Marjolin’s Ulcers: A Case Series and Literature Review

Background. A Marjolin’s ulcer describes malignant degeneration in any chronic wound. The majority of cases arise in burn scars and are often latent for decades. Materials and Methods. This case series presents 6 patients with an average age of 63 years with Marjolin’s ulcers (both acute and chronic). A review of the literature was also undertaken. These cases underscore the aggressive course and poor prognosis associated with Marjolin’s ulcers and the importance of recognizing the potential for malignant transformation of a chronic wound. Results. In the reported cases, the ulcers were found on the upper and lower extremity, flank, and over the sacrum, emphasizing the propensity of these ulcers to arise in nearly any location. Squamous cell carcinoma is the most prevalent malignancy identified in Marjolin’s ulcers and was confirmed in all patients in this study. Patients underwent surgical resection, and all patients eventually succumbed to the disease. Conclusion. Based on observations and a review of the literature, early detection and aggressive management with wide local excision and prompt coverage yield optimal results when treating patients with Marjolin’s ulcers.

The earliest observation of malignant changes within burn scar epithelium dates back to the first century by Aurelius Cornelius Celsus.¹ The French academic surgeon Jean-Nicolas Marjolin is honored with the eponym.² Marjolin’s ulcer classically refers to squamous cell carcinoma arising in thermal burn scars, although the term has more recently been used to describe malignant degeneration in any chronic wound.^3,4 Marjolin himself simply documented chronic ulcers arising from scar tissue in the first edition of Dictionnaire de Médecine, published in 1828.^2,5 The association of malignancy and thermal burn scars was first reported in the literature in 1833 by the English surgeon Caesar Hawkins in his article “Warty Tumours of Cicatrices.”² After Marjolin’s death, the term Marjolin’s ulcer was first used by Professor Robert William Smith in 1850 and later by Dr. John Chalmer Da Costa and Dr. John Addison Fordyce, which helped establish the eponym in the medical vocabulary.²

  Upwards of 75% of reported Marjolin’s ulcers occur in burn scar sites.⁶ The overall rate of malignant transformation in burn scars is no more than 2%.⁷ Malignant degeneration has also been reported in chronic ulcers from trauma,⁸ frostbite,⁹ discoid lupus erythematosus,⁹ skin graft sites,⁹ pilonidal abscess,⁹ pressure ulcer,^9-12 snakebites,^9,13 venous stasis ulcers,^9,13 leprosy ulcers,¹⁴ hidradenitis suppurativa,¹⁵ and osteomyelitis.^3,16

  Marjolin’s ulcer has been seen in all age groups,⁸ though the average age of the patient tends to be near 50 at the time of diagnosis.¹⁷ There is a male-to-female ratio of 2:1.¹⁷ Marjolin’s ulcers have the ability to develop in almost any anatomical location, although their incidence is highest in the lower extremities.^6,17 Though rare, malignant degeneration in chronic wounds continues to occur sporadically. The current report examines 6 cases over a 15-year period at the Medical College of Wisconsin (Milwaukee, WI) affiliated hospitals (Table 1). The retrospective review was done in compliance with the Institutional Review Board guidelines. Included are 3 illustrative cases of the series.

Case 1. An 80 year old male presented with a 22 cm x 20 cm enlarged, painful flank ulcer with foul drainage (Figure 1a). There had been an ulcer present for more than 50 years within a skin-grafted area following a burn. Punch biopsies revealed invasive moderately well-differentiated squamous cell carcinoma. No distant metastases were demonstrated on CT scans of the chest, abdomen, and pelvis. The entire lesion was widely excised to at least the level of Scarpa’s fascia. Centrally there was penetration deep to Scarpa’s fascia noted on frozen sections necessitating further excision. The wound was packed and permanent sections demonstrated a small area of positive margin deep in the center that was part of the paraspinous muscle fascia. This was further resected, and after the permanent sections revealed no tumor, a 19 cm x 18 cm split-thickness skin graft was applied (Figure 1b).

  Within 3 months, 2 fungating ulcerated masses were noted in the center of the grafted area (Figure 1c). An additional 15 cm x 10 cm excision was done that included part of the paraspinal muscles and the quadratus lumborum. Permanent pathology sections revealed negative margins but lymphovascular invasion was noted. A skin graft was applied and the wound healed. Irradiation (45 Gy) was administered locally but there was noted metastasis to the lung. The patient declined further therapy and died in hospice with progressive disease 4 months after excision of the recurrent Marjolin’s ulcer.

  Case 2. A 61-year-old male presented with a nonhealing right leg wound (Figures 2a and 2b). Both legs were amputated above the knee in Vietnam secondary to injuries sustained in a helicopter crash. He did not wear prosthetics. Three years prior to his consultation he developed a wound on his right stump that did not heal with local wound care. On exam the wound was foul smelling with poor quality granulation tissue and an ulcer measuring 22 cm x 20 cm wide with central ulceration and exposed bone. An x-ray showed hypertrophic osteitis of the distal femur. There was an additional 6 cm diameter area of unstable scar posteriorly within a skin-grafted area. As he did not wear a prosthesis, amputation higher on the proximal femur was recommended to include the ulcer and the unstable scar. During the operation, approximately 10 cm of femur was resected with the ulceration and the stump was covered with muscle and thigh skin or skin graft.

