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Lower Extremity Malignancies Masquerading as Ulcers
An ulcer is an area of epidermal and/or dermal loss that may extend to muscle or bone.1 In individuals >65 years old, lower extremity ulcers are a common reason for evaluation by the podiatrist, wound care specialist, primary care physician, vascular surgeon, or dermatologist. Common causes of lower extremity ulcers include trauma, blister necrosis, and infection, as well as autoimmune, immunopathic, and vascular factors.2
Lower extremity ulcers often have a vascular etiology and include venous ulcers, arterial ulcers, hypertensive ulcers, rheumatoid ulcers, and atrophie blanche.2 Using the General Practice Research Database from England and Wales, Margolis et al3 estimated the annual prevalence and incidence of venous leg ulcers in the elderly to be 1.69 (50,000 elderly patients per year between 65 and 95 years old) (95% CI, 1.65–1.74). The overall incidence rate per 100 person-years was 0.76 (95% CI, 0.71–0.83) for men and 1.42 (1.35–1.48) for women (positive predictive value was 98.3% with a 95% confidence interval, 90.0–100.0. Incidence is based on 100 person years of venous leg ulcers between 1988 and 1996). These vascular ulcers are seen most often in individuals with a history of cigarette smoking, obesity and/or diabetes.4
Reviews in the literature note that wounds of long duration such as lower extremity ulcers are known risk factors for the development of malignancies such as squamous cell carcinoma (Marjolin’s ulcer).2,5,6 In addition, when a tumor outgrows its blood supply or is traumatized, an ulcer may form. Such phenomena make it important to recognize that an ulcer that does not heal despite medical treatment may, in fact, be a malignant neoplasm.
A review of the literature does not support a specific time frame for considering the diagnosis of an ulcerative neoplasm. However, some clinicians advocate cutaneous biopsies either 3 or 4 months into the standard treatment course of chronic wound management, while others recommend routine biopsies, even at initial evaluation.2,7,8
“Ulcer-type” Malignancies
Some examples of malignancies that may masquerade as ulcers include basal cell carcinoma (nodulo-ulcerative type), squamous cell carcinoma, keratoacanthoma, malignant melanoma (nodular melanoma), late-stage (tumor stage) mycosis fungoides, angiocentric lymphoma (lymphomatoid granulomatosis), lymphomatoid papulosis, angiosarcoma, and metastasis to the skin from breast, colon, melanoma, or lung carcinoma.
Basal cell carcinoma. Among the various subtypes of non-melanoma skin cancers, the most common is the basal cell carcinoma (BCC).9 According to 2006 American Cancer Society statistics,10 BCC affects 800,000 Americans each year. The age-adjusted incidence of BCC in the US in 1994 was approximately 475 and 250 per 100,000 in Caucasian men and women, respectively. The estimated lifetime risk of BCC in the Caucasian population is 33% to 39% in men and 23% to 28% in women.9 Predisposing factors for acquiring BCC are white-skinned persons with an inability to tan, as well as heavy sun exposure in one’s youth. Having both of these risk factors increases susceptibility to BCC.11
Of the many BCC subtypes, nodulo-ulcerative BCC is the most likely to ulcerate; 60% of BCC are nodular or nodulo-ulcerative BCC.11 Clinically, nodulo-ulcerative BCCs usually appear as shiny, red nodules with overlying ulceration that can occur anywhere on the body, including the lower extremities (see Figure 1). “Rodent-ulcer type,” another subtype of BCC, looks as if a rodent was eating away at the area of involvement and may present clinically as a large ulcer with well-demarcated borders that has nodules typical of BCC, including characteristic translucency and telangiectasias.11
