Understanding the Zebras of Wound Care: An Overview of Atypical Wounds

Atypical etiologies account for approximately 5% to 20% of chronic ulcerations,¹ whereas 43% of chronic ulcerations are infected ulcerations, 22% are diabetic ulcerations, and 19% are vascular ulcerations.^2-5 Because of the lower proportion of atypical etiologies, research and industry interest in these ulcerations is lower than in the more common ulceration etiologies. The ability to recognize these so-called zebras, or wounds that are epidemiologically rare, can be critical to the treatment course and the patient’s overall well-being.⁶ An uncommon etiology should be suspected clinically when a wound does not show signs of healing with conventional care, when pain is out of proportion to the clinical presentation, or for the wound with an atypical clinical appearance.^6-8 Additionally, an etiology may be uncommon in the United States but typical in other countries.

Atypical wounds may be categorized into different groups, including inflammatory ulcers, vasculopathies, neoplastic ulcers, hematologic ulcers, infectious ulcers, hydroxyurea-induced ulcers, and heroin-induced ulcers.⁵ Ulcer categorization also may vary by the clinician evaluating the wound. In addition, many patients with diabetes may have components of vasculopathic, inflammatory, and infectious processes that contribute to the wound.³ A complete patient history should be obtained, and the pathophysiology of various comorbidities should be considered. This article provides a general overview of various atypical wound etiologies, presentations, and clinical appearances, as well as current treatment protocols.

Pyoderma gangrenosum (PG) is a relatively uncommon dermatosis of neutrophilic origin. It often presents as an ulcerative skin disorder, with accompanying inflammation. It most commonly presents as a papular or pustular distribution with violaceous undermined borders or as the result of pathergy (Figure 1). Pyoderma gangrenosum ulceration often has a purulent base with exuberant amounts of discharge.

Pyoderma gangrenosum presents in 3 to 10 per 1 million people per year.⁹ It can affect anyone from childhood through adulthood; however, women are more frequently affected than men. Most of those individuals in whom PG develops also have an underlying condition such as inflammatory bowel disease, arthritis, or various hematologic disorders.¹⁰ The exact mechanism of PG remains unclear, although neutrophil dysfunction, genetic factors, and systemic inflammation may play a role. Neutrophils are the prominent cell type in pathologic specimens.^11-13 Pyoderma gangrenosum is a diagnosis of exclusion; often, tissue biopsies show only acute and chronic inflammatory changes.

Pyoderma gangrenosum clinically manifests in various ways and is often classified into 4 subtypes: ulcerative (typical), bullous (atypical), pustular, and vegetative (superficial granulomatous). Ulcerative, or typical, PG begins as a tender papule, vesicle, or pustule.¹⁰ It typically appears at the site of trauma but may also appear on normal skin. It most commonly occurs in the lower extremities or the trunk. The edges of the area of ulceration usually are described as being bluish and are typically undermined. The ulcer base appears necrotic and purulent into subcutaneous fat or fascia. Resolution of these ulcers tends to lead to scar formation.¹⁰

Bullous, or atypical, PG is much less common than ulcerative PG. Bullous PG often affects the face and upper extremities. Affected persons present with a blue or blue-gray bulla that progresses to a superficial spreading ulcer to the affected areas. A strong association exists between bullous PG and hematologic disease.^14,15

Pustular PG arises during acute exacerbation of inflammatory bowel disease. Affected patients typically present with an eruption of painful, erythematous pustule formations, as well as fever and joint pain.^10,16 Vegetative PG presents as a mildly painful nodule, plaque, or ulcer and is often indolent. It is often similar in appearance to verrucae. The difference between verrucae and vegetative PG is that vegetative PG lacks undermining borders and purulent bases and often affects the head and neck.¹⁰

