Basal Cell Carcinoma Arising in a Chronic Venous Ulcer: Two Cases and a Review of the Literature

Although uncommon, all forms of chronic wounds, such as leg ulcers, have an increased risk of malignant transformation. While the most common type of skin cancer is the primary basal cell carcinoma (BCC), occurring predominantly in sun-exposed areas, the incidence of BCC arising from chronic wounds is very low. Along with an extensive review of the English literature, 2 atypical cases of BCC arising in a chronic venous stasis ulcer are reported. In addition, the clinical features that characterize, and may help in early diagnosis of, this uncommon entity are discussed.

   Basal cell carcinoma (BCC) is the most common form of skin cancer. Environmental and genetic factors predispose patients to BCC. Sunlight, particularly chronic exposure, is the most frequent association with its development. Tumor size can vary from a few millimeters to several centimeters in diameter. Most BCCs present as a small dome-shaped papule or nodule with a pearly appearance and well-rounded borders with adjacent crusting; these features are pathognomonic for BCC and are important markers for definitive diagnosis of these typically indolent lesions that enlarge slowly, tending to be locally destructive, but that rarely metastasize. Most BCCs occur on sun-exposed areas of the body, in particular on the head and neck, accounting for 80% of all cases of non-melanoma skin cancer. One-third od BCCs occur on areas of the body that are not exposed to sunlight, and approximately 8% occur in the lower extremities.¹  

   The biological basis for the low frequency of metastasis are the stromal dependence of tumor cells at the primary site² and the lack of microvasculature within primary BCC.³ The metastatic rate ranges from 0.0028% to 0.55%,⁴ and common sites are the lymph nodes, lungs, and bones. Despite the unusual metastatic risk, appropriate staging examinations to exclude lymph node or organ involvement are necessary, especially when specific risk factors for the development of metastatic tumor are present, such as large size, ulceration, and local invasion. A meticulous diagnostic exploration is indispensable, particularly with the suspicion of a tumor arising on a chronic wound, in an effort to exclude a misdiagnosed tumor and, eventually, to improve the prognosis.

  Chronic ulceration of the lower leg is a frequent condition, with a prevalence of 3%-5% in the population over 65 years of age.⁵ The current literature describes that 2.4% of ulcers arising from chronic venous stasis undergo malignant transformation⁶ and, of these, the most frequent tumor is represented by well-differentiated squamous cell carcinoma (SCC). On the other hand, BCC arising on a chronic venous leg ulcer is an extremely rare condition. Well-known risk factors for the development of malignancies of chronic ulcers are chronic inflammation such as pre-existing osteomyelitis;⁷ reduction of immune defense (as often observed in patients with diabetes);⁸ and traumatic injuries accompanied by chronic irritation.⁹ It is often difficult to differentiate between malignant transformation of a chronic wound into a carcinoma and malignancies presenting as ulcerations. In this paper, the authors report 2 cases of BCC arising in patients with a long-standing history of venous leg ulcers.

  Patient 1. A 93-year-old woman with a 10-year history of a chronic leg ulcer was admitted to the authors’ outpatient clinic at the Campus Bio-Medico di Roma University (Rome, Italy). The patient’s medical history included hypertension and peripheral vascular disease. She could not recall any trauma to the corresponding area. 

   The ulcer was 14 cm x 9 cm in size, with regular borders, localized erythema in the periphery, and shiny granulation tissue on its surface. Signs of chronic venous insufficiency were found on both legs, with bluish and tortuous varicosities, mostly in the left lower leg. At that time, the histopathology of skin biopsies performed on various sites of the ulcer were negative for malignant transformation. Furthermore, microbiological culture showed no signs of bacterial growth. The patient was treated by a home care team with advanced dressings, with an initial benefit to the healing progress of the wound. However, after 6 months, the ulcer increased in size and worsened in appearance. Physical examination revealed an almost circumferential ulcer, 16 cm x 11 cm in size, located in the inferior third of the leg (Figure 1a). There was a massive discharge of fluid across the ulcer bed, and margins were irregular, elevated, and violaceous in the upper portion (Figure 1b). The great saphenous vein was completely clotted on the ulcer bed and the periosteum of the tibia was visible in one small portion. This was especially concerning, as a violaceous border can sometimes indicate the presence of rare conditions such as pyoderma gangrenosum,¹⁰ and irregular margins can indicate the presence of tumor spreading.

  Due to these very specific changes and the patient’s worsening condition despite appropriate therapy, and in an effort to ascertain the nature of the tissues, multiple biopsies from the margins and the ulcer’s bed were performed. Specimens revealed the presence of a BCC with differentiated basal cells.   

The microscopic analysis showed nests of basaloid cells with hyperchromatic nuclei and poorly defined cytoplasm budding from the undersurface of the epidermis. Palisade cells at the periphery and haphazard arrangement of cells in the centers of the nests were present (Figure 2a and 2b). At the stromal-tumor interface, some clefts were also present, which is a common feature of the tumor (Figure 2c).   

Furthermore, bacterial cultures showed bacterial colonies of Staphylococcus aureus. The patient began antibiotic therapy with sulfamethoxazole/trimethoprim oral, 480 mg daily for 5 days. As secretions reduced, a total excision of the lesion was performed. The great saphenous vein, which was almost completely clotted, was ligated and removed. Muscle fascia also was removed because it had been extensively infiltrated by the tumor. The periosteum of the tibia was completely preserved. The definitive pathological development revealed a well-differentiated BCC arising on a venous ulcer, yet all the margins were free from tumor. A second surgical procedure for reconstruction of the defect included a split-thickness skin graft that healed without complication (Figure 3). A temporary lymphatic stasis of the foot was observed and treated with mechanical compression therapy. After a period of 2 years the patient was in good health, without symptoms, and tumor free.

