Marjolin ulcer: a rare clinical entity that every health professional should be informed about: a narrative review

Abstract

Marjolin ulcer is a term used to refer to malignant degeneration of aggressive nature associated with chronic burn scars or chronic wounds most of the time. Marjolin ulcers are more common in men and are usually diagnosed in the 5th decade of life. It usually has a relatively poor prognosis because it is diagnosed late, and the mortality rate is around 20% on the average. It is important for all healthcare professionals who provide wound care to be knowledgeable about this issue. The patients with chronic wounds and long standing scars should be followed-up closely in this regard. Early and effective treatment of burns and chronic wounds is mandatory to prevent this condition. Appropriate follow-up and early biopsy at the time of detection of any suspicious change improve the prognosis and survival of patients as this approach will provide early diagnosis of Marjolin ulcers.

Key summary points

• Marjolin ulcer is a term used to describe malignant degeneration of aggressive nature mostly seen in burn scars and chronic wounds.

• A marjolin ulcer usually has a relatively poor prognosis because of delayed diagnosis, and the mortality rate of this condition is around 20% on the average.

• It is important for all healthcare professionals who provide wound care to be aware of this disorder and to perform close follow-up of the patients at risk.

• Early and effective treatment of burns and chronic wounds, appropriate follow-up, and early biopsy at the time of slightest suspicious change can improve the prognosis and survival of patients as this approach will lead to early diagnosis of Marjolin ulcers.

Introduction

There are more than 100 reports of Marjolin ulcers in the literature, most of which are case reports [1]. The term Marjolin ulcer is used to refer to malignant change accompanying chronic burn scars or wounds [2]. The classical definition of Marjolin ulcer was first made in 1828 by the French surgeon Jean Nicholas Marjolin as malignant change developing in old burn scars [1, 2]. Later, chronic leg ulcers, chronic wounds, and malignant changes developing in chronic inflammatory skin lesions were also grouped under this name [2].

Epidemiology

Marjolin ulcers, which are more common in men (61.5%) than in women, are usually diagnosed in the 5th decade of life (mean age 55.3) [2, 3]. The most common cause of Marjolin ulcers is chronic burn scars (77%) [4]—(87.9%) [3], the second most common cause is osteomyelitis fistulas (2.4%) [2, 3]. Malignant transformation is observed in 0.77–2% of burn scars, while squamous cell carcinoma (SCC) develops in 0.2–1.7% of chronic osteomyelitis cases [1, 2]. Less common causes include venous insufficiency ulcers, pressure ulcers, diabetic foot ulcers, discoid lupus erythematosus scars, amputation stumps, frostbite, grafted sites, skin graft donor sites, snakebite, pilonidal sinus, hidradenitis suppurativa, saphenectomy scars, dermatitis artefacta, urinary and vaginal fistulas, external fixator application sites, or cutaneous radiation injury[1, 2, 5–10]. It is estimated that 1/300 of leg ulcers are malignant [1, 6]. However, the relative risk of development of non-melanoma skin cancer in patients with venous leg ulcers is 5.8% compared to general population [6]. In another study, Marjolin ulcers were detected in 13/1000 chronic ulcers anywhere in the body (e.g. arterial ulcers, diabetic ulcers, pressure ulcers and traumatic ulcers) [11].

Marjolin ulcers are most frequently localized in the lower extremities (81.5%) [12] (especially the plantar part of the foot), followed by the scalp and trunk [1, 2, 6]. Another study from our country reported that the most common localization was the foot (28.6%) and the second most common site was the scalp (25.4%) [13]. The majority of burn scar Marjolin ulcers (10/11 lesions) are localized in the extremities, and the majority of these lesions (7/10 lesions) are localized in the joint areas(especially the knee) [14]. Four percent of the lesions are localized in the trunk and head-neck regions. Areas such as the nose, eyelids and lips are very rarely affected [1].

