Squamous Cell Carcinoma Arising in a Chronic, Nonhealing Diabetic Foot Ulcer

Diabetic foot ulcers (DFUs) are a severe and costly complication of diabetes and may result in foot amputation. Case Report. A 69-year-old man with a 10-year history of type 2 diabetes, who was undergoing routine care for diabetes in the authors’ clinic, developed a DFU of his right foot of 4 years’ duration.The wound did not respond to conventional treatments, and imaging studies were normal. His 2 biopsies tested negative for malignancy. The DFU was fully removed surgically. Following surgical removal, squamous cell carcinoma (SCC) was diagnosed in the histologic study of the wound. Conclusion. Clinicians should consider a diagnosis of SCC in any chronic, nonhealing DFU. Early surgical resection of a chronic, nonhealing DFU may prevent development of SCC in an ulcer. 

Diabetes mellitus is 1 of the most common metabolic disorders worldwide. Diabetic foot ulcers (DFUs) are 1 of the most serious and costly complications of diabetes and may lead to lower extremity amputations; it is also the most common cause of nontraumatic foot amputations.¹ 

The lifetime risk for developing a DFU in patients with diabetes is 15% to 25%, and the global incidence of a DFU is 3% to 10% in this patient population.^2,3 The lifetime risk of having a lower limb amputation in patients with diabetes is 10 to 30 times greater than patients without the disease.⁴ 

Healing of diabetic foot wounds is difficult and requires a multidisciplinary approach.⁵ Prolonged wound closure can lead to a higher risk of complications such as infection. The most common pathogens in infected DFUs are enterococci and staphylococci (gram-positive bacteria) and Escherichia coli and Klebsiella (gram-negative bacteria).⁶ The main principles of the standard care treatment for DFUs are offloading, infection control, wound debridement, and hyperglycemia control. In some cases, despite all care and treatments, the wound remains nonhealing and may become chronic. When a wound fails to heal and repair over a 3-month period (a typical and timely reparative process to obtain integrity), it is defined as a chronic, nonhealing wound.

Impaired arterial or venous circulation, immunocompromised status, old age (> 65 years), diabetes, neuropathy, and spinal cord injury are known risk factors for developing a chronic, nonhealing wound.⁷ Chronic wounds are at risk for complications such as serious infections, gangrene, development of malignancy (squamous cell carcinoma [SCC]), and amputation in severe cases. 

Herein, the authors report a case of SCC arising in a long-lasting, nonhealing DFU.

A 69-year-old man with a 10-year history of type 2 diabetes, who was undergoing routine care for diabetes in the authors’ clinic, developed a DFU of his right foot of 4 years duration. During the 10-year history, his diabetes was controlled with metformin and acarbose. 

At first, an ulcer of 15 mm × 10 mm developed in the mid plantar surface (midfoot) of the right foot along the first metatarsal bone without exudate and inflammation. There was no significant vascular or neuropathic defect, no history of foot trauma, no overt infection, and no atypical changes. The wound surface was small but too deep; the wound surface was dry and clean with no sign of infection and discharge. There were a few granulation tissues in the wound margin. Due to the size and dryness of the DFU, it was followed by observation without treatment for 3 years.

After 3 years without any change, the wound became symptomatic with inflammation and infectious discharge. Following these symptoms, a triphasic bone scan was performed and revealed osteomyelitis in the proximal end of the right first metatarsal bone. As of result of this finding, he was admitted to the hospital and received parenteral antibiotics, including ciprofloxacin and clindamycin, for 3 weeks. At the same time, a magnetic resonance imaging (MRI) of his right foot was performed and was unremarkable without any lesion. Wound biopsy also was normal.

After hospital discharge, oral antibiotics continued for 1 year. After 1 year of antibiotic treatment started, the wound did not heal though the wound discharge reduced slightly. After 9 months from the first MRI, a second MRI of the right foot was performed and, again, was unremarkable. In addition, wound culture showed normal skin flora. 

Three months following the second MRI and 12 months from initial biopsy, a second wound biopsy of the right foot was performed and, again, was negative for malignancy. As the chronic, nonhealing wound persisted, general surgeons recommended to excise the wound. Local excision was performed, and the foot was repaired. About 12 weeks postoperatively, the wound closed completely without event. Pathologic examination of the lesion showed invasive, moderately differentiated SCC without any vascular or perineural invasion; it was an in-situ carcinoma (Figures 1, 2A, 2B). 

At 6-month follow-up, there was no recurrence of the DFU, and the patient was followed-up every 3 months for any reulceration or recurrence in regular intervals. 

In the patient case study reported herein, SCC was identified in a chronic, nonhealing DFU. Squamous cell carcinoma is the second most common skin cancer after basal cell carcinoma. 

To the best of the authors’ knowledge, only 5 cases of SCC arising in a DFU have been reported.^8-11 Squamous cell carcinoma often occurs in areas exposed to sunlight, though the foot is not a common site for this malignancy. The main risk factors of SCC include sun exposure, old age, skin types 1 (pale white skin, blue/green eyes, blond/red hair) or 2 (fair skin, blue eyes), and ethnicity. In addition, chronic inflammation and infection, such as a chronic wound (Marjolin’s ulcer), are associated with an increased risk of SCC.¹² In most patients previously reported.^8-11 like the present patient, SCC arised in old age (> 65 years). In this patient, at least 2 risk factors for SCC were identified: advanced age and a chronic wound.

Definite diagnosis of SCC is made by biopsy. Diagnosis of SCC in most previously reported cases was made by punch biopsy.^8,10,11 In the case reported by Park et al,¹³ similar to this case herein, the first and second wound biopsies did not identify malignancy, and SCC was identified only after immunohistochemical staining for various markers. However, in the present patient, 2 biopsies performed within a 12-month interval were negative for malignancy and could not detect SCC. This may be explained by recently developed SCC in the ulcer or by the nature of the tumor that was in situ and had no extension to other adjacent tissues. In addition, the present patient showed no vascular or perineural invasion.  

The tumor was removed completely by local surgical excision and, postoperatively, the wound closed in about 12 weeks. Now, follow-up is performed in regular 3-month intervals. 

In chronic, nonhealing DFUs with the presence of previously mentioned risk factors, diagnosis of SCC should be considered and ruled out. To diagnose this condition, wound biopsy is required. However, in some cases like the present, it may misguide physicians. It seems that early excisional biopsy is the best and safest treatment with high diagnostic accuracy for chronic, nonhealing DFUs.

Disclosure: Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences; and Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences

Correspondence:
Fatemeh Bandarian, MD, PhD
Diabetes Research Center
5th floor, Diabetes Clinic,
Cross Heyat, 
Shahrivar Ave., North Kargar St,
Tehran, Tehran 14417 Iran
fbandarian@tums.ac.ir

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