Metastatic Marjolin Ulcers: A Systematic Review and Single-center Experience

Abstract

Background:

Marjolin ulcers (MUs) are rare, aggressive cutaneous malignancies that arise from previously injured or chronically inflamed skin. MUs have a poorer prognosis than other types of skin malignancies, with higher nodal metastases and recurrence rates. Although surgical resection remains the primary treatment modality, the management and outcomes of patients with metastatic disease are not well characterized. We reviewed literature on treatment strategies for metastatic MUs and report our institutional experience so as to stimulate interest in this difficult-to-treat entity.

Methods:

A systematic review on metastatic MUs following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed using the English-language literature. An institutional case series is reported to capture the experience of a rural African hospital.

Results:

Of 180 publications reviewed, 9 studies with 129 patients, with a mean age of 50.3 years, were included in the study. Burn scars were the most common precursor (54%), with squamous cell carcinoma accounting for 97% of cases. Metastases involved the regional lymph nodes, lungs, and liver. Initial treatment included wide local excision or amputation, with or without adjuvant radiotherapy. Survival data were sparse. Our institutional cohort of 11 patients showed similar patterns of metastases.

Conclusions:

This review did not identify any effective treatment for metastatic MUs. The current management strategies are largely determined by institutional resource settings, but remain essentially palliative in their approach, highlighting the need for a standardized approach to achieve optimal patient outcomes.

Takeaways

Question: What are the demographics, treatment strategies, and outcomes of patients with metastatic Marjolin ulcers?

Findings: This review did not identify any effective treatment for metastatic Marjolin ulcers. The current management strategies are largely determined by the institutional resource setting but remain purely palliative in their approach.

Meaning: Burn prevention and appropriate burn care, including early excision and skin grafting, remain the most effective means of avoiding burn-related Marjolin ulcers, along with the associated morbidity and mortality.

INTRODUCTION

Marjolin ulcers (MUs) are rare, aggressive cutaneous malignancies that originate in areas of skin injuries sustained from a variety of insults.^1–3 Although classic MUs resulting from malignant degeneration of burn scars are mostly squamous cell carcinoma (SCC) on histology, other histological diagnoses have been reported.^2,4,5

Although there is no consensus, a number of theories that attempt to explain the etiopathogenesis of malignant degeneration have been proposed.^5–25 MU pathogenesis seems to be multifactorial, arising from the hostile microenvironment of long-standing scars. Chronic inflammation, hypoxia, and impaired extracellular matrix turnover foster persistent DNA damage, whereas poor lymphatic drainage and loss of resident Langerhans cells create an “immune-privileged” field in which dysplastic keratinocytes can evade surveillance.^10,11 Additional hits such as local toxins from repeated tissue breakdown, mechanical irritation, and possible infection promote further mutagenesis.⁹ Tumor clones may then acquire active immune-evasion strategies (such as antiapoptotic signaling or epithelial-to-mesenchymal transition) and may harbor p53, Fas, or HLA-DR4 alterations, aberrant long-noncoding RNAs, and other epigenetic changes.^19,25 With current knowledge and evidence, the multifactorial theory, a convergence of environmental, immunologic, and genetic factors, best explains both the aggressive biology of this carcinoma and the wide range of treatment options currently explored for its management^24,26 (Table 1).

Table 1.

Theories of Malignant Transformation in Chronic Scars

Etiologic Theory	Key Mechanism(s)
Chronic irritation/repeated inflammation6–11	Long-standing ulceration, bacterial toxins, cytokine-driven oxidative DNA injury, and proliferation in poorly vascularized scar tissue
Traumatic implantation of epithelial elements12,13	Displacement/implantation of epidermal nests into dermis during trauma; later malignant transformation in a proinflammatory milieu
Cocarcinogen/initiation–promotion14,15	Initiating carcinogen creates latent neoplastic clones; noncarcinogenic stimuli (eg, wound healing, chronic irritation) promote tumor outgrowth
Immunologic privileged site10,11,16,17	Scar tissue destroys lymphatics and distorts vasculature → reduced antigen presentation and lymphocyte trafficking; favors tumor immune escape
Active immunologic evasion by tumor clones9,18,19	Antiapoptotic signaling, EMT, and cytokine loops sustain tumor growth and spread
Impaired lymphatic drainage and poor vascularity10,11	Carcinogens and inflammatory mediators trapped; atypical cells persist
Hereditary/genetic susceptibility20–22	Host HLA associations and tumor suppressor/apoptosis pathway alterations (eg, p53 deletion, Fas mutations) predispose to carcinogenesis in scars
Ultraviolet radiation (contextual cofactor)23	Ultraviolet exposure to scar further depletes Langerhans cells and induces oncogenic mutations (eg, in TP53), compounding the loss of local immune surveillance
Molecular microenvironment: ECM turnover and EMT9	Transcriptomics shows impaired ECM remodeling and epithelial-to‑mesenchymal transition programs in MUs versus conventional cSCC
Epigenetic and noncoding RNA dysregulation11,25	Aberrant lncRNAs/mRNAs disrupt the p53 pathway and immune response
Multifactorial interaction (environmental + immune + genetic)5,10,18,19,24	Combined insults drive malignant transformation, supporting multimodal therapy

