Atypical Ulcers: A Stepwise Approach for Clinicians

Chronic ulcers commonly present on the lower extremities and greatly affect quality of life.^1,2 Chronic leg ulcers are those that persist for more than 6 weeks and show no tendency to heal after 3 or more months of appropriate treatment.² While common causes of chronic ulcers include venous leg ulcers, diabetic foot ulcers, PIs and PUs, and arterial ulcers,³ it is estimated that autoimmune diseases may play a role in 20% to 23% of patients with a chronic leg ulcer.^4,5 The potential etiologies and workup of an atypical ulcer are reviewed herein.

Typical ulcers are commonly encountered in clinical practice and are frequently due to venous insufficiency, diabetes, ischemia, or pressure. Venous ulcers that result from venous hypertension are the most common type of lower extremity ulcer, affecting 1% to 3% of the US population.⁶ These ulcers are typically shallow, irregularly shaped wounds in the gaiter area with heavy drainage. Other symptoms suggestive of venous ulcers include varicose veins, edema, hemosiderosis, and stasis dermatitis.⁶

Ischemic or arterial ulcers occur in response to an acute or chronic peripheral arterial decrease in circulation and are most commonly due to atherosclerosis.⁷ These ulcers tend to present as an extremely painful so-called punched-out lesions, and they are associated with signs of ischemia, described below. Risk factors for ischemic ulcers include age, smoking, diabetes, hypertension, dyslipidemia, family history, obesity, and sedentary lifestyle.⁷

Diabetic foot ulcers are one of the most common complications of poorly controlled diabetes, with 5% of individuals with diabetes developing foot ulcers and 1% requiring amputation.⁸ The etiology is multifold and includes poor glycemic control, peripheral neuropathy, atherosclerosis, and poor foot care.

Pressure injuries represent a serious and costly health care challenge,⁹ with between 2% and 40% of patients experiencing a PI in acute care.¹⁰ Pressure injuries are defined as localized damage to the skin and underlying soft tissue over a bony prominence or related to a medical device.¹¹ These ulcers occur due to pressure, shearing forces, friction, and moisture beneath bony prominences; high-risk populations include the elderly and those bedbound with spinal cord injuries, traumatic brain injuries, or neuromuscular disorders.¹²

While all these ulcers are common and well described in the literature, clinicians may encounter atypical ulcers, which can be more challenging to diagnose. Early recognition of atypical ulcers and appropriate referral to an academic center are key in management.

The term atypical ulcer refers to a broad range of ulcers that result from inflammatory, neoplastic, vasculopathic, hematologic, infectious, drug-induced, and external etiologies (Table).^13-27

Inflammatory, hematologic, and vasculopathic ulcers are associated with conditions such as RA, SLE, scleroderma, mixed connective tissue disease, PG, vasculitis, calciphylaxis, antiphospholipid syndrome, and genetic prothrombotic states.²² Neoplastic etiologies include Marjolin ulcer, along with ulcerative malignancies such as nonmelanoma skin cancers, lymphomas, and sarcomas.¹⁷ Infectious causes can include bacteria, mycobacteria, fungus, protozoa, skin parasites, or arthropods.²⁸ Essentially, ulcers that are not secondary to vascular insufficiency, ischemia, neuropathy, or prolonged pressure may be categorized as atypical.

Clinical features of atypical ulcers include an exuberant or vegetative wound bed with hypergranulation or necrosis. The ulcers may have a violaceous border, surrounding inflammation, or adjacent satellite lesions.^28,29 Other clinical clues that may suggest an atypical etiology include an unusual location (on the foot or proximal to the midcalf), asymmetry, rolled edges, an ulcer in the center of a pigmented lesion, rapidly progressive ulceration, or severe intractable pain.^14,29

