# Electrochemotherapy as adjuvant treatment in a sinonasal mucosal melanoma in elderly patient: a case report

Silvia Carpenè, Barbara Silvestri, Martina Bertinazzi, Enrico Armato, Maurizio Amadori, Roberto Spinato, Francesca de Terlizzi, Giuseppe Azzarello

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Silvia Carpenè, Barbara Silvestri, Martina Bertinazzi, Enrico Armato, Maurizio Amadori, et al. Electrochemotherapy as adjuvant treatment in a sinonasal mucosal melanoma in elderly patient: a case report. European Archives of Oto-Rhino-Laryngology, 2024, 281, pp.3853 - 3858. 10.1007/s00405-024-08606-z. http://hal-05212806

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# Electrochemotherapy as adjuvant treatment in a sinonasal mucosal melanoma in elderly patient: a case report

Silvia Carpenè<fnref n="1" /> · Barbara Silvestri<fnref n="2" /> ID · Martina Bertinazzi<fnref n="1" /> · Enrico Armato<fnref n="1" /> · Maurizio Amadori<fnref n="1" /> · Roberto Spinato<fnref n="3" /> · Francesca de Terlizzi<fnref n="4" /> · Giuseppe Azzarello<fnref n="2" />

Received: 20 October 2023 / Accepted: 29 February 2024

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024

## Abstract

**Background** Sinonasal Mucosal Melanoma (SNMM) is a rare but aggressive disease. Surgery with free margins, when feasible, is the treatment of choice. In the last three decades, electrochemotherapy (ECT) has emerged as a local ablative procedure, performed with the Cliniporator, for cutaneous and mucosal tumours of different histology. We present a case report of an ECT treatment performed by means of a new endoscopic electrode, on an elderly patient affected by primary SNMM.

**Methods** An 88-year-old man with a diagnosis of SNMM (cT4aN0M0)—Stage IV, of the left nasal fossa presented at our institution. Symptoms were epistaxis and complete left nasal obstruction. He refused sinonasal extended surgery and radiotherapy. He underwent a tumor debulking followed by ECT exclusively for symptom control, with palliative intent.

**Results** The patient underwent SNMM debulking under general anaesthesia, followed by ECT on tumour margins. After the procedure, he had been free from symptoms for 5 months, with a good quality of life. Local recurrence was controlled with a new local debulking and ECT procedure on margins. The patient remained symptom free for the next 4 months. Seventeen months after diagnosis, the patient is mild symptomatic for sinonasal disease. Therefore, he developed a systemic disease progression.

**Conclusions** In our experience, ECT can be used as an adjuvant tool for symptom and local control in SNMM when extended surgery is out of curative intent or unfeasible. As expected, ECT does not appear to have any effect on systemic disease progression.

**Keywords** Mucosal melanoma · Electrochemotherapy · Stinger

## Introduction

Mucosal melanoma (MMU) is a rare disease, with an annual incidence rate of 1.5 per million [1]. It represents 1.3% of all melanomas and it may develop in any mucosal membrane.

Conjunctival melanomas (0.5 per million/year) and melanomas in the sinonasal cavity (0.5 per million/year) are the most common, followed by anorectal melanomas (0.4 per million/year) melanomas in the oral cavity (0.2 per million/year) and in gynaecological region [1].

It is one of the most aggressive subtypes, and thus exhibits a worse prognosis compared with the common cutaneous melanoma [2]. Due to the site of onset, MMU is typically detected at advanced stages and the prognosis is poor. Based on a retrospective study, the 5-year survival rate of MMU, considering all stages at the time of diagnosis, is 10–25% when compared to 93% for cutaneous melanoma [3, 4].

Although several forms of mucosal melanocytic benign lesions are reported, there is still a lack of defined MMU precursor lesions, leading to a weak understanding of the evolutionary trajectory of MMU despite molecular profiles unveiled by recent whole-genome sequencing data [5]. In contrast to cutaneous melanoma, MMU has more diverse

<footnote>Barbara Silvestri
barbara.silvestri@aulss3.veneto.it</footnote>

<footnote n="1">¹ Otolaryngology Unit, Azienda Unità Sanitaria Locale Socio Sanitaria (AULSS) 3 Serenissima - Ospedale di Mirano, Venice, Italy</footnote>

<footnote n="2">² Oncology and Haematology Unit, Azienda Unità Sanitaria Locale Socio Sanitaria (AULSS) 3 Serenissima - Ospedale di Mirano, Venice, Italy</footnote>

<footnote n="3">³ Otolaryngology Unit, Azienda Unità Sanitaria Locale Socio Sanitaria (AULSS) 3 Serenissima - Ospedale di Mestre, Venice, Italy</footnote>

<footnote n="4">⁴ IGEA Biophysics Lab. Carpi, Modena, Italy</footnote>
mutation patterns, with about 14% cKIT mutation [6], less
than only 5% of BRAFV600E mutations, other mutations
are rare [7, 8].

There is no common staging system for all types of
mucosal melanomas, only for those of the head and neck
region we refer to the specific AJCC 8th ed [1, 4].

