A 63-year old woman, who had had extensive. buttock in her childhood, was admitted to a regional hospital. She complained of a nonhealing

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1 POLSKI PRZEGLĄD CHIRURGICZNY 2009, 81, 9, /v Marjolin s ulcer case report and literature review Tomasz Wojewoda, Wojciech M. Wysocki, Jerzy Mituś Z Kliniki Chirurgii Onkologicznej Centrum Onkologii Instytut im. M. Skłodowskiej-Curie, Oddział w Krakowie (Departament of Surgical Oncology, M. Skłodowska-Curie Memorial Institute of Oncology in Cracow) Kierownik: prof. dr hab. J. Mituś We report squamous cell carcinoma (SCC) arising within a burn scar. The eponym Marjolin s ulcer was derived from a French surgeon Jean Nicholas Marjolin, who observed and classified cellular changes in burned skin and coined the term ulcere cancroide. We review literature and current diagnostic modalities and treatment of this not so uncommon disease. The pathophysiology of Marjolin s ulcer is unclear. Two per cent of skin malignancies are estimated to arise within burn scars. According to concurrent epidemiological analyses, squamous cell carcinoma is the most frequent malignancy to arise within burned/chronically wounded skin (75-96%), followed by basal cell carcinoma (12%), melanoma (3%), sarcoma (isolated cases). If Marjolin s ulcer diagnosis is established, wide local excision (at least 2 cm lateral margins) comprising fascia should be performed. The wound could be closed with transposed cutaneo-subcutaneous flap or with free flap. Long term treatment outcome is relatively good, but strict and prolonged follow up is mandatory. Key words: skin cancer, ulceration, burn scar Approximately patients are hospitalized annually in Poland due to burns. Often a large scar is a consequence of a burn. Many years later squamous cell skin carcinoma may develop within the scar. It is difficult to diagnose cancer within a scar (or other chronic skin lesions such as venous ulcers, chronic wounds, etc.) and prognosis in such cases is worse than in typical skin cancer other than melanoma. Here we report a case of classic Marjolin s ulcer (i.e. squamous cell carcinoma that developed within a burn scar) as well as review literature in this area and discuss modern principles of diagnostics and treatment of this not so uncommon disease. Case report A 63-year old woman, who had had extensive 2 nd and 3 rd degree burns of left thigh and buttock in her childhood, was admitted to a regional hospital. She complained of a nonhealing ulceration that appeared within a scar a few months ago. A specimen was taken from the lesion and squamous cell carcinoma was diagnosed. The patient was referred to an oncological center. Clinical examination revealed an extensive, burn scar on the posterolateral surface of her left thigh and buttock. An ulceration of 10 cm diameter, with heaped-up edges (fig. 1) was found in its center. Regional lymph nodes looked suspiciously. Computed tomography (CT) imaging was performed, demonstrating an irregular thickening of the skin and subcutaneous tissue (the biggest thickness of the lesion, in the area of trochanter major, was 30 mm), on the area of 6 x 10 cm, from the level of iliac joint to half of the length of the shaft of the femur. No muscle or large vessel infiltration was found. Other examinations were done, to assess stage of the cancer, however no metastases were found in the lungs or abdominal cavity.

2 Marjolin s ulcer case report and literature review 415 Ryc. 1. Rozległa blizna oparzeniowa z dużym owrzodzeniem Marjolina położonym centralnie Fig. 1. Extensive burn scar with large Marjolin s ulcer located in its center During the surgical procedure, the whole ulceration with a 2 mm margin of healthy tissue and femoral fascia, was excised. The skin defect was covered with a cutaneo-subcutaneous flap (fig. 2). After the surgery, small marginal necrosis of the flap was observed but otherwise the postoperative period was uncomplicated. The final microscopic diagnosis was carcinoma planoepitheliale spinocellulare exulcerans cutis G1 (squamous, spinocellular ulcerating carcinoma of the skin) ; the tumor was excised with lateral margins and deep, at least 1 cm, margin. The patient was not qualified to adjunctive treatment and undergoes strict clinical follow-up. Discussion Probably the first to report development of a tumor in old burn scars and chronic, non- healing wounds, was Aulus Cornelius Celsus in the 1 st century. In 1828 French surgeon Jean-Nicolas Marjolin observed a phenomenon that involved formation of ulcerations within burn scars and coined a term ulcère cancroïde (however he did not define clearly what he had in mind probably he never suspected malignant nature of the ulceration). The eponym Marjolin s ulcer, derived from his name, was used for the first time by Da Costa who reported malignant tumors arising in ild burn scars (1, 7). Etiopathogenesis of Marjolin s ulcer is not completely clear. Some theories of suggested pathomechanisms of malignant formation were summarized in tab. 1, prepared by Koval Vern and Criswell (4). The most recent theory ( immunological isolation ) stipulates injury of lymphatic circulation in scar tissues, leading to impairment of immune mechanisms that suppress malignant transformation and tumor progression. Ryc. 2. Stan po wycięciu wrzodu Marjolina z zachowaniem odpowiednich marginesów Fig. 2. Status after excision of Marjolin s ulcer with adequate margins Table 1. Theoretical patomechanisms of formation of malignant Marjolin s ulcer (adapted from Koval-Vern and Criswell 4) 1. Scars predispose to skin cancer 2. Inflammation and chronic irritation promote carcinogenesis 3. Genetic predisposition 4. Toxins released by burned tissue result in autolysis and heterolysis 5. Impaired perfusion of scar tissues results in ulceration and injury of the barrier that inhibits formation of metastases 6. Isolation that excludes scar cells from the supervision of immune system and absence of lymphatic vessels in the scar

