The outbreak of the novel Coronavirus disease 2019 , consisting in a severe acute respiratory syndrome often associated to multiple organ dysfunction, has rapidly spread globally, being declared a pandemic by the World Health Organization (WHO) on 11 March (Coronavirus disease 2019).
The risk to develop a severe illness by COVID-19 increases by age, comorbidities, and presence of underling medical conditions influencing immune system. Based on early statistical data, the case-fatality rate (CFR) in the patients over 60 years old is much higher than overall rate: 14.8% in patients over 80 years, 8.0% in patients aged 70-79 years, and 3.6% in patients aged 60-69 years (Ramella et al. 2020) . The proportion of deaths over 60 years old accounts for 81% of the total deaths in the national wide, which implicates aged people are more vulnerable to the SARS-CoV-2 (Verity et al. 2020) . Moreover, the overall fatality rate is 3.8% for patients with cancer, as a comorbid condition was 7.6% (Zhang et al. 2020; Huang et al. 2020; Aggarwal et al. 2020) . In general, cancer patients must be considered more exposed and frail, because of their immunologic state, directly due to the cancer and the need for immunosuppressive anti-cancer treatments.
In particular, patients with cancer recently undergone chemotherapy and surgery seems to have more risk of COVID-19, with more severe clinical events and rapid evolution; therefore, they need to be more intensively followed (Liang et al. 2020) . Some limited data on immunosuppressed cancer patients indicated a 3.5 times higher risk of needing mechanical ventilation compared with patients without cancer (Zhang et al. 2020) .
Therefore, a correct management of the risk related to the circulation of SARS-CoV-2 involves many specific implications in the particular context of the geriatric oncology.
A relevant geriatric branch of gynecological oncology concerns women suffering from vulvar carcinoma, more critical because typically older and frail due to comorbidities and physical performance often aging related. Moreover, the high aggressiveness of this cancer turns every choice risky, when proceeding with treatment delivery or deciding to postpone/omit them, according to the priorities (Ramirez et al. 2020) .
Gemelli University Hospital is one of the larger COVID-19 referral centre in Italy and, at the same time, one of the larger Italian Oncological Centers. In our institution, a vulvar cancer multidisciplinary team (Vul.Can MDT) is responsible for personalized treatment strategies and management. It is structured in a core team, supplemented by a group of support specialists. The core team includes two dedicated members (one senior and one young) for seven central specialties: gynecologic oncologist, plastic surgeon, radiation oncologist, medical oncologist, radiologist, nuclear medicine physician, and pathologist. The group of support specialists includes one dedicated member for each complementary specialty: geriatric oncologist, infectivologist, general surgeon, urologist, nutritionist, pain therapy anesthesiologist, psychooncologist, physiatrist, and physiotherapist. Moreover, a midwife is dedicated to the case management and a nurse provides advanced wound care. A total number of about 260 cases are annually discussed within the multidisciplinary tumor board (MDTB): about 120 are addressed to surgical procedures, among which about 30 combined with plastic surgery, 50 to radiotherapy evaluation, 15 to chemotherapy, and 10 to electrochemotherapy (ECT).
Since COVID-19 is expected to remain a primary focus of the medical leadership for a very long time, in the full absence of vulvar cancer-specific guidelines oriented to the pandemic context, we are trying to respond to the urgent need to address the possible changes of resource allocation, clinical care, and treatment delivery for vulvar cancer patients.
The aim of this paper is to focus a proposal of a personalized workflow for vulvar cancer patients and to define the specific measures that can be adopted to reduce the ongoing risk of infection during treatments.
All the contents have to be considered as an expert opinion guidance, to be considered during the extraordinary period of the pandemic emergency and do not overcome the current available international guidelines, the national and regional recommendation as well as the clinical decision obtained after interdisciplinary discussion.
The project was designed and approved in the frame of Vul. Can MDT and three steps process were defined.