cSCC, cutaneous squamous cell carcinoma; ECM, extracellular matrix; EMT, epithelium-to-mesenchyme transition.

Patients with MUs in sub-Saharan Africa demonstrate shorter latency periods and younger age at diagnosis compared with other regions.^2,26–28 Delays between initial injury and malignant transformation contribute significantly to morbidity and mortality, particularly in resource-limited settings where cultural, economic, occupational, and healthcare-access barriers further delay diagnosis and treatment. Kowal-Vern and Criswell⁵ reported that only 5% of 412 MU patients underwent grafting at initial injury; similarly, other studies suggest burns left to heal secondarily are more prone to malignant degeneration.^3,29 Additionally, racial differences may influence the type of histological malignancy expressed in MUs.³⁰

Patients with MUs undergo varied treatments, commonly beginning with biopsy, followed by wide local excision or limb amputation, with subsequent defect coverage using skin grafts or flaps.^2,3,31 Limb amputation does not enhance survival if negative margins can be achieved through wide local excision.²⁶ Although regional lymph node dissection may be indicated, its role remains controversial,^10,29,32 because even clinically or radiologically suspicious nodes have a positive yield of about 30% following either lymph node biopsies or dissection.³³ This low yield may reflect impaired lymphatic drainage secondary to scarring from burns.³⁴ Some authors advocate radiotherapy to regional lymph node basins in cases with confirmed regional metastases^29,35,36 (Table 2). MUs have a poorer prognosis than other skin malignancies, with higher nodal metastasis and recurrence rates, both predictive of mortality.^10,24,26

Table 2.

Treatment Modalities and Indications in the Management of MUs

Treatment Modality	Description and Indication
Surgery	Wide local excision, amputation, lymphadenectomy, sentinel lymph node biopsy1
Radiotherapy	Adjuvant therapy for close margins or lymph node involvement29
Chemotherapy	Metastatic disease, often in conjunction with surgery37
Immunotherapy	Anti-PD-1 therapy (such as pembrolizumab, cemiplimab) for advanced cases18

In the United States, advanced cutaneous SCC constitutes 5% of cutaneous SCC, but contributes to 60% of disease-related deaths. The current standard for advanced SCC (locally advanced or metastatic SCC that cannot be managed by surgery and/or radiotherapy) is systemic immunotherapy. Although specific treatment protocols for metastatic MUs remain undefined, promising outcomes with systemic immunotherapy in advanced SCC provide optimism for managing metastatic MUs.^37,38

Cheng et al⁴ recently published a systematic review on the prognostic factors of MUs. Kowal-Vern and Criswell,⁵ in a review, reported regional lymph node metastases in 22% in 412 patients with MUs; 14% had distant metastases. To our knowledge, no systematic review focusing on metastatic MUs, including diagnosis, treatment, and outcomes, has been published in the English language. The many reports on MUs in both English and non-English scientific literature point to the pervasiveness of this infrequent but preventable pathology.^39–41 At a time when the gold standard in disease management must be evidence-based, and with the acknowledgement that MUs represent a lethal, albeit rare, yet highly preventable disease entity, the lack of consensus management protocols for MUs, coupled with the paucity of data on metastatic MUs, is concerning; hence the need for this systematic review.

This review sought to summarize current demographics, treatment strategies, and outcomes of patients with metastatic MUs. Additionally, the senior author’s institutional experience is highlighted to provide further insight into the presentation and management of these malignancies in a resource-limited setting.

