Impact of COVID-19 on a rare disease (uveal melanoma) in a national reference unit of intraocular tumors in Spain

Abstract

Objective

To analyse the impact of the COVID-19 pandemic on the diagnosis and management of uveal melanoma (a tumour included in the Orphanet catalogue of rare diseases) in a Spanish national reference unit for intraocular tumours during the first year of the pandemic.

Method

An observational retrospective study of patients with uveal melanoma in the National Reference Unit for Adult Intraocular Tumors of the Hospital Clínico Universitario de Valladolid (Spain) was performed, analysing the pre- and post-COVID-19 periods: from March 15, 2019 to March 15, 2020 and from March 16, 2020 to March 16, 2021. Demographic data, diagnostic delay, tumour size, extraocular extension, treatment and evolution were collected. A multivariable logistic regression model was used to identify factors that were associated with the variable: enucleation.

Results

Eighty-two patients with uveal melanoma were included, of which 42 (51.21%) belonged to the pre-COVID-19 period and 40(40.78%) to the post-COVID-19 period. An increase in tumour size at diagnosis and in the number of enucleations was observed during the post-COVID-19 period (p < 0.05). Multivariable logistic regression demonstrated that both medium-large tumour size and patients diagnosed in the post-COVID-19 period were independently related to an increased risk of enucleation (OR 250, 95%CI, 27.69–2256.37; p < 0.01 and OR 10; 95%CI, 1.10–90.25; p = 0.04, respectively).

Conclusions

The increase in tumour size observed in uveal melanomas diagnosed during the first year of the COVID-19 pandemic may have favored the increase in the number of enucleations performed during that period.

Resumen

Objetivo

Analizar el impacto de la pandemia por COVID-19 en el diagnóstico y manejo del melanoma uveal (tumor incluido en el catálogo de enfermedades raras por Orphanet), en una unidad de referencia nacional española de tumores intraoculares, durante el primer año de pandemia.

Materiales y métodos

Se realizó un estudio retrospectivo observacional de pacientes con melanoma uveal en la Unidad de Referencia Nacional de Tumores Intraoculares del Adulto del Hospital Clínico Universitario de Valladolid (España), analizando los periodos pre- y post-COVID-19: del 15 de marzo de 2019 al 15 de marzo de 2020 y del 16 marzo de 2020 al 16 de marzo de 2021. Se recogieron datos demográficos, demora diagnóstica, tamaño del tumor, extensión extraocular, tratamiento y evolución. Se utilizó un modelo de regresión logística multivariable para identificar los factores que se asociaron a la variable: enucleación.

Resultados

Se incluyeron 82 pacientes con melanoma uveal, de los cuales 42(51,21%) pertenecían al periodo pre-COVID-19 y 40(40,78%) al periodo post-COVID-19. Se observó un aumento del tamaño tumoral al diagnóstico y del número de enucleaciones durante el periodo post-COVID-19 (p < 0,05). La regresión logística multivariable demostró que tanto el tamaño tumoral mediano-grande como los pacientes diagnosticados en el periodo post-COVID-19 estaban relacionados de forma independiente con un riesgo mayor de enucleación (OR 250, IC95%, 27,69-2256,37; p < 0,01 y OR 10; IC95%,1,10-90,25; p = 0,04, respectivamente).

Conclusiones

El incremento del tamaño tumoral observado en los melanomas uveales diagnosticados durante el primer año de pandemia por COVID-19 pudo favorecer el aumento de las enucleaciones realizadas en dicho periodo.

