Approach to the differential diagnosis of leg ulcers

INTRODUCTION — Leg ulcers are an increasing problem worldwide and represent a major health care burden [1]. Patients with leg ulcers are managed by clinicians in multiple specialties, including primary care, vascular surgery, plastic surgery, podiatry, wound care, and dermatology.

A leg ulcer is a physical finding that can result from multiple etiologies, rather than a diagnosis (table 1). Thus, determination of the cause is essential for selecting appropriate treatment and determining the need for further evaluation. The most common causes of leg ulcers are venous insufficiency, arterial insufficiency, and neuropathic disease (table 2).

The etiologies and approach to the differential diagnosis of leg ulcers will be reviewed here. Specific etiologies of leg ulcers and wound management are reviewed in detail separately.

●(See "Overview of lower extremity chronic venous disease".)

●(See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

●(See "Evaluation of the diabetic foot".)

●(See "Screening for diabetic polyneuropathy".)

●(See "Clinical assessment of chronic wounds".)

●(See "Basic principles of wound management".)

●(See "Overview of treatment of chronic wounds".)

DEFINITION — The term "ulcer" describes destruction of the epidermis that extends into the dermis and may reach subcutaneous fat or deeper tissues.

COMMON CAUSES — Venous, arterial, and neuropathic ulcers account for up to 90 percent of leg ulcers. In a survey study in which wound care professionals in Germany reported the etiologies of chronic leg ulcers in over 31,000 patients, venous insufficiency, arterial insufficiency, and mixed venous and arterial insufficiency accounted for 48, 15, and 18 percent of chronic ulcers, respectively [2].

Venous insufficiency — Chronic venous disease is the most common cause of leg ulcers. Examples of risk factors include advancing age, female sex, obesity, pregnancy, prolonged standing, and a history of deep venous thrombosis. (See "Overview of lower extremity chronic venous disease", section on 'Epidemiology and risk factors' and "Overview of lower extremity chronic venous disease", section on 'Risk factors'.)

●Clinical features – Venous insufficiency ulcers frequently affect the "gaiter" area of the leg, which extends from the mid-calf to ankle (table 2). The skin immediately above the medial or lateral malleolus is the most common site, with the medial aspect affected most frequently. Ulcers are typically shallow with irregular borders with yellow, fibrinous exudate overlying the wound bed. Pain is mild to moderate. Arterial pulses are normal unless there is concomitant arterial insufficiency. (See 'Arterial insufficiency' below.)

Additional clinical findings in chronic venous disease include telangiectasias of the feet and ankles, peripheral edema, venous varicosities, and brown discoloration of the lower legs and feet due to hemosiderin deposition in tissue macrophages. Stasis dermatitis characterized by erythema and scaling may be present around ulcers (picture 1). Lipodermatosclerosis, also known as sclerosing panniculitis, may develop in the setting of long-standing venous hypertension and insufficiency. Lipodermatosclerosis presents as induration and fibrosis of the lower medial leg, which may be erythematous and painful and mistaken for cellulitis (picture 2). (See "Clinical manifestations of lower extremity chronic venous disease" and "Stasis dermatitis".)

●Diagnosis – Venous ulcers are diagnosed by clinical examination. Noninvasive venous imaging with duplex ultrasonography assesses reflux and obstruction in the superficial, deep, and perforating veins and is indicated if the diagnosis is not clear or if surgical intervention is being considered. (See "Diagnostic evaluation of lower extremity chronic venous disease".)

Arterial insufficiency — Peripheral arterial disease (PAD), a manifestation of atherosclerosis, leads to reduced blood flow to the extremities and may result in tissue necrosis and leg ulcers. Examples of risk factors for PAD include diabetes, smoking, hypertension, and hyperlipidemia [3]. Patients may have a history of myocardial infarction, angina, or stroke. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Risk factors'.)

