According to the World Health Organization (WHO) statistics, cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, that is about one in six deaths in general (1). In 2020, сhronic myeloid leukemia (CML) was diagnosed 474,519 times (2.6% of all diagnosed cancers), whereas melanoma of the skin is the 17th most common cancer worldwide – it was diagnosed 324,635 times (1.8% of cancers). Non-melanoma skin cancers (like basal cell carcinoma and squamous cell carcinoma) are often not fully recorded by cancer registries - registrations of these cancers are often incomplete, because most cases are successfully treated via surgery or ablation (2). That is why the reported global incidence of skin cancers is possibly underestimated.

At the same time, it’s very important to register all cases of melanoma and non-melanoma, especially because they may be associated (just like other types of cancer) with Covid-19 pandemic (3, 4). Indeed, Costa et al. presented a theoretical framework describing how Covid-19 could influence the development of blood cancers (3). Another study suggested that an abnormal immune response to viral infections can indirectly trigger leukemia promoting gene mutations and that SARS-CoV-2 can also significantly interact with the renin-angiotensin system, which is believed to play a role in the development of cancerous blood cells (5).

Some researchers also report the possible carcinogenic effect of the drug used in the treatment of leukemia - Imatinib mesylate (Gleevec) (6) and the occurrence of other types of cancer in the background of already existing chronic leukemia (7). It is also known, that Covid-19 alone or even SARS-CoV-2 vaccine booster dose can trigger non-melanoma skin cancer often preceded by multiple cutaneous adverse reactions (8, 9).

The aim of our study is to analyze the available data concerning the possibility of the influence of CML and the drug Gleevec or its analogs (which are used as the drug of choice in the treatment of leukemia) on the risk of future skin cancer developmend. Additionally, since our patient recoverd from Covid-19 before the onset of leukemia and skin neoplasms, the study also focused on the analysis of the potential effect of a previously transmitted viral disease (in particular - Covid-19), on the likelihood of cancer development.

We describe a clinical case of a patient (man, 49 years old, director of the private agriculture company) diagnosed with two melanomas and one other skin cancer within two years. The patient is also suffering from CML, which appeared after recovering from Covid-19 and has been taking the drug Gleevec from the time of leukemia diagnosis (Figure 1).

The patient did not experience any sunburns in the past as he was never tanning - before Covid-19 that occurred in 2020, he was healthy, with no chronic diseases. He was working mostly in the office and have always led a healthy lifestyle (sports, sauna, no smoking).

After skin lesion removal in 2022, the patient was not undergoing any pharmacological treatment against skin cancer. He also did not experience any side effects following Gleevec administration. Generally, the patient report excellent results of treatment and feels good.

During the first year after surgery, the patient did the ultrasound examination of lymph nodes and dermoscopy for skin lesions once every 3 months (later - once every 6 months). He also did regular blood tests for leukemia. No recurrence was reported

Description of our clinical case indicates, that the primary disease was Covid-19, soon after which the patient was diagnosed with leukemia. Although anamnesis familiae suggests possible genetic predisposition of the patient to leukemia, it is reasonable to suppose that SARS-CoV-2 infection can create a microenvironment that is ideal for neoplastic transformation and malignant conversion. Indeed, epidemiological studies suggest that chronic inflammation may be linked to 15–20% of cancer deaths worldwide (10, 11). This assumption is also confirmed by some case studies concerning CML in children – they were admitted to the hospital with leukemia shortly after recovering from Covid (12).

Moreover, Costa B.A. et al. (3) report three cases of leukemic process development in previously healthy young patients (aged 31-35), with correct blood analysis results, in which the clinical manifestation of leukemia appeared approximately 2-3 months after SARS-CoV-2 infection. Taking into account the rapid development of cytopenia after recovering from Covid-19, the authors suggest that SARS-Cov-2 infection plays a role in leukemogenesis, mainly by provoking the imbalance of the renin-angiotensin system (RAS). The virus interacts with the RAS by binding to angiotensin-converting enzyme 2 (ACE2), which is believed to be involved in tumor hematopoiesis (13) (14). ACE2 tightly binds SARS-CoV-2 receptor-binding domain (RBD) which allows the virus to penetrate cells of various tissues, including bone marrow (15). This causes downregulation of ACE2, which leads to excessive angiotensin-II concentration and resulting immune cell activation and lung injury (16) (17). Moreover, non-physiological levels of angiotensin-II can lead to a leukemic transformation of bone marrow hematopoietic cells. The role of the RAS system in tumor growth is also confirmed by other researchers (18, 19).

There are also other potential mechanisms of cancer development following SARS-CoV-2 infection In particular, Covid-19 has been associated with T-cell exhaustion and activation of oncogenic pathways, including JAK-STAT, MAPK, and NF-kB (20, 21). Moreover, in 2016 Ma-Lauer et al. reported, that the part of coronavirus nonstructural protein (Nsp3) increases CHY zinc-finger domain-containing 1 (RCHY1)-mediated p53 degradation associated with apoptosis (22).

In our case, it was after Covid-19 that the patient was diagnosed with chronic myeloid leukemia, two melanomas, and one skin cancer within one year. Therefore, the possibility of the influence of Covid-19 on carcinogenesis is very high and requires further research.

