The Challenges of Melanoma during COVID-19 Pandemic

Diagnosis, tratament and follow-up of patients with melanoma during COVID-19 pandemic is quite challenging. These patients are often immunocompromised, but, on the other hand, management of this malignant skin cancer should not be delayed. It is necessary to diagnose and stage the melanoma as soon as possible, in an attempt to provide a better prognosis. There are few data regarding the treatament of melanoma during COVID-19 pandemia. However, the general recommandations suggest testing all cancer patients prior administration of the therapy. The European Society for Medical Oncology (ESMO) provided guidelines regarding therapy of this skin cancer during COVID-19 pandemic. Every patient is different, and it is always important to evaluate the risks and benefi ts.

excisional biopsy 10 . Th e safety margin, of initial biopsy, is 1-3 mm, around the lesion, and a cuff of subcutaneous fat deep of the tumor 11,12 . Also, an incisional, partial biopsy may be performed instead of complete biopsy. Th is last method should be avoided as it may inaccurately stage the melanoma, or even negatively aff ect treatment planning 13 .
Althought an excisional biopsy was performed, we should complete removal of the lesion, with a wider and deeper excision, as soon as we get the initial histopathological report of the biopsy. In this case, the histopathological examination is also essential as it must confi rm clear margins. Th e most commonly, a margin of 0.5 cm is adequate: rare, these patients experience recurrence. So, in this situation, we have another exemple why we cannot delay the complete removal of melanoma 13 .
When it comes to these patients, an important aspect should also reff er to the right time to perform sentinel lymph node biopsy. When recommanded, it is necessary to be performed before wide excision of the primary melanoma, or in the same operative setting. Th e purpose is to minimize disruption of the lymphatic channels and optimize the accuracy of lymphatic mapping, as well as identifi cation of the correct sentinel lymph nodule. Th us, this intervention can be delayed, as there is no evidence that infl uences survival 14,15 .
Any of the patients mentioned before should be tested for COVID-19 if they develop fever, or lower respiratory symptoms, such as dyspnea, hypoxia or cough. However, patients with melanoma should also be tested for other causes of respiratory symptoms: infl uenza, bacterial pneumonia or others disorders that may mimic symptoms of COVID-19 16 .
Adjuvant therapies are indicated to improve survival: targeted therapies or immunotherapy 17,18 .
Some authors suggest that 70% of patients with melanoma suff er from mutations in genes of key signaling pathways. It seems that mutations produce cell proliferation and malignant phenotype 19 . In fact, these therapies (small molecule inhibitors or antibodies) are directed against mutated proteins 20 . Because, often, in case of melanoma we challange with mechanisms of resistance to therapy, a synergy between strategies (immunotherapy, targeted therapy, chemotherapy) which target multiple pathways, would be the correct ma-

INTRODUCTION
In December 2019, several cases of pneumonia of unknown origin were diagnosed in Wuhan, China. Shortly, the scientists discovered a new type of coronavirus. Th ey named it severe acute respiratory syndrome-coronavirus 2, or SARS-CoV-2 1 .
On March 2020, the WHO (World Health Organisation) declared COVID-19 infection pandemic, and indicated three priorities for all countries: protection of people at highest risk of severe disease, as patients with comorbidities (for exemple, cancers), protection of health workers, and supporting all the vulnerable countries in containing infection 2 .
Pandemia with this new coronavirus has a defi ng impact on medical care. Regarding patients with dermatological conditions, one of the most aff ected group of patients by this pandemic, are the ones with melanoma, because they are immunocompromised hosts, and are more likely to develop severe forms of infection 3 . On the other hand, melanoma is a serios skin cancer, whose diagnosis and treatment cannot be postponed 4 .

