Uncommon leg ulcers in the lower extremity

Article Outline

• Abstract
• Methods
• Results
• Discussion
• Conclusion
• Author contributions
• Appendix
• Appendix I: Participating centers
• References
• Copyright

Objective

To determine the prevalence of uncommon ulcers, unrelated to venous or arterial etiology, in patients presenting to vascular clinics.

Methods

This was a multicenter prospective study of consecutive patients presenting with lower extremity ulceration. The settings were university hospital outpatient centers and venous clinics. A total of 799 limbs in 710 patients with leg ulcers were evaluated. Patients with venous ulcer disease and with evidence of arterial disease with an ankle-brachial index less than 0.7 were excluded from the study. Out of 710 patients, 17 patients with a total of 21 limbs fit the criteria for inclusion. All limbs included in this study underwent physical examination, ankle-brachial index measurements, duplex ultrasonography, and skin biopsies.

Results

The mean age of patients with uncommon ulcers was 65.6 years, and the mean duration was 5.5 years. A total of 2.1% of all leg ulcers seen were due to uncommon etiology unrelated to venous or arterial pathology. Most of these ulcers were located in the medial lower calf (n = 19). In six patients with ulcers, the histology did not reveal any specific cause; five had a neoplasia, three had chronic inflammation, two had sickle cell disease, two had vasculitis, one had rheumatoid arthritis, one had pyoderma gangrenosum, and one had ulcer due to hydroxyurea.

Conclusions

The prevalence of leg ulcers unrelated to arterial and venous disease that presented with signs and symptoms of chronic venous disease was 2.1%. Their etiology is variable, most often including vasculitis, neoplasia, metabolic disorders, infection, and other rare causes. Early identification of uncommon ulcers may facilitate timely and appropriate management.

Chronic leg ulceration is a common condition with limited epidemiologic data. Some studies report prevalence rates between 0.18% and 2% of the European population¹, ² and up to 5% of the population over 65 years of age.¹ The overwhelming majority of leg ulcers are of venous origin, cited in the literature from anywhere between 45% and 90% of all leg ulcers.¹, ² The second most common cause of leg ulcers is arterial occlusive disease, followed by neuropathic ulcers. Interpretation of these data has been complicated by the recent shift toward arterial and mixed ulcers, likely because of the aging population and improved detection of arterial disease.¹ The high prevalence of risk factors for atherosclerotic occlusion, especially in Western populations, also contributes to the increasing incidence of ulceration.² Proper identification of the etiology of leg ulcers is imperative for appropriate management, because incorrect treatment may cause significant harm.²

Venous ulcers are classically located in the gaiter area with the appearance of an irregular border, fibrinous debris, extensive granulations, and weeping; the surrounding skin may demonstrate edema, hemosiderin pigmentation, hyperkeratosis, atrophie blanche, or cellulitis.¹, ² Some ulcers that appear to be venous are of other etiologies. Carcinomatous growth can be masked as a deteriorating leg ulcer.³ Case reports have described livedoid vasculitis or calciphylaxis in patients who were otherwise expected to have venous ulcers.⁴, ⁵ However, information on ulcers with uncommon etiologies is lacking. Therefore, this study was performed to determine the prevalence of these ulcers in patients presenting to a vascular clinic.

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Methods 

A total of 710 patients and 799 limbs with leg ulcers from various centers were evaluated. Patients with leg ulcers of nonvenous etiology and nonarterial ischemic disease were included in the study. They were selected from consecutive patients with leg ulcers (class 6 according to the CEAP classification⁶) attending a venous clinic. The ulcers were associated with signs and symptoms of chronic venous disease. These included pain, swelling, burning sensation, itching, heaviness, restless limb, skin discoloration, and lipodermatosclerosis. They were located on the medial malleolus, lateral malleolus, or calf. Patients with foot ulcers were not included in the study. Appreciable arterial disease that may have contributed to the ulcer formation was eliminated by including only those patients with an ankle-brachial index of greater than 0.7. These patients were also excluded from the multicenter study and therefore were not available for this study. Patients with foot ulcers were unlikely to have venous disease and were excluded as well.

