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Atypical Ulcers: Wound Biopsy Results From a University Wound Pathology Service
Abstract
Chronic wounds are an increasing health burden across the continuum of care and encountered by a wide variety of healthcare providers and physicians of all specialties. The majority of chronic wounds are caused by vascular insufficiency, neuropathy, or prolonged pressure. Wounds caused by other underlying health conditions or external factors such as radiation or spider bites are usually referred to as atypical. Although a wound biopsy generally is recommended in the case of refractory, nonhealing ulcers or when wounds present with atypical signs and symptoms, little is known about the distribution of atypical ulcers. A retrospective, descriptive study was conducted to describe the proportion and differential diagnosis of atypical ulcer biopsies received during a 2-year period by the wound pathology division in the division of Dermatopathology at the University of Miami Department of Dermatology and Cutaneous Surgery. Of the 350 wound biopsies received for diagnostic purposes, 104 (29.7%) were due to atypical causes. The majority of specimens were neoplasms (n = 24). Pyoderma gangrenosum was the most common atypical diagnosis encountered (n = 14). Vasculitis, predominantly leukocytoclastic vasculitis, and external causes were diagnosed in 16 and 15 biopsies, respectively. This study represents the first published case series of atypical ulcer biopsy results from a wound pathology division. Although the prevalence results cannot be generalized and are likely lower in the general population of patients with nonhealing wounds, the results confirm the usefulness of obtaining wound biopsies to provide a definitive diagnosis and to guide care.
Potential Conflicts of Interest: none disclosed 
Introduction
Wounds generally are defined as chronic when they fail to proceed chronologically and in a timely manner (ie, over a period of 3 months) through the stages of healing to achieve structural and functional integrity. In the United States, the incidence of chronic wounds is an estimated 6 million per year.1 The majority of chronic wounds originates from vascular insufficiency, neuropathy, or prolonged pressure. Atypical wounds are those not secondary to these causes, but rather the result of, among others, infection, metabolic disorders, neoplasms, and inflammatory processes (see Table 1). An estimated 10% of lower extremity ulcers are due to these less frequent etiologies.2
An initial wound patient visit typically comprises a detailed history, a thorough physical examination, and consideration of the need for a wound biopsy. A biopsy usually renders useful diagnostic information to inform management decisions and is especially important when treating an atypical wound. The spectrum of atypical wounds is wide, and knowledge about the rate of various atypical wound diagnoses encountered is limited. A retrospective, descriptive study was conducted to describe the proportion and differential diagnosis of atypical ulcer biopsies received by the wound pathology division in the division of Dermatopathology at the University of Miami Department of Dermatology and Cutaneous Surgery.
Methods
A convenience sample of 350 ulcer biopsies submitted to the University of Miami Wound Pathology Service between January 2008 and December 2010 was retrieved and reviewed. Of the 350 biopsies reviewed, 104 (29.7%) were diagnosed atypical. The biopsies originated from geographically diverse wound centers throughout the US and were obtained by their respective physicians. All biopsies were evaluated and diagnosed by the wound pathology division in the division of Dermatopathology at the University of Miami Department of Dermatology and Cutaneous Surgery. Patient demographic information, ulcer history data, and diagnosis results were entered in an Excel spreadsheet for descriptive analysis. 
Results
The mean age of patients was 61 years. The gender distribution was 2.3:1 (female to male). The average duration of the biopsied ulcer was 15.5 months. The database included most known types of atypical ulcers — eg, malignancy, external causes, inflammatory conditions, metabolic disorders, bullous diseases, infections, hemoglobinopathy, hypertension, and connective tissue disease. Malignancy, the most prevalent category (23% of atypical wounds), comprised melanoma and nonmelanoma skin cancers, as well cancers involving smooth muscle and eccrine glands. Inflammatory conditions included vasculitis (17% of atypical wounds) and pyoderma gangrenosum (PG) (13.5% of atypical sample) (see Table 1 and Table 2). Diagnosed external causes ranged from radiation and arthropod to factitial disease. Nine biopsy results were diagnosed as calciphylaxis (better termed calcific uremic arteriolopathy [CUA]). Bullous diseases included both congenital and acquired types. In addition, both bacterial and fungal organisms were included in the listed diagnoses. The remaining diagnoses were sickle cell disease (n =1), hypertension (n = 10), and systemic lupus erythematosus (n = 6). 