●Clinical features – Arterial insufficiency (ischemic) ulcers typically occur distally on the toes or on areas of bony prominence, such as the heel, malleoli, and shin (table 2). Ulcers have well-demarcated edges, giving them a "punched-out" appearance, often with an overlying necrotic eschar (picture 3). Unlike venous ulcers, arterial ulcers typically are very painful.

Patients with PAD may complain of intermittent claudication or, later, rest pain. On examination, decreased hair density, shiny and thin skin, diminished or absent peripheral pulses, or prolonged capillary refill time (>3 to 4 seconds) may be present. Prolonged pallor with leg elevation to 45° for 1 minute (Buerger's test) supports vascular compromise. Peripheral dry gangrene may occur with disease progression. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Clinical features'.)

●Diagnosis – Peripheral arterial disease should be confirmed with ankle-brachial index (ABI) testing. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Diagnosis of lower extremity PAD'.)

Neuropathy — Diabetic neuropathy is responsible for the vast majority of neuropathic ulcers. Diabetic patients may have up to a 25 percent lifetime risk of developing a foot ulcer. Other causes of peripheral neuropathy (eg, spinal cord disorders [injury or spina bifida], tabes dorsalis, alcohol abuse, nutritional deficiencies, and autoimmune diseases) may result in similar ulcerations.

●Clinical features – Neuropathic ulcers are painless and occur over pressure points on the foot or heel (table 2). Ulcers have a punched-out morphology and typically occur within a thick callus (picture 4A-B). Associated clinical findings of diabetic neuropathy include claw toes, neuropathic (Charcot) arthropathy, and reduced sweating resulting in dry, scaly feet. (See "Evaluation of the diabetic foot", section on 'Inspection'.)

●Diagnosis – Sensory examination confirms decreased sensation in the involved areas. Ulcers can become deep, and underlying osteomyelitis should be considered when ulcers do not heal with off-loading therapies. (See "Management of diabetic foot ulcers".)

LESS COMMON CAUSES — There are multiple less common causes of leg ulcers, including physical injury, infection, vasculopathy, pyoderma gangrenosum (PG), panniculitis, malignancy, medications, and brown-recluse spider envenomation (table 1).

Physical injury — Physical injury to the skin may cause ulceration. Ulcers may result from pressure, thermal injury (burns or cold injury), radiation exposure, iatrogenic injury, or factitial (self-induced) injury. Of note, traumatic ulcers on the lower legs can demonstrate prolonged healing in older individuals and patients with underlying venous hypertension or arterial insufficiency.

●Clinical features – Ulcer features vary depending on the inciting injury. In particular, pressure ulcers often occur in sites overlying bony prominences; on the lower extremity, the heels are common sites [4]. The appearance of pressure ulcers ranges from shallow open ulcers to deep ulcers that expose bone, tendon, or muscle (picture 5 and figure 1). (See "Clinical staging and general management of pressure-induced skin and soft tissue injury" and "Assessment and classification of burn injury".)

●Diagnosis – With the exception of factitial ulcers, diagnosis is largely straightforward and relies on historical evidence of skin trauma.

Infection — Primary infectious ulcers may result from bacterial, fungal, spirochete, or protozoal infections, either by direct inoculation or systemic spread.

Staphylococcal and streptococcal skin infections are common bacterial infections that may result in ulceration. Cutaneous ulcers also may result from atypical mycobacterial infections, late-stage syphilis (gummas) (picture 6), deep fungal infections (eg, coccidioidomycosis, blastomycosis, histoplasmosis), and protozoal infections (eg, leishmaniasis (picture 7)). These infections most commonly, but not exclusively, occur in immunosuppressed patients.

●Clinical features – Clinical features vary according to the type of infection. Furuncles secondary to methicillin-resistant Staphylococcus aureus (MRSA) may progress to form larger abscesses, cellulitis, or ulcerative, necrotic plaques. Ecthyma, a form of nonbullous impetigo caused by Streptococcus pyogenes (with frequent contamination with S. aureus), produces punched-out shallow ulcers with a purulent necrotic crust and surrounding erythema (picture 8). Ecthyma gangrenosum, a systemic (or blood-borne) Pseudomonas aeruginosa infection characterized by bacterial invasion of the media and adventitia of arteries and veins, results in the rapid development of gangrenous ulcers with black eschar (picture 9). Ecthyma gangrenosum usually occurs in immunocompromised patients. (See "Impetigo" and "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Ecthyma Gangrenosum'.)

