Etiology of Chronic Leg Ulcers in a Dermatologic Wound Clinic: A Retrospective Observational Study

Chronic wounds are defined as wounds that are difficult to heal or do not follow a normal healing process.^1,2 However, this well-established definition is not complete due to the absence of specific indications regarding the duration of chronicity. There is a lack of consensus about the timeframe used to define chronicity: Martin and Nunan³ defined a chronic wound as a barrier defect that has not healed in 3 months, whereas Leaper and Durani⁴ defined a wound as chronic when it has not decreased in size by 20% to 40% after 2 to 4 weeks of optimal treatment, or when there is a failure of complete healing after 6 weeks. The fact that the very definition of “chronic wound” is not standardized often leads to difficulties in comparing data from different studies.

Chronic leg wounds have several etiologies, and vascular genesis is the most common.⁵ Other conditions frequently associated with leg ulcers are diabetes mellitus, trauma, and prolonged pressure (decubitus ulcers),⁶ constituting about 95% of chronic leg wounds.⁷ Other causes, which are generally defined as rare, account for approximately 5% of chronic leg ulcers.⁸ This category consists of many different etiologies: inflammatory, infectious, neoplastic, drug-related, and others. These ulcers may present with atypical features. Vasculitic ulcers often emerge as multiple polymorphic lesions presenting with purpura or erythema, and they are generally very painful. Neoplastic ulcers are characterized by the presence of hypertrophic granulation tissue that does not tend to heal, easy bleeding, and raised edges.

Although wounds are categorized as skin diseases, the various etiologies lead to a multispecialty approach to care and treatment that often results in an incomplete evaluation of the cases. The main purposes of the present study were to 1) characterize the genesis of chronic leg ulcers, defined as persisting at least 6 weeks, treated in a dermatological wound clinic and 2) compare these data with those available in the literature.

This single-center, retrospective observational study was conducted at the Dermatologic Wound Center of the Dermatologic Clinic of Spedali Civili in Brescia, Italy, in accordance with the Declaration of Helsinki and was approved by the Local Ethic Committee (Protocol Number 4360). The authors identified all patients with chronic leg ulcers who were treated in the clinic from January 1, 2010, through December 31, 2019. Data were collected from electronic medical records. Only patients with chronic leg wounds who underwent at least two or more clinical consultations and received a defined diagnosis were enrolled. Patients were referred to the center from their general practitioners.

The diagnosis was supported by an accurate clinical history collection, a clinical examination by a dermatologist, and, according to the suspected diagnosis, blood tests. In case of uncertain genesis or suspected neoplasia, a skin biopsy was performed for histological evaluation. The total number of leg ulcers biopsied was 56. Ankle brachial index (ABI) was calculated for every patient at the first clinical visit. A rheumatological consultation was made in cases of vasculitis or suspected rheumatological disease. Patients with previously undiagnosed vascular insufficiency underwent color Doppler echocardiography and were evaluated by a specialist. Patients who had a single dermatologic access were excluded from the study, as were those who had skin ulcers located in other anatomic sites.

Statistical analysis was accomplished with SPSS v25 (IBM). The Kolmogorov-Smirnov test was used to analyze normal distribution of collected data. Categorical variables were summarized as percentages and continuous variables by calculating medians and range (minimum and maximum values).

In our wound clinic, 813 patients were treated during the study period, but only 465 patients were eligible for the study. A total of 348 patients were not enrolled because they did not meet the inclusion criteria: 286 patients had chronic ulcers in other anatomical sites and 62 patients could not receive a definite diagnosis. Among enrolled patients, 172 (37%) were males and 293 (63%) were females. The mean age was 74.05 years (SD ± 13.58). The minimum age was 18 years, and the maximum age was 99 years.

A total of 238 patients (51.1%) had a diagnosis of vascular ulcer, which included venous (160 patients, 34.4%), arteriosus (56 patients, 12%), and mixed (22 patients, 4.7%) ulcers (Table). The second most represented etiology was inflammatory, representing 15.3% of cases (n = 71). Inflammatory ulcers refer specifically to those ulcerations in which inflammation is the primary pathologic process resulting in lesion formation.⁹ This group included cutaneous vasculitic ulcers (34 patients, 7.3%), which are the result of a vascular damage caused by an immunologic and/or inflammatory mechanism,⁸ sclerodermic ulcers (17 patients, 3.7%) in patients with a diagnosis of systemic sclerosis, ulcers associated to panniculitis (4 patients, 0.9%), and ulcerated pyoderma gangrenosum (16 patients, 3.4%). Leg ulcers caused by traumatic events constituted the third most common cause (43 patients, 9.3%).

Regarding less common causes of chronic wounds, 28 patients had iatrogenic ulcerations associated with chronic treatment with hydroxyurea (14 patients), methotrexate (11 patients), or radiodermatitis (3 patients). A total of 28 patients had pressure injuries/ulcers caused by the body weight’s downward force on the skin and subcutaneous tissue that lie between a bony prominence and an external surface, such as a mattress or wheelchair cushion.¹⁰ Neoplastic ulcers were identified by biopsy in 15 patients: 10 squamous cell carcinoma, 3 basal cell carcinoma, and 2 Kaposi sarcoma. Eleven leg ulcers were diagnosed as primary infective: Staphylococcus aureus (8 patients) and Mycobacterium ulcerans (3 patients) were isolated on leg ulcer swabs.