  Pathology revealed squamous cell carcinoma with clear margins but extension of the tumor to within 6 mm of the margin in one area. Computed tomography and positron emission tomography (PET) scans were obtained. These showed a solitary lymph node with positive uptake. The patient underwent percutaneous lymph node biopsy. Cytopathology demonstrated the node was positive for squamous cell carcinoma. The tumor board recommended irradiation and not lymphadenectomy. Irradiation (60 Gy) was administered to the right inguinal and iliac nodes. Repeat PET demonstrated persistent uptake in the right inguinal and external iliac basin. A plastic surgery consultation recommended therapeutic lymph node dissection but this was not done. Thirty weeks postoperatively, magnetic resonance imaging (MRI) and PET scans showed likely recurrence at the stump as well as persistent inguinal and iliac adenopathy. The patient later died from metastatic disease.

  Case 3. A 50-year-old male, who was paraplegic secondary to a car accident 20 years earlier, presented with a foul-smelling sacral ulcer. He had a previous successful flap closure of a sacral pressure ulcer. The ulcer in the present case measured 25 cm x 18 cm and had been present for nearly 2 years, but had increased in size dramatically in the previous year. Gross infection and necrotic material was present. The granulation tissue appeared unusually friable and exophytic in some areas and partially eroded sacral cortex was palpable. The patient underwent wide local debridement and partial sacrum resection and closure with bilateral rotational flaps. Several areas of the deep margin on permanent section revealed keratinizing squamous cell carcinoma.

  Within 2 weeks of surgery wound breakdown and partial necrosis of the flap occurred. A CT scan showed extensive erosion of the sacrum. The patient was then taken back to the operating room for debridement (Figure 3a and 3b). The sacrum was completely necrotic and was excised, as was a portion of the left ilium. The wound was left open pending review of the final pathology report, which again revealed tumors at both the bone and deep soft tissue margins. Further workup showed widely metastatic disease, and the patient died a few months later.

Currently the term Marjolin’s ulcer most accurately describes malignant degeneration of a chronic inflammatory skin lesion, regardless of the origin of the lesion or the type of cancer that develops in the lesion.^3,4 Seventy-one percent of Marjolin’s ulcers develop as a squamous cell carcinoma, although basal cell carcinoma, melanoma, fibrosarcoma, angiosarcoma, liposarcoma, leiomyosarcoma, osteosarcoma, dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, malignant schwannoma, and mesenchymal tumor have also been identified.¹⁷ According to Bozkurt et al¹⁸ the wound may also appear as pseudoepitheliomatous hyperplasia.¹⁸ When Marjolin’s ulcer occurs in its squamous cell form it is a very aggressive malignancy but constitutes only 2% of all squamous cell carcinomas.¹⁹

  Marjolin’s ulcers typically take years to develop though, on occasion, acute onset has been documented.²⁰ Latency has been described as the time between initial injury and the confirmation of a pathologic diagnosis of Marjolin’s ulcer.⁶ There is variation in the latency period, but many studies report at least 2-3 decades between the injury and malignant transformation.^3,6,18 Marjolin’s ulcers can be classified as acute or chronic,²¹ with malignant transformation that takes place within 12 months of a burn considered acute.^2,21 Although the overwhelming majority are squamous cell carcinomas, basal cell carcinoma is relatively more common in acute transformation² and in scars resulting from a superficial burn injury.⁵ It is thought that there is an inverse relationship between latency period and patient age at the time of burn injury, with older patients having a shorter latency period.⁷ The report by Baskara et al²⁰ which describes the development of a Marjolin’s ulcer in a 72-year-old within 9 months of a plantar pressure ulcer provides some validation for this premise.

  The exact mechanism for the development of Marjolin’s ulcer in burns or other wound types has not yet been defined,^2,6,8 but is likely multifactorial, affected by both environmental and genetic factors.⁴ Key factors in the development of Marjolin’s ulcers seem to be a slow healing process and chronic instability of scar tissue.⁸ Marjolin’s ulcers tend to favor locations where there is constant trauma or a compromised blood supply.⁸ It has been suggested that in the chronic wound, decreased vascularity combined with weakened epithelium creates a susceptibility to carcinogens.⁶ It has also been proposed that the relative avascularity of scar tissue leads to a locally depressed immunological state or immunologically privileged site leaving the body without an adequate cell-mediated response.²² Release of toxins by lysis of scar tissue may have a direct mutagenic effect on cells.^4,8 Mutations in the p53 gene and Fas gene may disrupt regulated apoptosis and cell homeostasis, respectively, and have been identified in patients with Marjolin’s ulcers.^23,24 Chronic irritation and repeated attempts at healing provide a prolonged stimulus for cellular proliferation and may increase the rate of spontaneous mutations.⁴ The evidence supporting this theory is represented in many cases of Marjolin’s ulcer occurring at skin zones that have been exposed to long-term irritation,^4,18,20 including areas where clothing might cause trauma. These findings support the idea that chronic irritation is an inciting factor.¹⁸