In the first step, a specific Interdisciplinary Task Group, coordinated by one gynecologist (SMF) and one radiation oncologist (VL), defined preliminary postulates and guiding principles of vulvar cancer patient workflow. In the second step, the proposal was subjected to the evaluation of the Senior Members of the Vul.Can MDT and in addition, considering the issues of the project, to the infectivologist and the geriatric oncologist (GG-gynecologist, LT-radiation oncologist, SG-plastic surgeon, GCol-geriatric oncologist, GCor-medical oncologist, ET-infectivologist) who also defined management protocols, stratified for disease prognostic categories and COVID-19 status. In the third step, final evaluation was supplied by a Master Team (GS, AF, MAG, and GM) for validation.
Postulates were considered as the basic elements for the construction of renewed clinical/management pathways. Definitions were considered the way to classify elements and recognize priorities to propose targeted treatments for each category of patients (Table 1) .
The team produced two types of recommendations: one concerning safety regulations for patient flow management and hospital environments; in particular, these have been declined in Table 2 , according to three categories of relevance, referring to care pathways, patients, and health care providers. The second section about personalized treatment protocols in the COVID-19 era.
Since the outbreak of the pandemic, we have managed an outpatient flow of 80 patients with about 40 surgical procedures. We only recorded one case of SARS-CoV-2 infection in a patient's family member. No patient showed signs of infection due to the strict protocols of social distancing and isolation initiated even before the lockdown for the frail patients such as those typically affected by vulvar cancer.
Several clinical conditions have been distinguished and analyzed below, taking into account in vulvar cancer patients the frailty condition, the COVID-19 status, the stage of disease and the available treatments including surgery, radiotherapy, chemotherapy, and electrochemotherapy. The risk-benefit ratio and morbidity of these approaches were afforded in the MDTB meetings that are a requirement of utmost importance for any personalized strategy.
No clear guidelines exist regarding this group of patients, however, in case of acute symptomatic syndrome, the care of the COVID-19 should be reasonably considered a priority compared to anti-cancer treatments. Therefore, in patients who are candidates for diagnostics, surgical or medical treatments, it should be advisable to postpone these procedures after the complete recovery from COVID-19. Concerning palliative treatments they should be performed only when acute, severe, and extremely urgent and should be faced with the least invasive treatment: for example, in case of acute and irreversible bleeding from a bulky proliferative lesion, hemostatic radiotherapy or embolization could be provided, paying attention to carefully trace and secure the hospital staff and pathways used for the urgency. The clinical pathways for the management of women with vulva cancer who are infected with Sars-CoV-2 are shown in Fig. 1 .
Given the high risk of an unfavorable outcome from COVID-19, even treatments of asymptomatic or pauci-symptomatic cases, should be jointly discussed in the MDTB, strongly considering to postpone vulvar cancer cure after negative laboratory test are gained. Time interval for lab test repeat should be defined on the base of infectivologist's opinion, usually 2 weeks from the first diagnosis. In case of negativization of laboratory tests, oncological care could safely continue; in case of persistence with no symptoms, the MDTB should decide whether to proceed with the treatments limited to cases deemed urgent (e.g. aggressive disease, severe cancer-related symptoms). However, in these cases, the least invasive treatments should be carefully chosen, considering consequences related to treatment delivery or delay. Moreover, any chosen treatment should be carried out in COVID-19 dedicated pathway.
Non-COVID patients may become positive for SARS-Cov-2 during administration of prolonged anti-cancer treatments, such as radiation therapy and chemotherapy. Continuous surveillance, repeating lab tests periodically (usually every 10-15 days), can favor early diagnosis of viral infection and prompt introduction to COVID-19 dedicated pathways, when disease is still pre-or pauci-symptomatic.
The possible decision to complete, discontinue or postpone the ongoing anti-cancer treatments requires a focused discussion in the MDTB, carefully considering risk-benefit balance, based on many contextual parameters, such as frailty, presence of COVID-19 symptoms, cancer aggressiveness and time to complete the ongoing therapies.
In case of discontinuation, treatments could potentially be resumed after recovery, whenever it is still possible and beneficial. Usually two consecutive negative laboratory tests (collected > 24 h apart), and a waiting time of at least 3-7 days from symptoms resolution and imaging restoration could be considered as adequate (Istituto Superiore della Sanità 2020).
In any case, we suggest to share as clearly as possible the benefits, risks, and final decisions with patient and possibly caregivers.
To minimize the exposure of patients to hospital-related risks, diagnostic procedures and patients' access should be limited at most.