Discussion
This study represents the first published case series of atypical ulcer biopsy results from a wound pathology division. To the authors’ knowledge, no similar work exists from either dermatopathology or pathology services. In this convenience sample, 29.7% of wounds were found to have a diagnosis of atypical. Because this is the first publication evaluating histologic diagnosis of atypical ulcers, no comparisons between these observations and those of other pathology services can be made. Because not all ulcers are biopsied and because physicians are more likely to order biopsies for wounds that fail to heal or present with atypical characteristics, the prevalence observed in this study is probably higher than the national average. Less likely, but possible, is that under-biopsying of wounds leads to missed diagnoses. More probable is that chronic wounds due to common causes may not require a biopsy; biopsies are usually reserved to diagnosis wounds that are unusual in appearance, location, or symptomatology or for nonhealing wounds.2
The suspicion that an ulcer is atypical arises when the clinical presentation differs from what is commonly encountered.3 A wound should be evaluated for an atypical etiology if it is present on a location unusual of a common chronic wound, appears different from a common wound, has unusual symptoms, including pain out of proportion to that of a common wound, or does not respond to conventional therapy.3 Common wounds such as venous ulcers, arterial ulcers, diabetic ulcers, and pressure ulcers are located at medial and lateral aspects of the leg, anterior aspect of the leg, all aspects of the foot and toes, and over bony prominences, respectively. Pain is commonly a sign of infection, but it also may be associated with inflammatory causes of atypical ulcers including PG and vasculitis. Ulcers that do not heal at the expected rate despite receiving treatment should be biopsied to elucidate an undiagnosed etiology or an additional cause. In a retrospective analysis4 on venous leg ulcers and diabetic foot ulcers, a healing rate of 1.5 mm/week had the highest positive predictive value of wound closure at 12 weeks. It is assumed one reason a wound may not heal is because the diagnosis is incorrect, so slow or nonhealing wounds often necessitate a biopsy. At the wound pathology division, a number of stains are used to assist in rendering diagnoses. Table 1 highlights the histopathologic features and special stains.
Atypical Diagnoses
PG. PG was the most common atypical diagnosis encountered, with a total of 14 cases. Among the biopsies received, PG was also the most common suspected diagnosis physicians indicated they wanted to confirm. A combination of clinical and pathologic features often is needed to render a diagnosis, but it should be noted that one of the main values of pathology for PG is to exclude other causes of atypical wounds. Therefore a diagnosis consistent with PG, as opposed to diagnostic of PG, is rendered.
Of the 41 samples sent specifically to rule out PG, five (12.2%) were consistent with PG. The other nine diagnoses of PG were made when the term rule out PG was not included in the pathology submission. PG is difficult to discern; usually a diagnosis of exclusion when pathognomonic and histopathologic features are lacking commonly leads to misdiagnosis of PG.5 In a retrosective study, Weenig et al6 observed a misdiagnosis rate of 10%, causing substantial treatment risks. Despite possible extension of the wound due to pathergy and risk of misdiagnosis, biopsy helps exclude other causes of ulceration. Although no curative treatment exists for PG, long-term remission occurs. Treatment options include topical or intralesional steroids, systemic anti-inflammatory and antibiotic therapy, and immuosuppressants including systemic steroids, cyclosporine, and infliximab.5,7
Malignancy. Malignancy was another common atypical wound etiology. Malignancy may be associated with wounds in two ways: 1) chronic wounds may transform into malignancies, and 2) malignancies including nonmelanoma skin cancers, lymphomas, and sarcomas may ulcerate. Malignant conversion is a slow process with an average time to diagnosis of 25 years;8 it is assumed the risk of malignancy increases with ulcer duration. The most common malignancy is squamous cell carcinoma (SCC);9 it was found in 11 patients in this study. Of these 11 SCCs, only one specimen was sent specifically to rule out malignancy.
Marjolin’s ulcers are seen in up to 2% of chronic wounds. SCCs that arise from Marjolin’s ulcers are aggressive and have high metastatic potential (30% risk) compared to 3% risk in SCCs originating in normal skin.10 Recognition of Marjolin’s ulcer in a long-standing wound is imperative to improve prognosis. Treatment modalities include Mohs micrographic surgery or excision with appropriate margins with or without adjuvant radiation, topical 5-fluorouracil, methotrexate, lymph node dissection, and if needed, amputation.11,12
Basal cell carcinoma (BCC) (n = 9) was found almost as frequently as SCC. Two samples from recurrent, intermittent ulcers were noted: one with a 35-year and the other with a 20-year history. Due to their chronicity, these were likely Marjolin’s ulcers.