●Diagnosis – The diagnosis of infectious ulcers requires identification of the causative organism via swab cultures for aerobic bacteria or tissue culture for bacteria, fungi, and atypical mycobacteria. For tissue culture, incisional or punch biopsies should be obtained from the edge of the ulcer, placed on a sterile gauze pad moistened with nonbacteriostatic saline, and sent for culture in a sterile urine cup. In addition, ulcer edge tissue should be sent for histopathologic examination, including special stains for infectious organisms, since this may yield a more rapid diagnosis than culture. Culture can take up to six weeks for certain mycobacteria and fungi.

In addition, secondary bacterial infection can complicate chronic ulcers caused by venous insufficiency, arterial insufficiency, neuropathic disease, or other etiologies. Clinical signs such as exacerbations of erythema, warmth, edema, exudate, worsening pain, and malodor warrant investigation for secondary infection [5]. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Infectious complications of pressure-induced skin and soft tissue injury".)

Vasculopathy — Vasculopathic disorders can cause lower extremity ulcers by means of inflammatory processes that cause destruction of blood vessel walls (vasculitis) or vessel occlusion leading to ischemia.

Vasculitis — Vasculitis of small or medium-sized cutaneous blood vessels can result in leg ulcers. Small-vessel vasculitis can be idiopathic or a consequence of infections, drugs, mixed cryoglobulinemia, autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome), or malignancies (particularly hematologic malignancies). Inflammation of both small and medium-sized cutaneous blood vessels is associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and microscopic polyangiitis. Inflammation of medium-sized blood vessels occurs in cutaneous and systemic polyarteritis nodosa. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

●Clinical features – The characteristic clinical finding of cutaneous small-vessel vasculitis is palpable purpura. Palpable purpura may develop an overlying necrotic vesicle or bulla that becomes ulcerative. Subcutaneous nodules, necrotic ulcerations, retiform purpura, and livedo racemosa are features of medium-sized vessel involvement. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.)

●Diagnosis – An accurate diagnosis of vasculitis requires the detection of vasculitis on a skin biopsy as well as consideration of the patient history, physical examination, and other laboratory findings. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

The depth of the biopsy should reach the subcutis. In cutaneous small-vessel vasculitis, biopsy of an early but palpable lesion is most informative [6]. Biopsies demonstrate leukocytoclastic vasculitis (infiltration of postcapillary venules by neutrophils undergoing degranulation and fragmentation) and fibrinoid necrosis of the involved vessels. Similar changes occur in vasculitis of medium-sized vessels involving the small arteries in the deep reticular dermis and fat. Performance of direct immunofluorescence studies to identify immunoglobulin or complement deposits is an important component of the evaluation of cutaneous vasculitis. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

The detection of vasculitis involving only a few dermal vessels in a biopsy specimen may not be sufficient to confirm a diagnosis of vasculitis. In a retrospective study of punch and excisional specimens from 56 patients with leg ulcers, vasculitis of fewer than three dermal vessels in specimens obtained from the edge of an ulcer was a nonspecific finding [7].

Livedoid vasculopathy — Livedoid vasculopathy (LV) is a chronic, painful, ulcerative skin condition, most common in young and middle-aged women [8]. While the pathogenesis of LV is not clearly understood, hypercoagulable states and impaired fibrinolysis have been implicated [9]. (See "Livedoid vasculopathy".)

●Clinical features – LV is characterized by crusted, painful, stellate, shallow ulcerations that are slow to heal (picture 10). The disease is often bilateral, involving the skin around the ankle and dorsal foot. The ulcers heal with white, atrophic, stellate scars with telangiectasia, known as atrophie blanche. The terms "atrophie blanche" and "livedoid vasculopathy" have been used interchangeably in older literature. However, atrophie blanche is now recognized as a healing pattern that can occur as a result of both LV and chronic venous insufficiency. (See "Livedoid vasculopathy", section on 'Clinical features'.)