METHODS

Protocol, Databases, and Search Strategy

We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for this systematic review.⁴² The search strategy included the following terms: “Marjolin*,” “burn,” “scar,” “carcinoma*,” and “metast*.”

Selection Criteria, Data Extraction, and Synthesis of Included Studies

Eligibility criteria included the following: (1) any publication that included metastatic MUs; (2) published at any time before August 31, 2024; (3) discussion of management strategies specific to metastatic MUs; and (4) follow-up of patients for a minimum of 1 year. We searched PubMed and MEDLINE, Embase, African Journals Online, and Bioline International (https://www.bioline.org.br/).

Two reviewers (J.L. and P.M.J.) with the assistance of a third reviewer (D.N. or A.H.C.) performed title and/or abstract screening, full-text review, and data extraction using Covidence (Veritas Health Innovation, Melbourne, Australia). The senior author reviewed any abstracts/articles during instances of disagreement. After article screening, a standardized Google Sheets (Google LLC, Mountain View, CA) with the abstracted data was created. Extracted variables included authors, country and year of publication, total number of patients, number of patients with metastasis, histological diagnosis of malignancy, cause of original injury, anatomical site of MU, latency period, treatment method, follow-up period, survival, and location of metastasis.

Kijabe Hospital Experience

Patient data for the institutional series were retrieved from different sources, including the hospital’s electronic medical records, older paper-based patient charts (transition to electronic medical record occurred in September of 2019), operating room records, and the Department of Pathology database. All patients with metastatic MUs managed at the hospital between 1995 and 2024 were included in the study. All included patients had a histological diagnosis of malignancy at the ulcer site, based on biopsies and/or excised specimens.

Ethical Approval

Ethical approval for the study was given by the Kijabe Hospital Institutional Scientific Ethics and Research Committee (KH/ISERC/02718/0041/2024).

RESULTS

Using the search criteria, 180 articles were screened, of which 9 met the inclusion criteria^{29,35,43–49} (Fig. 1). The 9 studies with adequate extractable data had a total of 129 patients with metastatic MUs, with a mean age of 50.3 years at diagnosis, and a mean latency period of 25.2 years. Data on the mean age at diagnosis and mean latency period could not be extracted for 32.5% and 62% of the 129 patients, respectively. The male-to-female ratio was 1.2:1; however, data on patient gender could not be extracted for 96 patients. MUs resulted from burn scar in 70 (54.3%) patients, soft tissue scar in 23 (17.8%) patients, chronic osteomyelitis in 6 (4.6%) patients, and coronary artery bypass graft scar in 1 (0.8%) patient. The cause was not specified for 29 (22.5%) of the included patients. Of 111 patients in whom the primary anatomical site of the MU was specified, the lower extremity, upper extremity, trunk, and scalp were involved in 76.6%, 20.7%, 1.8%, and 0.9%, respectively. The primary anatomical site involved in the MU was not reported in 18 (14%) of the patients.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram

The histological diagnosis of metastatic MUs was SCC in 125 (96.9%) patients and malignant melanoma in 4 (3.1%) patients. Metastasis to regional lymph nodes was reported in 94 (72.9%) patients, whereas the lungs (32, 25.6%) and the liver (2, 1.5%) were sites of distant metastases.

Treatment of MUs (Systematic Review)

Treatment for MUs varied: wide local excision was performed in 73 (56.6%) patients; of these, 25 (34.2%) had both wide local excision and lymph node dissection. Amputation was performed in 31% (40 of 129) of the patients. Only 26 (20.2%) patients were treated with radiotherapy (Table 3).

Table 3.