Vasculitis. Vasculitis, or inflammation and necrosis of blood vessels, often is due to deposition of circulating immune complexes. Vasculitis was found in 16 wound biopsies; leukocytoclastic vasculitis was the type most commonly diagnosed. Vasculitis due to Wegener’s granulomatosis and rheumatoid factor were also diagnosed. The diagnosis of these painful ulcers usually warrants evaluation for a specific cause and for other organ system involvement. The extent of skin and other organ involvement drives treatment; options include nonsteroidal anti-inflammatory agents, systemic steroids, and steroid-sparing immunomodulators.13
Atypical infection. Biopsy results also included infectious etiology with two cases caused by an atypical mycobacterium, Mycobacterium scrofulaceum. Atypical mycobacterial infection characteristically occurs in immunosuppressed individuals or as a result of direct inoculation. Skin manifestations include granulomas, superficial erosions, sinus tracts, and ulcers depending on the causative bacteria. Once the organism has been identified, appropriate antimicrobial therapy can be implemented. In some instances, treatment may require surgical debridement and/or excision.
Metabolic causes. CUA, a metabolic disorder and a cause of ulceration typically seen in patients with end-stage renal disease (ESRD), also was diagnosed. Secondary hyperparathyroidism, a sequelae of ESRD, elevates calcium-phosphate product level leading to vascular, subcutaneous, and cutaneous calcification. Ulcers from CUA are usually bilateral and symmetric and exhibit a peripheral border of vesicles. Although concerns proliferate about the condition worsening as a result of obtaining a biopsy, an accurate diagnosis remains paramount, necessitating biopsy.
Generally recommended treatment options for CUA include cinacalcet, bisphosphonates, sodium thiosulfate, and parathyroidectomy, but the prognosis for CUA remains poor.
External causes. External causes of atypical ulcers seen at the authors’ center included radiation, factitial dermatitis, and spider bite. Ionizing radiation, a treatment for cancer, can cause obliterative endarteritis of microvasculature, leading to tissue ischemia and ulceration. Unfortunately, wounds evolving from these causes are difficult to treat. Current options include wound excision and hyperbaric oxygen.
Factitial ulcers — ie, wounds that are the result of self- injury — are unique. They typically have a linear border and are located in easy accessible areas such as the extremities, abdomen, and anterior chest. Once diagnosed, treatment entails wound occlusion with a dressing or cast to limit access to the ulcer.
Frequently unnoticed at first, spider bites by Loxosceles reclusa (brown recluse) or Lactrodectus mutans (black widow) also may lead to ulceration. In this study, the biopsy results showed three ulcers were caused by spider bites. Treatment options for Loxoscelism include cooling, analgesics, systemic steroids, and oral dapsone. Latrodectism may be treated with cooling, calcium gluconate, and specific antivenin.
Conclusion
Chronic wounds are prevalent and frequently encountered by healthcare providers. Obtaining a biopsy of refractory nonhealing wounds is increasingly recommended; in the case of atypical ulcers, biopsy is recommended. In the case of atypical ulcers, biopsy is a valuable tool to obtain a correct diagnosis. Almost 30% of biopsies send to the authors’ wound pathology division were consistent with atypical etiologies. Although the number of diagnosed atypical wounds most likely is higher than the national average, the results confirm the value of histopathology in the diagnosis and treatment of patients with nonhealing wounds. Prospective studies and randomized, controlled trials are needed to further elucidate these observations/conclusions to help clinicians decide when to obtain a biopsy.
Dr. Tang is a Resident, and Dr. Vivas is a Post Doctoral Research Associate, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL. Ms. Rey is a student. Dr. Kirsner is a Professor, Vice Chairman, and Stiefel Laboratories Chair, Department of Dermatology and Cutaneous Surgery; and Dr. Romanelli is an Associate Professor, Director of UM/JMH Psoriasis Biologics Clinic, and Director of Dermatopathology Fellowship, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine. Please address correspondence to: Robert S. Kirsner, MD, PhD, Professor of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023-A, Miami, FL 33101; email: rkirsner@miami.med.edu.
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