Malignant Transformation of a Site of Prior Diabetic Foot Ulceration to Verrucous Carcinoma: A Case Report

The case of a 62-year-old Caucasian man with type 1 diabetes who developed malignant transformation of an area of prior diabetic foot ulceration (DFU) is reported. He had significant hallux valgus deformity, multiple episodes of healing and breakdown, and eventual transformation to verrucous carcinoma (VC). This case report highlights the malignant transformation of a site of previous DFU to VC, which, to the best of the authors’ knowledge, has not yet been described in the literature.There has been little research performed that examines VC in the diabetic population. This case report also highlights the importance of clinical suspicion for malignant transformation as well as the use of subsequent biopsy when necessary.

Skin cancer is the most commonly diagnosed cancer in the United States.¹  Cutaneous squamous cell carcinoma (SCC) is estimated to be the second most common type of skin cancer in the United States behind basal cell carcinoma (BCC), and it accounts for about 20% of nonmelanoma skin cancers.^1-3 The actual number of cases is challenging to approximate since they are not required to be reported to cancer registries.¹ Marjolin’s ulcers, a subtype of SCC, are ulcers that have undergone malignant transformation arising from chronically inflamed skin, such as preexisting scar tissue or open ulcerations.⁴ The exact incidence of Marjolin’s ulcers is unknown. About 1% of cutaneous skin cancers arise in chronically inflamed skin and approximately 95% of these are SCCs.⁵ It has been suggested⁶ that decreased vascularity, weakened epithelium, or chronic irritation creates a susceptibility to carcinogens in nonhealing chronic wounds. The transformation from ulcer to malignant disease is typically slow, with latency periods averaging 29 years according to Kerr-Valentic et al.⁶ 

Verrucous carcinoma (VC) is a wart-like, low-grade, uncommon, well-differentiated form of SCC. It was originally described by Ackerman in 1948 as a low-grade SCC in the oral cavity,⁷ and these lesions can be referred to as epithelioma cuniculatum (EC) when they occur on the foot.⁸ Verrucous carcinoma is usually unilateral, although 2 bilateral presentations have been reported.⁹ These lesions rarely metastasize but do have the potential for local destruction into the deeper structures (ie, bone).^7,10,11 The exact incidence is unknown, but VC most commonly presents in men aged 52 to 60 years, and about 100 cases have been described in the plantar foot.^11,12 Although the clinical presentation varies, the lesions can present as a slow-growing, warty tumor and can be confused for verruca vulgaris. The time from onset to presentation varies, diagnosis is challenging, and a deep tissue biopsy is required. The pathogenesis of VC is still unknown; however, human papilloma virus types 2 and 16 have been detected in a few cases involving the lower extremity.^11,13 

The prevalence of diabetic foot ulcers (DFUs) is 4% to 10%, the annual population-based incidence is 1% to 4.1%, and the lifetime incidence may be as high as 25%.¹⁴ There is a 28% to 100% recurrence rate of DFUs between 1 to 4 years following healing.¹⁵ The highest location of re-ulceration is at a site of prior ulceration. The pathophysiological abnormalities associated with diabetes mellitus disrupt the normal wound healing process and wounds have the tendency to become chronic. 

The case of a 62-year-old Caucasian man, with a past medical history significant for type 1 diabetes mellitus, diabetic neuropathy, chronic renal insufficiency, hypertension, hyperlipidemia, and diabetic retinopathy, who was well known to the Podiatry Clinic at Michigan Medicine (Ann Arbor, MI) is reported. He was not taking any immunosuppressive medication (ie, steroids, chemotherapy, etc.) and denied cigarette and alcohol use but reported marijuana use. His last recorded hemoglobin A_1c was 7.7% (normal ≤ 7%).¹⁶ He had palpable pedal pulses and triphasic dorsalis pedis and posterior tibial pedal pulses bilaterally, and he had diminished protective sensation via 10 g of force of a 5.07 Semmes-Weinstein monofilament to the forefoot bilaterally in addition to diminished vibratory sensation via tuning fork. In addition, he has a history of second digit amputation on the right foot and second and third digit amputations on the left foot. He had been treated for long standing DFUs to bilateral feet (over the course of 7–8 years), specifically to the right hallux and left plantar medial first metatarsal head, both due to significant hallux valgus deformities in the setting of peripheral neuropathy. The left foot ulceration had periods of closure and periods of recurrence over approximately a 2-year period, and this wound healed with local wound care and implementation of adequate offloading. At a 1-month follow-up visit, the wound was noted to be healed (Figure 1), and a pre-ulcerative hyperkeratotic lesion was present without evidence of ulceration underneath. 