Management of PG typically consists of localized wound care, including normal saline or mild antiseptic cleansing before dressing changes. Promotion of a moist wound environment without the dressing sticking to the base is necessary because of the pain experienced with these wound types. A typical dressing for PG includes alginates on the surrounding skin to avoid maceration in combination with absorptive dressings overlying the base. The use of wet-to-dry dressings, debridement, caustic substances (eg, silver nitrate), or any other type of dressing that would cause wound pathergy must be avoided.^17,18 The application of topical corticosteroids to surrounding wound areas to decrease inflammation has been suggested, but this idea is supported by very few retrospective studies.^19,20 The topical steroid used must be high potency (eg, clobetasol propionate) and should be applied twice daily to affected areas and used as an adjunct to other local wound care.^19,20 Cellular- and tissue-based products are increasingly being used in the management of PG. Chan et al²¹ described the use of surgical debridement followed by application of fetal bovine tissue to provide a wound bed with well-vascularized tissue. Debridement is important for successful healing and is becoming increasingly common in the surgical management of PG. The use of cadaver allograft results in integration of the graft and carries a lesser risk compared with the risk associated with harvesting autografts.²² Pharmacologic use of dapsone (an antineutrophilic agent), cyclosporine, and tumor necrosis factor alpha (TNF-α) inhibitors has also shown to be an effective adjunctive therapy to local wound care. Few studies have been done on the use of TNF-α inhibitors in the management of PG, but significant improvement was reported in a case series of 4 patients with PG.²³ Referral to a pain management specialist should be considered if a patient has pain out of proportion to the clinical presentation of the ulceration.^19,24,25

Calciphylaxis occurs in people with chronic kidney disease. Laboratory values used to evaluate the risk level for development of calciphylaxis include bone morphogenetic protein, complete blood count, liver function, inflammatory markers, hypercoagulation, parathyroid levels, and autoimmune indicators. Morbidity associated with calciphylaxis is related to nonhealing wounds, and the 1-year mortality rate in patients with calciphylaxis ranges from 45% to 80%.²⁶ Sepsis is the leading cause of death in patients with calciphylaxis.

Painful skin lesions, livedo reticularis, violaceous plaques, and indurated lesions are markers of calciphylaxis (Figure 2). These lesions typically have a presentation that coincides with the bursting of small blood vessels near the skin, creating a purplish appearance and a lace-like pattern. After these areas blister and ulcerate, patients are at increased risk for infection. These ulcerations may resemble eschar in appearance. These patients are also at risk for vascular calcifications, which increases the likely associated comorbidities. Definitive diagnosis requires biopsy and histological evaluation. Calcification with microthrombi and hyperplasia of small dermal and subcutaneous arteries are histologic features of calciphylaxis.

After management of renal disease, the most common first-line treatment for calciphylaxis is intravenous sodium thiosulfate. Other treatments include wound care management, hyperbaric oxygen therapy, pain management, and close monitoring of calcium and phosphorus levels.²⁷ Sepsis is a reason for the high level of morbidity associated with calciphylaxis. Infected wounds associated with calciphylaxis must be treated promptly. Surgical debridement and/or maggot therapy have both been shown to be viable options. Debridement has been shown to be most effective when combined with a healthy wound bed and skin grafting. One study reported a 62% survival rate after surgical debridement compared with a 27% survival rate when surgical debridement was not performed.^28,29

Lichen planus has a presentation that helps differentiate it from other wounds. It presents in the form of pruritic, polygonal, erythematous, and/or flat lesions, and it frequently occurs in patients with diabetes (Figure 3). There are many variants of lichen planus in the general population. Histopathologic examination reveals similar features between lichen planus and lichen planus variant lesions. Papules often present with a dry, shiny surface in streaks known as Wickham striae.³⁰ The lesions tend to favor flexor surfaces of the forearms, wrists, and ankles, as well as the hands, shins, and trunk. Oral lichen planus is also common and appears as white stripes with a reticular pattern. Lichen planus affects both men and women equally. Histopathologic features include wedge-shaped areas of hypergranular tissue in the epidermis that have a defined border. On microscopic examination, lichen planus also demonstrates saw-tooth acanthosis (overgrowth) of the rete ridges. These lesions usually self-resolve within a few years after onset. The treatment goals are to shorten the time to resolution and to provide symptomatic relief of the lesions and ulcerations. In addition to wound care management, management typically consists of topical corticosteroids or cyclosporine.^30,31

Necrobiosis lipoidica is a granulomatous disorder characterized by groups of papules that coalesce into well-circumscribed erythematous patches and plaques with yellow-brown centers (Figure 4). These lesions subsequently atrophy and ulcerate, especially when they are subjected to trauma.^31-34 The patches and plaques that form in the early stages of necrobiosis lipoidica have decreased or no sensation.³⁵ The ulcers, which form in the late stage of the disorder, may become painful, whereas the preulcerative lesions are generally asymptomatic. The complications of ulceration in necrobiosis lipoidica include secondary infection and progression to squamous cell carcinoma (SCC).³⁶ These lesions are most frequently located on the anterior surface of the leg but may also occur on the dorsal surface of the foot or the heel. First-line treatment typically involves corticosteroids. A recent case study noted success with a regimen of prednisone 1 mg/kg daily for 1 week, followed by 40 mg daily for 4 weeks and a titrated dose reduction regimen for another 4 weeks.³⁷ Other treatments include immunosuppressants, such as calcineurin inhibitors, cyclosporine, necrosis factor inhibitors, topical retinoids, hyperbaric oxygen, and ultraviolet phototherapy.³⁶