●Diagnosis – A skin biopsy is used to confirm the diagnosis. Characteristic findings are hyaline thrombi in the mid and upper dermal blood vessels with fibrinoid changes in vessel walls. Further evaluation for hypercoagulable states, paraproteinemias, cryoprecipitable proteins (cryoglobulins or cryofibrinogen), and collagen vascular disease may be helpful as indicated by history and physical examination. (See "Livedoid vasculopathy", section on 'Diagnosis'.)

Thromboangiitis obliterans — Thromboangiitis obliterans (TAO; Buerger's disease) is a vaso-occlusive inflammatory vasculopathy affecting small and medium-sized arteries, veins, and nerves of the extremities. The pathophysiology of TAO is characterized by inflammatory thrombi occluding vessels, with sparing of the vessel walls.

A rare disorder, TAO most commonly affects young to middle-aged male smokers. Exposure to tobacco is considered essential to initiation and progression of the disorder. (See "Thromboangiitis obliterans (Buerger disease)".)

●Clinical features – The legs are affected more often than the arms. Affected individuals present with ischemic symptoms of the extremities, which may progress to digital gangrene and ulcerations (picture 11A-B). Raynaud phenomenon and superficial thrombophlebitis are other common features [10]. (See "Thromboangiitis obliterans (Buerger disease)", section on 'Clinical features'.)

●Diagnosis – TAO is a clinical diagnosis requiring a compatible history (including tobacco use), physical findings, and diagnostic changes on angiography. Angiography demonstrates involvement of the small and medium-sized arteries, segmental occlusions, and "corkscrew"-shaped collateral vessels around areas of occlusion (image 1). (See "Thromboangiitis obliterans (Buerger disease)", section on 'Diagnosis'.)

Microvascular occlusion disorders — Occlusion of small cutaneous blood vessels may occur by multiple mechanisms, such as platelet plugging (eg, thrombocythemia, heparin-induced necrosis), cryoagglutination (eg, cryoglobulinemia, cryofibrinogenemia), bacterial infection (eg, ecthyma gangrenosum), embolism (eg, cholesterol emboli, oxalosis), coagulopathies (eg, antiphospholipid syndrome, protein C or S deficiency, warfarin necrosis), and calciphylaxis [11]. The clinical features vary with etiology. Overall, cutaneous ulcerations resulting from microvascular occlusion typically are very painful and retiform purpura are a common associated finding (picture 12A-B). The approach to diagnosis is also dependent on the etiology; histologic examination often is useful.

Examples of clinical and histologic findings of specific microvascular occlusion disorders include:

●Cryoglobulinemia (type I) and cryofibrinogenemia – Patients with type I cryoglobulinemia or cryofibrinogenemia may exhibit retiform acral purpura or skin necrosis leading to ulceration (picture 13). Involvement of other acral sites including ears and nose may also occur, especially with cryoglobulinemia. Livedo reticularis, the Raynaud phenomenon, and acral cyanosis are additional common clinical findings. Histopathologic examination of early sites of involvement reveals bland hyaline thrombi or red cell occlusion of superficial dermal blood vessels. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Type I cryoglobulinemia' and "Disorders of fibrinogen", section on 'Cryofibrinogenemia'.)

●Cholesterol emboli – An abrupt onset of widespread livedo reticularis plus distal retiform purpura is strongly suggestive of cholesterol emboli (more common) or oxalate emboli (rare). Peripheral gangrene and ulcerations occur in a subset of patients [12]. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".)

Cholesterol embolization is most common in men over age 50 with atherosclerotic disease. Cholesterol emboli may occur spontaneously but are more commonly seen within hours to days of arterial catheterization. Thrombolytic therapy and starting anticoagulation therapy (warfarin blue toe syndrome) have also been implicated, but a causal relationship is not well established. Full-thickness punch or incisional biopsies to fat in sites of retiform purpura may demonstrate characteristic elongated clefts in deep dermal arterioles.