Inflammatory

PG is a rare, neutrophilic dermatosis that most commonly affects females and adults over the age of 50 years (Figure 1, Figure 2).³⁰ Recent data suggest a prevalence rate of 5.8 PG cases per 100 000 adults.³⁰ PG is considered an autoinflammatory disease with a multifactorial etiology, including neutrophilic dysfunction, inflammatory mediators, and genetic predisposition.^31,32 Pathergy, an exaggerated response to a minor skin injury, is a well-described phenomenon of the disease.³² It may be associated with an underlying systemic disease, such as IBD, rheumatologic conditions, and hematologic disorders (Figure 3).³²

Vasculitis describes inflammation of the blood vessel wall that can affect any organ, including the skin, leading to necrotic ulcers.³³ Vasculitic ulcers can present along a spectrum of other cutaneous pathologies and represent a reaction pattern, not a specific disease entity. Pathologies associated with vasculitic ulcers include PAN, LCV, and AAV.³³

PAN is a rare, necrotizing vasculitis that targets the medium-sized arteries, generally excluding the lungs (eFigure 4).³⁴ Variants include systemic idiopathic form, idiopathic generalized PAN, and 2 clinical variants: cutaneous PAN and hepatitis B virus–associated PAN.³⁴ Cutaneous PAN is restricted to the skin, predominantly involving the area below the knee, and rarely transforms into idiopathic generalized PAN.³⁴ Other cutaneous manifestations of PAN include livedo reticularis, tender subcutaneous nodules, petechiae, purpura, cutaneous necrosis, and digital autoamputation.³⁵

LCV is a small-vessel vasculitic condition that most commonly manifests as palpable purpura on the lower extremities. It also may have joint symptoms, such as arthralgias or arthritis involving the knees and ankles (Figure 5).³⁶ Painful, necrotic lower extremity skin ulcers may also be seen in patients with LCV.³⁷ The condition is often secondary to drugs, infection, or both, and typically follows a benign, self-limited course.³⁶

AAV also targets small vessels and include granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome).³⁸ These conditions are rare autoimmune diseases with various presentations that range from a skin rash to multisystem involvement.³⁸ Lower extremity ulceration has been reported as a presenting sign in all types of AAV.^39-41

Lymphocytic vasculitis has been reported in patients with COVID-19 that affects the toes, feet, heels, and hands.^15,42 Cutaneous vasculitis in COVID-19 infection has mostly been reported in children and adolescents who do not have COVID-19 pneumonia.^15,43 The condition is typically transient and is associated with a good prognosis.⁴³

Cryoglobulins are immunoglobulins that can precipitate at low temperatures and may cause vasculitis due to precipitation in small- to medium-sized blood vessels. Cryoglobulinemia is classified into 3 types based on immunoglobulin composition.⁴⁴ Type I is associated with hematologic malignancies, including Waldenström macroglobulinemia and multiple myeloma.²² In these conditions, serum viscosity increases—due to formation of large IgM complexes that lead to peripheral vascular occlusions that manifests as stroke, Raynaud phenomenon, or ischemic limb ulcers. Hyperviscosity may also lead to acral purpura, especially in cold weather.²² Type II and type III cryoglobulinemia are mixed types. Type II is composed of polyclonal IgG and monoclonal IgM. Type III is composed of polyclonal IgG and/or polyclonal IgM. Type II accounts for 50% to 60% of cryoglobulinemias, whereas type III accounts for 25% to 30%.⁴⁵ The IgG component is always polyclonal with both kappa and lambda light chains. Other conditions, such as hepatitis C, may involve mixed cryoglobulinemia. Thus, liver function and hepatitis panel should be part of the initial workup.