Duplex ultrasonography was used to investigate the veins in the lower extremity from groin to ankle. The femoropopliteal veins; deep calf veins; great saphenous veins, small saphenous veins, and their tributaries; nonsaphenous veins; and perforating veins were evaluated in all limbs. Reflux was considered to be present when the retrograde flow lasted longer than 1 second in the femoropopliteal veins and more than 0.5 seconds in the superficial and deep calf veins. Evidence of thrombosis was documented by the noncompressibility of the vein, visualization of the thrombus, filling defects on color mode, intraluminal webs, recanalized intraluminal channels, and wall thickening. Limbs with reflux or obstruction were excluded.

The physical examination, the ankle-brachial index, and the ultrasound investigation were performed by specialists in vascular medicine or vascular surgery. The participating centers had at least 3 years of experience in examining patients with chronic venous disease. All limbs that were included in this study underwent skin biopsies. A 3-mm punch biopsy or incisional biopsy provides a full-thickness tissue sample with minimal scarring.⁷ The data were inserted in a customized Microsoft Access database (Microsoft Corp, Redmond, Wash).

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Results 

Out of 799 patients with leg ulcers, 17 patients with 21 ulcerated limbs were included in the study (Table I). Four patients had bilateral ulcers. The mean age was 65.6 years (SD, 15.2 years), and the mean duration of the ulcers was 5.5 years. The location of the ulcers was predominately on the medial aspect of the lower calf (n = 19): one was located in the anterolateral and one in the posterior aspect of the calf. Three patients demonstrated venous reflux by duplex ultrasonography. Two of them underwent stripping of the great saphenous vein and stab avulsions of the varicosities. The third patient had injection sclerotherapy of a calf tributary. The deep veins were normal in all three patients, and no other venous abnormality was found. Despite of the successful treatment for the reflux, the ulcers still persisted. The third patient had also an ankle-brachial index of 0.7, which decreased to 0.58 after exercise. He had a significant stenosis in the superficial femoral and popliteal arteries. Both lesions were successfully treated with percutaneous transluminal angioplasty, and the ankle-brachial index increased to 0.92. The ulcer was reduced in size after the arterial and venous treatment but never healed. None of the patients had trauma, deep venous thrombosis, superficial venous thrombosis, congestive heart failure, chronic renal failure, hepatic failure, diabetes mellitus, or dependency.

Table I. Characteristics of the ulcers found on 21 patients

ABI, Ankle-brachial index; u, upper calf; m, mid calf; l, lower calf; med, medial; nl, normal; abx, antibiotics; post, posterior; ant-lt, anterior lateral.

The size of the ulcer varied. The largest diameter ranged from 2 to 14 cm. The ulcers had characteristics of a chronic wound. Most of them were highly inflamed and had necrotic tissue and hyperproliferation in the surrounding skin. On closer inspection, there were different characteristics in many ulcers, but this information was not systemically collected. When the patients were found not to have arterial or venous disease, they were sent to a dermatologist and had a skin biopsy.

Three patients were being treated with antibiotics for cellulitis with concurrent lymphedema. Two other patients were also being treated with antibiotics. These two patients were given antibiotics by their referring physicians but were not shown to have an infection. Obesity was not an exclusion factor, and two of our patients with undetermined pathology were obese, with a body mass index of 34 and 39 kg/m².

Pathology was identified in 15 limbs of 13 patients (Table II). Two patients had no histologic analysis because the biopsy specimens were lost in the pathology department and the patients refused to have another biopsy performed. Two of the four patients with bilateral ulcers had undetermined pathology despite histologic study. Two patients with venous reflux had a histologic diagnosis of squamous cell carcinoma (SCC). One patient each had ulcer pathology that revealed Kaposi sarcoma, carcinoma, basal cell carcinoma (BCC), pyoderma gangrenosum, and hydroxyurea. The patient with the Kaposi sarcoma was immunosuppressed. Histologic diagnoses were obtained in two patients with bilateral ulcers. One patient had nonspecific vasculitis; the other had pathology that confirmed sickle cell anemia.