There are also some data indicating, that malignant melanoma itself could be associated with the SARS-CoV-2 virus (4). Following SARS-CoV-2 infection we often observe upregulation of proinflammatory molecules like S100 calcium-binding protein B (S100B), high-mobility group box-1 (HMGB1), osteopontin (OPN), tumor necrosis factor-alpha (TNF-α), and other cytokines that promote hyperinflammation. The same immunoregulatory proteins that contribute to the Covid-19 “cytokine storm” are also produced by melanoma cells and various other cancers promoting tumorigenesis (4). The authors suggest, that previous SARS-CoV-2 infection may provoke malignant tumor de novo development, its aggressive growth, or recurrence. Moreover, high concentrations of Covid-19-associated pro-inflammatory proteins like TNF-α, interleukin (IL)-1α, IL-1β, IL-6, and ferritin increase depigmentation or hypopigmentation of the skin by interfering with tyrosinase synthesis, which is an enzyme catalyzing the rate-limiting pigmentation step. All these molecular events can also cause flare-ups of chronic inflammatory skin diseases and appearance of adverse skin reactions (like for example urticaria, pernio-like reactions of the acral sites, herpes zoster, morbilliform rashes, diffuse hair loss) which can potentially lead to the development of different non-melanoma skin cancers (8). To sum up, the ability of SARS-CoV-2 to increase the expression of proinflammatory and oncogenic molecules may have a pro-carcinogenic effect and may contribute to the emergence or development of various types of cancers, especially in patients who suffered from severe form of Covid-19 (4).

It is also worth mentioning, that although the exact methods of Covid-19 treatment in case of our patient remain unknown, there are some concerns that Molnupiravir (antiviral drug) can potentially cause cancerous mutations or birth defects (23).

It is already known that CML is a myeloproliferative neoplasm, the mechanism of which is the clonal proliferation of tumor-altered polypotent stem cells of the bone marrow. Thus, some researchers claim, that blood cancers like CML may trigger or may be associated with the occurrence of other malignant neoplasias (24). The exact etiological factors of CML development remain unclear, but it is known, that as a result of translocation of the 9th and 22nd chromosome’s long arms, the Philadelphia chromosome (Ph) arises. Consequently, the BCR and ABL1 genes merge forming the chimeric BCR-ABL1 gene – its product (the bcr-abl protein) exhibits constant tyrosine kinase activity, which leads to increased proliferation of the bone marrow stem cells, inhibition of apoptosis and impaired adhesion of leukemic cells to the bone marrow stroma. As a consequence, the acceleration phase and blast crisis occur, which are characterized by the accumulation of cytogenetic aberrations, resistance to treatment and an unfavorable prognosis. That is why leukemia may increase the risk of other tumors development (7). However, authors indicate, that the higher incidence of secondary malignancies in CML patients can result from many additional factors like for example: genetic predispositions, exposure to risk factors (common for CML and other cancers), the CML treatment itself and the increased medical surveillance in first years after diagnosis (7).

As far as genetic predispositions are concerned, there are some studies highlighting the role of genetic pleiotropy in the pathogenesis of leukemia and non-melanoma skin cancer. It was showed, that a single pleiotropic locus (6p25.3) is responsible for the observed association between susceptibility to squamous cell carcinoma and increased chronic lymphocytic leukemia risk. Mentioned study also proves, that genetic susceptibility to chronic leukemia increases basal cell carcinoma risk (25).

In case of our patient, there can be some genetic predispositions to cancers, especially to CML. On the other hand, it is difficult to draw evident conclusions about the direct/indirect effect of existing CML on other tumors formation, due to the previous Covid-19 disease, which can directly provoke carcinogenesis or create favorable conditions for tumor appearance. However, there are some data about melanoma and non-melanoma skin cancers occurrence during the course of hairy cell leukemia (26), so the hypothesis of leukemia-associated cancers is highly probable and requires further investigation.

Interestingly, our patient was treated with tyrosine kinase inhibitor (TKI) Gleevec (Imatinib mesylate) for a long time. According to the data from Occupational Safety and Health Administration (OSHA) (27). Gleevec inhibits the BCR-ABL tyrosine kinase, which is a constitutive, abnormal tyrosine kinase coded by the gene located on the Philadelphia chromosome in CML patients. This medication is also used to treat other types of cancers (such as acute lymphoblastic leukemia, gastrointestinal stromal tumors, and myelodysplastic/myeloproliferative diseases). It inhibits proliferation and induces apoptosis of BCR-ABL positive cell lines as well as of fresh leukemic cells in case of Philadelphia chromosome-positive CML (27). Gleevec is also an inhibitor of tyrosine kinase receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), so it inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib decreases proliferation rate and induces apoptosis in GIST cells, which express c-Kit mutation.

Despite the positive effect of Gleevec continuous administration (it prolonged patient’s survival) there are some concerns regarding its possible impact on secondary malignancies development (28). A long-term observational, population stidy of CML patients showed, that risk of secondary malignancies was increased (29, 30). However, it was not increased in case-control studies of CML patients treated with TKI (31, 32). So far, it is impossible to select patients in the observed populations for the effect of specific CML treatment on the risk of secondary malignancies (6). Therefore, the question if secondary malignancies occur after long exposure to TKI remains unanswered.

The main limitation of our study is a short follow-up period (lack of information about long-term outcome) and limited data about severity of CML and antibiotics used during Covid-19 treatment. Our patient was one of the first hospitalized patients during pandemic, so there were no proven, permanent treatment protocols at that time.

In the future, it would be advisable to perform long-term follow-up studies on large cohorts of CML patients treated with TKIs. As large cancer registries often do not include complete data on treatment methods, it would be helpful to create a base of CML patients taking part in case-control studies.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

OBo: Conceptualization, Investigation, Project administration, Supervision, Writing – original draft. ER: Formal Analysis, Investigation, Writing – review & editing. RH: Data curation, Visualization, Writing – review & editing. CB: Data curation, Visualization, Writing – review & editing. OBe: Data curation, Investigation, Visualization, Writing – review & editing.