Marjolin ulcers most commonly present as well-differentiated SCC (88.9% of all cases; especially in burn scars, almost all; but 54% in chronic ulcers). Basal cell carcinoma (BCC) (11.1% of all cases, 38% in chronic ulcers) and even malignant melanoma (MM) (8% in chronic ulcers) are also encountered [2, 11, 13]. SCC transformation was reported in 2% of burn scars, but BCC development was reported in 0.3% of such scars [1]. Marjolin ulcer development has been reported in 1.3% of chronic ulcers [11].

For comparison, let’s briefly mention cutaneous SCCs (cSCC); cSCC is the second most common malignancy of the skin and its annual incidence in the USA is estimated to be 700,000. cSCC has a very good prognosis in most cases following surgical excision. However, regional lymph node metastasis is seen in 3.7–5.2% of cases and 1.5–2.1% of cases lose their lives due to cSCC [15]. cSCC is frequently seen in the head and neck region due to chronic actinic damage and is frequently seen in men. cSCC located in the lower extremities is less common, and although there is not much information about lower extremity cSCCs in the literature, this condition is more common in older women and in African Americans [16]. It has been shown that 6% of cSCCs in white women and 3% of cSCCs in white men are located in the lower extremities [17]. Marjolin ulcers in the form of SCC constituted 10.3% of all cSCC cases reported from a tertiary plastic surgery clinic [4].

Etiopathogenesis

Virchow suggested that chronic irritation is effective in the development of carcinoma, but the exact pathogenesis of Marjolin ulcer development is not fully known [1]. Many factors probably play a role in the development of Marjolin ulcer and there are different theories [1, 2, 18]. Table 1 summarizes the theories proposed in Marjolin ulcer etiopathogenesis.

• (i) Toxin theory: Toxins released from damaged tissues with vascular insufficiency and nutritional deficiencies may trigger malignant change [1, 18].
• (ii)Co-carcinogen theory: Although burns are not carcinogenic themselves, they cause the tissue to become more sensitive to other chemical and physical carcinogens such as ultraviolet light, and latent malignant cells proliferate when they are exposed to these co-carcinogens [1, 18]. In the initiation and augmentation theory, which can be discussed together with this theory, cancer development in healthy cells is examined in two stages. In the initiation period, healthy cells turn into latent malignant cells and in the augmentation period, they are activated by a co-carcinogen, such as infection. Another theory that can be discussed here, the ultraviolet radiation theory, states that UV radiation reduces the number of Langerhans cells, disrupts cutaneous immunological detection, and causes changes in the p53 gene, and this gene is important in stopping tumor growth [18].
• (iii)Immunologically protected zone theory: It has been suggested that immunological factors may be effective in the carcinogenesis of scar malignancy [1]. The probability of malignant transformation may increase in the presence of a suppressed immune system, and this may be valid in lupus cases. Another theory suggested is that scar tissue causes an inadequate immunological response to tumoral cells. Fibrous scar tissue, avascularity and the resulting obstruction of lymphatics may prevent early recognition of non-self malignant cells by inhibiting lymphocyte mobility [12]. In short, scarring may facilitate tumoral growth by disrupting physiological immunological control [18]. Lymphatic obstruction may also delay or prevent the presentation of tumor-specific antigens. The relative avascularity of scar tissue acts as an initial barrier against metastasis, causing the tumor to grow to a critical size, and explains why these lesions grow slowly and metastasize later. However, once tumor cells eventually penetrate the thick scar tissue and reach the underlying patent lymphatic vessels, systemic spread generally occurs very rapidly [2].
• (iv)Chronic irritation theory: Continuous mitotic activity and cellular atypia associated with the regeneration and repair processes resulting from chronic irritation observed in fold areas may result in malignant transformation. Repeated cutaneous trauma affecting any scarred skin area may also trigger malignant transformation by using the same mechanism [2, 18].
• (v) Traumatic epithelial graft theory: Epithelial elements engrafted into the dermis trigger inflammation and impair regeneration [18].
• (vi) Theory of inheritance: It has been determined that HLA-DLA4 is associated with cancer growth and disturbances affecting p53 gene and this has been observed in patients with Marjolin ulcers [18]. P53 positivity increases as cancer differentiation decreases in SCC and this positivity also increases as tumor invasion depth increases in MM [19]. Mutations in the apoptosis regulator FAS gene have also been found in Marjolin ulcers, and these mutations facilitate malignant degeneration in scars [18].