Demographics of Included Studies in the Systematic Review

Author, Country, Year	Total, N	Sex, n	Cause of Scar/Injury Type	Site	Age at Diagnosis (% Whole Cohort)	Mean Latency Years (Metastatic Cohort)	Type of Surgery	Histology, (n, %)	Site of Metastases	Radio	Other
Lifeso, Saudi Arabia, 199035	31	NS	Soft tissue scar-23; COM: 6; unknown: 2	LL (83.9%), UL (16.1%)	51 (NS)	16.1 (NS)	Amputation: 28; WLE: 3	SCC (31, 100)	LN: 31	20 (WLE + irradiation to node beds)
Copcu, Turkey, 200343	6	NS	Burn (100%)	LL (50%), UL (50%)	39 (NS)	19 (NS)	WLE + LND: 6	SCC (6, 100)	LNs: 6
Tiftikcioglu, Turkey, 201044	52	NS	Burn (100%)	LL (77.4%); UL (22.6%)	48 (NS)	35.9 (NS)	WLE: 35; WLE and LND: 13; amputation and LND: 4	SCC (52, 100)	Liver: 2; lung: 26; LNs: 24
Challa, India, 201445	4	M: 3; F: 1	CABG scar (1, 25%), burn 3, 75%)	Back (1, 25%), chest (1, 25%), LL (1, 25%), UL (1, 25%)	50 (54.5)	4.8 (6.5)	WLE (palliative): 1; WLE+LND:1; amputation+LND: 2	SCC (4, 100)	LN: 3; lung: 1
Shen, China, 201546	17	M: 5; F: 3; NS: 9	NS	LL (88.2%), UL (11.8%)	64.15 (59.6)	13.42 (NS)	Amputation and LND: 10; WLE+STSG: 2; WLE+flap: 1	SCC (13, 76.4), MM (4, 23.6)	LNs: 14; lung: 3	1	Refused treatment: 1; interferon: 1
Burusapat, Thailand, 202147	5	M: 5	NS	NS	32.2 (61.4)	27.8 (33.3)	WLE: 1; amputation: 3	SCC (5, 100)	LN: 3; lung: 2		Refused treatment: 1
Mousa, Egypt, 202229	8	M: 6; F: 2	Burn (100%)	NS	55.4 (57.1)	29.7 (36.3)	Amputation: 3; WLE+STSG: 5	SCC (8, 100)	LN: 8
Mitra, India, 202448	1	M: 1	Burn (1, 100%)	Scalp (1, 100%)	40 (40)	20 (20)	WLE + STSG, Adj mold brachytherapy: 1	SCC (1, 100)	Preauricular region: 1
Chaturvedi, India, 201949	5	NS	NS	NS	48.8 (NS)	26.4 (NS)	WLE + STSG + LND + Adj RT: 5	SCC (5, 100)	LN: 5	5
Totals	129	M: 1.18; F: 1; NS: 96	Burn (70, 54.3%), soft tissue scar (23, 17.8%), COM (6, 4.6%), CABG scar (1, 0.8%), NS (29, 22.5%)	LL (85, 65.9%), UL (23, 17.8%), trunk (2, 1.5%), scalp (1, 0.8%), NS (18, 14.0%)	50.3 (68.5)	25.2 (28.0)		SCC (125, 96.9), MM (4, 3.1)	LNs (94, 72.9%), lung (32, 24.8%), liver (2, 1.5%), preauricular region (1, 0.8%)	Radiation in combination with surgery: 26	Refused treatment: 2, interferon: 1

Adj, adjuvant; BKA, below-knee amputation; CABG, coronary artery bypass graft; F, female; LL, lower limb; LND, lymph node dissection; LNs, lymph nodes; M, male; mets, metastases; MM, malignant melanoma; NR, not reported; NS, not specified; radio, radiotherapy; STSG, split thickness skin graft; UL, upper limb; WLE, wide local excision; √, given.

Patient Outcomes

The majority of the studies did not include patient mortality data in their reports.

Kijabe Institutional Results

A search of the plastic surgery operating room logs and pathology department database produced a total of 11 patients with metastatic MUs. Included patients were managed between 1995 and 2016; none of the patients presenting between 2016 and 2024 had metastatic disease. Included patients were predominantly women (n = 9), with a mean age of 35.6 years (range 15–58 y). It was not possible to estimate the mean latency of the MUs for patients, as more than 70% did not know the time lapse between initial injury and the time they first noticed the nonhealing wound (Table 4). The majority, however, had experienced burns as children younger than 10 years. The majority of patients in this series (82%) had extremity ulcers; 6 involved the upper extremities, and 3 involved the lower extremities.

Table 4.