Management of BCC includes excision, cryosurgery, curettage and/or electrosurgery, radiation therapy, and Mohs micrographic surgery. The latter is intended to achieve the highest cure rate with the smallest surgical defect and best aesthetic result through on-site, real-time, microscopically controlled, staged surgical removal of the cutaneous malignancy layer-by-layer, section-by-section.12,13 If the BCC is superficial, topical treatments such as 5-fluorouracil or 5% imiquimod may be used.11 Currently, surgical excision is the standard of care for BCCs; however, high 5-year recurrence rates indicate potentially incomplete removal of these lesions.14 Because of the repeated cycles of surgical removal required for proper treatment, curettage with electrodesiccation (another acceptable treatment modality for the surgical removal of BCC) is sometimes associated with poor cosmetic results and increased recurrence rates compared with even standard excision.14
Squamous cell carcinoma. Another example of a non-healing chronic malignant ulcer is squamous cell carcinoma (SCC). Potential causes of these malignant tumors of epithelial keratinocytes include exposure to sunlight or ionizing radiation, ingestion of arsenic,15 and a history of burn scars in the ulcerated area. Chronic stasis is a risk factor for lower extremity ulcerations; when venous insufficiency is present, it is not uncommon for SCCs to form ulcerative lesions and subsequently be misdiagnosed as a common, venous stasis ulcer. This ulcerative neoplasm, also known as Marjolin’s ulcer, arises from chronic open wounds or burn scars. The exact mechanism of its development remains unknown.6,16,17
The incidence of SCC is not as high as BCC. According to the American Cancer Society (2006), SCC afflicts more than 200,000 Americans while BCC affects 800,000 Americans each year.10 Although generally more common in men, the legs of women are more frequently affected.1 Clinically, SCC may be found anywhere on the body, including the lower extremities (they are most common on the head and neck), and appear as scaly, erythematous papules, nodules, or plaques that may ulcerate (see Figure 2).
Management of SCCs and BCCs is similar and includes excision, cryosurgery, radiation therapy, curettage and/or electrosurgery, and Mohs surgery. Because these tumors may metastasize, treatment should be aggressive. According to Smoller,15 the overall rate of metastases from SCC is low (1% to 2%); however, it is quite difficult to assess.15 Tumors arising in old burn scars, sites of radiation, and chronic osteomyelitis have a much higher rate of metastasis.15
Keratoacanthoma. Keratoacanthoma (KA) is similar to SCC. Clinically, KA appears as a single, skin-colored or tan-to-red, dome-shaped nodule with a central keratinaceous crater or ulcer on sun-exposed skin (see Figure 3). Keratoacanthoma grows faster than SCC — it may become as large as 2.5 cm within a few weeks.15,18 Keratoacanthomas usually appear on the face or upper extremities as well as the legs, where they can grow rapidly. Possible etiologies include exposure to ultraviolet (UV) radiation and chemical carcinogens such as tar. Human papilloma (HPV) virus also has been linked to keratoacanthoma as a possible cause. Management most often requires surgical resection because 10% of these ulcers may develop into frank SCC.18,19
Malignant melanoma. Malignant melanoma (MM) is the most serious of all the skin cancers.12 Melanoma accounts for 4% of all skin cancers but is responsible for more than 77% of skin cancer-related deaths.12 Nodular melanoma has the greatest potential to ulcerate. One review article suggests that 16% of melanomas are the nodular type.20
Nodular melanoma grows rapidly. The median age for an individual with this type of tumor is 50 years. Nodular melanoma occurs in all populations but is more prevalent in the Japanese.20 Risk factors for MM include increased sun exposure, light skin color, family history of melanoma, and presence of a precursor lesion, including Clark’s dysplastic melanocytic nevus or numerous congenital melanocytic nevi. Clinically, nodular melanoma may be an ulcerated papule or plaque with colors ranging from blue to black to gray21(see Figure 4).