Table 1.

Etiopathogenesis of Marjolin ulcer

I. Toxin theory II. Co-carcinogen theory III. Immunologically protected zone theory IV. Chronic irritation theory V. Traumatic epithelial graft theory VI. Inheritance theory

Survivin is a member of the inhibitor of apoptosis proteins family and this protein down regulates cell adhesion molecules and hence can enhance metastasis. It was shown to be increased in Marjolin ulcers and its expression was associated with lymphatic spread of the tumors [20]. In the core region of the Marjolin ulcers of the scalp, invasion related cell adhesion molecules (claudin-1, desmoglein-3, E-cadherin) and other invasion associated genes have been shown to be highly expressed and this finding suggests highly invasive ability is present in the core area of Marjolin ulcers [21].

Many authors agree that the prolonged healing process seen in severe burn wounds and the resulting chronic abnormal keratinocyte biological activity are the main potential risk factors for the development of scar carcinoma. Although there is insufficient information on possible predisposing factors, trauma and ultraviolet light are thought to be possible predisposing factors, and the fact that Marjolin ulcers are more frequently located in the extremities, scalp, and neck regions supports this view [1].

Clinical presentation

The time period required for the development of Marjolin ulcers varies between 1 and 75 years following the injury and they usually develop after an average of 30–35 years [2]. However, there are also reported cases who develop Marjolin ulcers in a time period as short as 6 weeks to one year following injury to the skin [2, 22]. As a general rule, the younger the patient at the time of injury, the longer it takes for the malignant change to develop; and in older people, a shorter time period is observed [2, 6]. Marjolin ulcers are divided into two main types according to the development period after the injury; acute (within the first year) (7.2%) [3, 22] and chronic (developing > 12 months after the injury) [1].

Marjolin ulcers can also be classified according to the histopathological type of the tumor [1]. Marjolin ulcers generally present as SCC but BCC, MM and other malignancies may also be associated with Marjolin ulcers. Other malignancies that can be seen include keratoacanthoma, liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, eccrine syringofibroadenoma and Merkel cell carcinoma [1, 3]. Acute Marjolin ulcers are generally seen in more superficial burn scars and in the form of BCC. If acute Marjolin ulcers develop as SCC, this is usually seen in the group who are older than 50 years of age and this group of patients have more keratotic skin [1].

Marjolin ulcers are clinically seen as the classical triad of nodule formation, induration and ulceration in the scar area [2]. Clinically, the presence of a chronic, different-looking, non-healing, raised-edge, and peripherally indurated ulcer on a pre-existing long-standing scar (Fig. 1) is diagnostic of malignant epithelial transformation and should raise the suspicion of a Marjolin ulcer until proven otherwise [1]. Marjolin ulcers have two main morphological features; a well-differentiated exophytic form (Fig. 2) (usually has a better prognosis) and a poorly differentiated ulcerative form (often has a poor prognosis) [6]. Other clinical findings suggestive of Marjolin ulcers include raised or increased granulation tissue or spontaneous pain in a chronic ulcer that persists for more than 3 months (Table 2) [2, 6]. Morphologically, Marjolin ulcers are often seen as rapidly growing, infiltrating, flat lesions with raised edges, while sometimes they can be of the papillary type, which is slowly growing, bulging outwards, and resembles granulation tissue [1, 2]. Bone invasion can be observed in Marjolin ulcers, and this invasion is especially seen in Marjolin ulcers located in the scalp area [1].

Fig. 1.

Chronic, non-healing ulcer with indurated edges in an old burn scar

Fig. 2.

