THE ASSOCIATION BETWEEN malignancies and chronic wounds may take several forms (Table 1). In one instance, a wound may degenerate into malignancy. A malignant clone may arise within a wound over time, likely through chronic antigenic or nonspecific stimulation. This is most commonly seen with squamous cell carcinoma and is termed Marjolin’s ulcer, after the author who originally described this phenomenon.
Malignancies may also present as wounds. A classic example of this is basal cell carcinoma that outgrows its blood supply and erodes and subsequently ulcerates. The term rodent ulcer has been applied to a basal cell carcinoma that has an ulcerated portion because it appears to have been eaten away by a rodent.
In addition, wounds may be coupled with malignancy. Chronic wounds resulting from vasculitis or pyoderma gangrenosum have been linked to malignancy, most commonly lymphoreticular malignancy. Furthermore, treatment for malignancy may result in the development of chronic wounds. The use of hydroxyurea has been linked to the development of leg ulcers, and the use of ionizing radiation for the treatment of tumors may lead to the development of refractory ulcers.
Cutaneous malignancies are often observed during the routine examination of a patient’s skin in the course of wound care practice. Due to the prevalence of skin cancers, health care practitioners involved with wound management are likely to encounter these cancers as part of their practice. This article focuses on two ways in which malignancies and wounds are related: the malignant degeneration of chronic wounds into cancer and malignancies that present as chronic wounds.
Malignant Degeneration of Wounds
Although rare, malignancies found within chronic wounds are well documented. 1–6 Marjolin first reported this in 1827 when he observed that the borders of a chronic wound underwent malignant changes 1; therefore, a chronic wound that develops into a malignancy is referred to as a Marjolin’s ulcer. Incidence varies depending on the series, but an estimated 1.7% of chronic wounds undergo malignant degeneration. 1,3 This typically affects 40- to 70-year-old men who have had osteomyelitis and chronic wounds on the lower extremities of 20 to 50 years’ duration. 2 However, reports have been published of malignant degeneration of a chronic wound as early as 18 months after the development of the wound. 3
The most common scenario in which chronic wounds have been associated with the development of squamous cell carcinoma is in the presence of a draining sinus tract of chronic osteomyelitis. This phenomenon was first reported by Hawkins in 1835 in 1 of 7 “Cases of Warty Cicatrices” and, although rare, is well documented. 1–3 Other malignancies have also been found in the draining sinus tracts of chronic osteomyelitis and wounds, including basal cell carcinoma, adenocarcinoma, fibrosarcoma, sarcoma, and plasmacytoma.
Other chronic wounds are at risk for malignant degeneration as well. The development of squamous cell carcinoma has been reported in chronic wounds secondary to burns, trauma, hidradenitis suppurativa, radiotherapy, and diabetes, among others 6,7 (Figure 1). In addition, malignancies such as sarcoma, lymphoma, melanoma, basal cell carcinoma, and squamous cell carcinoma have been reported to develop within the wound bed of chronic venous ulcers. 4–15 The risk of developing one of these malignancies within a venous ulcer is 21%. 4
It appears that squamous cell carcinomas occur more frequently than basal cell carcinomas in venous ulcers. 7,11 These malignancies occur more frequently in women, possibly because women’s legs are exposed to sunlight more often than men’s. 5,16 This suggests that chronic ulcers that develop into malignancies share some of the same risks of developing malignancy as nonulcerated skin.
Another risk factor for the development of squamous cell carcinoma in nonulcerated skin is human papilloma virus; however, the role of papilloma virus in the malignant transformation of a wound has not been well studied.
Malignancies that Present as Chronic Wounds
Cutaneous malignancies may present as chronic wounds. The incidence of malignancies that initially present as ulcers is rare (3%) 17; malignant transformations are even rarer. 9,17 It is often difficult to distinguish primary malignant ulcers from malignant transformations. In general, when malignancies present as ulcers, they often go misdiagnosed for a long time because they are mistaken by practitioners for nonmalignant ulcers. The diagnosis of primary malignancy should be considered if the ulcer has a relatively short duration and the patient does not have a history of prior radiotherapy.
A handful of reports describe different types of malignancies that present as ulcers, such as Kaposi’s sarcoma, lymphoma, melanoma, basal cell carcinoma, and squamous cell carcinoma. 11,16–23 In a study by Hansson et al, basal cell carcinoma was found to be the most common type of malignancy 17 (Figure 2). In this series, basal cell carcinoma accounted for 60% of the malignancies and squamous cell carcinoma accounted for 15%. The patients with carcinomas were found to be significantly older when compared with patients who had nonmalignant ulcers.
Kaposi’s sarcoma typically presents as patches, plaques, or nodule and, rarely, as an ulcer. 18–20 Schmidt et al, however, reported that 1 of 20 reported cases of penile Kaposi’s sarcoma presented as an ulcer. 18 This unusual presentation of Kaposi’s sarcoma has been related to coinfection with HIV or an immunocompromised state. Cutaneous lymphoma may present as various types of skin lesions and it, too, may rarely present as an ulcer 23 (Figure 3). Ulcerative cutaneous lymphomas are associated with a worse prognosis.