Infectious ulcerations are not typically seen in the United States; however, with travel and immigration, the number of such ulcerations in the United States may increase. Additionally, infectious ulcerations can be among the first indications of a compromised immune system. The 2 bacteria discussed herein are Mycobacterium and Leishmania.

Mycobacterium ulcerans causes Buruli ulcer.³⁸ Buruli ulcer typically presents as a painless ulceration, but it has a characteristic plaque that develops approximately 1 month into treatment³⁹ (Figure 5). The bacteria produce mycolactone, a toxin that causes immunosuppression and allows the bacteria to spread.³⁹ The ulceration typically has a white and yellow base and occurs in tropical regions. Granulomas are among the most important clinical features. In the absence of granulomas, these ulcers have the highest number of bacilli and low interferon gamma, indicating low cellular protection abilities.³⁹ Current antibiotic treatments are rifampicin 10 mg/kg per body weight daily and clarithromycin 7.5 mg/kg per body weight twice daily.³⁸ Local wound care, surgical debridement, and lymphedema protocols may also be necessary, depending on the progression of the ulceration. One study noted that surgical debridement plus antibiotic therapy allowed for a high healing rate and low recurrence rate, especially in rural areas.³⁹

Cutaneous leishmaniasis is the most common manifestation of leishmaniasis, which is caused by a Leishmania parasitic infection and is transmitted by sandflies.^40,41 The ulcer typically begins as painless nodules or papules on the skin and erupts into ulcerations after weeks or months (Figure 6).⁴⁰ Ulcerations have a varied clinical appearance and depend on a variety of parasite and host factors that are poorly understood.⁴² Typically, a tissue sample obtained from the ulceration is examined for parasitic infestation, or a DNA test for the parasite is performed. In an immunocompromised patient, the ulcerations resolve on their own in 2 to 6 months.⁴² If the ulceration sites become infected, antibiotic treatment is recommended. Scar revision may be necessary. If ulcerations are large or persistent, pentavalent antimonial drugs (ie, sodium stibogluconate or meglumine antimonate) 20 mg/kg per day are used for 20 to 28 consecutive days.¹ Amphotericin B, pentamidine isethionate, miltefosine, and thermotherapy can be used as alternative therapies if necessary.¹

Hidradenitis suppurativa is a chronic inflammatory disease that affects the hair follicles of apocrine sweat glands and is thought to be perpetuated by the microflora in the follicles^43,44 (Figure 7). Although this disease is associated with an array of comorbidities, such as metabolic syndrome, diabetes, atherosclerosis, irritable bowel syndrome, depression, and spondyloarthritis, the etiology is not well understood.⁴⁴ However, genetics and smoking are common factors in patients with this disease. The disease is usually clinically diagnosed and is characterized by inflammatory nodules, sinus tracts, abscesses, and fistulas. The most common areas affected are the perigenital and axillary areas. The wounds are typically painful and malodorous. Additional clinical information gleaned from skin biopsies, magnetic resonance imaging, and bacterial cultures can aid in diagnosis.

Treatment is often multimodal. Patients are encouraged to make lifestyle changes regarding smoking status, weight loss, and exercise.^43,44 Pharmacologic anti-inflammatory therapy may be beneficial. Dressings often include an absorptive layer with a silicone adhesive. Topical antibiotics can be useful in the management of infection. Surgical intervention may be indicated if wounds are deep or infected, or if it would aid in closure. Surgical intervention with resection and/or flap closure is well tolerated, with complete recovery reported in 59.7% of patients in 1 study.⁴⁶ Promising but limited results have been achieved with molecular level intervention, such as TNF antibody therapy or therapies targeted at interleukin 17 and interleukin 1-alpha antibodies.⁴⁷