Demographics of Patients in the Institutional Case Series

Year Treated		Sex	Cause of Scar	Site	Age at Diagnosis, y	Mean Latency, y	Type of Surgery	Histology	Type of Metastasis	Radio	Other
1995	1	F	Burn	Right arm	25	NR	NR	SCC	Axillary LNs	NR
2001	1	F	Burn	Right forearm	41	NR	NR	SCC	Axillary LNs	NR
2001	1	F	Burn	Right leg	27	NR	NR	SCC	Groin LNs	NR
2003	1	F	Burn	Left leg	58	24	BKA	SCC	Malignant left pleural effusion; SCC in fat surrounding groin LNs	√	Lost to follow-up
2011	1	F	Burn	Left popliteal fossa	15	>10	WLE + groin dissection	Poorly differentiated SCC	Groin LNs	√	Groin “abscess” drained elsewhere was metastatic LNs
2013	1	F	Burn	Right chest MU	38	12	WLE + supraclavicular LND	SCC	Supraclavicular nodes LN	X	Refused radiotherapy, and later rejected further treatment after recurrence in 2015
2013	1	F	Burn	Right arm	21	12	Forequarter amputation	SCC	Malignant pleural effusion	√	Died at 2 y postoperatively
2014	1	M	Burn	Right hand, later above-elbow stump	52	>30	Below elbow amputation	SCC; femur—metastatic poorly differentiated SCC	Supratrochlear LNs, ipsilateral neck of femur with pathological fracture, and right chest wall and malignant pleural effusion	√ (for fracture)	Lost to follow-up after hip fixation and radiotherapy
2014	1	F	Burn	Right arm	42	NR	Shoulder disarticulation	SCC	Axillary LNs	NR	Lost to follow-up after wounds healed
2014	1	M	Burn	Left arm	56	>40	Left forequarter amputation	SCC	Supraclavicular LNs	√	Lost to follow-up after radiotherapy
2016	1	F	Burn	Scalp	17	>10	WLE+ occipital LN dissection	SCC	Occipital LNs	NR	Lost to follow-up
Kijabe series (totals)	11	M: 2; F: 9	Burn (100%)	LL (27.3%), UL (54.5%), chest (9.1%), head (9.1%)	35.6	19.7	Amputation: 4; WLE + LN dissection: 3; shoulder disarticulation: 1; NR: 3	SCC (11, 100)	LN: 11	5

Adj, adjuvant; BKA, below-knee amputation; F, female; LL, lower limb; LND, Lymph node dissection; LNs, lymph nodes; M, male; mets, metastases; MM, malignant melanoma; NR, not reported; NS, not specified; radio, radiotherapy; UL, upper limb; WLE, wide local excision; √, given.

Treatment (Kijabe Hospital)

Five of 6 patients with extremity MUs and adequate clinical data were treated with limb amputations. Three patients underwent wide local excision with regional node dissection. Clinical charts were not available for 3 patients; all their data were extracted from the pathology database. Information on the surgical procedures and adjuvant treatment was not available for these 3 patients. Nine patients had histologically well- or moderately well-differentiated SCC, whereas 2 had poorly differentiated SCC.

Of the 8 patients with adequate clinical data, 5 received radiotherapy directed at the metastatic lesions after adequate surgical excision, whereas 1 patient refused adjuvant radiotherapy after surgery. Two patients could not afford radiotherapy and were lost to follow-up (Table 4).

DISCUSSION

This systematic review on the management of metastatic MUs did not find any standardized specific care directed at the management of the metastatic disease. Patients in both the systematic and institutional reviews received treatment based on institutional practice and resources. Nevertheless, of the 129 patients in the 9 included studies, 73 (56.6%) underwent wide local excision of the primary lesion, whereas amputation was the definitive treatment in 31% (40 of 129) (Table 3). In contrast, of the 8 patients in the institutional series that had adequate clinical data, 5 (62.5%) underwent some form of major amputation, whereas 3 underwent wide local excision with regional lymph node dissection, suggesting more advanced disease presentation in the small institutional series compared with the systematic review. Seventy-three percent of patients in the review had regional node metastases compared with 100% of those in the institutional series (Table 4). In addition, the institutional report is unusual in that 1 patient in our series had distant bone metastases involving the neck of the femur and ribs (Figs. 2, 3). Previous reports of MUs involving bone have all been part of a locally invasive process. Distant metastases in the systematic review were reported in the lung and liver^44,46,47 (Table 3). Although the lower limbs were the most common anatomical site of MUs (66%) in the systematic review, the upper limb (54.5%) was the most frequently involved site in the institutional report. The cause of this difference is unclear, as an earlier report from the same institution showed higher lower limb involvement in MUs.²

Fig. 2.