Additionally, many autoimmune diseases—including RA, SLE, scleroderma, and mixed connective tissue disorder—have been associated with lower extremity ulceration.^13,22 RA is the autoimmune disease most strongly associated with lower extremity ulcers.²² One study reported a prevalence of 4.37% for the development of a lower extremity ulcer in patients with RA.⁴⁶ Treatment with a biologic agent was associated with an increased likelihood of ulcer healing (P =.039). Other risk factors identified in that study include prolonged duration of RA (mean disease duration at ulcer development, 25.9 years), erosive disease, and seropositivity.⁴⁶ Vasculitis has been found to be present histologically in 50% to 55% of patients with an RA-associated leg ulcer.^46-48 Behçet disease is a systemic vasculitis characterized by recurrent oral ulcers, genital ulcers, and skin lesions (Figure 6). This disease is most prevalent in Turkey and is rare in the United States.¹⁶

Ulceration is a rare but well-known complication of SLE and may be secondary to immune complex-mediated vasculitis, as with RA, or may coexist with underlying prothrombotic states, such as antiphospholipid syndrome (Figure 7).^22,49

Digital involvement is not uncommon in scleroderma (eFigure 8). Lower extremity ulceration is less common, but it also may occur in patients with long-standing scleroderma and is associated with significant morbidity.⁵⁰ An underlying prothrombotic state should be considered in scleroderma-associated ulcers.

Other autoimmune conditions associated with ulceration include lichen planus and sarcoidosis. Ulcerative lichen planus is a rare subtype of lichen planus and most commonly occurs in female adults. The condition is associated with ulceration of the feet and anonychia of the toenails.¹³ Additionally, 5% of patients with cutaneous sarcoidosis may have an ulceration.⁵¹ Ulcerative sarcoidosis commonly presents as pretibial ulcers and may look similar to the lesions associated with necrobiosis lipoidica.^51,52

Necrobiosis lipoidica is an inflammatory dermatosis that most commonly presents in females between 20 to 30 years old.⁵³ The condition is associated with pretibial plaques that are tan to yellow in color and may ulcerate with violaceous rims, atrophic centers, and underlying telangiectasia.¹³ The disorder is associated with diabetes, with one study finding diabetes to be present in 23 of 35 patients with necrobiosis lipoidica.⁵⁴

Neoplastic

The following are several ways in which malignancy may be associated with ulceration: primary melanomas (Figure 9), nonmelanoma skin cancers, lymphomas, malignant fungating tumors (Figure 10), sarcomas, or transformation of a chronic ulcer into a malignancy. Marjolin ulcer is a cutaneous malignancy arising in the setting of previously injured skin, scars, or chronic wounds (Figure 11). It is most commonly associated with the development of SCC but it also is used to describe ulcers that degenerate to basal cell carcinomas and melanomas, among other cancers.⁵⁵ SCCs arising from chronic wounds tend to be more aggressive tumors, with higher rates of metastasis than SCCs arising from healthy skin.⁵⁶ Additionally, malignant fungating tumors present as nonhealing ulcers in patients with advanced cancer. These tumors are most prevalent on the breast but may occur in other parts of the body (eg, face, lower extremity). Treatment is usually palliative.¹⁹

Vasculopathic

Vasculopathy describes thrombotic microangiopathy, a thrombus in the arterial lumen that results in ischemia. Examples of vasculopathies include livedoid vasculopathy, calciphylaxis, pigmented purpuric dermatosis, and COVID-19–induced vasculopathy.^20,21 Livedoid vasculopathy refers to a small-vessel vasculopathy that causes recurrent bilateral leg ulcers, often involving the skin around the dorsal ankle and foot. Livedoid vasculopathy may be associated with connective tissue disorders and hypercoagulable states, but approximately one-third of cases are idiopathic (Figure 12).²² Calciphylaxis is a small-vessel vasculopathy that may mimic cutaneous vasculitis (Figure 13).⁵⁷ The condition most commonly affects patients with end-stage renal disease, but it may also occur in patients with earlier stages of chronic kidney disease or in those with normal renal function.⁵⁸ Pain may precede lesion appearance, followed by a dusky discoloration that rapidly progresses to a necrotic ulcer.⁵⁸ Depending on the lesion location, the condition is associated with significant morbidity and is usually fatal, with sepsis and heart attack as the most common causes of death.⁵⁹