Artefactual ulcers are often self-inflicted to serve a psychological need for the patient. Typically, a diagnosis of exclusion, these ulcerations are seen in women in their second or third decade and can pose a difficult challenge for practitioners.^45,46 The ulcerations are often sharply demarcated, with geometric or unusual patterns⁴⁶ (Figure 8). The ulcers often are located on the face, trunk, and extremities but not on areas of the body that are harder to reach. Affected patients often connect to the medical field themselves through work or family members needing extensive care and may have a history of borderline personality disorder, eating disorders, or other mental illness.⁴⁵

Psychiatric referral and therapy are the most important aspect of managing these ulcerations, with an emphasis on recognizing hidden stressors and on cognitive behavioral therapy.⁴⁵ Topical occlusive dressings and standard good wound care are also mainstays of treatment. Occlusive dressings have been shown to prevent further self-mutilation.⁴⁶

Hydroxyurea is an antineoplastic agent used to manage many different types of cancer, including leukemia, head and neck cancer, malignant melanoma, and polycythemia vera. Adverse effects of this drug include alopecia, discoloration of the nails, diffuse hypopigmentation, and leg ulcerations. According to the literature, leg ulcerations develop in 9% of patients undergoing long-term, high-dose hydroxyurea therapy for myeloproliferative disease.⁴⁸ Controversy exists concerning whether the ulcers are caused by the myeloproliferative diseases themselves or by the treatment for those diseases. It has been shown that these diseases can impair cutaneous microcirculation.⁴⁹

Hydroxyurea has been found to kill proliferating cells during the synthesis phase of the cell cycle.⁵⁰ Thus, its use could impair keratinocyte and collagen fiber synthesis.⁴⁹ A simple trauma to the skin, such as rubbing, could cause ulceration. Most ulcerations occur near the malleoli or the Achilles tendon region. The typical presentation is a well-defined, shallow ulceration with a fibrotic base (Figure 9). Another finding is of necrotic areas within the wound bed.^48,50

The preferred management of hydroxyurea-induced leg ulcers is the discontinuation of the drug. Healing can take 1 to 9 months after discontinuation of hydroxyurea. Other reported therapies include topical granulocyte-macrophage colony-stimulating factor, recombinant human erythropoietin, or bilayered bioengineered skin substitute.⁵²

Large epidemiologic studies have shown that up to 79.7% of leg ulcers have a vascular etiology (venous, peripheral arterial disease, or mixed).³ Approximately 20% to 23% of patients have wounds caused by other, more complex vascular etiologies.³ Two atypical complex vasculopathies are livedoid vasculopathy and thromboangiitis obliterans.

Livedoid vasculopathy is uncommon. This distinct hyalinizing vascular disease affects only 1 in 100 000 individuals per year.⁵² The pathogenesis of livedoid vasculopathy is not fully understood, but it is related to intraluminal thrombosis of the dermal microvessels, resulting in occlusion and tissue hypoxia.⁵³ Ulcerations caused by livedoid vasculopathy are characterized by atrophic plaques with hyperpigmented borders and telangiectatic vessels (Figure 10). The dorsal aspect of the foot and ankle are most often affected.⁵⁶ The aim of treatment modalities is to improve microcirculation, prevent infection, and provide wound care and pain control.⁵⁴ After these ulcerations heal, they form white atrophic scars.

Thromboangiitis obliterans, also known as Buerger disease, is a nonatherosclerotic, segmental, inflammatory disease that most commonly affects the small-sized to medium-sized arteries and veins of the extremities. This disease is characterized by highly cellular and inflammatory occlusive thrombus with relative sparing of the blood vessel wall.⁵⁵ It affects men more commonly than women and is associated with cigarette smoking. Thromboangiitis obliterans is most prevalent in the Mediterranean, Middle East, and Asia because of the homemade cigarettes with raw tobacco smoked in those geographic areas.⁵⁶

Patients typically present with reports of claudication of the extremities (Figure 11), but pain during rest and ischemic ulceration may occur.⁵⁷ Erythrocyte sedimentation rate and C-reactive protein level are usually normal, and autoantibodies are typically negative.

