Growing, dyspigmented lesions

Case #1: Necrobiosis lipoidicaNecrobiosis lipoidica (NL) is a rare granulomatous skin disease historically associated with diabetes mellitus. Although originally named necrobiosis lipoidica diabeticorum by Urbach in 1932, necrobiosis lipoidica more accurately reflects the nature of the disease as it may...

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Case #1: Necrobiosis lipoidica

Necrobiosis lipoidica (NL) is a rare granulomatous skin disease historically associated with diabetes mellitus. Although originally named necrobiosis lipoidica diabeticorum by Urbach in 1932, necrobiosis lipoidica more accurately reflects the nature of the disease as it may occur independently of diabetes mellitus.^1,2

While historically associated with diabetes mellitus, the incidence of necrobiosis lipoidica among diabetic patients is reported as 0.3%, and the prevalence of diabetes mellitus among patients with NL ranges from 11% to 65%, according to various studies.^3,4 NL tends to occur more frequently in women than in men.³ Although NL can occur at any age, the average age of onset of necrobiosis lipoidica in diabetic patients is 30 compared with 41 for non-diabetic patients.³

There are many theories on the pathogenesis of necrobiosis lipoidica, but the exact underlying etiology remains unclear. The most popular theory proposes that glycoprotein deposition in the vasculature produces secondary microangiopathy and the formation of the characteristic skin findings. Alternative studies suggest that the skin findings are secondary to tissue hypoxia, although this is less widely accepted.⁵ Other theories include the deposition of immunoglobulins in blood vessels, abnormal collagen crosslinking, and neutrophil migration and macrophage proliferation caused by trauma, inflammation, or metabolic changes.⁶

Because the literature on necrobiosis lipoidica primarily consists of case reports of small patient sample sizes, risk factors for developing the condition are not well defined and are subject to debate. While the relationship between necrobiosis lipoidica and diabetes mellitus remains controversial, diabetes mellitus has been found to be the most prevalent comorbidity of necrobiosis lipoidica. Other potential risk factors include hypertension, obesity, and dyslipidemia.⁷ Among diabetics, there is evidence that higher HbA1_c levels, longer diabetes duration, and a higher daily insulin requirement correlate with necrobiosis lipoidica.⁸

Necrobiosis lipoidica usually presents as a single papule to few erythematous papules with an enlarging, active border. It is most commonly found on extensor surfaces of the lower extremities; however, it can also affect the face, scalp, trunk, groin, and upper extremity.^3,5 Early lesions initially have a brownish-red center that later progresses to more yellowish-brown in color with an atrophic and waxy center.^5,7,9 Eventually, the lesions slowly develop into irregular, well-demarcated violaceous plaques with overlying telangiectasias, which is thought to result from collagen degeneration.^5,10 Most lesions are asymptomatic, but as many as 30% of patients may experience exquisite pain if the lesions become ulcerated.⁷ In rare cases, squamous cell carcinoma may develop in older, ulcerated lesions.^5,7,10

A diagnosis of necrobiosis lipoidica can usually be made clinically, but a biopsy may be performed in case of equivocal findings and to rule out squamous cell carcinoma.^7,8 Histologically, NL has two characteristic patterns: palisading and pseudotuberculoid, and lesions may contain features of both patterns.^11,12 Palisading granulomatous lesions are characterized by linear tiers of hyalinized and necrobiotic collagen aggregates in the lower dermis surrounded by a rim of inflammatory cells and occur more frequently in diabetic patients.² The pseudotuberculoid pattern consists principally of epithelioid histiocytes with an increased number of lymphocytes, plasma cells, and giant cells. In contrast to the palisading pattern, necrobiotic collagen is not usually present, although some collagen may be hyalinized and occurs more frequently in nondiabetic or pre-diabetic patients.¹¹

The differential diagnosis of necrobiosis lipoidica includes erythema dyschromicum perstans, granuloma annulare (GA), necrobiotic xanthogranuloma, rheumatoid nodules, and sarcoidosis. Although early forms of each disease may be nearly indistinguishable, granuloma annulare can be distinguished by its failure to develop the epidermal atrophy and characteristic yellow color of necrobiosis lipoidica.¹ Necrobiotic xanogranuloma can be distinguished from necrobiosis lipoidica clinically because of its association with paraproteinemia and histologically by the presence of cholesterol clefts.^1,13 Rheumatoid nodules present in the context of severe arthritis and tend to arise near joints, especially the elbow, while necrobiosis lipoidica lesions tend to arise on the shins.^11,14 Sarcoidosis typically involves other organ systems and does not demonstrate the necrobiosis, hyalinization, and lipid depositions that are distinctive of necrobiosis lipoidica.^1,6

Necrobiosis lipoidica can be difficult to treat, and there are no large randomized placebo-controlled studies that dictate a specific treatment regimen. The most commonly used treatment includes topical, intralesional, and systemic corticosteroids to reduce inflammation and halt disease progression.^5,14 Steroid use, however, may cause glucose dysregulation in diabetic patients, so it is recommended to avoid their long-term use and use mostly at the lesion’s active borders.⁵

The effect of glucose control on necrobiosis lipoidica remains unclear.¹⁴ A combination of aspirin and dipyridamole to inhibit platelet aggregation has been proposed to treat necrobiosis lipoidica, although its efficacy has not yet been established.² Pentoxifylline, tretinoin, mycophenolate, mofetil, cyclosporine A, thalidomide, and topical tacrolimus have been reported as effective treatment modalities; however, further research is needed on their safety and efficacy. Antimalarial and immunosuppressive therapies such as methotrexate have also been proposed as treatment options.¹⁴ Various forms of phototherapy have been shown to be successful and may be used as a second-line treatment.⁹ Trauma should be avoided to reduce the risk of ulcer formation.^2,5

The patient in this vignette was biopsied and diagnosed with NL. She was started on topical clobetasol 0.05% ointment and told to apply it to the active borders of her lesions. She noticed a significant slowing in the rate of growth of her lesions.

