Diagnosing A Painful, Discolored Lower Extremity Ulceration

A 48-year-old woman initially presented to our institution with concern over a painful discolored papule on her lower right leg. The patient denied any history of trauma or triggering events. Her past medical history included hidradenitis suppurativa and hypertension. The discolored plaque on her leg progressed rapidly to an expanding, full-thickness, painful ulceration.

The ulceration was located on her anterolateral lower leg and was characterized by violaceous borders, a granular base extending to subcutaneous tissue, mucopurulent slough to the wound bed and a gradually expanding serpiginous shape.

The frequent misdiagnosis of this condition can lead to a delay in treatment. A skin biopsy with histopathologic analysis is helpful in excluding other more common causes of ulcerative disease. A biopsy of the ulceration and histopathology showed neutrophilic infiltration of the skin.

Key Questions To Consider

1. What factors are important in the diagnosis of this papule?
2. What are common different diagnoses for this condition?
3. What are treatment recommendations for this condition?
4. Is surgical management of this condition recommended?

Answering The Key Diagnostic Questions

1. One would diagnose pyoderma gangrenosum based on the condition’s typical clinical presentation, a history of associated systemic disease, histopathology and exclusion of other disorders.
2. Common differential diagnoses for pyoderma gangrenosum include skin infection, venous insufficiency, peripheral arterial disease (PAD), burn wound, insect bite, cutaneous autoimmune disorders, cutaneous malignancy, cutaneous vasculitis and necrobiosis lipoidica.
3. Recommended treatment for pyoderma gangrenosum includes local wound care and anti-inflammatory or biologic medications that reduce neutrophilic inflammation.
4. Surgery is not recommended for pyoderma gangrenosum as the pathergic phenomenon can lead to subsequent wound decline with surgical manipulation.

What You Should Know About Pyoderma Gangrenosum

Based on clinical presentation, histopathology and associated hidradenitis suppurativa, I diagnosed the patient with pyoderma gangrenosum.

Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatitis that presents clinically with severe skin ulcerations. Originally, the thought was that pyoderma gangrenosum resulted from a purulent streptococcal skin infection that progressed to tissue necrosis.¹ This theory was later disproven and researchers found pyoderma gangrenosum to be a noninfectious disorder characterized by the accumulation of neutrophils in the skin.¹ The etiology and pathogenesis of pyoderma gangrenosum remain poorly understood. Many cases of pyoderma gangrenosum are idiopathic but this disorder can also be associated with systemic disease. Pyoderma gangrenosum is a rare disorder estimated to affect three to 10 individuals per million.² It most commonly occurs in middle-aged women.

Pyoderma gangrenosum is non-infectious and characterized by a neutrophilic infiltration of the skin. The hypothesis is that immunologic factors and neutrophil dysfunction lead to recurrent skin inflammation and subsequent ulceration.^3,4

Approximately 50 percent of pyoderma gangrenosum cases are associated with systemic disorders while the remaining cases are idiopathic.^3,4 Systemic disorders associated with pyoderma gangrenosum are classified as parainflammatory (paraimmune), paraneoplastic and drug-induced.⁵ Specific disorders that are commonly associated with pyoderma gangrenosum include: inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, myeloproliferative disorders, myelodysplastic disorders and monoclonal gammopathies.^3,6

Drugs that have been associated with pyoderma gangrenosum include pegfilgrastim (Neulasta, Amgen) (granulocyte colony stimulating factor), gefitinib (epidermal growth factor inhibitor) and isotretinoin.⁵ Genetic factors are believed to contribute to the development of pyoderma gangrenosum, especially in the setting of certain syndromes including PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and PASH (pyoderma gangrenosum, acne and suppurative hidradenitis).²

Making An Accurate Diagnosis Of Pyoderma Gangrenosum

Ulcerative (classic) pyoderma gangrenosum is the most common type of pyoderma gangrenosum. Ulcerative pyoderma gangrenosum is characterized by well-defined, painful skin ulcerations with blue/violaceous margins, mucopurulent wound beds and an expanding serpiginous shape.^4,5,7 The clinical course of these lesions can either present with a rapid onset and progression with severe necrosis, or with a slow onset and progression with spontaneous regression. Ulcerative pyoderma gangrenosum occurs most commonly on the lower extremities. There are other clinical variants of pyoderma gangrenosum including pustular, bullous and vegetative types.

The diagnosis of pyoderma gangrenosum remains difficult. Diagnosis of pyoderma gangrenosum is mainly clinical but can be supported by histopathology. Histopathologic analysis of pyoderma gangrenosum can be variable depending on the stage of lesions, site of biopsy and type of pyoderma gangrenosum.^2,5 Given this variability, histopathologic analysis can support but does not provide a definitive diagnosis of pyoderma gangrenosum. The most common histopathologic feature of pyoderma gangrenosum is massive neutrophilic infiltration in the absence of vasculitis or granuloma formation.⁸ This is variable, however, with granuloma formation occurring in cases of pyoderma gangrenosum associated with Crohn’s disease.^9,10

Differential diagnoses of pyoderma gangrenosum include: skin infection, venous insufficiency, PAD, exogenous skin injury (burn, insect bite), cutaneous autoimmune disorders, cutaneous malignancy, cutaneous vasculitis and necrobiosis lipoidica.^2,3,6

Relevant Insights On Treatment And Prognosis

Treatment of this patient consisted of infliximab (Remicade, Janssen Immunology) infusions (every four to eight weeks), local wound care with pimecrolimus cream (Elidel, Ortho Dermatologics) and non-adherent wound dressings. After approximately two years, the wound healed with atrophic scar tissue at the site of prior ulceration. The patient remained on infliximab infusions for treatment of her hidradenitis suppurativa.

