and deep perivascular infiltrate composed primarily of lymphocytes, plasma cells (as seen in this patient), and eosinophils is also present. Connective tissue degeneration (necrobiosis) is prominent. In between the inflammatory cells, degenerated collagen and extracellular lipid deposition is apparent. Although NL and GA can look similar, there is no mucin deposition seen in NL. Unlike in sarcoidosis, there are no asteroid bodies present in NL. Endothelial cell enlargement, fibrosis, and hyalinization also are found, which eventually lead to blood vessel wall thickening and even obliteration (14).

Oikarinen et al. demonstrated histologically that large areas of skin in lesions from 10 patients with NL were devoid of normal appearing collagen and elastin. They also demonstrated a reduction in the fibroblastic ability to synthesize collagen (17). Although the pathogenesis has not yet been elucidated, immunologically mediated vascular disease has been proposed as the main inciting event leading to the degradation of both collagen and elastin. Immunoreactants including IgM, IgG, IgA, and C3 have been found deposited in the blood vessel walls of both involved and uninvolved skin of those with NL (18). Multiple other theories have been proposed including increased platelet adhesion, increased thomboxane-2 production, and increased blood viscosity as pathogenic mechanisms (14). Ultimately, it is felt that both inflammatory mediators and the inflammatory cascade play a central role.

As aforementioned, there have been multiple attempted treatment modalities for NL, without any one demonstrating significant efficacy. Thalidomide has been used off-label for many inflammatory conditions. Our past experience with Thalidomide in lower extremity NL has demonstrated not only significant resolution of NL ulcerations, but also significant improvement in the clinical and histological appearance of these lesions. The proposed mechanism in the success of Thalidomide for NL is not known. However, we propose that its efficacy is likely secondary to its anti-inflammatory and anti-angiogenic properties. The most important risk associated with Thalidomide usage in women of childbearing potential is that of the teratogenic effects on a fetus-especially with respect to limb development. It may also result in thrombosis and sedation.

This patient has only been taking Thalidomide for a little over a month. Although it is too soon to determine whether it will be efficacious in reducing the size and appearance of this large NL plaque, based on our previous experience with it, we are optimistic it will be successful in this case, as well.

References:
1) Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticosteroids. Br J Dermatol. 1992; 126(6): 542-545.
2) Handfield-Jones S, Jones S, Peachey R. High dose nicotinamide in the treatment of necrobiosis lipoidica. Br J Dermatol. 1988; 118(5): 693-696.
3) Littler CM, Tschen EH. Pentoxifylline fot necrobiosis lipoidica diabeticorum. J Am Acad Dermatol. 1987; 17(2 pt1): 314-316.
4) Rhodes EL. Necrobiosis lipoidica treated with ticlopidine. Acta Derm Venereol. 1986; 66(5): 458.
5) Finlay SB, Marks R. A randomized double blind comparison of aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica. Acta Derm Venereol. 1981; 61(3): 270-271.
6) Boyd AS. Tretinoin treatment of necrobiosis lipoidica diabeticorum. Diabetes Care. 1999; 22(10): 1753-1754.
7) Nguyen K, Washenik K, Shupack J. Necrobiosis lipoidica diabeticorum with choloroquine. J Am Acad Dermatol. 2002; 46(2Suppl): S34-36.
8) Wilkin JK. Perilesional heparin injections for necrobiosis lipoidica. J Am Acad Dermatol. 1983; 8(6): 904.
9) Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporin. Australas J Dermatol. 2004; 45(2): 119-122.
10) Reinhard G, Lobmann F, Uerlich M, Bauer R, Bieber T. Successful treatment of ulcerated necrobiosis lipoidica with mycophenolate mofetil. Acta Derm Venereol. 2000; 80(4): 312-313.
11) De Rie MA, Sommer A, Hoekzema R, Neumann HA. Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A. Br J Dermatol. 2002; 147(4): 743-747.
12) Clayton TH, Harrison PV. Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus ointment. Br J Dermatol. 2005; 152 (3): 581-582.
13) Kolde G, Muche JM, Schulze P, Fischer P, Lichey J. Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology. 2003; 206(2): 180-181.
14) Bolognia JL, et al. Dermatology. Mosby: Edinburgh. 2003.
15) Jones EW. Necrobiosis lipoidica presenting on the face and scalp. An account of 29 patients and a detailed consideration of recent histochemical findings. Trans St John Hosp Dermatol Soc. 1971; 57(1): 202-220.
16) Tokura Y, Mizushima Y, Hata M, Takigawa M. Necrobiosis lipoidica of the glans penis. J Am Acad Dermatol. 2003; 49 (5): 921-924.
17) Santos-Juanes J., et al. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica, J Eur Acad Dermatol Venereol. 2004; 18(2): 199-200.
18) O'Toole EA, et al. Necrobiosis lipoidica: only a minority of patients have diabetes mellitus. Br J Dermatol. 1999; 140: 283-286.
19) Oikarinen A, et al. Necrobiosis lipoidica: ultrastructural and biochemical demonstration of a collagen defect. J Invest Dermatol. 1987; 88: 227-232.
20) Quimby SR, et al. The cutaneous immunopathology of necrobiosis lipoidica diabeticorum. Arch Dermatol. 1988; 124: 1364.

This case was presented by Drs. Maria J. Canizares, Jeffrey E. Petersen, and Daniel J. Santa-Cruz.