1. Introduction

Immunosuppressed patients represent a group of a heterogeneous population, including patients with primary and secondary or acquired immunodeficiency. The latter group includes patients who have undergone splenectomy, chemotherapy, and/or radiation therapy; patients taking immunosuppressive drugs including organ transplant recipients; patients with hematological disorders; and patients infected with human immunodeficiency virus (HIV). The immunosuppressed state may be further aggravated by diabetes mellitus, chronic kidney or liver disease, advanced age, malnutrition, etc. With advances in medical sciences, the life expectancy of these patients is increasing, so the side effects of chronic immunosuppression are more common.

Immune deficiency impairs the recognition and elimination of tumor cells and the defense against oncogenic viruses, thus increasing the risk of developing cancer [1]. The most common malignancies associated with impaired immune status are nonmelanoma skin cancers (NMSCs) [2], which can be numerous, fast growing, and aggressive. After surgical resection, local recurrence and/or distant dissemination occurs often, in about 40% of cases [3].

Surgical excision is the standard treatment for NMSC, but other local treatment modalities such as topical 5-fluorouracil, photodynamic therapy (PDT), cryotherapy, topical imiquimod, topical nonsteroidal anti-inflammatory drugs such as diclofenac and piroxicam, radiotherapy, and ECT can be chosen [4–6]. Systemic treatments include immunotherapy, molecularly targeted therapy, or chemotherapy.

The management of these tumors is essentially not different from that of nonimmunosuppressed patients and is dependent on the histological type, size, localization (high-risk sites), number of tumors, symptoms (pain, bleeding, and ulceration), previous treatments, patient history of NMSCs, general condition, comorbidities, and preference of the patient [7]. However, the treatment of multiple tumors is challenging for several reasons. The large number of tumors means that surgical treatment can only be performed in several sessions, imposing a great burden on patients. With regards to systemic immunotherapies, the response is inferior to that of the immunocompetent population and adverse events may represent major risks. In organ transplant recipients, immune-checkpoint inhibitors are associated with an increased risk of rejection [8]. Sonic hedgehog inhibitors, used in the treatment of multiple or advanced basal cell carcinoma (BCC), may cause dysgeusia and weight loss, which may be difficult to bear for this vulnerable patient population.

ECT is an effective and widely used treatment for skin and subcutaneous tumors. The procedure is based on a combination of electroporation and a chemotherapeutic agent. During electroporation, an electrical pulse is applied, which causes a temporary increase in the permeability of the cell membrane, allowing substances (e.g., chemotherapeutic agents) to pass through the cell membrane that previously could not or only slightly penetrate the cell. The molecules entering the cells become “trapped” intracellularly, since electroporation is reversible, so that once the electrical impulse is removed, the cell membrane is restored. The molecules exert their cytotoxic effects and cell death occurs [9].

Preclinical studies have demonstrated that ECT induces immunogenic cell death and that the levels of certain proinflammatory cytokines (IL-1β, IL-10, IL-6, TNF-α, and IFNγ) and markers specific for macrophages and natural killer (NK) cells are elevated after treatment [10]. Studies to date have shown that the treatment in immunocompetent mice is more effective and the tumor response is longer lasting compared to immunodeficient animals [11].

ECT has the advantage of being able to treat several tumors at the same time and offers a high objective tumor response, a favorable side effect profile, repeatability, and a favorable esthetic outcome.

The aim of our study was to evaluate the efficacy, toxicity, and impacts on the quality of life of ECT for NMSCs in immunosuppressed patients compared to nonimmunosuppressed patients.

2. Materials and Methods

Fourty-four patients were included in our analysis, who underwent ECT at the Department of Dermatology and Allergology in Szeged, Hungary, between 2016 and 2024. All patients gave written informed consent (ethical approval: ECT-REPRO-002, 9/2016-SZTE). The patients had a life expectancy of more than three months, had not received any other anticancer treatment for skin tumors for at least two weeks prior to ECT, and their Eastern Cooperative Oncology Group (ECOG) status was at least 1. Exclusion criteria were documented allergic reaction to bleomycin or if the patient had previously received bleomycin treatment at a dose greater than 400,000 IU/m². Furthermore, a history of moderate to severe neuropathy, abnormal coagulation parameters, clinically manifested cardiac arrhythmia, epilepsy, and pregnancy or lactation were among the exclusion criteria.

All patients had a histopathologically verified diagnosis of keratinocyte skin cancer. The study population consisted of two distinct groups: one comprising immunosuppressed patients and the other consisting of nonimmunosuppressed individuals.

ECT treatment was performed according to an international standardized protocol (European Standard Operating Procedures of ECT [ESOPE]) [12] using a CE-marked Cliniporator (IGEA Ltd, Modena/Carpi Italy) electric pulse generator. Due to the localization and/or the high number of malignancies, the procedure was performed under general anesthesia. Bleomycin was administered intravenously at a dose of 15,000 IU/m². Either row or hexagonal needle electrodes were used, with repositioning of the electrodes as necessary to deliver multiple pulses for larger lesions. Eight electric pulses were delivered over 100 ms at a frequency of 5000 Hz and an amplitude of 1000 V/cm (according to the electrode distance) between 8 and 28 min after bleomycin administration (at the pharmacokinetic peak of the drug concentration).

After treatment, patients were followed regularly (every 3 months) and prospective data collection was carried out. During visits, tumor response, side effects, and quality of life questionnaires were recorded, as well as photographic documentation and the appearance of novel tumors were also documented.

3. Results

Comparative data analysis was performed between immunosuppressed (n = 14) and nonimmunosuppressed (n = 30) patients.