3 416 T. Wojewoda et al. Most commonly the tumor develops in: burn scars of the skin (76.5%), chronic, non-healing posttraumatic wounds (8.1%), venous ulcerations (6.3%), fistulas in purulent osteitis (2.6%) (3). According to concurrent epidemiological analyses, squamous cell carcinoma is the most frequent malignancy to arise within burn scars and chronically wounds (75-96%). However, it is not the only direction of malignant transformation occurring in such situation. Often basal cell carcinoma (12%), melanoma (3%) as well as sarcoma (isolated cases) are found (1, 6, 7, 10). Two forms of squamous cell carcinoma can be differentiated on the basis of the course of malignancy formation: 1) acute form (mean time between injury and malignant transformation is form 4 weeks to 1 year); 2) chronic form (mean time of malignant transformation is approximately 35 years (1-75 years)) (5, 9, 11). Other authors tend to push the cut point between acute and slow malignant transformation somewhat further to 5 years after the injury (7). Against popular belief, malignant transformation within chronic skin lesions is not that uncommon. Malignancy is estimated to arise in 2% of burn scars (3). It can be easily calculated that since new cases of skin cancer were found in 2008 in USA, including (16%) of squamous cell cancer, 2% (3200) of squamous cell cancers were Marjolin s ulcers (6). In Poland, the proportion indicates, that an estimated number of Marjolin s ulcers is approximately 25 per year (annually approximately 8500 skin cancers are detected in Poland). Marjolin s ulcer occurs in men twice as often as in women. Most commonly it is located on lower extremities (53.3%), upper extremities (18.7%), trunk (12.4%), face and nape (5.8%), scalp (9.8%) (3). Apart from histological differentiation of squamous cell carcinoma (G1-3), macroscopic form of the tumor is also important to assess prognosis: 1) exophytic tumor, characterized by prolonged and relatively benign course and low probability of formation of distant metastases; 2) infiltrative form, characterized by rapid formation of ulceration and worse prognosis and high probability of metastatic spread. List of selected prognostic factors in patients with Marjolin s ulcer according to Phillips et al., is provided in tab. 2 (7). However we must emphasize that presence of metastases in regional lymph nodes is the single most important prognostic factor. Treatment of Marjolin s ulcer involves a local, wide excision of the ulcer with at least 2 cm margin of healthy tissue and fascia. The skin defect is covered by a free skin graft or cutaneosubcutaneous flap from adjacent region (5). Metastases in regional lymph nodes are detected at the time of diagnosis in 20-36% of patients. According to most authors, currently regional lymph nodes should be removed only when presence of metastases is confirmed by microscopic examination or when lymph nodes look clearly suspiciously in physical examination. Some are proponents of elective excision of regional lymph nodes when the primary tumor is relatively undifferentiated (G2 G3) and/or when the tumor diameter exceeds 10 cm. Bostwick et al. suggest that an elective lymphadenectomy should be performed 2-4 weeks after excision of the primary tumor. Such recommendation stems from an observation that sometimes metastases appear immediately after surgical excision of the primary lesion (1, 2). Esteman et al. suggest that biopsy of a sentinel node should be performed, indicating that it is an effective method, that could be an alternative to elective excision of regional lymph nodes (2). However, it is difficult to reconcile this view with the current theory of immunological isolation, stipulating that the scar tissue, where the malignancy Table 2. Prognostic factors in Marjolin s ulcer (adapted from Phillips et al. 7) Better prognosis Worse prognosis Time between injury and tumor formation <5 years >5 years Lcation head, nape, upper limbs trunk, lower limbs Clinical picture exophytic form infiltrative form Differentiation G1 G2 and G3 Extensiveness of T cell infiltration around the tumor dense infiltrates slight infiltrates Regional and remote metastases (at the time of diagnosis) absent present

