The Value of a Biopsy in Chronic Ulcers: A Case Series

In the United States, chronic wounds affect more than 6 million individuals, and chronic lower extremity wounds affect between 2.5 million and 4.5 million people.^1-3 Chronic wounds are defined as wounds that do not exhibit significant evidence of healing within 3 months, despite standard treatment.⁴ Malignant transformation of chronic lower extremity ulcers is rare, and skin cancer identification in chronic foot ulcers is even more so, possibly due to lacking guidelines.^1-3 The importance of early diagnosis and implementation of biopsy plays an important role in identifying the underlying pathology of nonhealing ulcers, as primary cutaneous malignancies may mimic chronic ulcers and can go untreated if misdiagnosed.^2,5 It can be especially difficult to differentiate between the malignant transformation of a chronic wound and a primary malignancy with ulceration. Biopsy of chronic wounds can identify malignancy and help clarify the nature of the wound, especially the barriers to healing and increased risk of infections.^6-8 Some clinicians may be hesitant to perform a biopsy because the resulting wound may have delayed healing. However, the US Food and Drug Administration recommends biopsy as an objective tool to exclude infectious, immunologic, or neoplastic disease in chronic wounds.⁹

Biopsy

A biopsy is performed to examine a removed sample of involved tissue for the presence of disease. Skin biopsies most often include punch biopsy, tangential shaving of the skin, or excising a sample with a scalpel.¹⁰

Based on the level of difficulty of the procedure, a biopsy can be performed in various clinical settings.¹⁰ To safely perform more difficult biopsies, such as liver, bone, or kidney biopsies, and determine where exactly to perform the extraction of tissue, imaging guidance is often used; such imaging includes ultrasound, x-ray, computed tomography, and magnetic resonance imaging (MRI).¹⁰ For skin lesions, imaging guidance is unnecessary, and the procedures are most often performed in an ambulatory setting. ¹⁰

The National Comprehensive Cancer Network (NCCN) recommends that a skin biopsy be performed on any suspicious lesions, and the biopsy should include a specimen obtaining deep reticular dermis.¹¹ Superficial biopsies often miss the causative component of the infiltrative histology of the tumor, especially in wounds and scars.¹¹

Malignant transformations of chronic ulcers

A Marjolin ulcer (MU) is a cutaneous squamous cell carcinoma (SCC) associated with chronic wounds.^6,7,12 These carcinomas arise after the malignant transformation of chronic ulcers associated with scars and chronic wounds.¹² Marjolin ulcers are classified as either acute or chronic.¹⁵ Acute MUs are extremely rare and occur within 12 months of the development of an ulcer, whereas chronic MUs most commonly occur after 12 months.¹⁵ Although basal cell carcinoma (BCC) is more common than SCC, SCC is a more common type of malignancy that develops in chronic wounds and scars.^10,12,13 Marjolin ulcers are more difficult to manage, and in general, have a poor prognosis.¹²

The NCCN recommends that cutaneous squamous cell carcinoma (cSCC) workup begins with the collection of medical history and physical examination and includes a full-thickness biopsy of the epidermal atypia, excluding actinic keratosis.¹¹ The NCCN also states that if the incisional biopsy only provides clinical information for micro-staging the tumor, narrow margin excisional biopsy should be obtained, including the accurate measurement of thickness and anatomic level of invasion.¹¹

Primary cutaneous malignancies may mimic chronic ulcers.⁷ Thus, it can be challenging to differentiate between the malignant transformation of a chronic wound and a primary malignancy with ulceration. The authors present 3 cases of biopsy-proven cutaneous malignancy in chronic foot ulcers, where 1 case represents the malignant transformation of a wound and 2 cases demonstrate primary malignancy masquerading as chronic wounds.

Case 1

A 50-year-old male presented for evaluation of a nonhealing surgical wound involving the right great toe amputation site. The patient underwent amputation of the great toe to treat a diabetic foot ulcer complicated by osteomyelitis 4 months prior. Despite conventional wound care—including debridement, combination dressings, and offloading—the wound progressively enlarged, exhibited atypical skin changes, and was concerning for MU. Past medical history consisted of poorly controlled type 1 diabetes, hypertension, and anxiety. The patient smoked approximately 1 pack of cigarettes per day. The patient had no previous history of nonhealing wounds, peripheral arterial disease, immunocompromised state, rheumatologic disease, or skin cancer.

Physical examination was remarkable for a wound measuring 0.9 cm × 0.8 cm × 0.3 cm involving the right hallux amputation site (Figure 1). The wound was diagnosed as a Wagner grade 2. The periwound consisted of a hyperkeratotic plaque with verrucous changes. A right Charcot foot with rocker-bottom deformity was also present. An MRI of the right foot excluded osteomyelitis. An ankle-brachial index of 1.01 and a toe pressure of 113 mm Hg excluded a peripheral arterial disease etiology. Due to the chronic nature and progressive wound worsening, a 5-mm punch biopsy was performed to rule out malignant transformation. Histopathologic examination revealed verrucous epidermal hyperplasia. The patient subsequently underwent surgical excision of the wound with rotation flap closure. Histopathologic examination of the biopsy performed during surgery revealed verrucous SCC with positive margins. The patient was then referred to a surgical oncology specialist for wide local excision and split-thickness skin grafting.