Pathological femur fracture managed with internal nail fixation and radiotherapy.

Fig. 3.

Chest wall metastases with pathological rib fractures.

Follow-up

Loss to follow-up most likely contributed to the low mortality in our institutional series: the single mortality was reported by relatives 2 years after a forequarter amputation. The patient had been admitted a few months earlier for a malignant pleural effusion (Fig. 4, Table 4). Because our hospital is a referral institution, patients in this series were referred from as far as 600 km away. Further, our hospital does not provide radiotherapy services, so patients are “disconnected” from them upon referral for radiotherapy.

Fig. 4.

Patient presenting with a malignant pleural effusion 2 years after a forequarter amputation.

Burn injury is largely a disease of the poor.^50,51 MUs are, therefore, a disease of the poorest of the poor, another likely contributor to loss to follow-up. Shen et al⁴⁶ reported that 45.1% of their patients received external herbal remedies as treatment, whereas 25.5% received no treatment at all.

Surgical site infection surveillance studies at our institution have consistently been 100%, and although these studies were designed differently, the loss to follow-up of patients with metastatic MUs is nevertheless disconcerting.^52,53 Loss to follow-up of patients with MUs is, however, not peculiar to our series; Huang et al⁵⁴ reported a 45% loss to follow-up in their series in a high-resource setting. The poor follow-up is concerning because it forms an important surveillance tool and is integral to the National Comprehensive Cancer Network guidelines for skin cancer.⁵⁵

Metastases

In both the systematic review and institutional series, regional lymph nodes were the most common sites of metastases, involving 73% and 100% of patients, respectively, whereas the lung and liver in the review and lung/pleura and bone in the institutional series were sites of distant metastases. Node-dominant patterns with secondary pulmonary spread were seen in 4 included studies^35,43,45,46 and the institutional series. The authors posit that the lower rates of regional lymph node metastases reported in the systematic review may be because authors of the included studies likely reported the most distant metastatic disease site encountered and therefore did not report on regional nodes when there was evidence of liver metastases, for example.

Compared with MUs that have not metastasized, the outcomes following metastatic MUs are very poor.⁵⁶ For well-differentiated lesions that are limited to the skin, the estimated 5-year survival rate is 60% and 69% for patients treated by wide local excision and amputation, respectively.²⁶ The majority of the studies did not include mortality data, and therefore, it was not possible to evaluate the effect of MU metastases on mortality. Tiftikcioglu et al⁴⁴ reported that on average, their series of patients with lower extremity MUs survived 7.6 years after diagnosis. Patients with high-grade tumors had less than 2-year survival, whereas those with large tumors were more likely to have lung metastases. Similar to the experience reported in our review, they reported regional lymph node, liver, and lung metastases in their series of 62 patients.⁴⁴

A number of authors contend that the histological grade of the tumor is the most important prognostic factor in MUs.^4,35 Cheng et al⁴ found that tumor site on the head and neck, a high tumor histological grade, the presence of lymph node metastasis, and a tumor diameter of 10 cm or less were predictors of poor prognosis, whereas lymph node metastasis was the only significant predictor of distant metastasis. Chaturvedi et al⁴⁹ reported that moderately differentiated SCC and positive lymph nodes independently predicted recurrence.

Radiotherapy

Luo et al³⁰ in a review of 102 patients reported that although local bone involvement and regional lymph node metastasis were associated with a higher local recurrence in their series, lymph node metastases and the use of radiotherapy did not influence survival. It was not possible to extract data specific to patients with metastatic MUs from their report, and therefore, the study was excluded from the study synthesis. Similarly, although Aydoğdu et al⁵⁷ managed 15 patients with MUs, all of whom received radiotherapy and chemotherapy, they did not clearly differentiate between locally advanced disease and regional or distant metastases, and their study was therefore excluded. Shen et al⁴⁶ did not use radiotherapy as a first-line therapy for their patients because of concerns that radiotherapy might induce further malignant change, whereas Mousa et al²⁹ believed that radiotherapy should be reserved for unresectable nodal disease or palliation, underscoring the ongoing controversy surrounding its role.