Exophytic desquamated and hyperkeratotic papular lesions in a pre-existing burn scar

Table 2.

Clinical changes suggestive of Marjolin ulcer development in chronic wounds or scars

• Non-healing ulcer with raised edges and peripheral induration on a chronic scar • In a chronic ulcer lasting more than three months: (the underlying bullets all should be subtitle of this phrase) • Rounded and outward-leaning wound edges • Rising or increased granulation tissue • Foul-smelling discharge • Increase in size • Bleeding on contact • Crusting • Spontaneous pain

Diagnosis

The most important criterion for the diagnosis of a Marjolin ulcer is the clinical history [1]. Samples should be taken for culture from lesions when infection is suspected. The definitive diagnosis of Marjolin ulcer can be made only by histopathological examination. As a general rule, a biopsy should be performed for all chronic non-healing ulcers to rule out malignant transformation [2]. If ulceration is present in any burn scar, a biopsy should definitely be performed [1]. A punch biopsy is sufficient for diagnosis; it should be taken from the suspected area of the wound or from multiple areas to prevent false-negative results [2]. In the literature, it is recommended that incisional, excisional or punch biopsies should be taken from different areas of the wound [6]. Some authors recommend that benign ulcerative lesions should be followed-up with annual biopsies [2]. In chronic pressure ulcers that have persisted for more than ten years, a biopsy should definitely be performed to exclude malignancy, especially if there is any change in the nature of the ulcer (e.g., raised granulation tissue or bleeding) [1]. Since malignant change is focal in burn scars, when malignant change is suspected, incisional or, more appropriately, excisional biopsy must be performed [1, 23]. If the suspicion is strong, repeated incisional biopsies can be performed even if the first biopsy is negative for malignancy [23].

Histopathologically, SCC is the most common Marjolin ulcer type, and among them spinocellular SCC is the most common. In histopathology of SCC type marjolin ulcers, keratin pearl formation, lymphatic and perineural infiltration, pseudoepitheliomatous hyperplasia and chronic inflammation are frequently observed. In general, minimal or no keratinization is seen, and a pseudo-glandular appearance with pleomorphism is present in these lesions. In poorly differentiated SCC lesions, a decreased inflammatory response is noted. Marjolin’s foot ulcer can also be seen as verrucous SCC and can be confused with viral warts [2].

Taking the location of the tumor into account, plain radiographs are useful in evaluating the bones in the process of planning the surgical treatment. Computed tomography (CT) shows the bone structures in detail, and magnetic resonance imaging (MRI) is useful for examining the soft tissue and bone structures [1, 2]. It has been shown that PET-CT can be helpful in differentiating Marjolin ulcers from benign inflammatory chronic non-healing ulcers in burn scars and in determining the depth of invasion [24]. Lymph nodes should be evaluated clinically in all patients, and high-resolution USG examinations can also be performed in this regard. Routine blood laboratory tests may also be required in the preoperative evaluation of patients. Investigations should be performed for distant metastasis, especially in advanced tumors; for this purpose, chest X-ray, brain CT and abdomen USG examinations can be performed [1].

Staging and grading generally determine the prognosis. Malignant tumors are generally staged according to their size, lymph node involvement and the presence of metastasis (TNM), and Marjolin ulcers are also staged according to this system. There is a positive correlation between the duration of ulceration and the possibility of malignant transformation. The degree of differentiation of the tumor is classified into 3 degrees; grade I: when > 75% of cells are differentiated, grade II: when 25–75% of cells are differentiated and grade III: when < 25% of cells are differentiated [2].

A multidisciplinary approach is required for treatment and follow-up upon diagnosis of a Marjolin ulcer. In this respect, the collaboration of oncology, dermatology, plastic surgery and wound care specialists is appropriate [6].

Treatment and follow-up

The biological behavior of Marjolin ulcers is more aggressive compared to other common skin cancers. The primary therapeutic aim should be to prevent this scar complication by appropriately treating burns, treating fragile scars and regular follow-up. Therefore, it is recommended that deep burns should be covered with skin grafts or flaps as soon as possible. If this aggressive scar complication develops, it is important to treat these tumors aggressively with wide excision combined with radiotherapy at an early stage, taking the possibility of prolonged survival and enhanced recovery rates into account [1].