●Oxalosis – Oxalate embolism can occur in patients with primary hyperoxaluria. Patients develop hyperoxalemia and hyperoxaluria leading to recurrent urolithiasis that begins in childhood and subsequent progression to renal failure. Skin manifestations of oxalosis present after the onset of renal failure and include acrocyanosis, livedo reticularis, and cutaneous necrosis. Histopathologic examination reveals birefringent yellow-brown crystals within and around vessels in the deep dermis or fat. (See "Primary hyperoxaluria".)

●Calciphylaxis – Calciphylaxis, also referred to as calcific uremic arteriolopathy, presents with painful indurated reticulate purpuric plaques that progress to necrosis and ulceration (picture 12A, 12C). Calciphylaxis is most commonly seen in patients with renal failure, often in the setting of diabetes. Prognosis is poor [13]. (See "Calciphylaxis (calcific uremic arteriolopathy)".)

Biopsies of involved skin must include the subcutaneous tissue; calcium deposits are found in the media of blood vessels in the fat. Perieccrine calcium deposition may be a highly specific but not sensitive finding in calciphylaxis [14]. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Diagnosis'.)

Sickle cell disease — Leg ulcers can occur as a complication of sickle cell disease. The ulcers most commonly occur on the medial and lateral malleoli and are usually painful and intractable [15,16]. The mechanism for ulcer development is not fully understood but may involve impaired blood flow, endothelial dysfunction, thrombosis, inflammation, and delayed healing [17]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Leg ulcers'.)

Pyoderma gangrenosum — Pyoderma gangrenosum (PG) is a neutrophilic dermatosis often associated with an underlying systemic disorder, such as inflammatory bowel disease, arthritis, or hematologic disease (eg, acute and chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, IgA monoclonal gammopathy) [18]. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Associated disorders'.)

●Clinical features – PG classically presents as single or multiple rapidly progressive painful leg ulcers with necrotic borders and surrounding erythema (picture 14A-B). The initial clinical finding is a pustule, which then develops an overlying necrotic bulla that ulcerates with purulent drainage. The lower leg is a common site of involvement [19]. PG may exhibit pathergy, the induction or worsening of PG in sites of trauma.

In its acute phase, PG may be accompanied by systemic symptoms or signs, such as fever and leukocytosis. In addition to the classic form, there are bullous, pustular, superficial granulomatous, and peristomal variants. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

●Diagnosis – PG is a diagnosis of exclusion, since there are no specific clinical, pathologic, or laboratory findings. Biopsies of an acute PG ulcer may demonstrate a neutrophilic infiltrate in the dermis, often with a surrounding mononuclear cell infiltrate. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Diagnosis'.)

Panniculitis — Panniculitides are disorders characterized by inflammation of the subcutaneous fat. Panniculitides associated with lower extremity ulcers include erythema induratum (nodular vasculitis) and panniculitis caused by alpha-1 antitrypsin deficiency or pancreatic disease. (See "Panniculitis: Recognition and diagnosis".)

●Erythema induratum – Erythema induratum typically occurs in young or middle-aged women and involves the lower legs, especially the posterior calves. The disorder presents with tender subcutaneous nodules and plaques that may ulcerate and drain (picture 15A-B).

Biopsy demonstrates a mixed septal and lobular inflammatory cell infiltrate with vasculitis in most cases. Erythema induratum was classically described as a tuberculid associated with M. tuberculosis; however, erythema induratum may also be idiopathic or associated with other infections or drugs. (See "Cutaneous manifestations of tuberculosis", section on 'Erythema induratum of Bazin'.)

●Alpha-1 antitrypsin deficiency – Alpha-1 antitrypsin deficiency produces a neutrophil panniculitis in a small subset of patients [20]. Patients develop tender erythematous or purpuric nodules and plaques on the lower trunk and extremities. The nodules and plaques may ulcerate, drain an oily discharge, and heal with scarring. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Skin disease'.)