Vascular derangements through endothelial damage and thrombosis have been established as a prominent feature of COVID-19.^21,60 Emerging evidence suggests that SARS-CoV-2 may lead to a multisystem vasculopathy.⁶¹ In contrast to the lymphocytic vasculitis described previously, COVID-19 can also lead to predominant cutaneous manifestations in adults with severe COVID-19 pneumonia (eFigure 14).⁴³ Thrombotic microvascular injury is thought to underlie this disease pattern.⁶²

Hematologic

Patients with sickle cell disease and other hemoglobinopathies are at increased risk of chronic leg ulcers.²² The etiology of chronic leg ulcers in sickle cell disease is thought to be multifactorial, including vaso-occlusion with subsequent venous insufficiency, vasculopathy and inflammation secondary to chronic hemolysis, and enhanced hypercoagulability (Figure 15).^22,63,64 Antiphospholipid syndrome can also cause occlusion in the small dermal vessels, resulting in livedo reticularis, splinter hemorrhages, superficial thrombophlebitis, and leg ulcers (Figure 7).²² Other prothrombotic states predisposing to ulceration include factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III deficiency, protein C and S deficiency, and hyperhomocysteinemia. Patients with prothrombotic states warrant a referral to a hematology specialist for further workup and evaluation for anticoagulation therapy.⁶⁵

Infectious

Atypical infections associated with ulceration include acanthamebiasis, amebiasis, anthrax, atypical mycobacterium (Buruli ulcer), ecthyma gangrenosum, diphtheria, tularemia, leishmaniasis, tropical ulcer, histoplasmosis, and bacillary angiomatosis.^13,17,23 Atypical mycobacterial infections may be seen in patients who are immunocompromised and can result in granulomas, superficial erosions, sinus tracts, and chronic ulcers.¹⁷ Buruli ulcer is a necrotizing cutaneous disease caused by Mycobacterium ulcerans. The condition is most common in the region of West Africa and in other tropical countries. The mode of transmission is currently unknown, but proximity to contaminated water sources has been identified as a risk factor.⁶⁶ Ecthyma gangrenosum is characterized by the rapid evolution of a localized lesion to a necrotic ulcer or the presence of multiple ulcers at different stages, most commonly due to Pseudomonas aeruginosa.⁶⁷

Drug-induced

Hydroxyurea and methotrexate have both been reported to cause lower extremity ulceration.^13,24 Hydroxyurea-induced
ulcers are commonly found on the malleoli in patients with myelodysplastic disorders after years of hydroxyurea use. Biopsy findings are nonspecific, and cessation of hydroxyurea typically results in ulcer healing.^68,69 A number of adverse cutaneous effects have been described in association with methotrexate use, including erythematous eruptions, blisters, toxic epidermal necrolysis, exacerbation of photosensitivity, nodulosis, alopecia, and urticaria.^70,71 Methotrexate-induced ulceration has most commonly been reported in psoriasis treatment within preexisting psoriasis plaques or in previously damaged areas of skin.¹³ Importantly, cutaneous findings may precede hematologic signs of methotrexate toxicity.⁷⁰

Injection drug use, including heroin and cocaine, may also cause ulceration. Repeated injection into the femoral vein can damage the vessel, leading to narrowing of the lumen and venous hypertension with subsequent ulceration.²⁵ Cocaine contaminated with levamisole, an antihelmintic used only in veterinary medicine due to adverse effects in humans, has been reported to cause vasculitis, vasculopathy, and skin necrosis (Figure 16). Skin lesions are most common on the lower extremities, ears, and face. Positive ANCA serologies and agranulocytosis may also be present.^26,72

Skin popping, which is the practice of injecting nonprescription drugs directly into the skin without venous access, can initiate a local inflammatory response, cause microvascular and lymphatic occlusion, and introduce bacteria into the skin, leading to necrotic ulcers and recurrent cellulitis.²⁷ Patients may also self-induce ulceration as part of a psychological disorder in which a person desires to be considered ill, termed dermatitis artefacta.^73,74 Mechanical and chemical devices are most commonly used to induce skin damage. The condition should be considered in the patient with an uncommon presentation of a disease that is unresponsive to treatment. Immediate psychiatric evaluation is required for any patient with this condition.^73,74