Several theories explain why malignancies develop within chronic wounds. The exact mechanism is unknown; however, it is postulated to be an example of wound healing gone awry. Some believe that constant irritation and infection, chronic ulceration, repeated trauma, or exposure to noxious environmental agents lead to development of malignancies. 7,15 Chronic irritation with repeated damage and attempted repair of the damaged cutaneous tissue may be a contributing factor in the initiation of carcinogenesis. 24 Stimulation leading to prolonged inflammation may result in selection of a malignant clone. Arons et al 25 believe a sequence of events is involved in wound carcinogenesis. Normal tissue is subjected to trauma, which leads to acanthosis, followed by basal cell hyperplasia, pseudoepitheliomatous hyperplasia, basal cell atypia and, finally, an epidermoid carcinoma. 25
Other theories include the induction of dormant neoplastic cells. 14,26 There is a 2-step process by which normal cells are converted into cancer. 26 During the initiation phase, normal cells become dormant neoplastic cells. The promotion phase allows dormant cells to change into a tumor by the stimulation of a cocarcinogen, such as infection.
In addition, toxins that are released from damaged tissue lead to the mutation of cells and, eventually, a tumor. 27 These toxins cause injury to the vasculature and/or to the lymphatic system, causing lack of nutritional support for the damaged cells. Cellular deficits lead to altered mitosis of the resultant scar. The scars caused by healing of damaged tissue are poorly nourished and cannot tolerate infection or wound exudate as well as normal tissue. 24 Future damage is poorly tolerated and leads to mutagenesis and cancer. Scar tissue is less organized and more likely to ulcerate and degenerate into cancer. 26
Some believe that trauma results in the implantation of epidermal cells into the dermis. 26,27 This causes a foreign body reaction within the dermis and alters the normal regenerative processes of the tissue. Any insult to this tissue in the future will not be endured in the same manner as normal tissue, resulting in cancer.
Several studies by Zhao et al 28–30 show evidence that could link proteins to radiation-induced malignancy in skin ulcers. Telomerase reverse transcriptase expression in the cytoplasm and nuclei of squamous cells, smooth muscle cells, fibroblasts, and lymphocytes was found in virtually all malignant skin ulcers. 28 The overexpression of c-erb-B2 and p21 oncoproteins in the cell membranes of squamous epithelial cells, among others, was found in 92% and 92.9%, respectively, of malignant skin ulcers. 29 Finally, MDM2, p53, and NCAM protein overexpression was found in 36%, 8%, and 32% of malignant skin ulcers, respectively. 30
Controversy surrounds the proper time to obtain a biopsy of a wound base and its margins. Some clinicians advocate performing biopsies of wounds that have been present for longer than 3 months and that have not responded to standard therapy; others recommend performing biopsies of wounds that are older than 4 months. 6,17 Some clinicians routinely biopsy all wounds. Given the uncommon nature of malignant degeneration of a chronic wound or a malignancy presenting as a chronic wound, some authors suggest that only suspicious wounds undergo biopsy. These include wounds that have increased in size despite appropriate treatment; malodorous wounds; painful wounds; wounds with excess granulation tissue that extends beyond the margins; wounds with an irregular base or margin; and wounds that experience a change in drainage, excess bleeding, or exophytic growth. 4–7,9,11,12,17 Biopsies may also be performed on wounds that are not responding to standard therapy to determine if other factors, such as inflammatory or infectious causes, may be impacting wound healing.
Until recently, amputation was the treatment of choice for squamous cell carcinomas that arose within chronic wounds associated with chronic osteomyelitis. 1–3 The rationale was the high death rate associated with primary excision. In some cases, wide local excision was preferred for small mobile tumors. 27 However, amputation was formerly indicated when (1) the cancer was adherent to underlying tissue and could not be separated, (2) wide local excision would leave an open articulation surface, (3) there was uncontrollable suppuration, (4) there was bone necrosis, (5) there was decreased functional capacity after wide local excision, and (6) there was erosion into a large vessel. It has been found that patient outcome improves when amputation is performed, even in the absence of other adjuvant therapy. This suggests that improved survival is based on complete local excision rather than treatment of distant metastatic disease.
Several reports have shown that other methods of ensuring complete local excision are also useful, 1–3 including Mohs micrographic surgery. The presence of regional or distant metastases should be excluded prior to local surgery. Then, using the Mohs technique, the tumor is followed microscopically through serial sections to ensure complete eradication. This technique may be limb saving. However, there are certain circumstances under which Mohs cannot be done. If distant metastases are present or regional lymph nodes are involved, Mohs would not be curative. In addition, if a functional limb is not a possible outcome, amputation, with subsequent use of a prosthesis, may be more desirable. 1
Lymph node dissection may be performed if palpable nodes persist for longer than 3 months after primary excision. However, there is much controversy regarding lymph node dissection. 27 Some believe that first determining a lesion’s level of differentiation is important because this will predict metastatic potential and aid in determining the need for lymph node dissection. Because enlarged lymph nodes are often associated with chronic osteomyelitis, a period of observation (3 months, for example) should be undertaken after treatment of the tumor to allow for the inflamed nodes to regress. If they persist, node biopsy is warranted. Treatment is often based on the grade of the malignancy. Others believe that the necessity of lymph node dissection increases with increasing grade. For example, Grade 1 (well-differentiated) lesions require lymph node dissection only if they are palpable. Grade 2 (moderately differentiated) lesions and Grade 3 (poorly differentiated) lesions typically require lymph node dissection.
In some cases, such as squamous cell carcinoma or basal cell carcinoma that develop in venous ulcers, successful outcomes using wide excision with skin grafting have been reported, suggesting that this may be sufficient treatment in certain instances. 4–7 In the case of melanoma, treatment depends on the depth of invasion and the size of the lesion. Kaposi’s sarcoma has been successfully treated with excision, radiation, chemotherapy, or interferon. 20 Lymphomas have been treated with excision and appropriate chemotherapeutics and radiation. 21
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