Epidermoid Cancers that Masquerade as Venous Ulcer Disease
Squamous cell cancer (SCC) represents a type of epidermoid carcinoma of the skin; 20% of all dermatological malignancies are SCC, second only to basal cell cancers (BCC). Clinicians agree that damage from the sun may manifest many years after exposure. In the United States, clinicians uncover approximately 600,000 new cases of SCC and BCC each year. Sun-exposed surfaces of the head and neck on fair skinned individuals appear most vulnerable, although tumors arising from non-sun exposed areas have been reported in the literature.1
Immunosuppression plays an important role. Many of these cancers are associated with human papilloma virus (HPV) types 5 and 8.2 Clinically, they usually present as shallow ulcerations with a crust and elevated borders. Pathologists usually grade tumors by the degree of differentiation based upon how closely the tumor resembles normal squamous epithelium (ie, well, moderately, poorly). These lesions represent locally aggressive cancers with the possibility of recurrence, especially in poorly differentiated tumors. A small but definite risk of metastasis occurs with SCC yet varies depending upon the site and histologic type. Metastasis usually involves the regional lymph nodes but rarely the lungs and skin. Ultraviolet radiation exposure represents the major known risk factor in the occurrence of non-melanoma skin cancers (NMSC), in which HPV may be a cofactor for SCC.
Many lesions originally diagnosed as venous ulcers show characteristics strikingly similar to skin cancers and might represent sites of primary carcinomas (see Figures 1 and 2). Therefore, detecting the frequency of malignancy in patients previously diagnosed with venous ulcer disease and evaluating the possibility of uncommon Marjolin's ulcer could yield important diagnostic data.
Materials and Methods
All charts of patients with a preliminary diagnosis of venous ulceration evaluated between January 1 and December 31, 2000 at a wound center in Florida were reviewed. Patients were identified based on IDC-9 codes for varicose veins with stasis ulcer (454.0), varicose veins with ulcer and inflammation (454.2), and venous peripheral insufficiency (459.81). To be included in the review, the following criteria for diagnosis of a venous ulcer also had to be met3: ulcer location on the medial or lateral aspects of the lower legs and the presence of varicosities, brawny edema, and/or hyperpigmentation in the affected extremity. After obtaining all charts, documentation related to follow-up and biopsy results was abstracted.
Results
Sixty (60) patients met the criteria for a diagnosis of venous ulcer disease. Of these, 20 underwent biopsies because their lesions were documented to appear clinically suspicious for epidermoid skin cancers (ie, raised borders, chronic scaling).
Biopsy results showed malignancy in 15 of the 20 lesions. Seven had well-differentiated SCC; one had mixed squamous/basal cell and one had squamous/stasis dermatitis; one lesion was a moderately differentiated SCC; three were BCCs; one was a malignant melanoma; and another ulcer had SCC that appeared to emanate from a sinus tract caused by osteomyelitis (Marjolin's ulcer). Thus, in this cohort of patients, 25% of ulcers initially classified as venous ulcers were found to be malignant lesions.
Discussion
Marjolin's ulcer. Marjolin's ulcers historically represent squamous cell malignant tumors that arise from chronic wounds. In strict terms, lesions include carcinomas that traditionally transform from the chronic open wounds of pressure sores (decubiti) or burn scars. Clinicians usually observe aggressive cancers that possess a propensity for local recurrence and lymph node metastases. Sinus tracts secondary to osteomyelitis, fistulas, and venous ulcers have a propensity to develop these cancers.4 One study reports an incidence of 1:1,000 occurrences in patients with chronic venous stasis disease.5 Van Eygen et al6 recently discovered a 30-year-old venous leg ulcer that had undergone malignant conversion to an invasive well-differentiated spinocellular epithelioma.
Clinicians historically observe Marjolin's ulcer's in patients with syphilis and lupus vulgaris, in amputation stumps, small pox vaccinations sites, epidermolysis bullosa scars, granulomas inguinale, lyphogranuloma venereum discoid lupus scars, fistulas from hidradenitis suppurativa and acne conglobata, pilonidal sinus tracts,7 skin graft donor sites, puncture wounds, dog bites, and blunt trauma. Squamous cell cancer is the most commonly observed type of Marjolin's ulcer, followed by basal cell carcinoma. In addition, Ghazi et al8 documented three instances of malignant melanoma arising from a burn scar. Alconchel et al,9 Akiyama et al,10 and others made similar observations. Burn scar carcinoma may present as a flat, indolent lesion with indurated and elevated margins and may exhibit foul-smelling drainage and underlying bone destruction; therefore, these lesions may easily be mistaken for infection.
Esther et al11 and Arons et al12 conclude that Marjolin's ulcers remain rare despite the wide prevalence of wounds in which they may develop. Researchers11 postulate that 30 years represents the average latency time between ulcer formation and documentation of malignancy, with a range of between 12 to 47 years. They also reported that, in burn patients, the lag period might be inversely proportional to the age of the patient at the time of injury. The lag times reported in the literature range from 25 to 40 years, with a maximum of 70 years. Fifty years represents the consistently reported average age of most patients with this diagnosis.13 The male-to-female ratio has been reported to be as high as 3:1.14 Clinicians also observe high rates of Marjolin's ulcer disease in patients with spinal cord injuries.