4 Marjolin s ulcer case report and literature review 417 develops, does not contain lymphatic vessels (4). Limb amputation is performed only when there is infiltration of bones, large vascular, nervous trunks, when serious infection accompanies the malignancy (gangrene) and when an expected functional outcome of limb sparing procedure is unfavorable (5, 8). Chemotherapy and radiotherapy are not routinely used in the treatment of Marjolin s ulcer. 5-fluorouracyl and intraarterial methotrexate perfusion have been unsuccessfully used in tumors located in the limbs. Ryan and Martin reported 3 patients with primary inoperable Marjlin s ulcer, in whom the tumor regressed following local use of a cream containing 5-fluorouracyl, which allowed radical resection to be undertaken (1). Radiotherapy is useful as an adjunctive therapy or in patients, in whom a tumor cannot be excised due to extensiveness of malignant process. Aydogdu et al. (1) discuss eligibility criteria for radiotherapy in their review paper; these criteria were summarized in tab. 3. Five year survival after radical treatment of Marjolin s ulcer is 52%, while respective figures for 10 and 20 year survival are 34% and 23%, respectively. Metastases in regional lymph nodes and remote organs are observed in approximately 30% while local recurrence occurs in approximately 17% of patients (3, 8). Conclusions Marjolin s ulcer requires well planned and specialist diagnostic approach to make a quick diagnosis and proceed with adequate therapy. Table 4 summarizes general recommendations for management of patients at risk of Marjolin s ulcer or diagnosed with this disease, made on the basis of available literature. Table 3. Eligibility criteria for radiotherapy according to Ozek and Cankayal (adapted from Aydogdu et al. 1) 1. Inoperable, regional lymph nodes containing metastases 2. Marjolin s ulcer G3 with metastases in regional lymph nodes (after their excision) 3. Marjolin s ulcer with diameter > 10 cm, with metastases in regional lymph nodes (after their excision) 4. Marjolin s ulcer G3 and with diameter > 10 cm, without metastases in regional lymph nodes (after their excision) 5. Marjolin s ulcer in the head or neck with metastases in regional lymph nodes (after their excision) Table 4. General recommendations for management of patients at risk of Marjolin s ulcer or diagnosed with this disease 1. Whenever possible, excise and primarily close chronic, non-healing wounds 2. Monitor, at regular intervals, burn scars and chronic, non-healing wounds and inform patients who are at risk of Marjolin s ulcer, of such possibility 3. Prevent and treat infections of chronic wounds 4. In case of a suspected lesion, always take a specimen from the center and margin of the ulceration and subject them to histological verification 5. A specimen should be taken from venous ulcerations that do not heal despite 3 months of conservative therapy 6. Pay attention to the status of regional lymph nodes (risk of metastases in regional lymph nodes is higher in Marjolin s ulcer than in typical skin cancer) 7. Marjolin s ulcer should be excised with 2 cm margin of healthy tissue; the tumor shyould be excised with fascia 8. Clinically suspected or microscopically verified regional lymph nodes should be excised 9. Limb amputation is performed only when there is infiltration of bones, large vascular, nervous trunks and when an expected functional outcome of limb sparing procedure is unfavorable 10. Indications for radiotherapy and chemotherapy are established on an individual basis (see tab. 3) 11. After treatment the patient should be subjected to regular specialist follow-up

5 418 T. Wojewoda et al. References 1. Aydogdu E, Yildirim S, Akoz T: Is sugery an effective and adequate treatment in advanced Marjolin ulcer? Burns 2005; 31: Cobey FC, Engrav LH, Klein MB et al.: Brief Report: Sentinel lymph node dissection and burn scar carcinoma. Burns 2008; 34: Mahlon A, Kian S, Brooks HR et al.: Marjolin s Ulcer: Modern Analysis of an Ancient Problem. Plastic and Reconstructive Surgery 2009; 123: Koval-Vern A, Criswell BK: Burn scar neoplasm: A literature review and statistical analysis. Burns 2005; 31: Dupree MT, Boyer JD, Cobb MW: Marjolin s ulcer arising in a burn scar. Cutis Jul 1998; 62: 1 s Hatzis GP, Finn R: Marjolin s Ulcer: A Review of the Literature and Report of a Unique Patient Treated With a CO 2 Laser. J Oral Maxillofac Surg 2007; 65: Phillips TJ, Salman SM, Bhawan J et al.: Burn scar carcinoma. Dermatol Surg 1998; 24: Agullo J, Santillan AA, Miller WT: Marjolin ulcer (Imege of the month). Arch Surg 2006; 141: National Cancer Institutes website, Skin Cancer. http>// 10. Ozek C, Celik N, Bilkay U et al.: Marjolin s Ulcer of the Scalp: report of 5 Cases and Review of the Literature. J Burn Care & Rehabilitation 2001; 22: 65. Received: r. Adress correspondence: Kraków, ul. Garncarska 11