Although there is no definitive and proven treatment protocol for Marjolin ulcers, wide excision including 2–4 cm of normal tissue with inclusion of fascia and reconstruction with grafting or for extremity lesions performing amputation at a level proximal to the location of the lesion are generally applied [2, 6, 18]. In order to prevent iatrogenic seeding of tumor cells during excision, excision with electro-cautery is recommended first, and then an additional thin layer of normal tissue is excised with sharp dissection by using a scalpel is recommended to optimize wound healing [6]. All excised material must be sent for histopathological examination, and if tumor is observed at a deep margin, re-resection or amputation should be performed. Free flaps, cryosurgery, Mohs surgery, CO2 laser, intralesional interferon and photodynamic therapy can also be employed in the treatment. In Mohs surgery, complete excision of the lesion can be successfully performed by performing pathological examination together with repeated excisions, thus surgical margins are controlled during excision in this method. Today, Mohs surgery is considered the gold standard in the treatment of Marjolin ulcers. While the 5-year cure rate after surgical excision is 76%, 5-year cure rates of 90% can be achieved with the Mohs surgery method. However, Mohs surgery is more expensive and has longer operation time, and the number of surgical teams that perform this method are limited [2].

It is very important to close all surgical defects preferably with a graft (often split-thickness skin graft) or flap (often muscle flap) especially when important structures are exposed. Primary closure of surgical defects can be performed for early-stage malignancies [1, 2]. Perforator free flaps can be successfully performed by using the sural, peroneal, posterior tibial or medial plantar arteries. If these flaps are not suitable, the defect can be closed by using a fasciocutaneous flap or a skin graft [2]. Especially in burn scars located on the scalp, extensive tumor invasion into the bone can create a serious reconstructive problem after excision. Exposure of brain tissue or sagittal sinus damage in these patients can cause serious complications and increase the morbidity of the patient. In such cases, it is important to plan appropriate and sufficient flap tissue before surgery to provide reconstruction even in the worst-case scenario, and pre-operative tissue expansion methods may be employed for this purpose [25].

For reconstruction purposes following surgical excision, the proposed algorithm is as follows; (i) in the presence of sufficient donor area, tumors located in functional and cosmetically suitable non-weight-bearing areas where vital structures are not exposed should be excised with at least 2 cm margins and then resulting defect is grafted; (ii) in the presence of well-vascularized local tissue around the ulcer, tumors located in weight-bearing areas or when vital structures are exposed, tumor should be excised with at least 2 cm margins and then resulting defect is repaired with local flaps; and (iii) in the presence of poorly vascularized local tissue around the ulcer, tumors located in weight-bearing areas or when vital structures are exposed, tumor should be excised with at least 2 cm margins and then resulting defect is repaired with a free flap [13]. The point we must be careful about is that flap surgery may cause problems if surgical margins are not sufficient following therapeutic excision. The main problem will be sacrifice of unnecessary amount of tissue since it will be difficult to determine from where complementary resection should be performed. The reason for this situation is that the edges of the original defect resulting from excision of the lesion may be distorted following reconstruction with local flaps. However, if there is absolute need for flap reconstruction, surgical margins must be carefully considered and frozen histopathology in the operating theatre may be advised to be sure of clean surgical margins.

Although cutaneous malignancy development has been reported in an area where grafting performed in the past, development of any kind of skin malignancy is less common in burn areas treated with early skin grafting after burn injury in comparison with those burn injury wounds that have been left to secondary healing [2]. Similarly, if an ulceration develops in an old burn scar, this scar must be excised and grafted. In order to prevent malignancy development, excision of all scar tissue and subsequent pressure bandaging are recommended in these cases [2]. Early mobilization and physical therapy are required after all operations [1].