Management of MM includes wide surgical resection; however, melanoma must be staged before providing definitive therapeutic interventions. Staging is based on the primary tumor thickness (Breslow level), presence of regional lymph nodes, and any distant metastases.22 Clinical and histopathologic staging is utilized to determine the degree of surgical intervention, need for diagnostic imaging, and prognostic factors.21
Mycosis fungoides (cutaneous T-cell lymphoma). Mycosis fungoides (MF), also known as cutaneous T-cell lymphoma (CTCL), is a lymphoreticular disorder affecting memory helper T cells.23 This cancer also may masquerade as an ulceration, usually in the late or tumor stage of this disease. The tumor stage (considered late-stage MF) is most relevant to current discussion because it is most often responsible for cutaneous ulcerations.23 In this stage, large nodules are seen on infiltrative plaques. The nodules break down and form deep oval ulcers with necrotic bases (see Figure 5). Clinically, skin lesions develop as plaques, nodules, or ulcers associated with diffuse erythema. The randomly distributed lesions can be round, oval, arcuate, or annular.
Management of early cutaneous T-cell lymphoma includes phototherapy, topical and systemic retinoids, topical nitrogen mustards, and topical corticosteroids. Treatment for extensive plaque stage disease includes electron-beam irradiation plus chemotherapy. Therapeutic interventions for nodular stage CTCL (which may ulcerate) include systemic treatments such as recombinant alpha interferon or chemotherapy.17,24
Lymphomatoid granulomatosis. Another malignant neoplasm, angiocentric lymphoma or lymphomatoid granulomatosis, may involve not only the skin, but also the lungs, central nervous system, and kidneys. Lymphomatoid granulomatosis is associated with the Epstein-Barr virus. Uncommon in the US and Europe and more common in Asia, this T-cell lymphoma combines both inflammatory and neoplastic processes.25 IT is a rare disease of unknown prevalence.17,25 Its skin lesions, which are frequently present may be macules, papules, nodules, plaques, vesicles, or ulcerations.17,26 Usually, however, diffuse red plaques with purpura appear. This later gives rise to ecchymotic-like lesions with epidermal atrophy. On palpation, the ulcers may be firm with soggy borders. The lesions may be distributed anywhere but favor the gluteral regions and lower extremities.17,25 The prognosis is poor; the overall 5-year survival rate is <50%.27 Management includes prednisone and/or cyclophosphamide.28
Lymphomatoid papulosis. Lymphomatoid papulosis (LyP) or Macaulay disease is usually seen in adults 20 to 40 years of age. Typical presentation involves polymorphous lesions that may be pruritic, tender, or painful. These recurrent crops of pruritic papules may ulcerate,29 coming and going for decades with spontaneous regression. The lesions are recurrent and self-healing over 2 to 8 weeks; however, some resolving lesions may leave varioliform (smallpox-like lesions) and hyperpigmented and/or hypopigmented scars. Initially, the lesions are smooth but they may become hemorrhagic, hyperkeratotic, and/or ulcerative; they may be red-brown with hemorrhage and/or have central black necrosis (see Figure 6). They may be found on the trunk and extremities.30
Lymphomatoid papulosis has a relatively low risk of malignancy and its etiology is unknown; it is considered a chronic lymphoproliferative disease of the skin and may be classified as a low-grade T-cell lymphoma or a pseudolymphoma.31 A review of the literature suggests that in 10% to 20% of patients with this disease, mycosis fungoides, Hodgkin’s disease, or large cell lymphoma may ensue.31-33 Therefore, skin biopsies, (two or more on fully developed inflammatory papules without necrosis, should be performed.31
Lymphomatoid papulosis is difficult to manage. Historically, the course of the disease is benign; however, Zackheim et al33 have reported the development of CTCL in 39% of patients. Proof that treating lymphomatoid papulosis prevents the development of secondary lymphoma is lacking. Phototherapy may be utilized as well as electron-beam irradiation, methotrexate, and/or topical corticosteroids to prevent disease progression.30,34 To date, no treatment has proven to be consistently effective.29
Angiosarcoma. Angiosarcomas usually appear on the head and neck; however, it is not uncommon for them to affect the lower extremities. A highly malignant tumor of vascular endothelial cells, cutaneous angiosarcoma may present with an enlarging echhymosis, black nodules, or ulceration.35
