Necrobiosis lipoidica
Salient features
·
Plaques with violaceous to red–brown, palpable peripheral rims
and yellow–brown atrophic centers with telangiectasias
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The most common site is the shins
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Ulceration can occur following trauma
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The proportion of patients with diabetes mellitus varies from
15% to 65%
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Pathogenesis is unknown
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Pathology shows a palisading granulomatous dermatitis with
histiocytes and altered collagen that has a “layered” appearance and is often
accompanied by perivascular plasma cells
Introduction
Necrobiosis lipoidica,
originally known as necrobiosis lipoidica diabeticorum, is a disorder of
collagen degeneration with a granulomatous response and thickening of blood
vessels. Diabetes mellitus is present in
more than half the patients with necrobiosis lipoidica.
Necrobiosis lipoidica is a
distinctive skin disorder characterized clinically by well‐demarcated waxy red‐brown
indurated plaques with an atrophic yellow center, most commonly located on the
shins and may ulcerate, causing considerable pain, and histologically by full‐thickness dermal lymphohistiocytic perivascular infiltration
with extensive necrobiosis of collagen.
It is associated with diabetes (both type 1 and type 2) and
glucose intolerance.
Epidemiology
Incidence
and prevalence
Necrobiosis lipoidica is relatively uncommon.
Age
Necrobiosis lipoidica may occur at any age. When associated
with type 1 diabetes, it is seen at a younger age (third decade) than in type 2
or those without diabetes (fourth decade).
Sex
The female to male ratio is 3: 1.
There is no doubt that necrobiosis lipoidica is associated
with diabetes, although only about 1% of diabetics develop it and about two‐thirds patients with
necrobiosis lipoidica develop diabetes. One-third of patients have clinical diabetes,
one third has abnormal glucose tolerance only, and one-third have normal
glucose tolerance. The seventy of NL is not related to the severity of diabetes.
There is some evidence that diabetic patients who have
necrobiosis lipoidica are at higher risk of retinopathy and nephropathy than
diabetics who do not.
Pathophysiology
The precise pathogenesis of necrobiosis lipoidica remains
unknown. There is no HLA linkage. Immune complex vasculitis has been suggested
as the primary cause of the altered collagen seen in NLD, and this hypothesis
is supported by the presence of immunoreactants, principally IgM, C3 and
fibrin, deposited in vessel walls of lesional as well as uninvolved skin in
patients with NLD. It is has also been postulated that the microangiopathic
vessel changes seen in diabetic patients could contribute to the development of
collagen degeneration and subsequent dermal inflammation.
When
lesions favor the lower extremities of adults, venous hypertension as a
contributing factor needs to be considered. Both venous insufficiency and
hyperlipidemia have been proposed as triggers that incite an inflammatory
cascade in some patients. Elevated plasma levels of fibronectin, factor
VIII-related antigen, and α2-macroglobulin have been detected in patients with
NL, but the significance of these findings has not been determined. Theories
regarding abnormally elevated platelet adhesion, increased thromboxane A2 production, and increased blood viscosity
within NL lesions remain speculative.
Pathology
Biopsy specimens,
particularly from the palpable inflammatory border, reveal a diffuse palisaded
and interstitial granulomatous dermatitis, with “layered” tiers of
granulomatous inflammation aligned parallel to the skin surface involving the
entire dermis and extending into the subcutaneous fat septae. The epidermis is
normal or atrophic and absent if there is ulceration. Areas
of necrobiosis are usually more extensive and less well defined than in
granuloma annulare. There is degeneration of collagen and elastin within the
lesions. Histiocytes border the areas of necrobiosis. There are variable
numbers of langhans or foreign‐body giant cells. Extracellular
lipid deposition can be demonstrated via oil red O-stained frozen tissue
sections. There
is a associated superficial and deep perivascular infiltrate that is
predominantly lymphocytic but often contains plasma cells and occasionally
eosinophils, in contrast with granuloma annulare. Between the layers
of inflammatory cells, there are horizontal tiers of degenerated collagen. In
contrast to GA, there is no significant mucin deposition in the center of the
palisading granulomas.
Small superficial blood vessels are increased in number and
are telangiectatic. Deeper dermal blood vessels often show thickening of their
walls and proliferation of endothelial cells, fibrosis and
hyalinization; the latter can lead to blood vessel wall thickening or even
endarteritis obliterans. The vessel walls often contain a PAS-positive,
diastase-resistant material suggesting neutral glycosaminoglycans. Histologically, comedo‐like
plugs at the periphery of lesions represent the elimination of necrotic
material through hair follicles. Anesthesia in the lesions appears to be
related to a decreased number of nerves within them. In old atrophic lesions
there is considerable fibrosis in the dermis and subcutis.
Clinical
features
Typical lesions occur on the pretibial skin, and begin as a
firm, red- brown or
skin-colored papule that enlarges radially to
become a
well-demarcated waxy plaque of variable size. The sharply defined and slightly
elevated palpable indurated border
retains a brownish-red color, whereas the center becomes depressed with atrophic changes of epidermal thinning and acquires
a yellow-orange hue. Larger lesions are formed by centrifugal enlargement or
merging of smaller lesions acquiring a serpiginous or polycyclic configuration.