External causes

External skin damage through radiation, toxins, chemicals, or mechanical trauma may lead to ulceration. Skin damage occurs in 95% of patients undergoing radiation therapy for cancer.⁷⁵ Damage can range from grade 1 (faint erythema) to grade 4 (necrotic ulcers), and the severity depends on the radiation intensity and individual patient factors (Figure 17). The pathophysiology involves progressive obliterating endarteritis and fibrosis leading to tissue ischemia and hypoxia.⁷⁵

While most spider bites are harmless, a few spider species are capable of necrotic arachnidism, that is, venom-induced skin necrosis. Spiders of the genus Loxosceles, which includes brown recluse and fiddle-back spiders, are commonly found in South America, and their bites can induce necrotic arachnidism.⁷⁶ Their venom is thought to trigger an inflammatory response and to have a direct hemolytic effect on red blood cells. The bite can occur while an individual is sleeping or dressing and affected individuals may be unaware that the bite occurred.

General approach

The authors suggest a stepwise approach to guide clinicians in their decision-making when presented with a lower extremity ulcer. The algorithm shown in eFigure 18 was created based on the literature review, as well as clinical experience. It is hoped that this algorithm will help clinicians avoid unnecessary testing and provide guidance on the appropriate workup needed before specialty referral. While atypical ulcers may occur anywhere on the body, they commonly present on lower extremities; thus, the diagnostic algorithm is focused on ulcers occurring in this area.

Evaluation of a lower extremity ulcer should include a detailed medical history, including comorbidities, a focused wound history, and a thorough physical examination. Perfusion assessment is an essential first step in the evaluation of any lower extremity ulcer. For patients with suspected decreased arterial perfusion (nonpalpable pulses, thinning hair or hair loss, pale skin, delayed capillary refill times, coolness to the touch, claudication, and/or rest pain), vascular studies are warranted, such as the ankle-brachial index, toe-brachial index, waveforms, and segmental pressures. If these findings are abnormal, a referral to vascular surgery is indicated. In the setting of adequate distal arterial blood flow, the ulcer should be assessed for necrosis and debrided as needed. If there are no signs of ulcer healing after 4 weeks of dedicated wound care, it may be that the working diagnosis is incorrect, and an ulcer biopsy should be considered to help diagnose potential atypical etiologies.

It is also important to evaluate for signs of infection during initial examination because timely initiation of antibiotics may be critical. Signs of infection include worsening pain, foul-smelling purulent drainage, erythema or swelling of the perilesional skin, and fever. Tests to determine the presence of infection include CBC, basic or comprehensive metabolic panel, ESR, and CRP. Wound culture with Gram stain should also be obtained in such situations. An infectious diseases consult is warranted, and broad-spectrum antibiotics should be initiated until treatment options can be determined based on microbiologic data. If there is evidence of systemic infection (including fever, tachycardia, tachypnea, hypotension, or altered mental status), or in the case of an infection in an immunocompromised patient, hospitalization is recommended.⁷⁷ The authors recommend that infection be fully controlled prior to obtaining tissue samples for histopathologic analysis and DIF. If necrosis is present after the infection is treated, then the ulcer should be debrided and standard ulcer care should be performed. If the ulcer is not healing as expected, the clinician can proceed to biopsy and basic laboratory workup.