Introduction

Coronavirus disease 2019 (COVID-19) has had an unprecedented impact on health systems around the world since the World Health Organisation declared an international emergency in January 2020 due to the outbreak of a new strain of coronavirus that started in China.¹ Since then, restrictions taken to prevent the spread of the virus have had collateral effects on multiple diseases, delaying their diagnosis and treatment and consequently worsening their prognosis.^2,3

The diagnosis and treatment of chronic diseases such as cancer have been particularly affected by periods of isolation.³ Within these, uveal melanoma has been no exception.⁴

Uveal melanoma is the most frequent malignant primary intraocular tumour in adults, with the choroid being the most frequent site (65%), followed by the ciliary body and iris (14%).⁵ The estimated incidence is 4–7.4 cases per million inhabitants, varying according to published series.^5,6 Its low incidence, which places it within the catalogue of rare diseases, together with the complexity of its treatment, makes it necessary to centralise its diagnosis and treatment in multidisciplinary reference units. A retrospective study of patients in the UK⁴ showed a 43.2% reduction in de novo diagnosis of uveal melanoma during the period from March to June 2020. Likewise, the number of enucleations and stereotactic radiosurgeries increased significantly in said country.⁴ However, in Spain there are no studies evaluating the effect of COVID-19 restrictions on the diagnosis and treatment of uveal melanoma.

The aim of this study is to determine the impact of the COVID-19 pandemic on the diagnosis and management of uveal melanoma in a Spanish national reference unit for intraocular tumours during the first year of the pandemic.

Methods

A retrospective observational study of patients diagnosed with uveal melanoma at the national referral unit for intraocular tumours of the Hospital Clínico Universitario de Valladolid (Spain). Two periods were analysed: from 15 March 2019 to 15 March 2020 (period before the COVID-19 pandemic) and from 16 March 2020 to 16 March 2021 (period during the COVID-19 pandemic).

An expert multidisciplinary team made the diagnosis and treatment of patients with uveal melanoma, based on clinical features, funduscopic findings and multimodal imaging including: retinography, retinal autofluorescence, A- and B-mode ultrasound and orbital MRI.

Patient demographics (sex, age), delay between symptom onset and diagnosis, ultrasound size of the tumour, extraocular extension, indicated treatment and disease evolution were collected in a Microsoft Access database. Tumour size was classified according to the Collaborative Ocular Melanoma Study (COMS) criteria,⁷ taking into account baseline diameter, tumour height and distance to the optic disc.

Statistical analysis was carried out using the SPSS® statistical package (version 26.0.0.2, IBM, New York, USA). For quantitative variables, mean and standard deviation were calculated. For qualitative variables, frequencies and percentages of proportions were calculated. A multivariable logistic regression model was used to identify factors that were associated with the independent variable, i.e., enucleation. Variables that demonstrated a significant relationship with enucleation treatment were included in a stepwise variable selection method. P-values of less than 0.05 were defined as statistically significant.

This study adheres to the ethical principles comprised within the 1964 Declaration of Helsinki (last amended 2013).

Results

A total of 82 patients diagnosed with uveal melanoma were included, of which 42 (51.21%) were collected between 15 March 2019 and 15 March 2020 and 40 (40.78%) from 16 March 2020 to 16 March 2021. The differences between the two periods, in terms of demographics, tumour characteristics, delay in diagnosis, treatment and disease progression, are shown in Table 1.

Table 1.

Characteristics, management and evolution of patients diagnosed with uveal melanoma between the period before and after the start of the COVID-19 pandemic.

	2019−2020	2020−2021	Subs.
Demographic data
Sex Females	22 (52.38%)	18(45%)	0.517
Age	67.48 (SD 13.59)	60.95(SD 14.89)	0.042
Consultation delay (days)	110 (SD 79.03)	106 (SD 96.61)	0.886
Tumour characteristics
Right eye	19 (45.23%)	21 (52.50%)	0.652
Symptomatic	21 (50%)	28 (70%)	0.075
COMS size
Small	11 (26.19%)	6 (15%)	0.018
Medium	27 (64.28%)	20 (50%)
Large	4 (9.52%)	14 (35%)
Extra-ocular extension	0 (0%)	4 (10%)	0.052
Ultrasound size (mm)
Maximum base	11.55 (SD 3.50)	13.66 (SD 5.53)	0.040
Maximum height	4.92 (SD 3.27)	6.18 (SD 4.15)	0.025
Treatment
Observation	14 (33.33%)	7 (17.50%)	0.020
Brachytherapy	23 (54.76%)	14 (35%)
Enucleation	5 (11.90%)	19 (47.50%)
Evolution
Metastasis	0 (0%)	1 (2.50%)	–
Death	0 (0%)	1 (2.50%)	0.488

COMS: Collaborative Ocular Melanoma Study.