Table II. Pathology results

SCC, Squamous cell carcinoma; BCC, basal cell carcinoma.

One patient with a combination of mild reflux and an ankle brachial index of 0.7 had an ulcer etiology of rheumatoid arthritis. Three patients with cellulitis receiving antibiotic therapy had pathology consistent with chronic inflammation.

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Discussion 

The differential diagnosis for leg ulcers is extensive. Fortunately, most of the conditions are rare and exist in the literature as small case series or case reports. The most common etiologies of leg ulcers can be grouped into venous, arterial, or neuropathic ulcers. In our study, uncommon leg ulcers accounted for 2.1% of all leg ulcers. Appendix II (online only) includes the results from a literature search for case reports of uncommon leg ulcers in adults. Clearly, our study has underestimated the prevalence of uncommon leg ulcers because many of those patients do not go to vascular clinics. This was also because in this study, only ulcers that had a venous appearance and location were included. Furthermore, the rest of the patients who had venous etiology and arterial disease did not have a biopsy performed. Therefore, other patients from the same pool were missed.

One patient in our study had pyoderma gangrenosum located on the medial aspect of the mid calf. It is an uncommon but impressive ulcer of unknown etiology. Fifty percent of cases are associated with chronic disease, and the other 50% are considered idiopathic.⁸ Lesions are most commonly found on the lower legs, but they may occur anywhere on the skin.⁹ Usually they begin as painful pustules, with rapid development of necrosis and ulceration. Fully established lesions show single or multiple ulcers with well-defined, raised, purple, serpiginous, and undermined borders.⁷ There are also several variants, and this can make the diagnosis difficult. Investigations including skin biopsy should be undertaken to rule out other etiologies.⁷ The initial goals of treatment are to address any underlying disorders and provide adequate wound care. Systemic treatment with corticosteroids followed by cyclosporine or other immunomodulatory agents has been successful in treating pyoderma gangrenosum.²

Leg ulcers are a common complication in patients with homozygous sickle cell disease and those with associated α-thalassemia, with prevalence rates from 8% to 10% of patients aged 10 to 50 years.¹⁰ Contributing factors to ulcer formation include vessel obstruction by sickled cells, increased venous and capillary pressure, secondary bacterial infection, and decreased oxygen-carrying capacity of the blood.⁹ The medial malleoli are the most common site of leg ulceration in sickle cell disease and in other chronic hemolytic anemias, suggesting perhaps that stasis may play a role in leg ulceration associated with chronic hemolytic anemia. These ulcers are often bilateral, persistent, and recurrent. This was illustrated in the patient in our study with bilateral ulcers on the medial aspect of the lower calves. Depending on the extent of the lesions, treatment modalities may include bed rest, debridement, wet-to-dry saline dressings, blood transfusions, and topical antibiotics.¹¹ Skin grafts and myocutaneous flaps may be required for extensive ulcers.

Rheumatoid arthritis and Felty syndrome are commonly associated with leg ulcers. Studies report that 9% to 10% of patients with rheumatoid arthritis¹², ¹³ and approximately 25% of patients with Felty syndrome have leg ulcers. The etiologies of these ulcers are frequently multifactorial. Concurrent venous or arterial disease is often contributory, as seen in our study with one patient who had rheumatoid arthritis with concurrent mild venous reflux and an ankle-brachial index of 0.7. Other causes include vasculitis, diabetes, deformities, trauma, or pressure from ill-fitting shoes.² Occasionally the cause is uncertain. Oien et al¹² reviewed 20 cases of leg ulcers in patients with rheumatoid arthritis and reported 1 patient with a leg ulcer of undetermined etiology. No further discussion was made regarding this finding. This nonvenous, nonarterial ulcer likely represents a less common ulcer similar to those seen in our study. Two patients had undetermined pathology despite histologic study.