Three clinical patterns of cutaneous angiosarcoma include nodular, diffuse, or ulcerated. The ulcerative pattern occurs most commonly in the upper extremity following radical mastectomy (Stewart-Treves Syndrome); however, in rare cases it has been known to develop on the lower extremities.36 Lymphedema-associated angiosarcoma may occur in an edematous lower extremity after radical inguinal lymphadenectomy for the treatment of metastases from malignant melanoma (Kettles Syndrome).37
Angiosarcoma may present as a cutaneous or subcutaneous nodule or nodules (see Figure 7). The tumor or tumors rapidly increase in size and number and often ulcerate. The prognosis in angiosarcoma is poor because of its high rate of metastases. The 5-year survival rate is approximately 12%.36
Management of angiosarcoma includes surgical resection and/or ultimately, in some cases, amputation. Metastases may develop early, especially to the lungs, pleura, and chest wall. Death occurs within 1 to 2 years after the onset of the tumor.36
Cutaneous metastases. A solitary nodule or multiple pink nodules that ulcerate in individuals with a past medical history of internal malignancy should prompt the physician to consider the presence of cutaneous metastases from internal malignancy. These cancers may spread via hematogenous and lymphatic routes or by local infiltration. Many primary cancers may spread to the skin, including breast, colon, lung and melanoma.38-40 A review of the literature suggests that the incidence is 0.7% to 9% of all patients with cancer.2
Clinically, cutaneous metastases may appear as a single subcutaneous nodule or a group of nodules (see Figure 8) that may be movable or fixed to underlying structures. These nodules also can present as indurated plaques. Most often, the epidermis of cutaneous metastases is intact; however, occasionally these lesions may be eroded or ulcerated. Patients with cutaneous metastasis have a poor prognosis. Suspicious lesions should be biopsied by either punch, excisional, or incisional methods.40 Management includes excision only if the patient is not terminal and one or only a few lesions are present.
Conclusion
Healthcare professionals frequently evaluate elderly individuals with ulceration3 of the lower extremities. If an ulcer does not heal despite adequate medical/surgical treatment, malignancy should be considered and a biopsy obtained. Options for cutaneous biopsies include punch biopsy, incisional biopsy, or excisional biopsy to include subcutaneous tissue of the ulcer and ulcer border. Clinicians should view lower extremity ulcers not only as a common finding in the elderly but also as an entity with a variety of clinical presentations and potential etiologies. Healthcare professionals managing chronic wounds may categorize an ulcer as vascular because of the presence of common risk factors such as diabetes, hypertension, obesity, and cigarette smoking. However, cutaneous malignancies such as nodulo-ulcerative basal cell carcinoma, squamous cell carcinoma, or keratoacanthoma of the lower extremities should always be considered, particularly if the wound is not responding to standard approaches. Particular instances of concern include a pigmented, ulcerative lesion, especially on the lower extremities in women (melanoma), pruritus presenting with a non-healing wound (tumor stage of mycosis fungoides), fever and/or profound weight loss (cutaneous metastases from internal malignancy), and any chronic ulcer unresponsive to standard medical and surgical therapies (lymphomatoid papulomatosis, lymphomatoid granulomatosis, and angiosarcoma, as well as the more common malignant neoplasms).
A detailed history and physical exam are imperative to elicit signs and symptoms that may prompt the healthcare professional to render a diagnosis of a malignancy presenting as an ulcer.
Although some malignancies of the lower extremities that masquerade as ulcers are rare, it is important for the physician to become knowledgeable regarding the clinical presentation of these lesions. The implementation of specific guidelines to determine the time frame necessary to address the malignant potential of a chronic wound and obtain a skin biopsy is warranted. Meanwhile, all healthcare professionals who manage chronic ulcers should maintain a high degree of vigilance for the development of malignancy within the confines of a clinically unresponsive ulcer. Such concern can easily be addressed with the prompt use of a diagnostic cutaneous biopsy that includes the ulcer and ulcer border. Some ulcerative neoplasms are amenable to simple excision in early stages; whereas, a delay in diagnosis may lead to metastases or even death.
Acknowledgment
The authors acknowledge DermaAtlas.com for contributing the clinical photographs.
Images courtesy of Dermatlas.com. Used with permission.
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