Smoking cessation is the mainstay of treatment, but pharmacologic intervention has shown promising results. Nicotine replacement is not recommended because of the persistence of claudication symptoms even after smoking cessation. Intravenous iloprost was compared with aspirin in 133 patients with thromboangiitis obliterans and critical limb ischemia.⁵⁸ At 28-day follow-up, 85% of the patients treated with iloprost (58/68) showed improved ulcer healing and pain relief, compared with only 17% of patients (11/65) in the aspirin group.⁵⁸

Basal cell carcinoma

Basal cell carcinoma (BCC) is a skin cancer that originates from the basal layer of the epidermis. Although BCCs are termed carcinoma, they are typically low in metastatic potential. However, they are locally invasive and relatively aggressive to the surrounding tissue. Basal cell carcinoma is common among White people and is rarely found in darker-skinned people. The lifetime risk among Caucasians for the development of BCC is approximately 30%.⁶⁰ It occurs more often in men than in women and is strongly associated with sunlight, with approximately 70% of BCCs occurring on the face.⁶⁰ Those who live closer to the equator are twice as likely to have a diagnosis of BCC than those who live farther from the equator. Smoking is associated with increased risk of BCC.^60-63

Basal cell carcinoma typically arises from ultraviolet radiation-induced carcinogens. Several mutations in proto-oncogenes and tumor suppressors have been identified as risk factors for BCC. It has been suggested that hyperactivity of the hedgehog protein family leads to the development of BCC.⁶⁴

Fifty percent to 80% of BCCs are the nodular type.⁶⁵ These present as flesh-colored or pink papules (Figure 12). It is characterized by a pearly appearance, with telangiectasias present within the papule. The periphery is often more raised than the center and is characterized as “rolled.” Fifteen percent of BCCs are superficial; these scaly, non-firm BCCs occur most commonly on the trunk.⁶⁵ They are usually asymptomatic and can grow to several centimeters in diameter if left untreated.

Basal cell carcinoma is usually diagnosed based on clinical examination and biopsy. Shave, punch, or excisional biopsy may be used in the diagnosis of BCC. Treatment typically consists of excision of the lesion. Prevention is critical to the overall treatment plan. Sun protection is estimated to reduce the chance of BCC by approximately 80%.⁶⁶ The use of other topical treatments, such as topical fluorouracil and the use of nonsteroidal anti-inflammatory drugs, has also decreased the risk of BCC.^67,68

Squamous cell carcinoma

Cutaneous SCC arises from epidermal keratinocytes and is a malignant tumor. It often presents as cutaneous lesions, including papules, plaques, and nodules; all these presentations can be smooth, hyperkeratotic, or ulcerative. It can occur on any skin surface, including the oral mucosa. Squamous cell carcinoma most commonly arises in fair-skinned individuals and in anatomic areas with high sun exposure. However, in dark-skinned populations, the most common anatomic locations are the areas of the skin that are not exposed to the sun.^69,70

Invasive cutaneous SCCs are well-differentiated indurated or hyperkeratotic papules or nodules. They measure 0.5 cm to 1.5 cm in diameter and may present as an ulceration (Figure 13). Poorly differentiated tumors typically involve ulceration, bleeding, and necrosis and are mostly asymptomatic. Both SCC and BCC can arise from metastatic implantation. Other variants of SCC are keratoacanthoma, verrucous carcinoma, and lymphoepithelioma-like carcinoma of the skin.^71-73 Marjolin ulcer is a variant of SCC that typically forms in previously traumatized, chronically inflamed, or scarred skin.⁷⁴

A histopathologic examination is crucial to confirm the diagnosis. A shave, punch, or excisional biopsy can be performed. Biopsies should extend into or through the midreticular dermis to determine the level of invasiveness.⁷⁵ Until a diagnosis is confirmed, disorders such as nummular eczema, psoriasis, PG, and venous stasis ulceration cannot be excluded. Typically, management consists of surgical excision of the lesion, but some topical medications, such as 5-fluorouracil, imiquimod, and ingenol mebutate, have been used in the management of lesions with minimal scarring risk.⁷⁶ Laser therapy and cryotherapy are also effective in the management of superficial lesions.⁷⁵ Radiation therapy is used in patients who cannot undergo surgical excision of the lesions.⁷⁶

Melanoma

Although the severity of BCC and SCC varies from case to case, the most serious form of skin cancer is melanoma (Figure 14). Patients find most melanomas on their own out of concern for discoloration or odd-looking blemishes. The incidence of melanoma increases with age, and the prognosis is based on timely diagnosis, management, and extent of invasiveness.