Esther et al11 noted that the majority of Marjolin's carcinomas represented high-grade (poorly differentiated or undifferentiated) malignancies. Bello et al15 described a well-differentiated lesion in a burn scar. Tumors arising from pressure ulcers appear more aggressive than those evolving from burn scars.16 Lifeso and Bull4 postulate that tumor grade characterizes the most significant prognostic factor. Primarily grafted burn scars seldom undergo malignant transformation and if this occurs, only a portion of the scar may change. Thus, the risk of obtaining a false-negative diagnosis is increased. When these lesions are suspected, procurement of small multiple or excisional biopsies becomes essential.19
Most Marjolin's ulcers occur on the extremities; whereas, more than 90% of epidermoid cancers occur on the face and neck.5
Etiology of Marjolin's ulcers and venous ulcers: comparing ulcer dynamics. The exact mechanism of malignant transformation of chronic wounds remains unknown; however, a number of theories have been suggested. The most intriguing hypothesis relates to and perhaps parallels venous disease. Esther et al11 postulated that malignant conversion occurs when the constant breakdown of tissue leads to local nutritional deficiency caused by the release of toxins by autolysis and heterolysis. This process yields an epithelium that cannot withstand the carcinogens produced by the skin as a result of excessive heat and radiation. In addition, poor antigen-antibody response in both local and regional lymph nodes leads to the obliteration of lymphatics in scar tissue. Immunosuppression may be a contributory factor. Repetitive trauma and a prolonged healing phase may predispose an area to malignant transformation.5,11
Theoretically, the "cancerous environment" is exacerbated by a lack of blood supply and loss of immunity in the scar tissue.5 Increases in vein pressure remain the leading cause of edema and subsequent venous ulceration in the lower extremity. This phenomenon usually occurs secondary to valve incompetence and subsequent failure of the pumping action of the skeletal musculature. Yet the mechanism that actually causes the ulcer remains multifactorial and is usually linked to microvascular compromise, venous hypertension, a history of deep vein thrombosis, family history, obesity, age, pregnancy, and the presence of mixed arterial and venous disease.18 Clinicians often observe abnormal tissue with lipodermatosclerosis, flaky skin, and brownish discoloration. The most common anatomical locations for venous ulcer disease also are prone to repetitive microtrauma, particularly at the medial lower leg or "gaiter area."
Cutaneous microangiopathy in chronic venous insufficiency precedes clinical changes in the skin.19 An increase in venous pressure may have an effect on the pressure gradient across the capillary bed, resulting in leakage of fluid and cells into the tissues of the leg; fibrinogen may leak through the intercellular pores causing the deposition of "fibrin cuffs." Browse and Burnand20 theorize that these cuffs form a barrier for nutrients passing from the capillary bed to the tissues, resulting in tissue death, tissue breakdown, and ulceration.
Some research suggests that neutrophils become trapped in the post-capillary venules of patients with chronic venous disease. Activated neutrophils potentially release a number of chemical substances such as Tumor Necrosis Factor, which may lead to local tissue damage.21 Chronic inflammation can predispose to "leukocyte trapping," causing adhesion molecules, decrease in nutritional support, and tissue destruction. Venous congestion may lead to aberrant changes in the microcirculation, cutaneous hypoxia, and lack of cutaneous vascular reserve, culminating in trophic skin changes.22
Similarities in the etiology of Marjolin's and venous leg ulcers include: insufficient nutritional support, tissue hypoxia, lack of blood supply, decreased tissue immunity, and repetitive microtrauma. Lag time represents the primary difference in the development of symptoms. Neither lesion appears predicated on exposure to ultraviolet (UV) light.
The Link between Epidermoid Cancers and Ultraviolet Light Exposure
People who reside in tropical climates such as South Florida are likely to have greater exposure to UV rays on their lower extremities than persons residing in colder climates. Further, participation in outdoor endeavors such as golf, tennis, and boating, in addition to wearing tropical attire (eg, short pants) increases one's risk of local, lower extremity microtrauma. Indeed, it has been suggested that for every 8- to 10-degree decrease in latitude, the incidence of skin cancer doubles.17
Exposing the lower extremities to UV rays appears to be common in tropical locales; this hypothesis, coupled with repetitive trauma, hypoxia, and nutritional deficiencies propagated by the microcirculatory abnormalities of venous disease may explain the increase in squamous cell cancers in this anatomical area.
Conclusions
A significant number of patients with a preliminary diagnosis of venous ulcers actually had malignancies, leading researchers to conclude that primary epidermoid cancers may mimic venous ulcers in appearance, location, and symptoms. Only one Marjolin's lesion was observed in this study, which supports the hypothesis that Marjolin's ulcer is a rare condition despite the propensity to develop at sites of many different types of wounds. The high percentage of primary cancers may be attributed to increased exposure of the lower extremities to the strong UV rays indigenous to areas such as South Florida. Because damage from the sun may manifest many years after exposure, clinicians should question patients who live in northern climates. Those presenting with venous ulcer symptoms and a history of previous domicile in a tropical climate may benefit from lesion biopsies to test for epidermoid cancers. Because this pilot study encompasses a relatively small sample of patients, data collection to provide a more accurate reflection of the rate of epidermoid cancers in these patients will continue.
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