Amputation is a widely accepted treatment method for any case of extremity lesions. Some authors recommend wide excision before amputation in case amputation may affect patient functions negatively [2]. Amputation is indicated especially in cases of bone and joint involvement, major vessel and nerve involvement or when poor functional outcome is expected after surgery and this form of surgical treatment is considered the most definitive treatment method to treat cancer and infection located in extremities [2, 18]. Some authors recommend wide local excision for grade I and small lesions and amputation for grade II or III extremity lesions [2].

There are also publications which show that intra-arterial methotrexate infusion is an effective treatment for SCC type Marjolin ulcers. Topical 5-fluorouracil has also been shown to be effective in small in situ lesions. However, data on these treatments is limited. In addition, antibiotic therapy should be applied according to culture results in the peri-operative period and foreign bodies such as shrapnel that may be present in the lesion should be removed [2].

If there is clinical or radiological evidence of lymph node involvement, regional lymphadenectomy should be performed. The approach to clinically negative lymph nodes is regional lymph node irradiation or sentinel lymph node biopsy suggested by some authors [6]. Although there is no consensus in the literature, sentinel lymph node biopsy is generally performed to evaluate clinically negative lymph nodes. However, in the presence of a palpable lymph node, lymph node biopsy or USG-guided cytological examination is recommended [2]. Clinically enlarged lymph nodes usually show histopathological tumoral involvement [1]. There is no consensus in the literature on the application of prophylactic lymph node dissection or radiotherapy in all cases of Marjolin ulcers, and the available information shows that there is no significant difference in terms of recurrence whether prophylactic lymph node dissection is performed or not [2]. However, in the presence of a clinically affected lymph node, regional lymph node dissection should be performed. The surgery and morbidity of lymph node dissection are challenging due to the presence of widespread burn scars generally seen in these patients [1].

Sentinel lymph node dissection, which is a minimally invasive procedure, is easy to perform and has low morbidity in cases where there is no clinically affected lymph nodes, and this method is quite useful in the diagnosis of lymph node involvement [1, 6]. Sentinel lymph node excision in Marjolin ulcers can change the treatment method and increase patient survival with low false positive results and high sensitivity [26]. If the sentinel lymph node is positive or if there is clinical or radiological lymph node involvement, regional lymphadenectomy is performed [6, 26]. As in many skin cancers, microscopic lymph node involvement detected by sentinel lymph node dissection is the most important factor determining disease-free and disease-specific survival. In cases where no clinical involvement is seen, sentinel lymph node dissection shows microscopic involvement in 4/6 cases. Sentinel lymph node dissection is particularly useful in Marjolin ulcers located in the head, neck, and trunk regions where lymphatic drainage direction cannot be predicted [1]. Tumor characteristics that predict microscopic regional lymph node metastasis in the presence of clinically normal lymph nodes include tumor diameter greater than 7.5 cm, tumor necrosis, tumor depth below the subcutaneous tissue, and peri-neural invasion. Prophylactic regional lymph node dissection is recommended in these high-risk patients[27].

Metastatic disease is treated with surgery, radiotherapy and adjuvant chemotherapy [28]. There is no consensus in the literature regarding chemotherapy and radiotherapy [2]. Radiotherapy is recommended for lymph node metastases that cannot be operated on, grade III lesions with positive lymph node involvement after regional lymph node dissection, tumors > 10 cm in diameter with positive lymph node involvement after dissection, grade III tumors > 10 cm in diameter with negative lymph node involvement after dissection or head and neck lesions with positive lymph node involvement after dissection [1, 2, 6]. However, other authors have also published that radiotherapy is relatively ineffective and they suggest that better results are obtained with intra-arterial limb perfusion. Similarly, published data on intra-arterial limb perfusion is insufficient. These methods can be considered as alternative treatment methods or adjuvant treatment methods in cases that are not suitable for surgery or do not want surgery, or in the presence of metastasis or recurrence [2].