Leg ulcers have been documented as a rare complication of long-term hydroxyurea treatment in patients undergoing therapy for myeloproliferative disorders.¹⁴ These painful, persistent ulcers may not manifest until after a duration of 2 to 15 years of treatment.² Usually located on the malleoli, the ulcer appears fibrous, with atrophic periulcerous skin. Twenty-four case reports were found in the literature between 1996 and June 2004. One multicenter retrospective study of 41 cases of leg ulceration during hydroxyurea therapy noted that 80% of the ulcers completely recovered after discontinuation of the drug; the rest had improvement and reduction in ulcer size.¹⁵ One patient in our study had a hydroxyurea ulcer on the medial aspect of the lower calf for 2 months. The duration of hydroxyurea therapy was 3 years. After the discontinuation of the drug, the ulcer was healed.

Calciphylaxis is a rare condition that can develop as a complication of secondary hyperparathyroidism, which most commonly occurs in patients with end-stage renal disease. Up to 4% of patients receiving renal dialysis may show signs of calciphylaxis.¹⁶ It is characterized by excessive calcium deposition in the skin, soft tissues, and arteries. Patients may present with a range of skin manifestations, from painful subcutaneous nodules to nonhealing extremity ulcers and gangrene.¹⁷ The exact pathogenesis remains uncertain. Ischemic necrosis preferentially affects cutaneous vessels of the trunk and limb girdle. There is often rapid onset, with large, painful plaques that evolve into full-thickness necrosis and gangrene, similar to that seen with warfarin-associated necrosis.⁷ Treatment includes local wound care, correction of the calcium/phosphorus ratio, and surgical evaluation for possible arterial revascularization and parathyroidectomy.¹⁶

Five patients had ulcers of neoplastic origin. Two patients with venous reflux presented with ulcer etiologies of SCC. As mentioned previously, stasis ulcers are likely to degenerate into malignancy.³ The ulcers may often be painless, appear hypertrophic or hemorrhagic with irregular borders, and exhibit a slow progressive growth. The duration of each ulcer with SCC in our study was 18 and 15 years. One epidemiologic study noted an increase in the incidence of SCC in venous ulcers.¹⁸ It is the second most common form of skin cancer and often arises on sun-exposed areas of middle-aged and elderly individuals of fair complexion. It can also occur on non–sun-exposed areas such as the genitals and mucous membranes. It is interesting to note that SCC is the most common type of skin cancer in African Americans, often involving skin that is not chronically sun-exposed.¹⁷ The ulcers with SCC in our study were in the gaiter area, a location consistent with venous ulcers.

BCC is the most common type of skin cancer, typically arising on areas of chronic sun exposure, especially the head and neck. However, 8% of BCC arises on the lower extremity.¹⁹ It may appear as a chronic ulcer refractory to treatment or may even appear as a benign ulcer with adequate granulation tissue, without the classic rolled pearly border or surface telangiectasia. One patient in our study had a histologic diagnosis of BCC. He had an ulcer that was located in the lower calf/malleolus. Most lesions of both SCC and BCC can be treated with various surgical modalities, including cryosurgery, electrodesiccation and curettage, excision, and Mohs surgery.²⁰

A variety of other atypical causes, as well as idiopathic or unknown causes of leg ulcerations, have been reported.²¹ For instance, vasculitis is a known condition that causes ulcerations.²² Scott et al²³ diagnosed leg ulcers in 38% of patients with systemic rheumatoid vasculitis. Both limbs in one patient in our series were diagnosed with vasculitis by ulcer biopsy, and this was the likely cause for persistence. The diagnosis of vasculitis as the causative agent for an ulcer is difficult, given the low yield associated with ulcer edge biopsies.²⁴ Furthermore, microbial colonization of the ulcer per se can cause a histologic picture of bacterial necrotizing vasculitis. Ulcers in four limbs in our patient population were not attributable to any of the known causes. The patients had a normal duplex scan and biopsy of the ulcer.

