Letter to the Editor in response to the article: “Squamous cell carcinoma arising in chronically damaged skin (Marjolijn’s Ulcer)”

I read with great interest the article “Squamous cell carcinoma arising in chronically damaged skin (Marjolin’s Ulcer)” by Miodovnik and colleagues that was published in your journal.¹

In their article, Miodovnik and colleagues, described their experience with 84 patients with cutaneous squamous cell carcinoma (cSCC). While in most of the nonulcer type cSCC, were located in sun-exposed areas, most of the cSCC in chronically damaged skin were located in the lower extremities, where sun exposure is minimal.² The response to immunotherapy with cemiplimab or pembrolizumab in the patients with cSCC that were located in chronically damaged skin in the lower extremities was is less beneficial than that observed in the nonulcer type cSCC patients. The patients with cSCC patients in chronically damaged skin were younger and had a significantly shorter median time to progression and shorter progression-free survival.^1,2 Several hypotheses can be proposed to explain the unfavorable prognosis of the patients with cSCC located in chronically damaged skin and their inadequate response to immunotherapy:

1. An aggressive tumor cell biology of this type of cSCC.^1,3,4

2. Delay in the diagnosis of malignancy in patients within this type of cSCC.^3,4

3. The presence of local iron overload within this type of cSCC.^5,6

Using diagnostic X-ray spectrometry, we demonstrate the presence of elevated iron concentration within the skin around chronic venous ulcers.^5,6 Using a variety of methods, others were also able to demonstrate the presence of localized iron overload within venous ulcers.⁷ It has been suggested that extravasation of erythrocytes occurs as a result of increased venous pressure. Disruption of the erythrocytes and decomposition of the hemoglobin is followed by dermal and subdermal iron deposition, which is stored as hemosiderin.^5-7 Data collected in the recent years suggest that iron deposition within the chronic venous ulcers may not be an incidental byproduct but may perpetuate damage to the skin where the venous ulcerations is located. The ferric ions that are present within the skin may contribute to the generation of free radicals, oxidative stress, activation of metalloproteinase and thus contribute to local tissue damage that inhibits the healing of the venous ulcer.^5,6

Local iron overload may also facilitate the malignant transformation of the venous ulceration. The presence of free radicals and oxidative stress may cause DNA injury (including genetic instability and mutations), damage to proteins and cell membranes and the creation of a pro-tumorigenic environment that promotes cancer cell proliferation, invasion, and metastasis.⁸ It had been reported that iron accumulation in the microenvironment of the cancer cells supports metabolic changes, making tumor cells more aggressive.⁸

Moreover, iron overload can also disrupt the balance and function of T-lymphocyte subsets, altering their surface markers and circulation within the immune system, thereby weakening their immune response against tumors.⁸ Lymphocytes, with limited iron storage capacity, may become more vulnerable to damage due to iron overload, further contributing to immune dysfunction in patients with iron overload.⁸ It can be hypothesized that some of the above-described pathophysiological processes may be responsible for the conclusion of Miodovnik and colleagues, that immunotherapy is less effective in patients with cSCC arising in the lower extremities around and within venous ulcers.

Funding

Not applicable.

Conflict of interest

None to declare.