Lifeso et al³⁵ treated regional lymph nodes with prophylactic radiotherapy to prevent or reduce local recurrence and distant metastases. Ozek et al⁵⁸ used the following criteria to determine which patients with MUs receive radiotherapy: patients with inoperable regional lymph node metastasis, those with grade 3 lesions, or tumor diameter larger than 10 cm, or lesions of the head and neck with positive lymph nodes after regional lymph node dissection. Thus, in the absence of standardized guidelines for the management of MUs, individual institutions/surgeons determine care algorithms specific to their own settings. Radiotherapy was used in 3 of the included studies.^35,46,49

Chemotherapy

A number of recent studies suggest that immunotherapy and/or chemotherapy may offer promise for either locally advanced or metastatic MUs, especially where surgical treatment alone is inadequate.^18,19,48 Mitra et al⁴⁸ successfully palliated a 20-year-old man with a metastatic MU refractory to surgical treatment, resulting in a stable disease burden 3 months after chemotherapy using a combination of docetaxel and cisplatin. Shalhout et al¹⁹ reported a 1-year survival rate of 60% in 5 metastatic MU patients treated with immune checkpoint inhibitors (pembrolizumab or cemiplimab) combined with standard care. However, Miodovnik et al¹⁸ reported limited benefit with cemiplimab or pembrolizumab, noting minimal or no response in 7 of 9 patients. They suggested combining chemotherapy with immunotherapy to overcome limited therapeutic response.^18,59

The mixed results in this review are inconclusive because of the small number of cases and the inconsistent directions of the reported outcomes. Surgical excision (wide local excision or amputation) is the most effective modality for the management of MUs. Additional interventions including regional lymphadenectomy, radiotherapy, chemo- and immunotherapy do not seem to improve survival.³⁶ Nevertheless, the search for effective treatments for advanced cutaneous SCC provides hope for patients with locally advanced or metastatic MUs.³⁸ Table 5 lists a number of unresolved issues in the management of MUs (both localized and metastatic) and suggests opportunities for further research.

Table 5.

Unresolved Issues in the Management of MUs and Recommendations for Further Research

Unresolved Issues in Managing Patients With MUs	Value of Solutions
The processes involved in malignant degeneration, and the factors that determine the type of malignancy expressed	Once determined, this would permit the development of treatment options targeted at specific steps along the pathway, or even manipulation to prevent malignant degeneration
The determinants of latency between injury and malignant degeneration	What factors influence the development of acute Marjolin ulcers?
The management of regional lymph nodes	The value of regional lymph node dissection has not been clearly determined
The indications for the use of radiotherapy	When should radiotherapy be used?
The indications for the use of chemotherapy and/or immunotherapy	What chemotherapy is suitable for MUs? What immunotherapy is active against MUs? Should combination chemo- and immunotherapy be used? For what indications?
The definition of palliative treatment	When is Marjolin disease palliative? What are appropriate interventions?
Recommendations and further research
Standardize reporting of histological grading of all MUs using the World Health Organization grading system in publications: (grade I: SCCs with greater than 75% well-differentiated cells; grade II: SCCs with 25%–75% well-differentiated cells; and grade III: SCCs with less than 25% well-differentiated cells)4	Will improve comparability and stratification of interventions, as well as prognosis and outcomes
Stage patients presenting with MUs using imaging modalities to assess for regional lymphadenopathy and distant metastases (especially the liver, chest, and bone)	Will enhance standardization of approaches to treatment
Create a global registry for MUs, to allow for data sharing, including treatment, follow-up, and outcomes	Will enhance the size and quality of data for analysis
Consider multisite treatment trials	With the anticipated increase in the pool of patients, treatment outcomes will become easier to predict
Declare burn injury a neglected surgical disease, as a separate entity from other injuries60	This will push governments and global health actors to prioritize burn prevention and care

Study Limitations

The authors acknowledge that MUs are a rare disease predominantly affecting low- and middle-income countries. The limited number of studies identified reflects the paucity of surgical research conducted in these regions. Consequently, this review, although emphasizing the challenges in managing metastatic MUs, may not be globally representative. Limiting inclusion to English-language studies is an additional limitation. Poor follow-up in the institutional cohort resulted in incomplete long-term outcome data. Despite these limitations, this review highlights the need for evidence-based guidelines to standardize care.

CONCLUSIONS

This review did not identify any effective treatment for metastatic MUs. The current management strategies are largely determined by the institutional resource setting, but remain purely palliative in their approach, highlighting the need for a standardized approach for optimal patient outcomes.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.