Three patients with cellulitis and lymphedema had chronic inflammation on the biopsy sample. Probably these patients do not need to have a biopsy, but it is difficult to make such a recommendation because the sample is so small. These patients had no other vascular disease. Usually patients with lymphedema and ulceration have arterial or venous disease or cancer.²⁵, ²⁶ The prevalence of lymphedema alone in a large prospective study was 2.5% (17/689).²⁷

An ulcer that fails to heal after 3 to 4 months of wound care should be biopsied. The biopsy should be performed of the ulcer edge for a diagnosis and to rule out malignancy. If a biopsy is intended to determine an uncommon cause of ulceration, including vasculitis, both the edge of the ulcer and the ulcer bed should be sampled.²⁸ Punch biopsies (3-4 mm) or a wedge or a rectangular biopsy using a scalpel will harvest sufficient tissue for histologic analysis. If malignancy is suspected, several biopsies should be obtained from the wound bed by using either a shave or punch method. If an atypical wound infection is considered, a biopsy for tissue culture should be performed.²⁹ A total of two patients with four limbs in our study had pathology reports showing undetermined pathology. If an unusual leg ulcer is present and the biopsy is not helpful, more specific tests should be part of the workup. For example, cryoglobulins may be associated with hepatitis C and leg ulceration. Therefore, hepatitis C serologies and serum levels of cryoglobulins may be helpful in making the diagnosis.³⁰ It is important to keep in mind that there are numerous staining techniques available to detect vascular pathology, micro-organisms, malignancies, dermatologic disorders, or storage diseases. The pathologist should receive detailed information about the clinical problem and the potential differential diagnoses.² In our case, an extensive battery of tests was performed, but all results were nondiagnostic.

In general, though, we recommend arterial and venous testing before any other test because the prevalence of vascular disease has been shown to be very high in many clinical and epidemiologic studies. Also, many ulcers have mixed etiology, and arterial and venous testing can demonstrate the vascular pathology that may contribute to the ulcer formation.

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Conclusion 

Extremely rare ulcers of numerous etiologies exist only as case reports scattered throughout the literature. We found uncommon leg ulcers in 17 patients out of 710 patients evaluated for leg ulcers. Vasculitic, bacterial, viral, metabolic, and neoplastic ulcers have been described in single case reports or small case series. Such ulcers and those refractory to initial treatment necessitate referral for further evaluation. As mentioned previously, biopsies are not always confirmatory. However, identification of these patients in the setting of a vascular clinic may provide more accurate data on the prevalence and etiology of uncommon leg ulcers. More importantly, it may facilitate the earlier identification neoplastic ulcers.³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³, ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸

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Author contributions 

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Appendix 

Additional material for this article may be found online at www.jvascsurg.org.

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Appendix I: Participating centers 

Nicos Labropoulos, Danielle Manalo, Jay Tiongson, Landon Pryor, Luis Leon, and Apostolos K. Tassiopoulos, Loyola University Medical Center, Maywood, Ill; Nima Patel and Peter J. Pappas, University of Medicine and Dentistry of New Jersey, Newark, NJ; Berndt Arfvidsson, Bo Eklof, and Robert Kistner, Straub Foundation, Honolulu, Hawaii; Kostas Delis and Andrew N. Nicolaides, St Mary’s Hospital, Imperial College, London, UK; Dimitris Tsantillas, Praxis für Gef. Chirurgie and Phlebologie, Augsburg, Germany; Paolo Zamboni, University of Ferrara, Ferrara, Italy; Athanasios D. Giannoukas, University of Thessaly, Larissa, Greece; Carmen L. Porto, State University of Rio de Janeiro, Rio de Janeiro, Brazil; Fanilda S. Barros, Angiolab, Vitoria, Brasil; and Carlos A. Engelhorn and Ana L. Engelhorn, Pontificia Universidade Catolica do Parana, Curitiba, Brasil.

APPENDIX II, Online only. Case reports of nonvenous, nonarterial ulcers in adults, 1966 to July 2006

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