key: cord-0793455-9wu5vz18
authors: Gualdi, Giulio; Porreca, Annamaria; Amoruso, Giuseppe Fabrizio; Atzori, Laura; Calzavara-Pinton, Piergiacomo; De Tursi, Michele; Buduo, Andrea Di; Marino, Pietro Di; Fabroncini, Gabriella; Fantini, Fabrizio; Fargnoli, Maria Concetta; Giannotta, Gaetano; Lacarruba, Francesco; Lotesoriere, Andrea; Merli, Martina; Micali, Giuseppe; Paradisi, Andrea; Puviani, Mario; Quaglino, Pietro; Rongioletti, Franco; Rubatto, Marco; Sbano, Paolo; Scalvenzi, Massimiliano; Soglia, Simone; Sollima, Laura; Villani, Alessia; Nicola, Marta Di; Amerio, Paolo
title: The Effect of the COVID-19 Lockdown on Melanoma Diagnosis in Italy
date: 2021-05-27
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2021.05.015
sha: 844b61ee47e545f14b0d125f57628a0517282289
doc_id: 793455
cord_uid: 9wu5vz18

The COVID-19 pandemic has led to lockdowns for much of the world. In Italy, all health procedures not directly related to COVID-19 were reduced/suspended, thus limiting patient access to hospitals. Any delay in cancer treatment presents the additional risk of tumors progressing from being curable to becoming incurable. Specifically, melanoma survival rate strictly depends on tumor thickness which, in turn, is a function of time. To estimate the impact on melanoma progression of the reduction in the dermatologic services during the COVID-19 lockdown, a retrospective observational cohort study was conducted, designed to compare the clinical/histologic characteristics of the primary melanomas removed in the first two months after the end of the lockdown (May-July 2020) in twelve Italian centers characterized by different COVID-19 case frequencies. The control group was represented by the melanomas removed in the same period of the previous three years. Overall, 1,124 melanomas were considered: 237 as part of the study group and 887 from the control group (average 295), with a 20% reduction. Breslow thickness – as well as high-risk histotypes and melanomas with vertical growth – increased for all melanomas. Ulcerated and high mitotic index melanomas increased, particularly in northern Italy. In Italy, the lockdown led to a significant worsening of melanoma severity, determining a staging jump, with a consequent worsening of the outcomes.

The ongoing SARS-CoV-2or COVID-19pandemic continues to be a significant concern for public health. Until May 2020, Italy was one of the countries with the largest outbreak outside mainland China (1) . The pandemic pressure threatened health systems of all the nations involved. In most countries, including Italy, the response to the pandemic was to contain the spread of the virus through immediate case detection and isolation, a rigorous close contact tracing with quarantine, and the application of strict limitations to people's movements and activities (2) (3) (4) .

The Italian population was confined in a lockdown from March to mid-May. This led to a reduction in the ordinary hospital activities for nonurgent and non-COVID-related cases. Among the hospital activities, specialized outpatients' clinics were forced to comply a marked reduction in face-to-face consultations (5) . In Italy, an 80-90% reduction in dermatologic consultations was occurred (5) . Most hospitals postponed appointments for elective surgery and non-urgent visits, to avoid any unwanted exposure in high-risk premises, including hospitals, to avoid crowding in waiting rooms and to focus on the management of COVID-19.

At the same time, the fear of contagion led numerous patients to cancel their scheduled visits. This circumstances may have led patients with medical conditions ,like melanoma, to have a delay in their diagnosis and management .

Concerning the cutaneous malignant melanoma (CMM) outcome, any delay can be critical. CMM severity strictly depends on tumor thickness which, in turn, is a function of the time to diagnosis. So far, several register-based theoretical models regarding the impact of the COVID-19 lockdown on melanoma progression have been proposed (6, 7) ; also, two single real-case series have been published, both showing a reduction in the number of patients undergoing melanoma excision during the lockdown period (8, 9) . To date, no studies have assessed the real-world quantitative and qualitative impact of the delay induced by the lockdown in melanoma patients.