The surface is often glazed in
appearance and telangiectatic vessels may be seen through thin atrophic
epidermis. Hypohidrosis and hypoesthesia or anesthesia may develop. Comedo‐like plugs may occur at the periphery of lesions. The plaques are
usually one to three; >80% occur on the shin; at times symmetric, and they are similar in appearance whether occurring in
diabetic or non‐diabetic individuals. They tend to be persistent and ulceration occurs in
approximately a third of lesions, usually following minor trauma, ulceration correlated with sensory impairment. Healed ulcers result
in depressed scars. Development of lesions secondary
to Koebner phenomenon has also been reported. Less typical anatomic locations
for NL include the arm, face and scalp, where the lesions may be more annular
or serpiginous in configuration and are often less atrophic.
Decreased
sensation to pinprick and fine touch, hypohidrosis, and partial alopecia can be
observed within NL plaques. Decreased S100 staining within the cutaneous nerves
of inflammatory plaques has been described, with degenerative neural changes
possibly accounting for the loss of sensation. Of note, the cutaneous nerves in
GA demonstrate normal S100 staining patterns. Although the lesions of NL are
typically asymptomatic, some patients report pruritus, dysesthesia, or pain.
Lesions that ulcerate after trauma or from transepidermal elimination of
altered collagen and elastic fibers can be very painful. Rarely, squamous cell
carcinoma has been reported to develop within lesions of NL. By dermoscopy,
comma-shaped vessels and an irregular pattern of arborizing vessels are
observed in early and more advanced lesions, respectively; whitish areas
correspond to degenerated collagen and yellow to orange patches to
granulomatous inflammation.
Differential
diagnosis
The major entity in
the histopathologic differential diagnosis for NL is GA. Whereas the inflammation in NL is diffuse and
involves the entire dermis extending into subcutaneous fat septae, GA is patchy
with discrete foci of granulomatous inflammation amid areas of uninvolved
dermis. There is usually deposition of mucin within areas of granulomatous inflammation
in GA but not in NL. In general, NL has more giant cells, plasma cells,
vascular changes, collagen degeneration, and extracellular lipid deposition
than GA.
Lesions of GA and
sarcoidosis generally do not exhibit the same degree of atrophy, telangiectasias
or yellow–brown color as NL lesions, although prominent telangiectasias can be
present in angiolupoid sarcoidosis and can occur following injections of
triamcinolone. However, there are reports of NL and sarcoidosis coexisting in
the same patient.
Disease
course and prognosis
Slow extension over many years is usual, but long periods of
quiescence or resolution with variable atrophy and scarring may occur- ‘Burnt
out’ necrobiosis lipoidica. Burned-out lesions are tan with telangiectasia.
Investigations
Skin biopsy is not usually necessary except in atypical
cases. Annual screening for diabetes is recommended.
Treatment
No treatment for NL
has proven to be effective. In patients with diabetes mellitus, control of
blood glucose levels usually does not have a significant effect on the course
of NL. Spontaneous remission after an average of 8 to 12 years was observed in
only 17% of patients with NL in one study.
First-line therapy includes
potent topical corticosteroids (including under
occlusion) for early lesions and intralesional corticosteroids injected
into the active borders of established lesions. Because the histologic changes
can extend well into normal-appearing skin in clinically active NL lesions,
some authors advocate the injection of intradermal corticosteroids into a rim
of clinically normal skin around expanding plaques in an effort to halt disease
progression. Topical tacrolimus 0.1% ointment led to improvement
of NL in uncontrolled case series.
In
addition to avoidance of trauma and local care of ulcers, therapies directed at
increasing fibrinolysis, decreasing platelet aggregation, and/or decreasing
thromboxane A2 synthesis have been
employed in order to decrease the microangiopathy and vascular thrombosis.
Pentoxifylline, stanozolol, inositol niacinate (inositol nicotinate),
nicofuranose, and ticlopidine hydrochloride are all agents that have been tried
in anecdotal reports or uncontrolled case series.
Based
upon case series of patients, several systemic anti-inflammatory medications
have been described as beneficial – antimalarials, niacinamide (500 mg TID),
mycophenolate mofetil (500 mg BID), doxycycline, colchicine, methotrexate, TNF-α inhibitors (recalcitrant ulcerated lesions), and
cyclosporine (severe ulcerations). In addition, 5-week courses of systemic
corticosteroids were found to be effective in a series of six patients with an
average follow-up period of 7 months, but this can be associated with side
effects such as elevation of serum glucose levels.
Multiple
prospective, uncontrolled studies have demonstrated improvement in ~50% of
patients with topical PUVA therapy. Lastly, there are case reports of
beneficial effects from UVA1 phototherapy, fractional CO2 laser, or photodynamic therapy.
Pulsed dye laser has been employed and may improve the
telangiectatic and erythematous components but skin breakdown can occur.
Surgical
therapy may be necessary in patients with severe, refractory ulcerations.
Excision to deep fascia or periosteum must be performed to minimize the chance
of recurrence. Split-thickness skin grafting is performed following excision.
Therapeutic ladder
First line
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No treatment
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Topical steroids
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Intralesional steroids
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Topical tacrolimus
Second line
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PUVA (topical)
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UVA1
Third line
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Multiple therapies of uncertain
value