The work-up should follow a fast track protocol, included at the first access:
-Integrated evaluation of the patient's general conditions with the assessment of the potential frailty -Gynecologic exam and biopsy of the vulvar lesion, if required -Pelvic and inguinal lymph node ultrasound, with needle-aspiration/biopsy if required Frailty syndrome may be defined as a state of increased vulnerability resulting from the aging-associated decline in reserve and function, across multiple physiologic systems that carry an increased risk for poor health-related outcomes including mortality (Fried et al. 2001; Rockwood and Mitnitski 2007; Colloca et al. 2018) . Starting from this definition, it is highlighted how it is important to define whether an oncological patient is frail or not to avoid both over and under-treatment and for a personalization of treatments (Fried et al. 2001) following the main international guidelines on cancer patients, we have distinguished the patients in "Fit" and "Frail" In this distinction, we have also considered the factors that lead to greater death rate and have adverse effects COVID-19 related. Moreover, we considered those who are older than 60 years of age to be elderly, since from this age onwards the greatest death rate and the greatest number of respiratory complications were highlighted. The number of comorbidities, physical and cognitive performances COVID-19 status definition The following patients' categories are defined according to reported symptoms, imaging and lab tests results (nasopharyngeal swab/antibody tests): Negative for COVID-19 (non-COVID): negative lab tests* (w/wo negative imaging and absence of specific symptoms) Positive for COVID-19 (COVID): positive lab tests* and/or pathognomonic radiological imaging (w/wo specific symptoms) Switching patient: a non-COVID patient who switch to positive during the course of treatment. Due to patients' high risk of conversion during anti-cancer treatments, especially if extended over time-a strict surveillance is needed, providing a programmed longitudinal repetition of the triage questionnaire and lab tests *Currently, the more widely recommended reference lab test is the nasopharyngeal swab, while many serologic tests are still under investigation; however, further rapid diagnostic tests could be available in the future (Ginocchio and McAdam 2011) Prognostic disease categories The following categories are defined according to the revised FIGO staging system of 2009 (Pecorelli 2009) Early stage: stage I (small volume, node negative patients) Locally advanced stages: stage II (diffusion to structures and organs bordering the vulva), stage III (groin lymph nodal involvement) Extra-regional advanced stages: stage IVa/b (diffusion to pelvic organs and/or lymph node) Metastatic disease: Stage IVb (distant organs metastasis) Treatment intention Type of planned treatment according to standard/international and institutional guidelines, stratified by intent Surgery
Radical-provided both in upfront setting to obtain complete free margin excision of the disease on primary tumor site and regional lymph nodes Debulking-surgical resection on residual disease after exclusive RT-CT; it is performed when complete response is not achieved to secure treatment effectiveness, mainly if minimal surgical effort is expected Palliative-focused on supplying the greatest benefit using the least invasive intervention, relieving local disease-related symptoms (pain, bleeding, poor quality of life) in patients with systemic spread, unresectable disease, or high operative risk Radiotherapy (± Chemotherapy) Adjuvant-given in addition to the primary surgery to maximize its local effectiveness in case of risk factors Neoadjuvant-given before surgery to reduce the demolitive approach in extended disease or to render operable an unresectable disease Exclusive (radical)-is given alone with radical intent on primary or recurrent disease Palliative/temporary control-hypofractionated radiotherapy delivered to achieve a relief of local disease-related symptoms (pain, bleeding) or a delay of disease progression, even in the absence of symptoms Chemotherapy
Neoadjuvant-before surgery to reduce tumor burden, to shrink surgical effort or to make the disease operable (mainly if radio-chemotherapy is not applicable) Adjuvant-after radical surgery, as additional treatment only in rare cases with advanced stages of particular histotypes (i.e. invasive Paget's disease) Palliative-aimed to favor relief from tumor-related symptoms and improve quality of life, even if a major survival advantage is not expected, provided a palliation/toxicity trade off Radiosensitizing-associated with radiotherapy, as systemic intravenous administration that provides a cooperative effect to improve local disease control and mitigate radiation related side effects. On the basis of this fast track protocol, the gynecologist should preliminarily assess the clinical stage and follow these advices:
Clinical early stage: if lymph nodes are negative at ultrasound assessment, given the accuracy of the ultrasound exam when performed by skilled examiner, considering the low risk for distant metastasis, we could suggest to omit additional imaging to complete systemic staging (Frumovitz et al. 2008; Gradishar et al. 2020) .