Palliative chemotherapy can be given in advanced stage disseminated disease or in patients who are not suitable for surgery. The chemotherapy protocol includes topical or systemic 5-fluorouracil along with cisplatin, methotrexate and bleomycin [6]. Immunotherapy with anti–programmed cell death protein 1 (PD-1) (pembrolizumab or cemiplimab) therapy was shown to be a promising option for advanced SCC associated with Marjolin ulcers [29].

Patients diagnosed and treated with a Marjolin ulcer should be followed-up regularly for recurrence and metastasis. Metastases frequently occur in the brain, liver, lung, kidney and distant lymph nodes. Routine chest radiography, abdominal USG and brain CT are recommended for metastasis screening. It has been reported that 54% of metastatic lesions are located in the lower extremities and the general metastasis rate in Marjolin ulcers is 20–30%. It has been reported in the literature that the use of electrocautery during surgical excision and lymph node radiotherapy or dissection reduces the risk of metastasis [2].

Prognosis

Marjolin ulcers usually have a poor prognosis due to their insidious course, and they can, not uncommonly, result in death [1, 6]. Marjolin ulcers have a higher regional spread and fatality rate compared to other skin cancers [1]. The average mortality rate of Marjolin ulcers has been reported as 21%. The most important determinants of prognosis are histological grade and status of lymph node metastasis [6]. Well-differentiated lesions are less aggressive and consequently have a better prognosis [2].

The characteristics of Marjolin ulcers with a good prognosis include a period of < 5 years between the injury and tumor development, localization in the head, neck and upper extremities, exophytic structure, grade I, and histopathologically intense T lymphocyte infiltration around the tumor, and no regional or distant metastasis at the time of diagnosis [18]. The characteristics of Marjolin ulcers with a poor prognosis include a period of > 5 years between the injury and tumor development, localization in the trunk and lower extremities, infiltrative structure, tumor size 2 cm or more, grade II and III, histopathologically trace T lymphocyte infiltration, and the presence of regional lymph nodes (high risk of death within 2 years) and distant metastasis at the time of diagnosis, and recurrent character [6, 18]. In addition, if a patient is alive after 3 years, it can be said that the prognosis after this period will be good because 95% of metastatic cases manifest themselves within the first 12 months [2].

An important factor that determines the prognosis of Marjolin ulcers is the histological type of the tumor. Prognosis of Marjolin ulcers with BCC or SCC is relatively better than those with MM or sarcoma. While 30.23% sentinel lymph node involvement and 11.63% distant metastasis have been reported in Marjolin ulcers with SCC, 66.67% sentinel lymph node involvement and 33.33% distant metastasis have been reported in Marjolin ulcers with melanoma [30]. The degree of differentiation in Marjolin ulcers with SCC is also important for prognosis. There is a high inverse relationship between the risk of metastasis and the level of differentiation. In other words, the most important factor determining prognosis and survival is the degree of differentiation of the tumor: the risk of metastasis in grade I tumors is 10%, the risk of metastasis in grade II tumors is 59%, and the risk of metastasis in grade III tumors is 86% [1].

The overall 3-year survival is 65–75%, while the 10-year survival is 34% [2]. However, in the presence of initial metastatic disease, the 3-year survival rate drops to 35–50% [6]. The 5-year survival rate varies between 40 and 69% (mean 52%). The 5-year survival rate has been reported as 60% in those who underwent wide excision and 69% in those who underwent amputation [2]. Twenty-year survival has been reported as 23% [6].

The general recurrence rate after excision is seen as 20–50% and 98% of these are seen within the first 3 years. In cases where the margins are clear after wide excision, there is no difference in terms of recurrence between amputation and local excision [2].