Case #2: Erythema dyschromicum perstans

Erythema dyschromicum perstans (EDP) is an asymptomatic, uncommon dermatosis characterized by a persistent ashy-gray discoloration of the skin.^15-17 The condition is commonly referred to as “ashy dermatosis” and was first described by Ramirez in 1957.¹⁸

Erythema dyschromicum perstans is more prevalent in Latin American populations, although it has been reported in patients from a variety of ethnic backgrounds.^16,19 There is no clearly established sexual predilection.^16,20 EDP more commonly presents in adulthood but may also be found in children and adolescents. One study found that although adults with erythema dyschromicum perstans are usually of Hispanic origin, children with EDP tend to be Caucasian.¹⁶

The etiology of erythema dyschromicum perstans is unknown. It has been associated with ingestion of ammonium nitrate, exposure to environmental contaminants, treatment of a parasitic infestation, HIV infection, atopy, hypothyroidism, and chronic hepatitis C.^16,17,21,22 It is thought to be caused by an abnormal immune response to antigens—particularly through the expression of cell adhesion and activation molecules that downstream damage melanocytes and keratinocytes in the basal layer of the epidermis.^17,23,24

EDP presents as oval to round ash-gray macules that slowly expand and coalesce to form irregular or polycyclic patches.²⁰ The lesions may be surrounded by an erythematous, slightly elevated border that eventually disappears within several months.^23,25 Although usually asymptomatic, some lesions may be mildly pruritic.²⁶ The most commonly affected regions are the trunk and proximal extremities, followed by the face and neck, without preference for exposed or unexposed areas.^{15,16, 20} Lesion distribution tends to be symmetric, although in very rare cases, erythema dyschromicum perstans may present unilaterally.¹⁵ Older lesions of hyperpigmentation may be surrounded by a rim of hypopigmentation and leave a permanent discoloration.¹⁹

The active phase erythematous border of erythema dyschromicum perstans exhibits different histologic features from the late-stage or central ashy area of the lesion. The inflammatory borders exhibit vacuolization of the basal cell layer, edematous dermal papillae, occasional colloid bodies, and a mild to moderate perivascular infiltrate consisting of small round cells, histiocytes, and melanophages.^15,20,23 Exocytosis of lymphocytes may also be visualized, with a slight predominance of CD8+ over CD4+ lymphocytes.¹⁷ Immunofluorescence often shows the deposition of fibrinogen at the dermo-epidermal junction.¹⁹

Late-stage lesions and the inactive central regions of lesions exhibit epidermal atrophy with discrete follicular hyperkeratosis.^16,19,25 The infiltrates may diminish over time, leaving only vacuolar alteration of basal cells, which may later resolve.^16,26 The characteristic ashy color of EDP is due to the accumulation of melanin granules within macrophages in the upper dermis.^16,19,20,23 The resulting pigmentary incontinence may be the only microscopic finding in older lesions.^20,26

The differential diagnosis of erythema dyschromicum perstans includes necrobiosis lipoidica, lichen planus, idiopathic eruptive macular pigmentation, incontinentia pigmenti, postinflammatory hyperpigmentation, and fixed drug eruption, among others. Differentiating between erythema dyschromicum perstans and lichen planus is a subject of controversy. Some researchers consider EDP a variant of lichen planus and suggest calling the condition lichen planus pigmentosus. ^24,26,27 Others believe that while late-stage erythema dyschromicum perstans may resemble lichen planus pigmentosus, the characteristic active erythematous border distinguishes the former condition from the latter.^16,20,22,28

Idiopathic eruptive macular hyperpigmentation may be differentiated by the lack of both initial border erythema and ash-gray color.^16,28,29,30 Although late-stage lesions of both EDP and incontinentia pigmenti may resemble each other, lesions of the former present initially as slowly spreading ash-gray macules, and lesions of the latter appear vesicular at first and progress to hyperpigmentation.^20,31 Unlike those with erythema dyschromicum perstans, patients with post-inflammatory hyperpigmentation tend to have a history of a preceding cutaneous insult such as drug or phototoxic reactions, infections, physical injury, allergic reactions, or inflammatory diseases.¹⁵ Fixed drug eruption may mimic erythema dyschromicum perstans as it presents with a broad spectrum of clinical manifestations but may be distinguished from EDP by the patient’s history, as fixed drug eruptions are induced by a drug or other causative agent.^20,32

Although many treatments have been previously tested, most remain ineffective due to persistent residual pigmentation of the lesions. Treatment with antibiotics, topical corticosteroids, keratinolytic agents, isoniazid, chloroquine, and psychotherapy have all had disappointing results.^16,25 Other therapeutic agents, such as dapsone,²¹ clofazimine,²³ and isotretinoin,³³ have shown initial success but more research is needed. One study showed that without treatment, 50% of children affected by erythema dyschromicum perstans experienced improvement of their lesions within 1 to 5 years.¹⁶ Many physicians choose not to recommend any specific treatment for the condition due to its benign nature and lack effective treatment options.

The patient in this case study was diagnosed with erythema dyschromicum perstans. The patient requested a biopsy, which confirmed the diagnosis. After being presented with the various treatment options, the patient declined treatment.

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Lindsey Limbaugh, BA, is a medical student, Emma Weiss, BA, is a medical student, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston.

References

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