From Chronic Leg Ulcer to Squamous Cell Carcinoma: A Case Report

We present a case of a delayed diagnosis of cutaneous squamous cell carcinoma in the lower extremity developed in chronic non-healing tropical ulcers. An 80-year-old female patient was referred to the hospital due to complaints of a chronic non-healing ulcer in her left lower extremity, which she had since 2008. Despite receiving conservative treatment, the ulcer did not heal, and it continued expanding in size and developing questionable changes in the wound. Upon further examination and multiple biopsies obtained, Grade 2 invasive squamous cell carcinoma was confirmed with left inguinal lymphadenopathy. After three cycles of immunotherapy, clinical improvement was observed. However, after 10 cycles of treatment, disease progression occurred. The patient refused an amputation of the affected extremity; therefore, she was offered palliative care.

Introduction

Cutaneous squamous cell carcinoma is the second most common nonmelanoma skin cancer worldwide, representing 20% of all skin cancers, and its incidence rates continue to increase every year [1]. Although the majority of patients with cutaneous squamous cell carcinoma have a good prognosis, metastasis may occur in 1%–5% of cases [2].

Risk factors that are associated with the development of cutaneous squamous cell carcinoma include chronic and cumulative ultraviolet exposure (UV), older age, immunosuppression, certain genetic syndromes, and fair skin [3]. Chronic wounds such as Marjolin’s ulcer may also lead to the development of squamous cell carcinoma [1].

Marjolin ulcer (MU) is a rare skin malignancy that develops in burn wounds, chronic non-healing wounds, and several other skin conditions such as pressure injuries, diabetic foot ulcers, tropical ulcers, etc. Squamous cell carcinoma is the most frequent histological type, and the most commonly affected area is the lower extremity [4]. Studies reported that squamous cell carcinoma in MU is more aggressive than other skin cancers. The prevalence of MU in burn scars is around 1%–2%, and approximately 1,7% of chronic wounds undergo malignant transformation. The average age of diagnosis is in the fifth decade of life. The latency period from initial injury to malignant transformation can last 25–30 years [5].

We present a case of a delayed diagnosis of cutaneous squamous cell carcinoma in the lower extremity developed in chronic non-healing tropical ulcers.

Case Report

A 80-years old female patient was admitted to the hospital in August 2023 due to complaints of chronic non-healing ulcer on her left lower extremity. Her comorbidities included cholelithiasis and atherosclerosis. She did not take any medications besides nonsteroidal anti-inflammatory drugs. The patient was a non-smoker and did not drink alcohol. She lived alone.

The patient had a tropical ulcer on her left lower extremity since 2008. Throughout the years, she visited a surgeon for conservative treatment of the ulcer, which consisted of compression and topical wound dressing. In March 2019, the patient was referred to an oncologist due to the ulcer expanding in size and developing granulations. A punch biopsy was performed. The histopathology report revealed no signs of malignancy. After three months, in June, another biopsy was performed, and the histology report showed a chronic ulcer with diffuse leukocyte infiltration and reactive epithelial hyperplasia without the presence of malignant cells.

In August 2023, the patient was referred to an oncology surgeon with complaints of the ulcer increasing in size. Following physical examination, the patient was found to have a large deep ulcer on the left lower extremity, which was approximately 10 × 15 × 3 cm. A thick layer of necrosis on the wound was observed, and a foul odor was present. The margins of the ulcer were hard and elevated (Fig. 1). The patient was assigned to biopsy. Histopathology report confirmed Grade 2 invasive squamous cell carcinoma. CT scan of the chest and abdomen showed a dense intraparenchymal lesion in the lower lobe of the right lung 0,6 × 0,8 cm, left inguinal lymphadenopathy 1,6 × 3,1 cm. The final clinical diagnosis was left lower leg cutaneous squamous cell carcinoma T4N1M1G2—specific left inguinal lymphadenopathy.

Fig. 1. Tumor with necrosis before the start of treatment with immunotherapy.

The multidisciplinary tumor board offered palliative immunotherapy. Upon admission and evaluation by a medical oncologist, the patient’s general condition was relatively satisfactory. Her performance status was ECOG 1, complete blood count was within normal range; biochemistry showed mildly increased CRP (14,90 mg/L), increased alkaline phosphatase (267 U/L), and mild hypocalcemia (2,16 mmol/L). A CT scan was performed, and no new abnormalities were observed. The patient received Cemiplimab 350 mg i/v 21-day cycle. After three cycles of immunotherapy, clinical improvement was observed–the tumor wound started healing.