The mean age of the immunosuppressed patients was 76 years (67–90 years), and 4 women and 10 men were included. Nine patients were diagnosed with a hematological disorder: 4 patients were treated with ruxolitinib (n = 3) and hydroxycarbamide (n = 1) for polycythemia vera, 1 patient received hydroxycarbamide for essential thrombocytosis (Figure 1), while 4 patients were immunosuppressed as a result of their underlying hematological conditions such as chronic lymphoid leukemia (CLL) (n = 3) or primary myelofibrosis (n = 1), without receiving specific immunosuppressive therapy. Two patients underwent renal transplantation; they were initially treated with calcineurin inhibitor (tacrolimus), which was switched to mTOR inhibitor (everolimus) due to the appearance of multiple NMSCs. One patient with Crohn’s disease was treated with azathioprine and one with rheumatoid arthritis was treated with low-dose methylprednisolone in addition to leflunomide, and the latter was also stopped due to the appearance of skin cancers. The duration of the immunosuppressive condition was not documented in 3 cases, and for the remaining patients, the mean time from diagnosis to ECT treatment was 11 years (0.5–27 years). In one patient, the duration of the immunosuppressive condition could not be precisely determined. In this case, primary myelofibrosis was diagnosed in our clinic 6 months prior to ECT treatment. The patient had a rapidly evolving, large verrucous carcinoma in the perineal region, which was previously surgically excised, but local recurrence and progression were observed, so we decided to perform ECT. Due to the absence of any preexisting conditions to account for the rapid growth, coupled with the presence of anemia, we sought a hematological consultation. This consultation prompted a bone marrow biopsy resulting in the diagnosis of primary myelofibrosis. The clinical data of the immunosuppressed patients are presented in Table 1.

The mean age of the control group was 72 years (31–89), and 24 male and 6 female patients were included. The patients were followed for a minimum of 6 months.

NMSCs located in the head and neck region and trunk and upper limbs, predominantly on skin surfaces exposed to light were treated. Treated lesions included actinic keratoses (AKs), BCCs, and squamous cell carcinomas (SCCs). None of the patients had known lymph node or internal organ metastasis at the time of treatment.

In the immunosuppressed group, a total of 156 tumors and 82 target lesions were treated. In the control group, we treated 183 tumors, with 157 target lesions. The average number of lesions treated per patient was 11 in the first group and 6 in the second group. The mean of the largest diameter of the tumors was 35.8 mm (12–160 mm) in the first group and 27.6 mm (9–105 mm) in the second group. Demographics, tumor characteristics, tumor response, toxicity, and quality of life results of the two groups are presented in Table 2.

3.2. Side Effects

We did not experience any systemic toxicity in our patients. Local side effects included odor, suppuration, hyperpigmentation, ulceration, and transient pain well controlled with analgesics. At 3 and 6 months after ECT, there was no significant difference in toxicity between the two groups (Fisher’s exact test, p > 0.05). Temporary crusts and hyperpigmentation of the treated area are shown in Figure 2.

4. Discussion

The risk of developing skin tumors is higher in immunosuppressed patients. Most data on this matter are available in patients who have undergone solid organ transplantation. These patients have the highest incidence of developing NMSCs. BCC is the most common NMSC in the general population. However, in organ transplant recipients, the most common one is SCC. In addition, precursor lesions of SCC are also common. AKs and field cancerization appear at a significantly younger age in transplant patients compared to the nonorgan transplant patient population [13]. In these patients, invasive skin tumors develop earlier at the site of an AK. In a cohort study conducted in 2021, 2852 transplanted patients were compared with the nontransplanted population, and the incidence of skin tumors in the first group was 9-fold higher [14]. In a study from 1999, they studied 2561 Norwegian patients who had undergone kidney and heart transplantation and found that the risk of SCC in this patient population was 65 times higher than in the general population [15]. A publication in 2020 compared disease-specific survival in patients with cutaneous SCC in the head and neck region in immunosuppressed and nonimmunosuppressed patients. The results of this study found a 2.32-fold higher risk of disease-specific mortality in the first group [16].

Based on data from the literature and our study, prevention, close collaboration of the involved medical professionals, and optimizing immunosuppressive treatment are of paramount importance in the care of immunosuppressed patients. ECT treatment may be an appropriate therapeutic modality for multiple cutaneous tumors in immunosuppressed patients.

5. Conclusions

In immunosuppressed patients, the incidence of NMSCs is higher and these tumors behave more aggressively compared to the tumors presenting in the general population. The prevention and proper treatment of these tumors are of paramount importance. ECT is a good choice for the treatment of skin tumors in immunosuppressed patients, as it can be used to treat many tumors effectively at the same time with few side effects. The treatment is well tolerated by this vulnerable patient population and can be repeated as needed, with favorable esthetic results. Further clinical studies are needed with a higher number of patients and also longer follow-up periods in order to evaluate the long-term efficacy of ECT in this special subgroup of patients.

Ethics Statement

This research was conducted in accordance with the Human Investigation Review Board, University of Szeged. All procedures involving human participants were approved by the Human Investigation Review Board, University of Szeged (ECT-REPRO-002, 29/02/2016). Informed consent was obtained from all individual participants included in the study. In addition, consent was obtained for the use of photographs depicting human subjects.

Conflicts of Interest

The authors declare no conflicts of interest.

Author Contributions

Conducting the clinical trial and practical application of electrochemotherapy: P.R., G.V., and E.K. Writing of the manuscript: P.R. Critical reading of the manuscript: E.K. and L.K. Supervision of questionnaire completion: P.R. Dermatological examination for control: P.R., C.H., and I.C. Oncological examination for control: H.Ó., E.B., J.O., R.G. Data analysis: P.R., E.S., B.T.P. All authors have read and approved the final version of the article.

Funding

This work was supported by the Univeristy of Szeged under the grant “Open Access Fund, Grant ID: 7370” for open access publication.