Case 2

A 60-year-old female presented for evaluation of a nonhealing wound involving the left plantar midfoot. The wound began as a scaly patch that progressively enlarged and ulcerated over 2 years; it was refractory to trials of antibiotics and 5-fluorouracil. Biopsies obtained by an outside dermatologist were negative for malignancy. X-rays of the left foot were unremarkable for bone infection. Past medical history consisted of idiopathic lower extremity and hand edema, esophageal stenosis, numerous actinic keratoses, and SCC on the chest. The patient had no previous history of nonhealing wounds, diabetes, peripheral arterial disease, immunocompromised state, rheumatologic disease, or smoking. Physical examination revealed a wound measuring 5 cm × 3.5 cm × 0.1 cm on the left plantar midfoot (Figure 2). Moderate green discharge without odor and extensive granulation tissue were present in the Wagner grade 1 wound. No fluctuance or soft tissue crepitus was noted.

Due to the chronicity of the wound and the patient's history of skin cancer, 5-mm punch biopsies were performed at the 12 o’clock, 3 o’clock, and 7 o’clock positions. Histopathologic examination was remarkable for SCC in situ at the 12 o’clock and 7 o’clock positions and superficial multicenter BCC at the 3 o’clock position. The patient was referred to a dermatologist for further assessment of the primary malignant lesions.

Case 3

An 89-year-old male presented for evaluation of a chronic wound present for more than 6 months. According to a physician who previously treated the patient, the wound was diagnosed as an ulcerated corn; it was refractory to standard treatment. The patient’s past medical history consisted of hypertension and degenerative joint disease. The patient had no previous history of nonhealing wounds, peripheral arterial disease, immunocompromised state, rheumatologic disease, or skin cancer.

The physical examination identified a wound measuring 2 cm × 1.5 cm × 0.1 cm on the medial aspect of the third digit on the right foot (Figure 3). The patient had strong bilateral distal pulses. Due to the chronicity of the wound, a 5-mm punch biopsy was completed to rule out malignancy. The corresponding pathology report revealed invasive malignant melanoma characterized as Clark level IV, Breslow depth of 6 mm, and pT4b pathologic stage. The patient was referred to an orthopedic oncology specialist, and the team recommended a transmetatarsal amputation. The patient elected for toe amputation and declined additional treatment.

The verrucous SCC in case 1 likely represented malignant transformation of an acute MU that resulted from the patient’s surgical wound. Although MUs typically evolve years after initial injury, 7% of MUs occur within 1 year of wound development.^14,15 As a result, a physician’s clinical suspicion for malignancy in a wound present for less than 12 months may be low, and the wound may go without biopsy as a consequence.

The nonmelanoma skin cancers identified on the plantar midfoot in case 2 represent primary malignancies. The patient lacked typical risk factors for development of a chronic ulcer and had a personal history of skin cancer. Most BCC occurs on areas of the body exposed to the sun, such as the face and neck. Plantar BCC is exceedingly rare and comprises less than 1% of all BCC cases.^16,17 Thus, diagnosis of plantar BCC may be delayed, and a chronic ulcerating lesion and associated patient morbidity may occur as a result; this was the case for the patient in case 2.

The ulcerated malignant melanoma in case 3 was misdiagnosed as an ulcerated corn. Delayed diagnosis and misdiagnosis of melanomas involving the foot frequently occur due to the overall low incidence of melanoma compared with other skin cancers (ie, <5% of cutaneous malignancies), the rare occurrence of melanoma on the foot, and the similar presentation between acral melanomas and other podiatric conditions.^15-17 Acral melanomas of are often misdiagnosed as common skin conditions, including fungal infections or warts and ulcerative conditions such as diabetic foot ulcers.^17,18 Given that melanoma is the deadliest skin cancer and misdiagnosis is associated with significant affects on patient survival, early detection and treatment are imperative for optimal patient prognosis.¹⁷

Wounds necessitating biopsy include lesions that are recalcitrant to standard therapy, are chronic in nature, and exhibit changes in character.^5,22-24 Conducting a biopsy procedure on chronic wounds can elucidate barriers to wound healing, such as infection, and provide delayed diagnosis of malignancy.^25,26 There is no consensus among the literature regarding when to perform a wound biopsy with the aforementioned characteristics. Previous studies have recommended performing a biopsy of a wound refractory to 4 or more weeks of standard therapy.^5,7 Robson et al²⁸ advised to perform a biopsy of any atypical wound present for longer than 3 months.

In general, a biopsy procedure is indicated for any nonhealing ulcer present for 3 months or longer. As demonstrated in the current cases, biopsy results of a chronic wound can identify a malignancy that could otherwise go undiagnosed and untreated.

Limitations of the study include the small number of cases. The small case number likely reflects an overall low rate of biopsy procedures performed in the management of chronic wounds at this practice site. A larger case series of wounds associated with underlying malignancy is required to provide additional support for conducting a biopsy of chronic wounds.

Chronic wounds cause significant morbidity for millions of individuals in the United States. This case series highlighted the importance of maintaining clinical suspicion for an underlying malignant process in a chronic ulcer in the appropriate clinical context. In all 3 presented cases, conducting a biopsy procedure was necessary in identifying malignancy. Based on available literature and the presented cases, the authors recommend biopsy be performed on any wound present for 3 months or longer, as the biopsy is a low-risk valuable objective tool in investigating barriers to wound healing.