In 1828, the French physician Jean NicholasMarjolin first described the ‘warty ulcer' that occurred on scars and termed it ‘cancroidal ulcer'. However, he did not know the warty ulcers he described were malignant. In 1903, Da Costa reported 2 cases of malignant ulcers on the lower extremities with a history of venous ulcers and considered them to be consistent with the ulcers described by Marjolin (7). Subsequently, the malignant ulcers occurring on chronic wounds or scars gradually began to be referred to ‘Marjolin ulcers'.

In 1990, Hahn et al (8) summarized the data of 19 patients with MU and found that they were mainly 40-60-year-old males; the ulcers were primarily in the lower limbs; the primary injuries were mostly burns, followed by chronic osteomyelitis; the mean latent period was 31.5 years; the rate of metastasis at the time of diagnosis was 32%; histopathological examination revealed that all were squamous cell carcinoma; and the average time for local recurrence was 8.8 months. Copcu et al (1) followed 264 patients with burns treated at the Izmir Ataturk Hospital from 1994 to 2001. The average follow-up time was 3.8 years. Their survey found 31 patients with MU (11.7%) and 14 patients with benign ulcers (5.3%). Chalya et al (9) conducted a retrospective study of patients with MU at the Bugando Medical Center, Tanzania, from 2001 to 2010. They found that MUs were not rare in their area. In 2005, Kowal-Vern and Criswell (10) found that the mean age at MU diagnosis in their study population was 50 years, and males were more commonly affected than females, with males accounting for approximately 62% of cases. Bazaliński et al (11) reviewed the history, etiopathogenesis, diagnosis and treatment of MU, and found that the early diagnosis of these wounds could reduce tissue damage and resection scope.

According to the available literature, MUs can be divided into narrowly-defined scar cancers, which occur in malignant tumors of scar ulcers (5,12) caused by traumatic or chronically inflamed skin, burns in particular (1,3). They are classified into acute and chronic MU based on the latency period. The latency period is #<1 year for acute MU and >1 year for chronic MU (11,13-15).

The lower extremities have the highest probability of developing MU. However, MU can also occur in multiple other parts of the body, including the neck, elbow, scalp, calvarial bones, dura mater, brain, breast skin, nose and other sites (16-21). The pathological types of MU include squamous cell carcinoma, basal cell carcinoma, malignant melanoma, sarcoma, squamous basal cell carcinoma, squamous cell melanoma and other neoplasms (10,22,23). Among these, squamous cell carcinoma is the most common pathological type of MU (10).

MU causative lesions include burns (70-90%), chronic venous ulcers, chronic injuries, scars, chronic osteomyelitis, radiation-induced wounds, diabetic foot, pressure ulcers, venous stasis, hidradenitis and others (11,24-27). There is currently no clear explanation as to the exact causes of MU. MU is considered to arise primarily from long-term chronic inflammatory stimulation that leads to mutations in focal cells. Harland et al (28) detected a homozygous deletion of the p53 gene in this burn-related carcinoma. Lee et al (29) demonstrated that some burn scar-related squamous cell carcinomas had Fas gene mutations in regions important for the apoptosis function, and suggested these to be involved in the pathogenesis of the disease. Sinha et al (30) identified transcriptional changes leading to malignancy by comparing differentially expressed genes in squamous cells in squamous cell carcinoma and MU.

MUs can often be accurately diagnosed based on the medical history and a physical examination. It should be suspected that the ulcer is malignant when its recovery is prolonged and the patient relapses, particularly when the secretions increase, exhibit malodor and are prone to containing blood. All patients can be further diagnosed by acquiring biopsies from the lesion. Pathological biopsies should be taken from multiple locations in the ulcer center and margin, and should go deep into the subcutaneous tissue to avoid missed diagnosis. Ultrasonography can be used as a primary modality to identify lymph node metastasis. Radiography and CT can distinguish common imaging features of MU, including bone destruction, soft tissue mass, and a periosteal reaction (31). An MRI provides excellent soft-tissue detail, such as tumor extent, depth, margins, underlying bone cortical or marrow involvement, or the involvement of adjacent neurovascular structures (32). Positron emission tomography-CT (PET-CT) is useful in differentiating MU from benign inflammatory conditions of chronic nonhealing ulcers. It reveals a relatively good correlation with surgical or pathological results in determining the invasion depth (33). PET-MRI is feasible and performs equally well as PET-CT in the majority of cancers, with the benefit that the human body is exposed to a far lower radiation dose (34). However, there are no reports on the use of PET-MRI for the diagnosis of MU.

There currently no standardized treatment protocol available for MU. The extensive resection of the tumor is necessary. Bang and Woo (35) suggested that an aggressive excision and reconstruction with free tissue transfer or regional flap transposition should be adopted for adequate ablation and definitive coverage, rather than skin graft and regular surveillance. It was recommended that the smallest skin margin removed around the outer ulcer edge should be at least 2.5 cm (11). There is no consensus as to whether to perform sentinel node biopsy (36). If the MU is accompanied by local or distant lymph node metastasis, lymph node resection is required. Similarly, if the sentinel lymph node biopsy is positive, it is recommended to perform routine lymph node resection. For MU of the limb, amputation or hemipelvectomy (37) may be considered if the bone and joint were invaded, rendering radical resection of the lesion difficult to complete. Amputation or hemipelvectomy may also be considered if the limb function is severely impaired following radical resection. For the early stages of MU, an aggressive combined approach that includes extensive excision, lymphatic resection, postoperative radiotherapy and/or chemotherapy, and amputation if needed, might increase the cure rate. However, there is no consensus on advanced disease treatment, as it often produces unsuccessful results. At present, it is not recommended to routinely prescribe radiotherapy and chemotherapy to MU patients because the sensitivity of MU to these treatments is low and because of the risk of radiation-induced cell carcinogenesis. However, radiotherapy may be considered if the MU pathology is of a poorly differentiated type, the cancer has invaded the bone, there is distant metastasis, or the patient cannot tolerate or refuses to undergo surgery.

The prognosis is dictated by the time from injury to malignancy development, size, location, degree of differentiation, lymph node status, and metastasis at the time of diagnosis (11,38,39).

The current literature review suggests that the diagnosis and treatment of MU should follow the flow chart illustrated in Fig. 5. It is hoped that the information provided herein will help standardize the diagnosis and treatment of MU.

In conclusion, Mus may not be an uncommon health issue with unique features. MU diagnosis and treatment guideline development would aid in the early detection and proper management of the disease, thus reducing the rates of missed diagnosis, recurrence, and mortality due to MU. However, large-scale MU clinical studies are limited; the staging criteria have not yet been established, and the choice of treatment options is mostly empirical or based on small sample observations rather than evidence-based practice. Multicenter clinical collaborative research is required to provide useful guidance for the precise diagnosis and treatment of MU.