Treatment modalities for pyoderma gangrenosum aim to reduce the neutrophilic inflammation that leads to ulceration. Treatment of pyoderma gangrenosum involves local or systemic immunosuppression, treatment of associated systemic disease and local wound care. One can often manage cases of mild disease with topical immunosuppressive agents including topical corticosteroids and topical calcineurin inhibitors. Cases with severe or widespread disease typically require treatment with systemic corticosteroids as well as numerous other anti-inflammatory agents including cyclophosphamide, cyclosporine, methotrexate and tacrolimus.^11-13

Recently, researchers have used disease modifying biologic agents that target tumor necrosis factor (TNF) and interleukin in the management of pyoderma gangrenosum.¹⁴ These agents include adalimumab (Humira, AbbVie), etanercept (Enbrel, Amgen) and infliximab.^5,15,16 Many of the medications clinicians use in the management of pyoderma gangrenosum are similarly utilized in the management of associated systemic inflammatory disorders and authors have found that treatment of associated systemic disorders leads to improved control of pyoderma gangrenosum.¹⁶

Wound care recommendations for pyoderma gangrenosum include routine wound cleansing and the application of moist, sterile wound dressings. Avoid using occlusive dressings, compression stockings and wound debridement as a pathergy response occurs with the use of these treatments with wound irritation leading to subsequent wound decline.¹⁷ Pyoderma gangrenosum ulcerations can be very painful and appropriate pain management is recommended. Monitor wounds closely for infection, especially in the setting of treatment with immunosuppressive agents. Researchers have reported several adjunct treatment options in the management of pyoderma gangrenosum, including skin grafting, hyperbaric oxygen and the application of porcine small intestine submucosa wound matrix.^18,19

The prognosis of pyoderma gangrenosum skin lesions is variable. Mild cases may spontaneously resolve while more severe cases may be chronic and recurrent. While many cases of pyoderma gangrenosum resolve with immunosuppressive treatment, clinicians may see resultant scarring at the site of prior ulceration. Skin trauma can trigger new lesions so protection at the sites of prior ulceration can help decrease recurrence.²⁰

In Conclusion

Pyoderma gangrenosum is a rare neutrophilic dermatitis that typically presents with inflammatory skin ulcerations on the lower extremities. Pyoderma gangrenosum ulcerations are characterized by an expanding, serpiginous ulceration with an undermining violaceous border and mucopurulent wound bed. The diagnosis of pyoderma gangrenosum is one of exclusion with biopsy and histopathologic analysis helping to rule out other dermatologic disorders. Pyoderma gangrenosum is often misdiagnosed, leading to a delay in treatment.

The treatment of pyoderma gangrenosum includes immunosuppressive medications in addition to addressing associated systemic disease. Wound monitoring is important, especially in the setting of treatment with immunosuppressive agents. Avoid surgery for pyoderma gangrenosum as pathergy can lead to further wound decline.

Dr. Hoffman is the Medical Director of the Orthopedic Clinic and an Attending Physician in the Department of Orthopedics at Denver Health Medical Center. She is an Assistant Professor in the Department of Orthopedics at the University of Colorado School of Medicine.

References

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10.    Talansky AL, Meyers S, Greenstein AJ, Janowitz HD. Does intestinal resection heal the pyoderma gangrenosum of inflammatory bowel disease? J Clin Gastroenterol. 1983;5(3):207-210.
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17.    Baranska-Rybak W, Kakol M, Naesstrom M, Komorowska O, Sokolowska-Wojdylo M, Roszkiewicz J. A retrospective study of 12 cases of pyoderma gangrenosum: why we should avoid surgical intervention and what therapy to apply. Am Surg. 2011;77(12):1644-1649.
18.    Davis JC, Landeen JM, Levine RA. Pyoderma gangrenosum: skin grafting after preparation with hyperbaric oxygen. Plast Reconstr Surg. 1987;79(2):200-207.
19.    Vlahovic T. Can Oasis (porcine small intestine submucosa) have an impact for pyoderma gangrenosum? Podiatry Today DPM Blog. Available at https://www.podiatrytoday.com/blogged/can-oasis-porcine-small-intestine-submucosa-have-impact-pyoderma-gangrenosum . Published August 27, 2013.
20.    Cordts T, Bigdeli AK, Harhaus L, et al. Pyoderma gangrenosum following complex reconstruction of a large-scale lower limb defect by combined Parascapular and latissimus dorsi flap. J Surg Case Rep. 2017;2017(1).