Biopsies of early alpha-1 antitrypsin deficiency panniculitis demonstrate a neutrophilic infiltrate of the fat followed by necrosis and destruction of fat lobules. Diagnosis is confirmed by serum evaluation of alpha-1 antitrypsin activity and genotype analysis. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

●Pancreatic panniculitis – Suppurative panniculitis is a rare complication of benign or malignant pancreatic disease [21]. Subcutaneous painful nodules develop on the lower extremities and trunk and may drain an oily material (picture 16). Systemic symptoms may include fever, abdominal pain, and arthritis; ascites and pleural effusions may also be present.

Histopathologic examination of pancreatic panniculitis demonstrates septal and lobular inflammation, plus the diagnostic changes of fat necrosis and characteristic "ghost cells" and saponification of the fat. (See "Panniculitis: Recognition and diagnosis", section on 'Enzymatic destruction'.)

Malignancy — Leg ulcers may arise as a feature of a primary cancer or as a result of malignant transformation of a chronic ulcer [22,23]. Various cutaneous malignancies can cause ulcers. In one study performed in a wound care clinic, malignancy was identified in 59 of 866 consecutive patients who received biopsies for leg ulcers that had failed to heal after at least three months of therapy (7 percent) [22]. Of the 59 malignant ulcers, the majority were nonmelanoma skin cancers (16 squamous cell carcinomas and 33 basal cell carcinomas). Cutaneous lymphomas (both B and T cell), Kaposi sarcoma, and other malignancies may also cause leg ulcerations.

Malignant ulcers often are not recognized immediately. Primary malignant ulcers may be assumed to result from other causes of ulceration, and malignant transformation of a chronic ulcer may become apparent only after an ulcer fails to respond as expected to treatment. Diagnosis is dependent upon histologic confirmation of malignancy. Ulcers that are enlarging or failing to heal despite treatment, occurring in scars, or with exophytic or irregular wound edges probably warrant biopsy to rule out malignancy, but a standard of care has not been determined in large studies.

Drugs — Drugs associated with the development of leg ulcers include warfarin, heparin, and hydroxyurea.

●Warfarin – Warfarin skin necrosis is a microvascular occlusion syndrome that begins two to five days after beginning warfarin without concomitant heparin therapy and results from a transient hypercoagulable state [24,25]. Pain is the initial symptom, followed by erythema, which then becomes hemorrhagic and necrotic (picture 17A-B). Retiform purpura may be adjacent to sites of skin necrosis. Warfarin-induced skin necrosis is more common in women than men and is most likely to occur in fatty areas, such as breasts, hips, buttocks, and thighs. A biopsy of involved skin demonstrates bland thrombi in dermal blood vessels. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

●Heparin – Heparin-induced thrombocytopenia is a thrombotic complication of heparin therapy resulting from the production of autoantibodies against platelet factor 4 in complex with heparin. Patients with heparin-induced thrombocytopenia may develop microvascular occlusion resulting in skin necrosis at sites of heparin injection or other sites, such as the distal extremities or nose (picture 18). The initial manifestation is erythema that evolves to purpura, hemorrhage, and necrosis. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

●Hydroxyurea – Hydroxyurea-related leg ulcers may occur in patients receiving chronic hydroxyurea therapy. The ulcers are clinically similar to ulcers of LV: painful, fibrous, persistent ulcers with surrounding atrophie blanche changes, typically near the malleoli or on the anterior lower leg [26]. The mechanism for ulcer development may involve drug-induced cytologic damage [26].

Brown recluse spider bite — Loxosceles reclusa envenomation is a rare cause of dermonecrotic lesions resulting in painful leg ulcers. The venom contains sphingomyelinase D, which may be responsible for neutrophil activation and skin necrosis (necrotic arachnidism). (See "Bites of recluse spiders".)

●Clinical features – The actual bite is often minimally painful; however, it is followed by the appearance of a tender erythematous plaque. The plaque develops central pallor followed by painful blistering and/or necrosis in about 40 percent of cases (picture 19A-B) [27]. (See "Bites of recluse spiders", section on 'Clinical manifestations of bites'.)