  Patient 2. A 67-year-old woman was admitted to the authors’ outpatient clinic with a chronic venous stasis ulcer, located in the inferior third of the left lower leg. Her medical history included type II diabetes mellitus, hypertension, and metabolic dysfunctions. The patient reported that the ulcer, arisen 2 years before, had increased in size and worsened despite topical treatment. Multiple skin biopsies had been performed at that time to investigate the nature of the lesion. However, neither cytological assessment nor biopsy were positive for malignant transformation. On admission to the outpatient clinic, physical examination revealed a circular shallow ulcer, 6 cm x 5 cm in size, with regular borders, raised edges, localized erythema in the periphery, and abnormal granulation tissue on its surface. Mild pitting edema was noted in the pretibial region and on the dorsum of her left foot. There was no undermining of the adjacent soft tissues and the ulcer did not involve the bone below. Doppler ultrasound suggested venous insufficiency. Based on the local clinical signs and the protracted course of the ulcer despite appropriate treatment, in an effort to ascertain the biological nature of the tissues, a skin biopsy of the lesion was performed. Microscopic examination revealed nests of atypical basaloid cells, and the patient underwent a total excision of the lesion. Preoperative analysis included an MRI of the lower leg, x-ray of the chest, and ultrasound examination of the regional lymph nodes. The definitive pathological analysis revealed well-differentiated BCC arising in a chronic venous stasis ulcer and excision margins free from tumor. Reconstruction was performed with a second procedure with a split-thickness skin graft. One year postoperatively, the patient remained symptom and tumor free.

  Chronic ulceration of the lower leg is a frequent condition, but the risk of its malignant transformation is uncommon. Squamous cell carcinoma is the most frequent tumor developing on a chronic leg ulcer, while secondary BCC arising on a chronic ulceration is an extremely rare condition and often a misdiagnosed complication.⁴

  Several studies were conducted to determine the frequency of skin cancer associated with chronic leg ulcers. In 2007, a retrospective study by Combemale et al¹¹ showed that of 80 patients and 85 tumors arising from malignant degeneration, 97.6% were SCC whereas only 2.4% were BCC. Eighty-eight percent of the ulcers were of venous origin with a mean duration was 27.5 years.

  Between January 2006 and May 2009, a prospective observational trial by Senet et al¹² showed that of 155 chronic leg ulcers on 145 patients, cancer frequency was 10.4%: 9 SCCs, 5 BCCs, and 2 nonepithelial skin cancers. Exudate, odor, and increased pain were features that suggested wound biopsy.¹³ No significant association was noted between cancer and excessive bleeding but, in accordance to the previous retrospective study by Combemale and colleagues, the abnormal excessive granulation tissue at the wound edges was significantly associated with skin cancer.

  As demonstrated by this study, malignant transformation in BCC is very rare and secondary malignancies mostly develop in ulcers of longer duration, probably as a consequence of the continuously increased cell division in and around the wound.⁵

  Some authors discuss venous stasis as a significant inducer of epidermal hyperplasia.¹⁴ Histochemical studies of venous ulcers revealed overexpression of transforming growth factor-α and epidermal growth factor receptors¹⁵ at wound margins. This long-standing hyperproliferative state may increase the risk of malignant transformation.¹⁶

  Ouahes et al¹⁷ examined the expression levels of proto-oncogenes (c-Has-ras and c-fos) in chronic wounds. They found elevated levels of c-Ha-ras in the basal layer of epidermis and c-fos protein was highest in the epidermal cells adjacent to the wounds. These results suggest that elevated levels of growth regulating proto-oncogenes may cause persistent epidermal hyperplasia in chronic wounds, predisposing the patients to malignant transformation.

  Signs of a possible malignant transformation include hyperkeratotic granulation in the ulcer, alterations in the margin, unusual pain, bleeding, or a protracted course despite appropriate treatment. Squamous cell carcinoma arising on chronic leg ulcers has a higher metastatic rate, compared with primary SCC.¹⁸ In addition, it is demonstrated that SCC on chronic scars (ie, Marjolin ulcer) is more aggressive than other forms.

  Unlike SCC, the growth of BCC on chronic leg ulcers of vascular origin is slow. However, a delay in diagnosis may result in a larger and deeper tumor, which are the major risk factors for lymph node involvement and distant metastasis.

  In the cases of both SCC and BCC, the goal of treatment is complete removal of the tumor with maximal preservation of function and physical appearance.¹⁹ In nearly all cases, conventional excision or Mohs surgery are standard therapies of choice.

  The precancerous potential of chronic leg ulcers is well-established but the number of reported cases is small. Leg ulcers can be a clinical feature of carcinoma, and carcinoma can be an evolution of leg ulcers. Some authors propose that only cases with prior negative biopsy should be accepted as secondary malignancies and, as in this case series, only a negative biopsy can prove the origin of the tumor.

  Close wound inspection and monitoring for unusual changes should be performed diligently on chronic wounds. Delay in diagnosis, in fact, may result in a worse prognosis, loss of the affected limb, or occurrence of metastasis. For this reason, patients with chronic leg ulcers should be educated thoroughly by their physicians and other health care workers about concerning clinical features and changes of ulcer appearance so they will be more apt to seek and receive early and prompt medical attention.

The authors are from the Campus Bio-Medico di Roma University, Rome, Italy.

Address correspondence to:
Igor Poccia, MD
Division of Plastic Surgery
Campus Bio-Medico University of Rome School of Medicine
Via A. del Portillo 200
00128, Rome, Italy
i.poccia@unicampus.it

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