The patient presented 1 month after noted wound closure with new verrucous changes to the site of prior ulceration on his left foot (Figure 2). The area of hyperkeratosis had become macerated and hemorrhagic with hair-like projections that extended into the underlying subcutaneous tissue. Palpation of the popliteal fossa and groin did not demonstrate palpable lymph nodes. The area measured approximately 3 cm x 3 cm and there were no signs of infection. This area appeared altered from the pre-ulcerative hyperkeratotic lesion that previously covered the site. There was no classic DFU malodor and no active drainage. Upon a review of systems, the patient denied any constitutional symptoms or pain. In addition, he denied skin lesions elsewhere on his body. Weight-bearing foot radiographs were performed and demonstrated no underlying osseous changes (Figure 3). 

Procedure
Due to the suspicious nature of the lesion, written informed consent was obtained for a left foot punch biopsy of the site. After prepping and draping the site in standard aseptic technique, time out and site verification was completed; a 6-mm punch biopsy was then performed in the center of the lesion. This biopsy included epidermis and dermal tissues. He tolerated this procedure well, and hemostasis was controlled with compression. The specimen was passed off the field into a 10% formalin specimen cup and sent to anatomic pathology at Michigan Medicine for identification. The biopsy site was left open to close by secondary intention, and a dry sterile dressing was applied (Figure 4). 

Histology/pathology
Hematoxylin and eosin (H&E) stain is the best way to analyze this pathology. There are no special stains required. The dermatopathology report described the lesion as a 0.4 cm x 0.8 cm punch biopsy of ragged, thickened skin. The histology was described as atypical, well-differentiated verrucous squamoproliferative lesion extending to all margins and consistent with VC. The case was discussed with another dermatopathologist who concurred on the findings (Figure 5). 

Treatment
Following punch biopsy and resultant VC diagnosis, the patient was referred to the Plastic Surgery Department, Cancer Division, at Michigan Medicine for further evaluation and management. The surgical intervention plan consisted of wide excision of the lesion with tumor-free margins in addition to partial first ray and hallux amputation with primary closure. Proximal soft tissue and bone margins were sent for pathology. A plan for future foot surgery was discussed with the patient at this time.

A transmetatarsal amputation was not performed at the time of tumor resection in order to evaluate proximal margins. A plan for transmetatarsal amputation was discussed with the patient and would be performed at a future date once proximal margins were noted to be tumor free and if the patient agreed. This was proposed in order to provide a more functional and biomechanically sound foot, as the patient has prior history of lesser digital amputations.

Verrucous carcinoma typically presents as ulcerated, verrucous, fungating, and polypoid masses with openings of sinus tracts onto the skin surface that exude foul-smelling, greasy material when pressure is applied.^8,17 Occasionally, the lesions may invade the underlying tissues and the adjacent bone, but these lesions rarely metastasize.¹⁷ When VC is noted on the foot, it is typically referred to as EC (or carcinoma cuniculatum).⁸ In this case, the patient did not re-ulcerate, but the tissue did have a verrucous appearance with hair-like projections (Figure 2 is prior to punch biopsy; Figure 4 is post punch biopsy). There were no appreciated malodourous drainage or sinus tracts in this case. Lack of all classic features might be attributed to an early diagnosis of VC.

Histologically, VC is seen to be composed mainly of well-differentiated, mature squamous keratinocytes with foci of cellular atypia.¹⁷ These microscopic findings were visualized in the present case as well (Figure 5). The transformation from an ulcer to malignant disease is typically slow, with latency periods averaging 29 years.⁶ In the present case, the transformation occurred rapidly over a period of 1 month. Differential diagnoses for this condition include verruca plantaris, dermatitis, eccrine poroma, keratoacanthoma, SCC, BCC, amelanotic melanoma, seborrheic keratosis, or verrucous skin lesions on the feet with diabetic neuropathy.^18,19 Due to the numerous differential diagnoses, delayed diagnosis is common. Chronic wounds and chronic skin irritation have been known to occasionally undergo malignant degeneration. There have been multiple case reports demonstrating the development of VC/EC in the foot^{,8-10,12,13,20-31} and only a few articles discussing this finding in the diabetic foot.^11,19,32-34 The mechanism for which ulcerations undergo malignant transformation is still unknown. Clinical suspicion is key when determining if sudden or progressive dermatological changes are concerning for malignant transformation.

Typically, when a wound or lesion does not respond as expected to standard care or if the lesion begins to change its appearance, a biopsy of the underlying tissue should be performed. If VC is of clinical concern, an excisional biopsy, incisional biopsy, or punch biopsy including the depth down to and including subcutaneous tissue should be performed. A punch biopsy was performed in the present case as the lesion was about 3 cm in diameter, and the procedure is easily performed in the clinical setting. A shave biopsy would not provide adequate information in this case, as the biopsy would not be deep enough to capture the atypia.^34-36 Traditionally, 4 biopsy techniques have been described when evaluating a soft tissue tumor or abnormal skin lesion: punch, excisional, incisional, and fine needle aspiration (FNA). Ideally, excisional biopsies are useful for both histological/pathological evaluation as well as skin closure if the lesion is less than 3 cm. The 3:1 length and width ratio provides easier skin closure when a lesion is excised.^35-39 For multiple lesions or with lesions larger than 3 cm, a punch biopsy, incisional biopsy, or FNA biopsy may be performed.^35-39 