We have recorded the melanoma cases referred to 12 Italian centers in different geographic locations in the two months immediately after the lockdown. We then compared these data to those from the same centers in the same period for the previous three years. The purpose of the present study was to assess the impact of the lockdown on both the modification of CMM prognostic factors and other CMM characteristics for the months immediately after the lockdown in Italian geographic areas differently affected by the pandemic.

A prospective database of all newly-diagnosed CMM cases recorded in 12 dermatologic institutions in Italy from May 1 to July 31, 2020 was collected. Centers were included according to their location (different COVID-19 case frequency areas) (10): Brescia, Lecco, Torino, Sassuolo for North Italy (high COVID case frequency); Chieti, Roma, L'Aquila, Viterbo for Central Italy; Catania, Napoli, Cagliari, Cosenza for South Italy. Centers were chosen based on the similarity of their relative workload in the respective geographic areas: high-workload centers were Brescia and Turin in the North, Roma in the Center, and Napoli and Catania in the South. The remaining centers had a lower patient workload but with a comparable size/population rate in their respective geographic areas.

The study period coincided with the end of the lockdown imposed by the COVID-19 emergency. The control group consisted of melanoma data collected from all the centers in the same period for the previous three years (1 May-31 July 2017, 2018, 2019). Clinical and histologic characteristics were recorded. All participating centers had not stopped their surgical activities during the lockdown months. Because the surgical procedure for each patient was longerto allow surgeons to change their protective gear and surgery rooms to be sanitized after each patientthe total number of daily surgeries was lower than prior to the pandemic; however, suspected melanoma surgery was prioritized in each center concerning other types of skin surgery.

The waiting list time for melanoma surgeryset to the maximum of 2 weekswas the same as in the pre-lockdown. The study was approved by the various local Ethics Committees.

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Patient gender and age, plus tumor location (face, head, neck, chest, abdomen, back, sacrum, arm, hand, leg, foot, genital) were evaluated. We also recorded the histologic variables of melanoma, including histologic subtype (in situ, superficial spreading, lentigo maligna, nodular, acral lentiginous, desmoplastic, and nevoid), Breslow thickness (mm), number of mitoses (calculated with the hot spot method/mm 2 ), ulceration (present vs. absent), and previous mole (present vs absent).

The primary outcome was the detection of any quantitative and qualitative differences in melanomas removed in the different periods, plus the assessment of the impact of the lockdown measures and people's behavior during the lockdown period. The secondary outcome was the evaluation of the impact of the lockdown measures on melanoma characteristics in various geographic areas and the for the risk for COVID-19 infection.

Descriptive statistics included frequencies and proportions for categoric variables. Median, 1 st , and 3 rd quartiles were reported for continuous nonnormally distributed variables. The chi-square tested the statistical significance in proportional differences, and the Mann U-Whitney test examined the statistical significance of the median differences between unpaired groups. All statistical tests were 2-sided, with the significance level set at P<.05. Analyses were performed using the R software environment for statistical computing (version 3.4.1; http://www.rproject.org/).

Overall, 1,124 melanomas were collected from the participating centers; of these, 237 were in the study group (post-2020 lockdown period) and 887 in the control group (298 melanomas in 2017, 288 in 2018, and 301 in 2019, respectively, with an average of 295 melanomas per study period).

We found a 20% reduction in the number of melanomas excised during the study periods (previous years vs post-lockdown). Melanoma cases that occurred during the period 2017-2020 in the three main geographic areas of Italy are reported in Fig.1a .

The absolute frequency of melanoma in 2020 and before 2020 (average frequencies of 2017, 2018, and 2019) by geographic area (Fig.1b) illustrate how the reduction in the number of cases is mainly characteristic of the Northern and Central areas (Chi-square test p-value = 0.020), while in the South the difference is not significant. The analysis of gender and age distribution in the various areas did not show any significant differences (Table 1) .