In the patient with a nonnecrotic ulcer with atypical features such as inflammation, violaceous borders, severe pain, and blistering, the workup may begin with a biopsy. Even in patients with known autoimmune disease, a biopsy can be helpful to rule out atypical infections and neoplastic change.²² The ulcer biopsy specimen should be sent for microbiologic, histopathologic, and DIF analysis. Deep 3-mm to 6-mm punch or full-depth thin wedge biopsies are the preferred method of sampling for most inflammatory dermatoses. For the patient who undergoes debridement in the operating room, it is helpful to also excise and submit adjacent viable tissue for histopathologic evaluation. The biopsy for DIF should include samples from the ulcer-skin interface and the intact perilesional skin.⁷⁸ Acute lesions—those with inflammatory change or blistering—should be biopsied, and older lesions with crusting and/or scarring should be avoided. A basic laboratory workup is recommended at the time of the ulcer biopsy, including evaluation of CBC, comprehensive metabolic panel, ESR, and CRP to evaluate for potential infectious, inflammatory, and autoimmune etiologies. The biopsy results and basic laboratory workup will guide further clinical decision-making.

Suspected neoplasia

If the histopathologic evaluation identifies evidence of neoplasia, then the patient should be referred to medical and surgical oncology and dermatology specialists for multidisciplinary care. A careful approach is suggested for tobacco users, because they are more prone to develop SCCs, keratoacanthomatous-type,⁷⁹ on sites of trauma on the lower extremities. An ulcerative or indurated lesion within a chronic wound or scar should raise suspicion for such malignant transformation.⁸⁰

Suspected PG

When clinical presentation suggests PG, histopathologic evaluation demonstrates neutrophilic infiltration, and other possible causes of ulceration have been excluded, a diagnosis of PG can be considered.⁸¹ Modified diagnostic criteria for PG include a biopsy of the ulcer edge demonstrating neutrophilic infiltrate and 4 of the following findings: exclusion of infection; pathergy; history of IBD or inflammatory arthritis; history of papule, pustule, or vesicle ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at the ulceration site; multiple ulcerations, at least 1 on the anterior lower leg; cribriform or so-called wrinkled paper scarring at healed ulcer sites; and decreased ulcer size within 1 month of initiating immunosuppressive medication or medications.⁸² Suspected PG necessitates further workup to identify underlying systemic conditions, which may be present in up to 50% of cases.⁸³ The most common systemic diseases associated with PG include IBD, RA, hematologic malignancies, and monoclonal gammopathy.⁸⁴

In addition to a thorough history and a physical examination specifically focused on potential systemic disease, the authors suggest a workup for an autoimmune etiology, including systemic lupus (ANA, anti-smith Ab, anti-dsDNA Ab, complement C3 and C4 levels), systemic sclerosis (anti-centromere Ab, anti-Scl70 Ab), mixed connective tissue disease (anti-ribonucleoprotein Ab), Sjögren syndrome (anti-SSA/Ro, anti-SSB/La), and RA (rheumatoid factor, anti-citrullinated protein Ab), as well as a hepatitis panel and age-appropriate malignancy screening.⁸⁵ In the case of a positive autoimmune panel, the clinician should consider a referral to rheumatology and dermatology specialists for further workup and treatment. Additionally, patients younger than 65 years should be referred to a gastroenterology specialist to undergo evaluation for IBD (including endoscopy and colonoscopy), and patients aged 65 years and older should be referred to hematology and oncology specialists for consideration of an underlying hematologic malignancy.⁸⁵

Suspected vasculopathy

Histopathologic findings of thrombotic microangiopathy are indicative of vasculopathy. Vasculopathy may be caused by degenerative, metabolic, and inflammatory conditions, or by coagulative disorders. For acutely ill patients, disseminated intravascular coagulation, purpura fulminans, thrombotic thrombocytopenic purpura, heparin-induced skin necrosis, and COVID-19–induced vasculopathy should be considered.⁸⁶ In stable patients, livedoid vasculopathy, cryoglobulinemia or myeloproliferative disease, antiphospholipid syndrome, and inherited mutations that cause hypercoagulability are included in the differential diagnosis.

The authors recommend a hypercoagulable workup consisting of activated protein C resistance, prothrombin G20210A mutation, factor V Leiden mutation, antithrombin Ab, protein C and protein S activity (functional) levels, factor VIII activity level, screening tests for lupus anticoagulants and anticardiolipin Ab, and fasting plasma homocysteine level.⁸⁷ Patients with antiphospholipid syndrome may have antibodies directed against cardiolipin, beta 2 glycoprotein 1, or cell-membrane phosphatidylserine.⁸⁷ A referral to hematology or oncology specialists can be made for further care.