Surgical excision is the treatment of choice for MMU [9, 10]. However, due to the lentiginous growth pattern, multifocal nature, and limitations of the specific MMU anatomic sites, it is extremely difficult for surgery to achieve wide negative margins, which leads to a high local relapse rate at 50-90% [11].

The role of radiotherapy (RT) in MMU is discussed but it has not been evaluated in prospective trials. Postoperative radiation to the primary site is typically indicated to improve local disease control but it doesn't affect the overall survival [12]. In addition, consideration should be given to the toxic effects of radiotherapy treatment in primary lesion sites adjacent to critical radiosensitive tissues such as the cranial nerves, brainstem, and brain, as occurs in lesions of the nasal fossa. [1, 12, 13].

For unresectable and metastatic MMU, targeted therapy and immunotherapy are constrained since MMU is deficient in dominant MAPK activating mutations that can be targeted and is less responsive to immunotherapy [14]. Furthermore, due to the side effects associated to this treatment, it has limited use in elderly patients with comorbidities. Therefore, to date, the first-line therapeutic modality for advanced MMU remains chemotherapy despite limited efficacy.

Electrochemotherapy (ECT) is a local tumour treatment that uses electroporation to temporarily permeabilize the cell membrane whereby a chemotherapeutic agent, such as bleomycin, can penetrate into the cell [15] and cause DNA breakage, which results in apoptosis [16]. The treatment can be single or repeated in different sites or on the same site to consolidate the treatment, and has a favourable cost/ benefit ratio [17]. It can be offered to patients who have previously been operated, irradiated, or have comorbidities precluding conventional chemotherapy. Being ECT a local treatment, it is usually administered with palliative intent, in order to control tumour growth and symptoms. ECT has been already used in MMU in several studies [18–21], but this is the first experience reported on the use of a new electrode, the stinger electrode, for the treatment of a sinonasal mucosal lesion.

Case report

A 88-year-old male presented at our institution in July 2021, with a bleeding lesion in the left nasal cavity. He was then submitted to bio-excision of the lesion under local

anaesthesia and subsequent staging with CT Total Body with
contrast medium and massive facial MRI (Fig. 1).

Histopathologic diagnosis was sinonasal mucosal melanoma (SMMU), wild type (BRAF WT, cKIT, NRAS non mutated), (stage cT4aN0M0). The patient refused the proposed surgical treatment.

Approximately 3 months later, the patient was re-eval-
uated due to progressive worsening of his general condi-
tions and resumption of epistaxis with anaemia and weight
loss. Endoscopic examination showed a rapid increase in
the size of the primary lesion with total extension in the
nasopharynx and partial occupation of the oropharynx, such
as to completely prevent breathing from the nasal cavities
and make feeding extremely difficult. In October 2021, the
patient was completely restaged by CT and MRI (confirmed
stage cT4aN0m0) and the clinical case was re-discussed by
our multidisciplinary board. Patients refused surgery and
radiotherapy treatment again. In light of the local extension
of the disease, a palliative surgery with the debulking of
the lesion and ECT of the margins with palliative intent,
for symptoms control, was proposed. The patient signed the
informed consent to the treatment. Approval from ethics
committee, and data protection authority was sought by the
Mirano Hospital Institution.

The ECT treatment was performed in accordance with
the European Standard Operating Procedures (ESOPE)
guidelines [22, 23], under continuous intravenous sedation
with Propofol and Esmeron. ECT was performed 8 min after
the end of slow bleomycin intravenous infusion (bleomy-
cin 15,000 IU/m2 of body surface area diluted in 100 cc
of physiologic solution in 10 min) with the application of
the new expandable stinger electrode. The electrode used
(Stinger E_L2_00_S4) has been developed by IGEA and is

<figure><img src="image_2.png" /><figcaption>Fig. 1 Facial MRI at first diagnosis, July 2021</figcaption></figure>

<figure><img src="image_3.png" /></figure>
dedicated to laparoscope/endoscope/laryngoscope approach, being equipped with a long connector cable (20 cm) and 4 expandable needles positioned at a fixed distance of 0.4 cm in a square geometry. When extruded from the holder, the needles are divergent with an angle of 10° with respect to the axis of the geometry. Total needles length is 4 cm, with an active part at the 2 cm extremity (Fig. 2).

The electrode was introduced, with the needles positioned inside the holder, into the nasal cavity in the proximity of the site of the lesion. Then the needles have been extruded and penetrated in the tissue, and they were charged to deliver the electric pulses to perform electroporation of the margins of the debulked lesion (Fig. 3). Nineteen applications of the electric pulses were performed with repositioning of the electrode, in order to completely cover the margins. The duration of the procedure was 60 min. The hospitalization time was 1 day. The procedure was well tolerated, without side effects. The site was medicated with Gentalyn and nasal washes with saline solution, an antibiotic prophylaxis with Cefazolin 2 gr was implemented.