As for CMM histologic characteristics, Breslow thickness increased in the cases that occurred after the 2020 lockdown period compared to CMMs in previous years. Median increases are 0.4-0.5 mm (Fig 2a) . A sub-analysis of the data by geographical areas showed a significant increase for Central Italy (0.5 mm before COVID vs 1.1 mm post-COVID) and South Italy (0.3 mm vs 0.9 mm), and an increasealbeit not significant, due to the presence of numerous anomalous valuesfor North Italy (0.4 mm vs 0.5 mm) (Fig 2b) . The presence of ulcerations also increased in the postlockdown cases, particularly in North Italy (Table 2a) .

Similarly, the number of mitoses showed an overall increase in the study group with a high mitotic index (˃4 mitosis/mm 2 ), particularly significant in North Italy (Table 2b) . Analyses according to histotype were conducted, grouping the cases based on risk. High risk included: nodular (NM), acral lentiginous (ALM), or other (animal type, spitzoid, nevoid), while low risk consisted in superficial spreading (SSM), lentigo maligna (LMM), and in situ (IS) melanomas. An increase in high-risk histotypes and a decrease in low-risk forms in the 2020 post-lockdown groups were present in all geographical areas (Fig. 3a) .

The evaluation of the CMM growth pattern (horizontal or vertical) showed that for all the geographical areas considered there was an increase in vertical growth phase melanoma in the post-lockdown period, compared with the control period (Fig. 3b) . No difference between the two study periods was found about the presence of a previous melanocytic nevus (Table 2c) . Nor was any difference detected as for the body distribution of melanomas.

CMM is characterized by an extensive degree of heterogeneity in terms of clinical and histopathological presentation (11) and genomic profile (12) (13) (14) 15) , which makes this disorder a significant public health issue. CMM is the cause of most skin cancer-related deaths and is currently the sixth most common cancer in most European Countries (16) . The most important prognostic factor for melanoma is depth (Breslow thickness), followed by ulceration and the number of mitoses. Recent evidence has shown that the ratio between the melanoma thickness or the mitotic index and the time to diagnosis is a strong prognostic factor (17, 18) . pattern that is characterized by a VG rate exceeding 0.5 mm/month in thickness and a slow-growing melanoma (SGM), the latter divided into two different subcategories: slow thin melanomas and very slow thin melanomas (22) . An early diagnosis and the excision of thin lesions offer the best hope of mortality reduction in the short term, while primary prevention may affect long-term results (23) .

We think that limited access to outpatient dermatologic clinics could have had an indirect impact on the clinical presentation and prognosis of melanoma patients in Italy. Two single-center case series from Italy demonstrated a numerical reduction in the patients undergoing melanoma excision (8, 9) . In one of the studies, the authors reported a similar proportion of in situ CMMs in the pre-and post-lockdown periods and an increase in thicker melanoma in the post-lockdown. They concluded that more health-aware people were more likely to overcome the lockdown limitations than patients who underestimated the severity of their lesions, leading to a delay in CMM diagnosis during lockdown (25) .

To date, some register-based theoretical models have been proposed concerning the impact of the COVID-19 lockdown on the progression of melanoma. The authors have hypothesized a considerable rise in melanoma upstaging cases in the event of a lack of adequate care of cancer patients (6-7). Some observers have even hypothesized a reduction in melanoma frequencies due to the limited exposure to the sun during lockdown for fair-skinned individuals, being confined at home (24) .