Clinical advanced stage: if groin or pelvic lymph nodes show metastatic involvement at ultrasound or if infiltration of cutaneous bridges, urethra, anus, or vagina are evident or suspicious, considering the higher risk for distant metastases, a whole-body assessment should be performed by conventional radiologic imaging (CT, plus or minus pelvic MRI) or metabolic imaging (by 18F FDG-PET/CT) (Salani et al. 2017; Kataoka et al. 2010; Robertson et al. 2016; Viswanathan et al. 2013; Collarino et al. 2018 Collarino et al. , 2017 Fiorentino et al. 2019; Alongi et al. 2019) .
In case of undefined clinical presentation, a case-bycase preoperative work-up should be planed after MDTB discussion.
Several clinical conditions have been distinguished and analysed below, taking into account all potential treatments among the surgical, radiotherapy, and chemotherapy options.
Radical surgery on primary tumor site and groin lymph nodes should be highly supported but keeping in mind that impact of surgical burden should be limited as much as possible. If plastic surgery is required to repair tissue defects, techniques producing minimal impact should be favored (Gentileschi et al. 2016 (Gentileschi et al. , 2017 . Medical therapies (RT and CT) should be guaranteed, anyway favoring the least possible impact. In particular, neoadjuvant treatment has not been included among the available treatment options because of the high cumulative morbidity of RT-CT followed by radical surgery, in the absence of a strong evidence of benefit compared to exclusive RT regimen (Montana et al. 2000; Moore et al. 2012) .
All these general principles fit for all stages. Possible modulations on the standard therapeutic choices are reported in Tables 3 and 4 .
Early stages Standard radical surgery with negative surgical margins should be performed on primary tumor site if possible. Sentinel lymph node procedure has to be always provided in all clinically N0 patients that meet the standard criteria (primary unifocal tumor < 4 cm) (Frumovitz et al. 2008; Gradishar et al. 2020 ). The remaining clinically N0 cases, not fit for the standard selection criteria, should be addressed to radical lymphadenectomy, with high rate of morbidity and complications, often unnecessary. Nevertheless, considering the need for reducing the severe morbidity related to this surgical procedure (DiSaia et al. 1979; Carlson et al. 2018 ), a sentinel lymph node biopsy could be considered instead of standard radical lymphadenectomy always after discussion in MDTB. Recent preliminary evidences showed the safety of the procedure even in this setting only if provided that an accurate ultrasound and metabolic (PET/CT) assessment of the lymph node status is performed by expert examiners . Possible modulation in radiation therapy approach is reported in Table 4 .
The standard treatment may include exclusive radio-chemotherapy (RT-CT) or radical surgery eventually followed by adjuvant RT.
Radical lymphadenectomy should be performed in all cases with proven or highly suspicious inguinal lymph node Remote triage It is a questionnaire which can be administered by telephone or via web, aimed at establishing the risk of contagion of the interviewee, in the time interval of the last two weeks, by asking questions Epidemiologically oriented, to investigate whether she had contacts, occasions or experiences at risk of contagion with SARS-CoV-2 Clinically oriented, to determine if she experienced clinical symptoms attributable to COVID-19 Hospital triage Patients with negative remote triage should be admitted to hospital triage (in person) Before accessing the outpatient service or the hospitalization, they should be subjected to a. Repetition of the questionnaire administered by remote triage b. Body temperature detection c. Lab test: always prior to hospitalization or in case of suspicion of SARS-CoV2 contagion In case of a negative hospital triage patient, should be admitted; in case of positivity, patient should be addressed to the COVID-19 pathway metastasis, taking care to completely harvest the superficial and deep lymph nodes of the inguino-femoral triangle.