Biopsy results may also indicate a combination of vasculopathy (thrombotic microangiopathy) and vasculitis (inflammation). In this case, the aforementioned hypercoagulable workup should be started. While a negative ANA test and normal inflammatory markers may indicate a reduced likelihood of autoimmune causes of vasculopathy, not all autoimmune diseases present with an elevated ANA titer. Further autoimmune workup should be guided by biopsy results, patient history, and physical examination. The patient should be referred to rheumatology or dermatology specialists for further care.

Suspected vasculitis

DIF, which shows immune complex and/or complement deposition, should always be requested with a skin biopsy to assess for vasculitis.⁸⁸ The age of the lesion biopsied is critical in the diagnosis of vasculitis, because diagnostic yield is highest within the first 24 to 48 hours of lesion onset.⁸⁹ Biopsies performed more than 48 hours after lesion appearance may have a negative DIF result because immune deposits rapidly degrade.^90,91 For many active inflammatory conditions, the biopsy specimen should include the advancing edge of the lesion without obtaining a significant amount of normal perilesional skin.⁹² Additionally, when medium-vessel vasculitis such as PAN is suspected, the biopsy specimen must include the subcutaneous fat where the medium-sized vessels are situated.⁹³ Supportive laboratory values for vasculitis include normochromic anemia, leukocytosis, thrombocytosis, and elevated inflammatory markers.⁹⁴

If the biopsy results are positive for vasculitis, the clinician should evaluate for possible secondary causes of vasculitis, including infections, autoimmune diseases, malignancy, and drugs.⁹⁴ The authors recommend an infectious diseases panel including hepatitis B and hepatitis C, HIV, QuantiFERON-TB Gold (Qiagen), rapid plasma reagin, a COVID-19 test, and the aforementioned autoimmune panel; age-appropriate malignancy screening; and obtaining a history of drug use over the past 6 months. Nearly any drug can cause vasculitis; the agents most commonly reported to cause ANCA-positive vasculitis include hydralazine, propylthiouracil and related drugs, leukotriene inhibitors, sulfasalazine, minocycline, D-penicillamine, ciprofloxacin, phenytoin, clozapine, and allopurinol. In drug-induced vasculitis, lesions typically appear to be in the same stage of healing, which is not always seen in other small-vessel vasculitis, including LCV.^95,96 A referral to a rheumatology and/or dermatology specialist is indicated to determine the type of vasculitis, extent of disease, and treatment.

Suspected infection

Microbiologic analysis should always be included in evaluation of an ulcer biopsy specimen. Infection requires treatment with antibiotics and may necessitate referral to an infectious diseases specialist. Atypical ulcers caused primarily by infection may be due to rare agents from the environment or opportunistic bacteria and fungi. An endemic distribution or a history of outdoor activity may aid in diagnosis.²⁸ Laboratory findings such as leukocytosis and elevated inflammatory markers are supportive of a diagnosis of infection. Infections may coexist with other ulcer etiologies and can interfere with wound healing. Immunosuppressants are the mainstay in the treatment of inflammatory ulcers, and it is vital to treat the infection before managing a potentially coexisting etiology.