The patient continued treatment with immunotherapy. During the course of the treatment, laboratory tests showed a mild increase in CRP, increased alkaline phosphatase and hypocalcaemia. The patient completed 10 cycles of Cemiplimab. However, despite the treatment received, the patient’s local status in the left lower extremity was worsening–the tumor had reached 15 × 30 cm in diameter (Fig. 2).

Fig. 2. Tumor after 10 immunotherapy cycles.

The patient was offered amputation of the affected extremity, which she refused. A CT scan of the chest and abdomen was performed, where disease progression was observed–left inguinal lymphadenopathy had increased in size and reached 3,5 × 5,3 cm.

The medical oncologist board decided to stop treatment with immunotherapy due to disease progression and the patient’s poor performance status. The patient was offered palliative care.

Discussion

Malignant transformation of burn scars and chronic wounds has long been recognized. In 1828, a French physician, Jean Nicolas Marjolin, was the first to describe malignant changes developing in a burn scar. Marjolin’s ulcer is a rare and particularly aggressive type of tumor that is commonly associated with burn wounds and scars. Other chronic conditions, such as chronic osteomyelitis, pressure ulcers, diabetic foot ulcers, etc., have also been linked to Marjolin’s ulcer. Squamous cell carcinoma is the most frequent subtype identified on histopathological examinations (up to 80%), although other subtypes, such as basal cell carcinoma, sarcoma, and mucoepidermoid carcinoma, have also been reported [4].

The tumor can occur in any age group, but it is less common in children. The average age of diagnosis is in the fifth decade of life. Marjolin’s ulcer is predominantly seen in males [4]–[6].

Marjolin’s ulcers are most commonly found in lower extremities (53,3%), followed by upper extremities (18,7%) and torso (12,4%) [4]. Visually, a malignant ulcer appears as an ulcerative lesion with nodule formation, rolled elevated margins, and excessive granulation tissue. It is also prone to containing blood and exhibiting a malodor [7].

Medical history, physical examination, and biopsies taken correctly from the lesion can help obtain an accurate diagnosis. Any ulcer that takes longer to heal despite adequate therapeutic management, changes in clinical appearance-expands in size, exhibits foul-smelling exudate, and is prone to containing blood should be considered malignant and promptly biopsied. Some authors recommend biopsies of multiple locations in the ulcer, such as the center and margin, and going deep into the subcutaneous tissue to avoid false-negative results [8], [9]. Our patient had undergone multiple biopsies, and only one revealed cancer cells. The possible reason could be incorrectly taken biopsies that did not reach deep layers of skin and an insufficient number of biopsies that resulted in false-negative results and caused a delay in diagnosis.

Squamous cell carcinoma arising in these lesions is reported to be more aggressive than other primary squamous cell carcinoma with high rates of metastases in regional lymph nodes. Histological staging, tumor grade, and anatomic location are significant prognostic factors for the recurrence and metastatic potential of the tumor [9]–[11]. Tumors located in the lower extremities, as in the presented case, seem to have a more aggressive behavior than tumors at other locations. It is reported that the metastasis rate of tumors in the lower extremities is 30% [12], whereas the overall metastasis rate is 54% [13]. Our patient had left inguinal lymphadenopathy at diagnosis, which is a negative prognostic factor as described above.

Leg ulcers of vascular origin are frequently found in individuals with advanced venous insufficiency. The risk of malignant transformation in this type of wound is low. Approximately 2,4% of venous ulcers may undergo malignant transformation [14], whereas Senet et al. (2012) reported 10,4% cases of Marjolin’s ulcers in 155 chronic leg ulcers [15].

Cancer patient’s socioeconomic status plays an important role in oncological outcomes. Studies have shown that social support positively impacts a patient’s physical health, emotional well-being, and survival [16]. In our case, the patient lived alone and had no relatives to get support from. She had a few acquaintances who showed interest in her health condition, although none wished to take responsibility for patient care. A lack of social support may increase mortality risk, poorer oncological outcomes, and lower overall survival rates [17], [18]. Moreover, the lack of support after the diagnosis can have a negative impact on the effect of the treatment itself [19].

Given the rare occurrence of this condition, further research is needed to determine the frequency of biopsies in patients with chronic non-healing ulcers for early detection of malignant changes in the wound.

Conclusions

Squamous cell carcinoma developing in chronic leg ulcers is known to exhibit aggressive behaviour. Chronic non-healing wounds with malignant degeneration not being recognized on time may lead to delayed diagnosis, less favourable prognosis and metastases. Therefore, early recognition is crucial and may improve a patient’s overall survival and quality of life. Moreover, correctly taking biopsies is essential in reducing false-negative results. Finally, patients with chronic leg ulcers should be monitored by a multidisciplinary team of specialists to prevent a delay in diagnosis.

Declarations

The present study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.