MANAGEMENT OF MELANOMA AND COVID-19
Melanoma is an aggresive form of skin cancer, with a high mortality 5 . It seems that melanoma is caused by the several genetic in mutations (located in the skin, eye, inner ear and leptomeninges) 6 .
As for the epidemiology of melanoma, it aff ects most frequently caucasians patients, equally males and females. It is important to diagnose this skin cancer early. Metastatis melanoma has often a poor prognosis. Th is is the reason why staging of melanoma is so important 7 .
Today, the diagnosis of melanoma is based on the staging manual of the American Joint Committee on Cancer, implemented in 2018. Multiple changes have been made to the previous guide: minimal changes in measurements of tumor thickness, removal of mitotic activity, expansion of the regional lymph node (N) categories based on number of positive regional lymph nodes, expansion of metastasis (M) categories based on location of metastasis, and expanded stage groupings in stage III disease to better stratify long term prognosis 8. Further more, staging corectly the melanoma, provides the best therapy for the patient 9 .
As mentioned previously, it is vital for the patient with melanoma to perform a skin biospy with histopathological examination, even during pandemia with COVID-19. Diagnosis of this tumor is established by As for high or medium priority, should be mentioned: patients with invasive primary melanoma T1b/ higher should benefi t from wide excison and sentinel lymph (but, as specifi ed previously, this can be delayed); we should perform wide excision for T1a or lower; As well as resection of oligo-metastatic disease 25 .
ESMO experts consider at high priority, patients who receive adjuvant systemic therapies for stage III melanoma: they should continue therapy if they are part of a clinical trial, providing patient benefi ts outweigh risks. High or medium priority is represented by patients who follow adjuvant targeted or immunotherapies, with stage III melanoma 25 .
Other recommandations of ESMO reff er to adevanced melanoma, non-operable stage III or IV. For these patients, systemic therapies should be administrated as follows: immunotherapies or targeted therapies for non-operable stage III/IV; patients who are part of a clinical trial should continue the treatment, or course, providing the patient benefi ts outweigh risks 25 .
Experts also defi ne priorities for radiotherapy for non-operable stage III/IV melanoma. With high priority, are patients with brain metastases, who have indication for stereotactic radiosurgery, threatening lesion or acute spinal cord compression. As for symptomatic metastases, irradiation is considered a high/medium priority. Low priority includes: adjuvant radiotherapy post radical lymphadenectomy and irradiation of asymptomatic, not threatening metastases 25 .

CONCLUSION
In conclusion, management of melanoma during CO-VID-19 pandemic is challanging. In most cases, therapy should not be delayed, as progression of the tumor is associated with worse prognosis. However, every case should be disscused separetely, and the best decisions should be taken, always balancing the risks with the benefi ts.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study.
During pandemia, the question we should ask is if is indicated to test these patients, tratted with immunosuppressive agents. Some authors support the idea that all cancer patients should routinely be tested, 48 to 72 hours prior to administration of the therapy, even if they are asymptomatic or have no knowledge of exposure to COVID-19 22 .
Unfortunately, there are few data regarding treatment of melanoma in case of COVID-19 positive patients. Some guidelines recommand not to discontinue undergoing therapy. However, there is no evidence on how to manage an asymptomatic patient, or a symptomatic one who follows immunotherapy or target therapy 23 .

ESMO GUIDELINES
Informations provided by Th e European Society for Medical Oncology (ESMO) indicate, for patients who follow chemotherapy, radiotherapy or immunotherapy, to be swabbed for COVID-19, before every treatment session. Furthermore, initiation or continuation of therapy should be discussed for each patient separately, whether it is positive, paucisymptomatic or asymptomatic 24 .
To synthesize, we will highlight the most important aspects related to melanoma management during the COVID-19 pandemic, specifi ed by ESMO. Th us, our high priority patients would be the ones new diagnosed with invasive primary melanoma, except the skin cancer is incipient (Tis or T1a, and we already performed a wide excision). Also at high risk are post-operative patients, who develop complications. ESMO defi nes high/medium priority, the patients who accuse new symptoms from treatment, and recommands us trying to manage them by telemedicine, if possible. In case of melanoma survivors, or patients who should have there follow-up only, because they do not have active treatment, maybe the telemedicine would also be a good idea. Th ese patients, together with the ones with dysplastic nevi, represent a low priority 25 .
When it comes to surgery in primary melanoma, there are 3 categories at high priority: curative resection for stage III, surgical management of complications or patients in neoadjuvant studies who had previously planned surgery 25 .