The 4 major subtypes of melanoma are superficial spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), and acral lentiginous melanoma. Melanomas that spread into the dermis are considered to have metastatic potential. The metastatic likelihood of melanomas is often predicted based on Breslow depth, that is, the thickness of the tumor measured from the epidermal granular cell layer to the deepest part of malignant cells into the dermis or fat.⁷⁷

The SSM is the most common type, accounting for nearly 70% of all melanomas.⁷⁸ These melanomas measure less than 1 mm in depth and are thin, and most of them are curable. The SSMs are often associated with an already existing nevus. They are typically multicolored macules or plaques with an irregular border. Nodular melanoma, the second most common type, accounts for approximately 15% of all melanomas and appears as dark pigmented pedunculated papules.⁷⁸ Unlike SSM, NM is uniform in color with symmetrical borders. The NM subtype is also relatively small, but it is not diagnosed until it is well over 2 mm in depth because of the lack of ill appearance. The LMM lesions are typically associated with sun-damaged skin and occur in older individuals. They typically begin as a tan macule. As the macule enlarges, it becomes darker with different colors.

Acral lentiginous melanoma accounts for less than 5% of melanomas.⁷⁹ This type typically occurs in darker-skinned individuals on the palms, soles, or underneath the nails. The acral lentiginous subtype may manifest with raised areas with ulceration and bleeding. This presentation is indicative of a deeper invasion of the dermis, and it is particularly important to foot and ankle surgeons because this subtype can appear to be a benign lesion such as a callus, wart, fungus, or ingrown nail, or even a nonhealing ulceration.^80,81

Treatment of melanoma consists of surgical excision with a wide margin. Most melanomas have a very low threshold for referral to a dermatologist. Suspicious lesions should be examined every 3 months after the first patient visit. Any variation in symmetry, borders, color, depth, or edges warrants biopsy and referral.⁸¹

Atypical wounds have a poorer prognosis and slower healing rate than typical wounds (eg, vascular wounds, diabetes wounds). The estimated 1-year survival rate after diagnosis of calciphylaxis, for example, is approximately 46%.⁸² Overall, for atypical ulcerations the average healing rate is 0.115 mm per day after identification and implementation of the appropriate treatment; this rate is slower than that for comparable ulcerations of a vascular etiology.⁵ One key aspect of a better prognosis, lower cost of care, and better quality of life is early and appropriate diagnosis and treatment. Biopsies are often vital in wound care to identify and differentiate various wounds. Biopsies are recommended for atypical and recalcitrant wounds to identify the etiology. It is important to note that multiple characteristics or histologic features can overlap in a biopsy with atypical wounds. A biopsy will still require an understanding of the presentation of these different wounds.⁸² A proper diagnosis for an atypical wound can greatly hasten wound closure, reduce the cost of care for the patient and the health care system by reducing the number of doctor visits, and improve the patient’s quality of life.⁸²

A new aspect of wound care involves the increased use of monoclonal antibodies for treatment.²³ Monoclonal antibodies have more specific targets and may have different adverse effects than other common medications.²³ For example, infliximab is used in the management of PG and atypical cancerous lesions. For etiologies that may be beyond the scope of expertise of a wound care specialist, such as malignant tumors, enlisting the help of other specialists or consultation with other wound experts is advised.

Because of the rarity of each wound etiology discussed herein, the literature is scant and relatively few patients are available for inclusion in high-level research. Because information is limited, no universal treatment protocol exists that can be used to manage most etiologies, and opportunities to develop new treatment modalities are limited even as medical technology continues to advance. A limitation of this review is that although many of the more common atypical wound pathologies and current treatment regimens are discussed, it is not all-encompassing and does not address all etiologies of atypical wounds. Additionally, some of the protocols specified have limited or poor-quality research support. Clinicians should systematically and thoroughly review each patient’s wounds and individualize care to optimize results.

The recognition of atypical wounds and implementation of the specific treatment protocol for each type is imperative to improving clinical outcomes and wound healing. An uncommon etiology should be suspected when a wound does not show signs of healing with conventional care after 4 weeks, is associated with pain out of proportion to the clinical presentation, or exhibits an atypical clinical appearance.^6-8 In such instances, a biopsy should be performed, or advanced clinical techniques used to assess the wound etiology. Because of the limited availability of patients with atypical wounds, the literature concerning specific pathologies is limited. More research into each pathology is needed, as is a universally accepted treatment protocol. Although this review does not include all atypical etiologies, the authors hope that it spurs clinicians to earlier suspicion and investigation of atypical wounds to improve patient outcomes.