The clinician should also consider the presence of colonizing bacteria if the ulcer has stalled, but there are no signs of infection.^97,98 A bioburden (the number of microorganisms that inhabit an ulcer) of greater than 10⁵ bacteria per gram of tissue is considered to cause infection and delay ulcer healing⁹⁹; this quantification has been questioned, however, and not every laboratory can perform the test.¹⁰⁰ Clinically, it may be difficult to distinguish between colonization and infection. Bright pink hypergranular tissue that bleeds easily may be a sign of a high bioburden. Classic signs of infection and inflammation are rubor, calor, tumor, dolor, and loss of function.⁹⁸ However, delayed ulcer healing may be the only clinical sign of infection.¹⁰¹Staphylococcus aureus, P aeruginosa, and B-hemolytic streptococci are commonly isolated organisms in infected and clinically noninfected ulcers.⁹⁸

Atypical ulcers may be resistant to treatment and have a slow healing trajectory. Wound bed optimization and adjunct care modalities are essential for successful management. Regardless of the etiology of the wound, the ulcer must be converted into a so-called healable wound and kept free of infection. A wound is healable if it is possible to remove the biofilm and nonviable tissue from the base and edge of the wound to facilitate healing.^102,103

Traditionally, several types of wound debridement techniques have been used in clinical practice, including autolytic, enzymatic, biologic, mechanical, and sharp. Various factors determine the choice of debridement method: suitability to the patient, wound type, anatomic location of the wound, and extent of debridement required.¹⁰⁴ Guidelines for frequency of sharp debridement of atypical ulcers have not been established; however, regular weekly debridement of most chronic wounds, as part of a multifaceted treatment strategy, usually results in improved healing.¹⁰⁵ Sharp debridement can cause considerable pain, and it may only be possible with adequate analgesia, either topical, injectable, or in the operating room under general anesthesia. Frequently, a combination of all 3 methods of analgesia is necessary.

Several dressings exist, from hydrocolloids, hydrogels, alginates, and collagen to cell-based biologic topical therapies. Many of these dressings have additional anti-inflammatory and autolytic debridement properties. However, the basic rule of effective wound care remains the same: maintenance of a moist healing environment.

Energy-based modalities can be helpful because of the pain-reducing, angiogenic, vasodilatory, and antibacterial capabilities. Low-frequency, noncontact ultrasound,¹⁰⁶ electrical stimulation,¹⁰⁷ and ultraviolet C light¹⁰⁸ offer less traumatic means of facilitating wound healing and reducing the bacterial burden. They are excellent adjuvant treatment options for wounds that do not positively respond to standard-of-care methods.

A standardized approach to the diagnosis and management of atypical ulcers is lacking. The coexistence of various comorbidities plays a key role in pathogenesis and treatment. The authors propose a stepwise method with the goal of assisting physicians in the clinical identification and laboratory workup of atypical ulcers.

A limitation of this review is that although the algorithm is intended to guide clinical decision-making, it may not be applicable to every patient and is not inclusive of all diagnoses. It may be necessary to individualize the diagnostic workup to the patient’s history and presentation. There is a very broad range of etiologies for atypical ulcers, and the authors attempt to simplify workup into 5 main categories: neoplasia, PG, infection, vasculopathy, and vasculitis. Many rare causes are not included in this clinical guide, including but not limited to calciphylaxis, Martorell ulcer (hypertensive ischemic leg ulcer), drug-induced causes, and external causes of atypical ulcers. If the clinical picture and laboratory findings are inconsistent with the algorithm, these rarer causes should be considered. Mixed etiologies may also be encountered in clinical practice. Of note, venous ulcers, the most common type of lower extremity ulcer, are not included in the algorithm and require a different workup. Some clinical suspicion for an atypical ulcer is required to best use the algorithm presented herein. If a venous ulcer is not healing properly, evaluation with a biopsy and consideration of atypical causes is warranted.

Any chronic ulcer that does not respond to standard therapies should be reevaluated for potential atypical etiologies. If perfusion is adequate and there are no signs of infection, the authors recommend an ulcer biopsy with microbiology, DIF, and histopathologic evaluation as the standard of care in diagnosis. Laboratory testing, including an autoimmune panel, a hypercoagulable panel, and an infectious diseases panel, can further aid in making a diagnosis. Atypical ulcers often require multidisciplinary care, with input from specialists in rheumatology, dermatology, infectious diseases, wound care, vascular surgery, and hematology/oncology. Communication between members of the health care team is essential for accurate diagnosis and treatment.