Our study provides real-world data of the effect of the lockdown on CMM clinical presentation in various parts of Italy, each characterized by different COVID-19 case frequencies and impact. The design of the study allowed us to assess the post-lockdown period, when the limitation in movements for the population was lifted. The total numbers of melanomas excised in this period were similar to those reported during the lockdown, when movement restrictions were in place, with a 20% reduction in frequency. These figures may suggest that the population was somehow still as afraid to visit hospital-based outpatient clinics just after the lockdown (May-June) as they were during the lockdown. Also, our model could be even more accurate than others, given that the well-documented phenomenon of seasonal fluctuation of melanoma diagnosis (25) cannot be a confounding bias, as in contributions comparing different months in the same year (pre-and post-lockdown, i.e., January vs May) (8) .

The hypothesis that the reduction in the number of melanoma diagnoses after the lockdown was due to the fear of visiting hospitals is supported by the evidence that the reduction is larger in North and Central Italy, where the incidence of SARS-CoV-2 was higher. We have theorized that patients from the North were more afraid to expose themselves to the high risk of the outpatient clinic environment. As a result, they would have been more likely to miss important dermatologic visits, leading to a delay in diagnosis. To the contrary, the outpatient clinics were still carrying out oncologic visits and excisions throughout the lockdown period did not help fill the gap.

A greater reduction has been also reported. (8) in a single-center study in Northern Italy, in which the number of excised melanomas dropped by 30%.

We think that due to the different models of melanoma progression, this significant decrease in the number of melanoma excisions during the lockdown period should be analyzed per the prognostic factors for melanoma.

An increase in high-risk histotypes and a decrease in low-risk forms in the 2020 post-lockdown groups were present in all geographic areas. We recorded a discrepancy among the prognostic features according to COVID-19 risk areas. Low to medium COVID-19 risk areas (South and Central Italy) showed a higher Breslow thickness in the post-lockdown period compared to previous years, and a higher incidence, although not An analysis of the growth phases and the melanoma histologic types also showed an overall increase in the high-risk forms in the post-lockdown group. We think that this evidence may still support the hypothesis that a delay in the diagnosis of melanoma and a worsening of the prognosis could be due to a combination of factors: patients missing outpatient or hospital visits during the lockdown, and again after the restriction period, for fear of COVID-19 infection and patients, being home-bound , did not prioritize their regular follow-ups visits.

The availability of surgery for melanoma patients was ensured during the lockdown so that, although to a lesser rate, faster-growing and more aggressive melanomas (higher mitotic rate and ulceration more identifiable by the patients as a lesion to be assessed) were preferentially excised over the slow-growing, less aggressive melanomas (slow radial growth) that are usually found in routine clinical assessment.

We did not find any significant differences between exposed and unexposed areas, neither did we find a greater number of de novo onset melanomas. This limited the chance that the reduction in the number of melanoma excisions after the lockdown could be due to a reduced selfdiagnosis of melanoma.

All qualitative indexes of melanoma progression showed an increase as determined by the factors just mentioned. During lockdown efforts must be made to ensure the patients with access to dermatologists so that melanoma screening and treatments are not delayed, to prevent a progression of the severity of the disease (26) .

Our results underline the importance of addressing, once the pandemic will be over, the need of minimizing the consequences of future lockdown on diagnosis and management of melanoma. We think that there is the need for a stronger sensitization of the high-risk melanoma population emphasizing the importance of body self examination, as well as the necessity of providing a sense of a safer environment for melanoma outpatient clinics, to encourage people to undergo the screening and analysis of suspicious lesions.

There was no funding source for this study. Corresponding and senior authors had full access to all the data in the study and were ultimately responsible for the decision to submit the paper for publication.

Acknowledgments: Novartis Pharma, Italy provided the English speaking editing for the manuscript.

The authors state no conflict of interest.

Funding sources: Novartis Pharma SRL has provided the native English speaker revision. Table 3 . Mitosis distribution in 2020 and Before. The Before 2020 absolute frequencies are computed as the averages of the years 2017, 2018 and 2019. P-value results from Chi-squared test. 6. exposed and non-exposed melanoma body localization in 2020 and and average from the three years earlier (2017-2018-2019).. P-values results from Chi-squared test.

Before 2020 p-value North 

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