After the procedure, the patient had been free from disease and symptoms for other 5 months, with a good quality of life. Tumour local recurrence was controlled with a new local debulking of the lesion and ECT procedure on margins. The ECT procedure was performed in March 2022 in a similar method applied during the first session. The procedure lasted about 1 h, 33 applications were performed with repositioning of the electrode (lesion with several implant bases: two at the level of the inferior turbinate residue and another at the level of the left nasal vestibule with extension to the most anterior portion of the septum) The patient had remained disease and symptom free for the next 4 months. Seventeen months after diagnosis, in December 2022, the patient is mild symptomatic for sinonasal disease. Therefore, he developed a systemic disease progression with liver and lung metastasis (stage pT4bNxM1c).

Discussion

Our old patient is still alive after 2 treatments of partial surgical resection and ECT of primary tumour and a recurrence occurred after 5 months from the first treatment. The patient is overall alive after 17 months from diagnosis, with systemic disease but with a good quality of life and ECOG 2. The new stinger electrode used was applied without complications and side effects. This is the first reported application in a sinonasal mucosal melanoma, but the electrode has already been applied in our centre in 2 patients with primary colorectal carcinoma within a multicentre protocol [24], without complications, side effects, and with good response. The patients were at risk of sphincteric functionality if treated with other more invasive therapies (surgery, radiotherapy): with the ECT approach they could avoid loss of this functionality and alleviate their symptoms. A similar approach was reported by Schipilliti et al. [25], where an endoscopic ECT application of stinger electrode was used in the treatment of obstructing rectal cancer without prospective surgery. A good response after ECT was described: concentric involvement of the rectum was reduced, and no stenosing lesions were detected.

Among possible alternative treatments, we could not offer him immunotherapy (neither single agent nor a combination) because of advanced age and comorbidities. We could not consider postoperative radiotherapy because the patients refuse it and furthermore, because he was not compliant to complete all cycle of radiotherapy. A positive collateral effect of ECT was the complete remission of epistaxis immediately after treatment: this is due to the vascular lock effect of electrochemotherapy well described by Markelc and Jarm [26, 27]. After a first rapid and short-lived vasoconstriction phase due to the short high intensity electric pulses, a second much longer-lived phase resulting

<figure><img src="image_4.png" /><figcaption>Fig. 2 Stinger electrode</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Fig. 3** Images of the treatment, collected during the first ECT procedure</figcaption></figure>

from disrupted cytoskeletal structures and a compromised
barrier function of the microvascular endothelium takes
place. However, tumour vascular endothelial cells are
also affected by the chemotherapeutic drug, which leads
to irrecoverable damage to tumour vessels and to a further
decrease in tumour blood flow within hours after applica-
tion of ECT. In fact, the antivascular effects of ECT were
also exploited for palliative treatment of bleeding mela-
noma metastases, with immediate cessation of bleeding
and very good antitumor effectiveness. This characteristic
of ECT seems to be of great interest even in the treatment
of vascular malformations [28].

Coming back to our specific case, even if real world
data cannot be compared with clinical trials data, we can
observe that the therapeutic option pursued gave satisfying
results, characterized by a good tolerability and safety, with

a prolonged overall survival of 17 months, not easily reach-
able by immunotherapy or radiotherapy alone.

In fact, a retrospective pooled analysis of patients
with advanced melanoma treated with nivolumab or
nivolumab+ipilimumab in clinical trials was published for a
total of 889 patients, including 121 with mucosal melanoma.
This analysis demonstrated a response rate of 23.3% for sin-
gle agent nivolumab and 37.1% for the nivolumab + ipili-
mumab combination. Median 5-year PFS was 3.0 months
for nivolumab and 5.9 months for nivolumab + ipilimumab,
while OS was 36% in the combination arm, and 17% in the
single agent [14].

Some studies on the treatment of cutaneous melanoma
(non-MMU) with ECT + Immunotherapy, have reported
interesting data on OS and PFS [29, 30]. The results suggest
that skin-directed therapy with ECT improves superficial

<figure><img src="image_6.png" /></figure>
tumor control in melanoma patients treated with pembrolizumab and prolongs PFS and OS with respect to pembrolizumab alone [31].

## Conclusion

In our experience, ECT can be used as an adjuvant tool for symptoms and local control in SNMM when extended surgery is out of curative intent or unfeasible [32].

**Acknowledgements** We would like to thank all nurses, operating room and oncology staff of the Azienda Unità Locale Socio-Sanitaria (AULSS 3) Serenissima, Mirano Hospital, Venice, Italy.

**Author contributions** Patient's treatment and data collection: SC and BS. Discussion of the case report: SC, BS, MB, EA, MA, RS, GA. Data reporting and manuscript preparation: SC, BS, FdT. Manuscript revision: SC, BS, MB, EA, MA, RS, GA.

**Data availability** The data of the study are available upon request.

**Declarations** The authors did not receive support from any organization for the submitted work. Francesca de Terlizzi is an IGEA employer.

**Conflict of interest** The only conflict of interest can be ascribed to the fact that the author FdT is an IGEA employer.

**Ethical statement** All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The participant has consented to the submission of the case report to the journal.

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