Considering metabolic causes of leg ulcers, we identified 3 entities in our group: diabetic foot ulcer, ulcerated necrobiosis lipoidica, and calciphylaxis. Diabetic foot ulcers were identified in 21 patients with a longstanding diabetes mellitus, type 1 or 2. Ulcerated necrobiosis lipoidica was diagnosed in 2 patients. This is a granulomatous disease presenting as indolent atrophic plaques that may present ulceration. Etiology is unknown, but it is often associated with diabetes.¹¹ Calciphylaxis is a rare disease usually associated with end-stage renal disease, as in our 3 patients. This condition depends on the pathological accumulation of calcium in the medial wall of small blood vessels along with fibrotic changes in intima. The progressive arterial calcification can affect multiple body organs, including the skin, brain, lungs, and muscle. Skin signs of calciphylaxis include painful and nonhealing nodules, plaques, and ulcers.¹²

Graft-versus-host disease is one of the most frequent and severe complications of hematopoietic stem cell transplantation and may present with different cutaneous manifestations, like ulceration. We diagnosed 2 cases of leg ulcers associated with this condition.

Two patients had sickle-cell leg ulcers as a complication of sickle-cell disease. The exact pathophysiology is not yet completely known; however, it is established the role of vasculopathy related to chronic hemolysis. These chronic wounds, which generally affects young patients, are very painful, resistant to treatment, and recurring.

The rarest etiology we identified was hypertensive, in only 1 patient. This condition involves small vessels in hypertensive individuals and is also called Martorell’s ulcers. These ulcerations present as painful lesions in hypertensive individuals who may have no overt evidence of arterial disease (there may be palpable pulses and normal ABI).¹³

Prevalence evaluation of leg ulcers by sex indicated that vascular genesis was the most common in both females and males, representing respectively the 51.9% and the 50.1% of the total. For males, the second most common cause was traumatic (11%) and the third inflammatory (9.3%), whereas for females the second most common etiology was inflammatory (18.7%), followed by traumatic (8.2%). Neoplastic ulcers were more represented in males than in females (5.8% vs 1.7%) (Figure 1).

Evaluating a stratification for age, 349 patients in the population were 70 years of age or older, whereas 116 patients were younger than 70. Vascular ulcers were diagnosed in 195 patients older than 70 years (55.9%), representing the first cause of leg ulcer in this subgroup, and in 43 patients < 70 years (37.1%). Considering inflammatory leg ulcers, 36 patients older than 70 years had a diagnosis of inflammatory ulcer, while an inflammatory genesis was found in 34 patients younger than 70 years (10.3% vs 29.3%), representing the most common cause of chronic leg wounds in younger-age patients (Figure 2).

Evaluating the prevalence of venous leg ulcers between sexes in our group, females were more affected than males (36.52% vs 30.81%).

This retrospective observational study found vascular genesis to be the most common etiology of chronic leg ulcers. According to the literature, venous leg ulcers due to chronic venous insufficiency usually range from 50% to 70% of leg chronic wounds.¹⁴ Despite being the most frequent etiology in the current study, venous leg ulcers represented only 34.4% of the total.

The second most common etiology in our population was traumatic in males and inflammatory in females. Prevalence of inflammatory leg ulcers was 20.5% in females (vs 9.9% in males) and included several entities, among which vasculitic ulcers were the most represented. In contrast to the literature reports that approximately 3% to 5% of skin ulcers could be ascribed to a vasculitic disorder,¹⁵ in our study their prevalence was higher (7.31%). This percentage is closer to one described in the observational retrospective study of Körber et al on 354 patients with chronic leg ulcers,¹⁶ in which vasculitic ulcers represented 8.6% of the total. In the same way, our data on the prevalence of ulcerated pyoderma gangrenosum (3.4%), commonly reported as a rare ulcer etiology, confirms the dermatologic data presented elsewhere in the literature.¹⁷ This may depend on the focus and the setting of data collection, which was a specialized wound clinic in both cases. In such a setting, patients could be partially preselected because of therapy-refractory wounds or referred by general practitioners due to a complex clinical situation, possibly suggestive of a rare disease entity.

The main limitation of the current study is the monocentric and retrospective setting. In addition, the epidemiologic data were collected in a second level center, where patients with atypical leg ulcers are usually evaluated. This may have led to underestimating the prevalence of common causes of leg ulcers, such as diabetes mellitus. The likely underestimation of diabetic foot ulcers is due to the fact that they are generally treated in an endocrinologic setting and referred to our clinic only in case of poor response to therapy or complications.

This retrospective observational study investigated the epidemiology of leg ulcers in a dermatologic wound clinic. The data collected from 465 patients during the 10-year study are in accordance with other findings in the literature, with vascular genesis being the most common etiology of leg ulcers, even when uncommon causes are also represented.

The authors hypothesize that the setting of data collection can affect the recorded prevalence of leg ulcer etiology because leg ulcers may be managed by general practitioners or treated in the hospital by different specialists. This disjointed evaluation can lead to errors not only in epidemiological data, but also in the management and treatment of patients. It is hoped that the current study may provide a stimulus for greater awareness of this issue and promote a more integrated and multidisciplinary approach to skin ulcers. Additional research is needed on this topic.

Paola Monari, MD¹; Giulio Gualdi, MD²; Sara Rovaris, MD¹; Anna Venturuzzo, MD¹; Chiara Rovati, MD¹;
and Piergiacomo Calzavara Pinton, MD¹

¹Department of Dermatology, University of Brescia, Spedali Civili Brescia, Brescia, Italy
²Clinic of Dermatology, Department of Medicine and Aging Sciences, University G. D’Annunzio, Chieti, Italy

POTENTIAL CONFLICTS OF INTEREST: none disclosed

Address all correspondence to: Sara Rovaris, MD, Department of Dermatology, University of Brescia, Piazzale Spedali Civili 1, Brescia, 25121 Italy;
email: s.rovaris@unibs.it