Local recurrence in Marjolin ulcers has been reported as 22.2% and regional lymph node involvement as 11.1% [12]. In another series, regional lymph node involvement in Marjolin ulcers has been reported as 6.2% and the local recurrence rate at 2-year follow-up as 6% [1]. In the presence of lymph node metastasis, 3-year survival rates drop to 35–50% [2]. Lymph node metastases occur frequently due to delayed diagnosis and underestimation of clinical findings. Risk factors for recurrence have been reported as being male, developing burns due to cooking oil, not receiving treatment at the time of the initial burn, sclerotic scar, supra-regional lymph node involvement, and not receiving treatment when the ulcer re-occurs. Marjolin ulcers located in the extremities tend to be more aggressive. While the recurrence rate in extremity non-melanoma skin cancers (NMSC) is 3%, the recurrence rate in SCC type Marjolin ulcers is reported as 9% and the metastasis rate as 38%. Marjolin ulcers developing in osteomyelitis fistulas are more often sarcomatous, more difficult to treat, and have a faster and higher mortality rate. It is thought that the malignant potential of Marjolin ulcers developing from scars may be lower than that of Marjolin ulcers developing from ulcers and fistulas, and as a result, their prognosis may be better [1].

Metastasis rates following amputation have been reported as 20–35% [2]. While the metastasis rate of cSCCs in general is 0.5–3%, the metastasis rate of SCCs developing on burn scars is on average 30–34% [1]. Distant metastasis (especially pulmonary) is frequently seen in Marjolin ulcers located on the trunk [31]. The metastasis rate of Marjolin ulcers developing on burn scars is 38%, while the metastasis rate of Marjolin ulcers developing on the basis of osteomyelitis is 14% [6]. Marjolin ulcers developing on pressure ulcers are even more aggressive [1]. The metastasis rate of SCCs developing from pressure ulcers is much higher at the rate of 61% [1, 6]. It has been reported that the Marjolin ulcers that occur in pressure ulcers developing after spinal cord injury are much more aggressive and end in death in all cases. Therefore, if chronic pressure ulcers have existed for more than 10 years and especially if there is any change in the nature of the ulcer, a biopsy should be performed to exclude malignancy [1].

Precautions and monitoring

The most important risk factors for tumors developing after burns are secondary healing, non-healing wounds, and fragile scars that are easily traumatized and ulcerate. However, these tumors are rare skin cancers seen in developing countries. Good health can prevent adverse outcomes such as Marjolin ulcers that may develop in chronically irritated skin. Precautions to prevent Marjolin ulcers include preventing burns, ensuring early epithelialization, preventing infections, applying skin grafts at an early stage, performing early surgery in case of any deterioration in the burn scar, and regular follow-up of patients with chronic wounds [1].

The accepted standard of care for burn patients is excision and grafting. However, caution should be exercised in secondarily healed burn scars, wounds that do not heal properly, and burn scars that ulcerate easily, and patients should be advised to attend regular medical check-ups and to immediately see their physicians if there is any change. If patients live far from the clinic that treated their burns, they should be warned to continue their follow-up by informing their physicians in their area that they are at risk for the development of burn scar tumors [1]. In recent years, the rates of Marjolin ulcers are decreasing as a result of early appropriate burn treatment with grafting if necessary and regular follow-ups [14]. If all these precautions are taken, the development of Marjolin ulcers can be prevented and patients can be treated appropriately at an early stage [1].

Conclusion

Marjolin ulcer is a term used to describe aggressive malignant degeneration in burn scars and any chronic wound. The disease usually has a poor prognosis because it is diagnosed late, and has an aggressive nature and the mortality rate is around 20% on average [6]. It is important for all healthcare professionals who provide care for patients with chronic wounds and scars to have knowledge about this condition and to follow such patients closely considering risk of development of this disorder. Early and effective treatment of burns and chronic wounds, appropriate follow-up, and early biopsy at the slightest suspicious change can improve the prognosis and survival of the patients with Marjolin ulcers.

Author contributions

Both authors (BA and HMA) contributed to the study conception and design, material preparation, data collection, writing and approval of the manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by anyone of the authors. The authors declare no conflicts of interest.

Consent for publication

Informed, written consent was received from all patients whose photographs are present in the manuscript: Yes.

Competing interests

The authors declare no competing interests.