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      Malignant Transformation in Diabetic Foot Ulcers—Case Reports and Review of the Literature

      case-report

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          Abstract

          An imbalance of regeneration and destruction of the extracellular matrix due to a plethora of chemo- and cytokines, elevated matrix metalloproteinases, bacterial contamination and repetitive painless tissue damage can lead the chronicity of a wound, especially in diabetic foot ulcers (DFU). Along general lines, wound healing and cancer development are similar. Therefore chronic wounds prepare a breeding ground for cancer development. Several characteristics such as increase in size, verrucous everted margins and contact bleeding are suspicious for malignant growth in a chronic wound. While previously the term Marjolin’s ulcer was attributed to a malignant tumor in (burn) scars, it is nowadays used for every malignant tumor in chronic wounds. Furthermore, chronic ulcers in diabetic feet are susceptible for malignant transformation. We describe two cases of squamous cell carcinoma in patients with DFU—a 71 year-old woman and a 67 year old man. Both received total tumor excision and split-skin grafts with good short-time results.

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          Most cited references42

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          Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds.

          In diabetic patients, wound healing is impaired. We studied the pathogenesis behind this clinical observation by characterizing the pattern of deposition of extracellular matrix (ECM) molecules and the cellular infiltrate in chronic (>8 wk) diabetic wounds, compared with chronic venous ulcers and an acute wound healing model. Punch biopsies were obtained from the chronic ulcer margins and control samples were collected from upper leg skin 5, 19, 28 d and 12 and 18 mo postwounding (p.w.). T cells, B cells, plasma cells, granulocytes and macrophages, and the ECM molecules fibronectin (FN), chondroitin sulfate (CS), and tenascin (TN) were visualized using immunohistochemical techniques. Expression of FN, CS, and TN was detected in dermal tissue early in normal wound healing (5-19 d p.w.). Abundant staining was seen 3 mo p.w., returning to prewounding levels after 12-18 mo p.w. In the dermis of chronic diabetic and venous ulcers with a duration of 12 mo or more, a prolonged presence of these ECM molecules was noted. Compared with normal wound healing: (i) the CD4/CD8 ratio in chronic wounds was significantly lower (p < 0.0027) due to a relatively lower number of CD4+ T cells; (ii) a significantly higher number of macrophages was present in the edge of both type of chronic ulcers (p < 0.001 versus day 29 p.w.); and (iii) more B cells and plasma cells were detected in both type of chronic wounds compared with any day in the acute wound healing model (p < 0.04 for CD20+ and p < 0.01 for CD79a+ cells). These data indicate that important differences exist in the cellular infiltrate and ECM expression patterns of acute, healing versus chronic wounds, which may be related to the nonhealing status of chronic wounds.
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            Interactions of cytokines, growth factors, and proteases in acute and chronic wounds.

            A healing wound represents a complex series of interactions between cells, soluble mediators, and extracellular matrix. Within this multifaceted environment, there are multiple regulatory points which control the ordered series of events that lead to normal tissue repair. An alteration in this physiologic network can lead to the development of a chronic wound. This article presents an update on the numerous mediators that exist within the wound environment in both acute normal healing and chronic nonhealing wounds. We also present a hypothesis which may provide a conceptual pathophysiologic mechanism with which to understand all chronic wounds.
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              The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer

              There is a long-standing association between wound healing and cancer, with cancer often described as a “wound that does not heal”. However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of RasG12V-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome.
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                Author and article information

                Journal
                Geriatrics (Basel)
                Geriatrics (Basel)
                geriatrics
                Geriatrics
                MDPI
                2308-3417
                07 November 2019
                December 2019
                : 4
                : 4
                : 62
                Affiliations
                [1 ]Department of Endocrinology, Diabetology and Geriatrics, Stuttgart General Hospital, 70374 Bad Cannstatt, 24 Prießnitzweg, Germany; l.lucke-paulig@ 123456klinikum-stuttgart.de
                [2 ]Department of Orthopedics and Trauma Surgery, Stuttgart General Hospital, 70374 Bad Cannstatt, 24 Prießnitzweg, Germany; c.vollmer@ 123456klinikum-stuttgart.de
                Author notes
                [* ]Correspondence: s.doerr@ 123456klinikum-stuttgart.de (S.D.); r.lobmann@ 123456klinikum-stuttgart.de (R.L.); Tel.: +49-711-278-44887 (S.D.)
                Article
                geriatrics-04-00062
                10.3390/geriatrics4040062
                6961039
                31703431
                93be0f36-6d88-473f-866e-a6b8f1504c27
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 September 2019
                : 06 November 2019
                Categories
                Case Report

                marjolin’s ulcer,chronic wound,wound healing,skin transplantation,matrix-metalloproteinases,ackerman carcinoma,squamous cell carcinoma,scc

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