In bold: p-value <0.05.

Multivariable logistic regression showed that medium-to-large tumour size (COMS) was independently related to an increased risk of enucleation (OR 250, 95% CI, 27.69–2256.37; p < 0.01) in both periods. Similarly, patients diagnosed in the pandemic period (2020−2021) had an increased risk of being treated by enucleation (OR 10; 95% CI, 1.10–90.25; p = 0.04).

Discussion

The restrictions during the COVID-19 pandemic had a notable impact on ophthalmology, affecting both outpatient and emergency care. According to reports from different countries, outpatient consultations diminished almost 60% in April 2020⁸ and ophthalmological emergencies decreased by 43%–73%^9,10 in the first months of the pandemic. The decline in healthcare for non-COVID-19 pathologies posed a risk for the detection of rare diseases such as uveal melanoma, as its diagnosis is often made incidentally in asymptomatic patients during routine screening or in symptomatic patients seeking care.⁴ Furthermore, the strict isolation measures implemented in Spain between 14 March 2020 and 9 May 2022,¹¹ prevented the transfer of rare disease patients to their respective reference units, either because of the closure of these units or because travel was not feasible.¹²

According to the study by Wang et al.⁴ analysing the impact of COVID-19 on the management of uveal melanoma in the UK, there was a significant decrease in referrals and new diagnoses during the first months of the pandemic with a significant rebound afterwards. However, according to our study, there were no differences in the diagnostic delay of uveal melanoma between the two periods analysed, probably due to the fact that the intraocular tumour unit remained active (the movement of patients from other provinces and autonomous communities during the months of strict isolation was a healthcare challenge) and due to the increase in symptomatic patients during the pandemic period in our centre (70% compared to 50% the previous year) who requested care, despite the fact that no statistically significant differences were found in this increase.

Regarding demographic data, no significant differences were found in terms of sex and laterality of the pathological eye; however, the mean age of patients diagnosed with uveal melanoma in the period 2020−2021 was lower than the previous year (60.95 SD 14.82; p < 0.05), following a distribution similar to other series described.¹³

The tumour size observed (both ultrasound and COMS) in the uveal melanomas analysed during the pandemic period was larger (p < 0.05) with 10 more cases of large tumours diagnosed and a larger base and height difference (2.11 and 1.26 mm respectively). Also, 4 patients were diagnosed with extraocular extension, while no cases were found in the pre-COVID era. Although not statistically significant, this increase in the number of extraocular extensions may be related to the larger size of the tumours observed in the pandemic, as their incidence increases in large or medium-sized tumours.¹⁴

The increase in tumour size observed during the pandemic period probably influenced the increase in the number of enucleations performed (47.50%, compared to 11.90% during the pre-COVID era) to the detriment of patients treated with brachytherapy or observation (p < 0.05). Thus, the risk of enucleation increased in patients during 2020–2021 (OR 10; 95% CI, 1.10–90.25; p = 0.04), especially in medium and large tumours (OR 250, 95% CI, 27.69–2256.37; p < 0.01). Similarly, the study by Wang et al.⁴ described an increase in enucleations performed during the early quarantine period. However, these authors believe that this increase was due to the tendency to decrease the risk of transmission during the restricted period, as more conservative treatments, such as brachytherapy, require admission and two surgical procedures, with a higher risk of transmission due to aerosols generated during general anaesthesia.⁴

In terms of the number of deaths and metastases in patients diagnosed with uveal melanoma, no significant differences were found between the two periods, although one death was observed at the time of the pandemic. Due to the natural history of this disease (metastases appear long after diagnosis in most patients), the effect of the pandemic on survival will be observed in the coming years.

In conclusion, the increase in tumour size observed in uveal melanomas diagnosed in the first year of restrictions caused by the COVID-19 pandemic may have been a factor in the increase of enucleations performed in that period, with the consequent impact on patients' quality of life and visual function. Longer-term studies are needed to analyse the rebound effect of restrictions in the coming years.

Conflict of interest

No conflicts of interest were declared by the authors.