Conversely, sentinel node biopsy of lymph node surgical staging could also be considered in selected clinically N0 cases, such as in FIGO stage III contralaterally to a metastatic groin or in FIGO stage II, beyond the standard selection criteria for SLN, limited to the conditions previously specified in early stage workflow. Moreover, complete Care pathways Provide for a clear separation of the care pathways addressed to non-COVID and COVID patients with vulvar cancer, organized in different spaces, days or times of access Combine care services provided remotely (by telemedicine) with those performed in person (at home and hospital), limiting as much as possible the patients' need for hospital access Standardize staff training for telemedicine and home support services Perform in advance remote triage to each patient who is scheduled for hospital access (both on an outpatient and hospitalization) (see Table 1 ) Repeat a hospital triage to all patients entering the hospital (see Table 1 ) Submit patients to diagnostic lab test prior to every major treatment or procedure (surgery, RT, and CT) and provide a longitudinal continuous bio-surveillance during and after treatments (see Table 1 ) Provide for laboratory diagnostic tests as reliable and rapid as possible Combine the largest number of activities deliverable during an outpatient visits or hospitalization, to minimize the number of patients' admissions (e.g. combine first gynecological examination with inguinal lymph nodes ultrasound, biopsy of suspicious lesions and pain management consultancy) Avoid as much as possible the use of waiting rooms: in any case provide for spacious settings, measures for interpersonal safety distance, adequate airing of the environment and supply with hand hygiene devices Limit the hospital access to visitors and accompanist, excepting for patients with severe disabilities and limited to the occasions in which assistance is not provided by hospital staff Activate protocols for the adequate and repeated sanitation, keeping safe environment to work and care for patients Discuss in a multidisciplinary board the precise planning for the optimal treatment course of any patient, to limit the number of elective procedures Provide web platform to perform multidisciplinary tele-conferences, to improve collaboration with distant health care providers that needs to refer to an expert dedicated team Provide specific indications about other proper healthcare facilities where to address patients to receive prolonged treatment, according to the type of therapy proposed and patient's residence Staff Limit the number of on-site staff members during frontal activities with patients Standardize protocols for the reduction of the risk of contagion, even in the non-COVID pathways, providing the use of most adequate personal protective equipment (PPE) and the interpersonal safety distance in the visit rooms (except for moments of clinical exam or diagnostic procedures) Minimize the time for clinical visits providing indirect or telematic supply for preliminary/informative procedures not requiring "in person" activities, such as clinical history and instrumental exams collection, some informative communications and consent procedures Assign a well selected medical staff to the services in which multitasking skills are required, to deliver the highest possible number of services at any single access of patients to the hospital: for example, gynecologists capable of performing the first dedicated oncological visit together with a diagnostic ultrasound examination and/or a vulvar or ultrasound-guided lymph node biopsy Split healthcare personnel into stable small work teams (to limit the effects resulting from a possible contagion of a team member to a small group only) Adopt protocols for continuous bio-surveillance of healthcare staff, repeating diagnostic laboratory tests for SARS-CoV-2 infection. Our proposal is: every 10-15 days, until other risk control measures are available Patients Advice patients to use PPE to enter the hospital; for those unprovided, supply them before entering services Carefully evaluate patients' frailty (basing on factors such as age, comorbidities and performance) related to the risk of a possible severe clinical evolution from COVID-19 Advise patients to limit their exposure only to family members or cohabiters, since they are recognized as a high-risk population. Ask the relatives of surgical candidates to donate blood Adopt adequate bio-surveillance protocols for patients during anti-cancer treatments, repeating diagnostic lab tests for SARS-CoV-2 infection.
Our proposal is 24-48 h before surgery and then every 10-15 days during the postoperative period, until 30 days after the healing of surgical wounds 24-48 h before the start of radiotherapy or chemotherapy, then approximately every 10-15 days during treatment and up to 30 days after the end of the treatments Ensure communication between patients and their relatives/caregivers by phone or video-call during hospitalization for anti-cancer treatments Supply integrative supportive care during hospitalization Ensure continuous and comprehensive remote supplementary home care during anti-cancer treatments, privileging video visits or telephone encounters for psycho-oncological support (intended for patients and their relatives/care givers), nutritional consultancy, palliative care and all the other integrative therapies omission of surgical staging could be considered after MDTB.