  Marjolin’s ulcer can be suspected based on a nonhealing ulcer in an area of abnormal or scarred skin.⁸ However, the suspicion must be confirmed with pathologic interpretation of tissue biopsy specimens taken from multiple locations of the ulcer and its margins to minimize a false-negative finding.^3,8 A standardized biopsy procedure involving excision biopsy that is limited by the size of the neoplasm has been proposed.¹⁸ This biopsy procedure may increase the percentage of correctly diagnosing the tumor but a more focused investigation may be needed to determine the minimum number of biopsies required.¹⁸ Also, the use of MRI has been found to be helpful in determining the degree of soft-tissue invasion of Marjolin’s ulcers on the extremities¹⁸ and the extent of bone destruction and periosteal reaction.¹³

  Tumor type,⁸ location,² and rate of metastasis⁸ affect prognosis. Location of the tumor is a key prognostic factor influencing metastasis, and the rates of metastasis in descending order of ulcer locations most likely to metastasize are lower extremities, trunk, scalp, face, neck, and upper extremities.² Marjolin’s ulcers tend to be more aggressive than other forms of skin cancer.⁶ In a review by Kerr-Valentic et al,⁶ the overall metastatic rate of Marjolin’s ulcers was approximately 27.5%. The rate of metastasis in Marjolin’s ulcers arising in pressure ulcers has been listed to be as high as 61%, a rate much higher than that resulting from burn scars (38%) and osteomyelitis (14%).¹² The overall survival for patients with Marjolin’s ulcer is 65%-75% at 3 years postdiagnosis, but falls to 35%-50% if metastatic disease is detected on presentation.²⁵ Palpable regional lymphadenopathy predicts death within 2 years.²

  Wide local excision and wound coverage with skin grafting or flaps is the treatment of choice.^6,18,26 Currently there is no universal consensus or treatment protocol regarding excision margins, lymph node dissection, or the use of neoadjuvant radiotherapy or chemotherapy.⁸ A combination of these procedures is often necessary.⁸ Based on their review, Bozkurt et al¹⁸ found a very low recurrence rate when 3 cm-5 cm margins were obtained. Amputation may be required in extremity lesions where there is invasion of major neurovascular structures,¹⁹ when adequate surgical margins are not possible, or if there is aggressive recurrence.⁶ In patients with inoperable metastatic disease, it is documented that adjuvant radiotherapy and chemotherapy can be useful as well.⁴ Lymphadenectomy is warranted if there is persistent adenopathy.^3,18

  Pressure ulcer malignancies are the most aggressive form of Marjolin’s ulcer, with a shorter latency period and a more progressive course.^20,27 Most pressure ulcer carcinomas form in the sacral and iliac areas.¹⁰ These areas have a rich lymphatic drainage to the pelvic region, which explains the high metastatic rate.¹⁰ The poor prognosis and high rate of metastasis emphasizes the importance of avoiding a late diagnosis or treatment.^4,8,10 There is little support for adjuvant chemotherapy in Marjolin’s ulcers,²⁷ but radiation therapy has been used as palliation.²⁸

  Paraplegic patients who develop large sacral and ischial pressure ulcers often have underlying osteomyelitis as well.⁴ It is important to distinguish whether the bone erosion is from infection or tumor. The soft tissue deficits that occur following wide excision of sacral malignancies are often too great to be reconstructed with conventional flaps.⁴ Various modifications of total thigh flaps or fillet-of-leg flaps can provide adequate tissue for wound closure.^4,8,29,30 Rarely, hemicorporectomy is indicated. This procedure has a high morbidity rate and requires lifelong supportive care, but may be the only hope for cure in advanced local disease without distant metastases.^8,31

Lack of adequate early wound care, where wounds are left to heal by secondary intention, can lead to malignant degeneration in both burn scars and other traumatic wounds. To prevent this wound degeneration into squamous cell carcinoma, it is imperative to provide early and definitive wound coverage or replacement of unstable scar tissue with healthy tissue. Although prevention is ideal, a high index of suspicion in chronic wounds is necessary so that early detection can prevent metastatic disease, which carries with it a poor prognosis.

Affiliations: Chase Tobin, BS is from the Eastern Virginia Medical School, Norfolk, VA; and James R. Sanger, MD is from the Medical College of Wisconsin, Milwaukee, WI.

Address correspondence to:
Chase Tobin, BS
270 W. Bute St, #1207
Norfolk, VA 23510
tobinca@evms.edu

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