●Diagnosis – The diagnosis is based upon witnessing the spider bite and correct identification of the spider. Most ulcers suspected to be caused by spider bites are actually due to infection or PG. In the absence of a witnessed bite and identification of the spider, other etiologies should be considered. (See "Bites of recluse spiders", section on 'Diagnosis'.)

PATIENT EVALUATION — The evaluation of patients with leg ulcers begins with a clinical evaluation aimed at narrowing the differential diagnosis. Given that the vast majority of ulcers are caused by venous insufficiency, arterial insufficiency, or neuropathy, the initial goal should be to identify patients with these conditions. Alternative diagnoses should be considered when patients have features that are not consistent with these etiologies or fail to respond to appropriate treatments.

History — Key aspects of the patient history that should raise suspicion for venous, arterial, or neuropathic ulcers are reviewed in a table (table 2). Additional information that may aid in identifying other causes includes:

●History of trauma at ulcer site – Traumatic ulcers, pyoderma gangrenosum (PG)

●Severe pain – Ulcers due to arterial insufficiency, microvascular occlusion disorders, or PG

●Rapid ulcer development – Infectious ulcers, PG, brown recluse spider bite ulcer

●Underlying thrombosis or coagulopathies – Venous insufficiency ulcers, microvascular occlusion disorder ulcers, livedoid vasculopathy (LV)

●Underlying autoimmune disease or hematologic disease – Ulcers due to vasculitis, PG, LV

●Other chronic disease – Ulcers due to arterial insufficiency (atherosclerosis), diabetic neuropathy (diabetes), PG (inflammatory bowel disease, arthritis), panniculitides (pancreatitis, alpha-1 antitrypsin deficiency, tuberculosis)

●Medication exposure – Warfarin-, heparin-, or hydroxyurea-induced ulcers

●Poor mobility – Pressure ulcers

●Smoking – Ulcers due to thromboangiitis obliterans

In addition, the clinician should review prior ulcer treatments. A failure to respond to treatment may suggest an incorrect diagnosis or malignant ulcer. (See 'Malignancy' above.)

Physical examination — The physical examination serves to identify physical features of the ulcer (eg, location, size, shape) and associated cutaneous or noncutaneous features that may aid in diagnosis. Findings that should raise suspicion for venous insufficiency, arterial insufficiency, and neuropathic ulcers are reviewed in a table (table 2). Because arterial insufficiency ulcers are common, routine palpation of pedal pulses is prudent. (See "Clinical assessment of chronic wounds", section on 'Vascular assessment'.)

Additional physical examination findings that may help to narrow the differential diagnosis include:

●Palpable purpura – Ulcers due to small or small- and medium-vessel vasculitis

●Retiform purpura or livedo racemosa – Ulcers due to microvascular occlusion disorders or medium-vessel vasculitis

●Nodules – Ulcer due to medium-vessel vasculitis or panniculitis

●Predilection for high-fat areas – Ulcers due to calciphylaxis or warfarin

●Atrophie blanche – LV or venous insufficiency ulcers

●Livedo reticularis – Ulcers due to microvascular occlusion disorders

●Oily drainage – Ulcers due to pancreatic panniculitis or alpha-1 antitrypsin panniculitis

The physical examination should also include an assessment for clinical signs of secondary infection (eg, warmth, erythema, swelling, purulent drainage, malodor) or osteomyelitis (eg, visible bone, ability to probe to bone). (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities", section on 'Clinical manifestations' and "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)

Biopsy — Biopsies are not necessary for the diagnosis of most ulcers but can be helpful when the diagnosis is unclear or ulcers fail to respond to therapy. Histopathologic examination may be particularly helpful when vasculitis, microvascular occlusion disorders, panniculitis, infection, or malignancy are in the differential diagnosis.