In case of perineal extensive disease, requiring large surgical demolition of structures bordering the vulva (urethra, vagina or anus), with possible functional impairment, and/ or large plastic reconstruction, upfront radical RT should be considered, both in node negative or positive patients, after MDTB discussion. In this case, RT should be delivered with radical intent and surgery would be performed only on residual disease with debulking intent.
The choice underlies the treatments previously carried out and the extent of disease. Surgery could still obtain radical results; radical RT-CT could be the favorite option in large relapses followed by debulking surgery in case of partial response. ECT or other palliative treatments for local control of disease (surgery or RT regimens) could take over if the radical intent can no longer be pursued (Certelli et al. 2020) .
Chemotherapy with or without palliative local treatments versus supportive palliative care programs are suggested. The MDTB choice should focus on possible benefits of proposed treatments (Weinberg and Gomez-Martinez 2019) .
In this setting, the MDTB discussion is particularly required to define the most balanced and personalized treatment plan.
Early stage Radical surgery has to be considered limited to cases requiring low surgical effort. In larger lesions, one option could be upfront palliative surgery, with minimally invasive approach on primary tumor site, even omitting sentinel node procedure in previous well staged cN0 cases. Another option could be the shift to other locoregional palliative treatments (e.g. RT regimens or ECT).
The most recommended choice might be the primary RT-CT treatment with exclusive intent. In case of minimal residual disease debulking surgery could still play a role. In large volume residual disease, we suggest to consider to omit surgery, evaluating switch to alternatives such as chemotherapy, interventional miniinvasive local therapy (brachitherapy, stereotactic RT, ECT) or palliative care.
Moreover, palliative primary tumor site surgery and/or selective lymphadenectomy could be considered.
Decisions regarding initiation of additional chemotherapy or further local treatments should be based on clinical MDTB judgment and potential for benefit based on expected response of subsequent available therapies.
Any patient home management should be encouraged, including telemedicine and phone calls. It is well kwon than only visual and clinical inspection permits early detection of Table 3 Flowchart of surgical indications, stratified for clinical presentation Color code: a) green is for one single viable option; b) yellow is for possibility to choose between multiple available options (MDTB discussion is required); c) red is for one single option that is to omit the treatment. SNB sentinel lymph node biopsy; IFLD radical inguino-femoral lym-phadenectomy; RT radiotherapy; CT chemotherapy; ECT electrochemotherapy; S perform according to Standard treatment; R Reduce the treatment intensity compared to standard; SW Swich to other therapies; P Postpone; O Omit Table 4 Flowchart of indications to radiotherapy stratified for intention Color code: a) green is for one single viable option; b) yellow is for possibility to choose between multiple available options (MDTB discussion is required); c) red is for one single option that is to omit the treatment. R1 microscopic residual disease on surgical margins; R2 macroscopic residual disease on surgical margins; RT radiotherapy; CT chemotherapy; S perform according to Standard treatment; R Reduce the treatment intensity compared to standard; SW Swich to other therapies; P Postpone; O Omit recurrence, preventing an incurable progression: thus, as a compromise, we suggest every 4 months follow-up evaluations alternating telemedicine and outpatient visits. Virtual consultation should provide questionnaires including specific items aimed to identify the early symptoms and signs of a possible recurrence. It would be very useful to ensure the presence of the care giver next to the patient, to collect advice from a person able to perform an elementary anatomical inspection and to offer additional information about the symptoms and disorders reported.
Results from each virtual consultation should be recorded and if any doubt arises about a possible relapse, a medical exam should be scheduled in a short time.
In this manuscript, we have summarized our internal guidelines to manage vulvar cancer in COVID-19 era.
Our model is focused on finding a compromise between the risks of SARS-CoV-2 infection and the need to ensure the best oncologic treatments.
In this scenario, the application of the current available guidelines still remains a priority.
Each deviation from standard or modulation of treatment options for particular conditions requires a critical approach, individually customized, within the frame of a MDTB discussion.
The experience of the referral centers with dedicated MDTBs needs to be shared and extended to other centers through the use of multimedia support.
This expert-opinion-based guideline could be considered as a resource in an unprecedented critical period, still evolving. Moreover, the suggestions provided have to be molded on national circumstances and existing health system regulations.