The benefits of a punch biopsy include potential access of a lesion’s depth and easy performance in a clinical setting with the use of local anesthesia. The limitations of such biopsy are that the lesion is not excised and the base of the lesion may not be within the base of the biopsy sample, occasionally missing potential important histological features for the pathologist to evaluate.^35-39 Occasionally, it is recommended to perform a punch biopsy in the center as well as along the margin of the area in question; punch biopsy sizes range from 2 mm to 8 mm and depend on the size of the lesion.^35-39 Incisional biopsy only removes a portion of the lesion and is reserved for when the lesion is too large to be excised or there are multiple lesions. Similar to the punch biopsy technique, sampling tissue from the center and margin of the lesion is recommended.^35-39 Fine needle aspiration obtains cells for evaluation, both within and around the lesion.^35-39 It should be noted that shave biopsy and saucerization have been described³⁵ but should be reserved for superficial lesions on the surface of the skin when depth of tissue invasion is not of clinical concern.

Treatment options for VC include wide excision with tumor-free margins, amputation of the affected area with incorporation of skin grafts and rotational flaps for larger defects, or Mohs micrographic surgery.¹⁹ Radiation or chemotherapy is not typically recommended as there is a low risk of developing anaplastic changes and metastasis.³⁴ In the present case, due to the significant hallux valgus deformity and history of recurrent ulceration at site of current VC, a partial first ray amputation was planned in order to excise the tumor to tumor-free margins in addition to removing the deformity. This patient was specifically explained that further amputations might be necessary to provide a biomechanically functional foot (ie, transmetatarsal amputation) as he had already undergone amputation of digits 2 and 3 on the affected foot. In some cases, a below-knee amputation is necessary if there is aggressive recurrence or proximal spread of the tumor.  To the best of the authors’ knowledge, the recurrence rates of VC (including and not including patients with diabetes) following wide excision is not known.

Immunosuppression status and hyperglycemia are potential risk factors for development of skin cancer in the diabetic population. Continued hyperglycemia and high serum levels of insulin or insulin-like growth factor have been proposed to be possible mechanisms for the carcinogenesis in patients with diabetes mellitus.⁴⁰ Hyperglycemia may contribute to malignant cell growth and overproduction of superoxide and reactive oxygen species.⁴⁰ The patient that was described in this specific case was not taking any immunosuppressive medication and his diabetes mellitus was the only source of immunosuppression. Patients with diabetes are at a higher risk to form nonmelanoma-type skin cancers (ie, SCC) than those without diabetes.⁴⁰ In addition, patients with diabetes who develop chronic ulcerations are at risk for developing malignant transformation to their wound site or prior wound sites; this further increases their risk of developing nonmelanoma-type skin cancers. 

Further research is needed on the subject of VC/EC and Marjolin’s ulcers, specifically in the diabetic population. The incidence and prevalence of VC/EC in the diabetic population is not known. To the best of the authors’ knowledge, there is no known classification system for VC/EC, and there is no known algorithm for chronic ulcerations and biopsy recommendations. Since patients with diabetes are at a higher risk for developing SCC-type lesions, it remains unclear if these patients are at a higher risk for developing malignant degeneration of chronic ulcerations or at prior ulceration sites. Further research evaluating a patient’s glycemic control (hemoglobin A_1c values) correlates with risk of developing malignant transformation. Due to the various presentations of VC, it is challenging to diagnose as each patient may present differently. In this case, some of the classic features were present but not all were noted. The authors believe this is due to the biopsy being performed early in the development of VC, but the timing of such classic features is not known.

This case is unique as VC developed at a site of prior DFU and occurred in a clinically healed area. To the best of the authors’ knowledge, this is the first case report demonstrating this finding. The authors suspect that the scar tissue that was present at the prior ulceration site was chronically inflamed since this area had healed and reopened multiple times. The presence of a severe hallux valgus deformity in the setting of peripheral neuropathy put the patient at risk for repetitive trauma to the area. This is compounded by the fact that the patient has type 1 diabetes and this puts him at risk for developing malignant transformation. Since this conversion was diagnosed quickly, it is likely that not all of the classic features had time to develop and the underlying bone appears uninvolved radiographically. It is critical to use clinical judgment when wounds change their classic characteristics and a biopsy (punch, incisional, excisional, or FNA) should be performed to evaluate the underlying pathology. 

Affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Hospital and Health Systems, Ann Arbor, MI

Correspondence:
Sari J. Priesand, DPM
Domino’s Farms
Lobby G, Suite 1500
24 Frank Lloyd Wright Drive
Ann Arbor, MI 48106
sarig@med.umich.edu 

Disclosure: The authors disclose no financial or other conflicts of interest.