In general, biopsies for diagnosis are performed from the edge of an ulcer. A punch biopsy to subcutaneous fat or a wedge biopsy from the ulcer edge are recommended. A biopsy from purpura or early necrosis at the ulcer edge may be particularly informative. A biopsy site may subsequently ulcerate in cases of PG (pathergy) and patients should be informed of this risk.

Biopsies to provide tissue for culture are also useful for evaluating ulcers for primary or secondary infection. (See 'Infection' above.)

Additional tests — The need for serologic, radiologic, or microbiologic studies is determined by the disorders being considered. Such studies may be performed to confirm ulcer etiology or to evaluate for an associated underlying disease. (See 'Common causes' above and 'Less common causes' above.)

Additional tests also may serve to evaluate for complications such as wound infection or osteomyelitis. However, routine wound swab cultures are not recommended in the absence of clinical signs of infection because bacterial colonization of ulcers is common [4]. (See 'Physical examination' above and "Clinical assessment of chronic wounds", section on 'Wound assessment' and "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

INDICATIONS FOR REFERRAL — Leg ulcers that do not heal within three months of conservative wound care, are associated with livedo racemosa/reticularis or purpura, increase rapidly in size, or worsen with debridement should be referred to dermatology for further assessment. Classic venous ulcers or worsening arterial ulcers should be referred to vascular surgery.

SUMMARY AND RECOMMENDATIONS

●Overview of causes – Leg ulcers are a common condition that can result in significant morbidity. The causes of leg ulcers are diverse (table 1). The most common causes are venous insufficiency, arterial insufficiency, and neuropathy. Physical injury, infection, vasculopathies, pyoderma gangrenosum (PG), panniculitis, malignancies, drugs, and spider bites are less common etiologies. (See 'Common causes' above and 'Less common causes' above.)

●Approach to patient evaluation – Although the differential diagnosis of leg ulcers is broad, the high frequency of venous insufficiency, arterial insufficiency, and neuropathic ulcers warrant strong consideration of these etiologies during patient evaluation (table 2). If findings are not consistent with these etiologies, less common causes of leg ulcers should be considered. (See 'Patient evaluation' above.)

•Findings suggestive of venous insufficiency – Clinical findings that suggest venous insufficiency ulcers include location on the lower leg, particularly near the medial or lateral malleoli, and signs of chronic venous disease, such as edema, varicosities, hemosiderin deposition, or stasis dermatitis. Venous ulcers are usually shallow with irregular borders and overlying yellow, fibrinous exudate. (See 'Venous insufficiency' above.)

•Findings suggestive of arterial insufficiency – Clinical findings that suggest arterial insufficiency ulcers are painful, well-demarcated ulcers with a "punched-out" appearance located on toes or pressure areas. Associated clinical findings may include a shiny appearance to the skin, local hair loss, diminished pulses, and dry gangrene. (See 'Arterial insufficiency' above.)

•Findings suggestive of neuropathic ulcers – Clinical findings that suggest neuropathic ulcers include painless, "punched-out" ulcers occurring over pressure points, usually on the foot or heel. A surrounding callus is common. Patients with diabetic neuropathy may also have claw toes, neuropathic (Charcot) arthropathy, and reduced sweating on the feet resulting in dry, scaly feet. (See 'Neuropathy' above.)

●Identification of less common causes – Careful assessment of the patient history and physical findings is often helpful for identifying less common causes of leg ulcers. Historical information such as the time course of ulcer development, underlying disease, or medication exposure can be useful. Recognition of associated physical findings such as palpable purpura, retiform purpura, or nodules can also aid in diagnosis. (See 'Patient evaluation' above.)

●Role of skin biopsy – Biopsies are not necessary for the diagnosis of most ulcers but can be helpful when the diagnosis is uncertain. In particular, histopathologic examination may be helpful when the differential diagnosis includes vasculitis, microvascular occlusion syndromes, panniculitis, or malignancy. Additional laboratory or radiologic studies may be helpful for confirming the cause of an ulcer or evaluating for a suspected infection or associated underlying disease. (See 'Patient evaluation' above.)