Background

The COVID-19 disease, caused by SARS-CoV-2 virus, attained the status of a pandemic by March 2020. The infection resulted in a major redistribution of health-care resources to combat this global public health emergency [1]. There was apprehension among medical fraternity as well as non-COVID patients regarding transmission of COVID infection which led to treatment delays. As a result of the pandemic’s exponential growth, hospitals, in conjunction with professional body recommendations, have deferred nonemergent surgeries [2]. These delayed surgeries include many potentially curative urologic oncologic surgeries [3, 4], such as partial and radical nephrectomies for renal cell carcinoma (RCC), which remains the preferred curative treatment for localized kidney cancer [5]. The patients who were suffering from malignancies were not able to balance the treatment of the malignancy with the safety from COVID-19 infection.

Renal cell carcinoma (RCC) encompasses a heterogeneous group of cancers derived from renal tubular epithelial cells [6] and is among the 10 most common cancers worldwide. Key advances in histopathological and molecular characterization of RCC over the past two decades have led to major revisions in its classification [7,8,9,10,11]. Major subtypes [6] with ≥5% incidence are clear cell RCC (ccRCC) [12], papillary RCC (pRCC) [13], and chromophobe RCC (chRCC) [14]. The remaining subtypes are very rare (each with ≤1% total incidence) [5], and in cases in which a tumor does not fit any subtype in the diagnostic criteria, it is designated as unclassified RCC (uRCC; ~4% total incidence) [15]. RCC incidence is increasing, and its main risks factors are competing with the higher risk groups for COVID-19 infection and complications: age >60 years, arterial hypertension, diabetes, obesity, and smoking [16]. Thus, during this pandemic time, many patients diagnosed with RCC, if immediately treated by inpatient procedures (as surgery), are under risk of developing this viral infection and its life-threatening complications [17]

Based on reports from the first countries affected by this infection, health authorities, and medical societies, in these times, the main efforts and health infrastructures must be prioritized in favor of COVID-19 battle, reserving in advance, hospital health care facilities, personal protection equipment, and human resources that must be dedicated for pandemic cases. Concomitantly, surgeries for benign affections are being postponed.

In this era of COVID-19 pandemic, most of the other diseases were overshadowed with the effect of COVID-19 treatment, which affected the management of other diseases including renal malignancies. Majority of the health care facilities were converted into COVID centers and normal routine works have been suspended affecting the management of various ailments.

The aim of this study was to study whether there is any stage migration or up staging in renal malignancies in the COVID era as compared to pre-COVID era due to delay in diagnosis and management.

Materials and Methods

The present study was a retrospective observational comparative study. In this study, we analyzed the patients, who presented with renal malignancies (RCC), to our institute over a period of 2 years. We evaluated a total of 184 patients. These patients were divided into the pre-COVID and COVID era patients, 91 patients of renal malignancies in pre-COVID era (March 2019–Feb 2020) and 93 patients in COVID era (March 2020–Feb 2021).

The patients in both groups were compared with respect to various parameters. The pre-op parameters assessed were demographic parameters like age and gender and tumor parameters, which included tumor size, pre-op clinical staging, lymph node status, and presence or absence of metastasis. Patients underwent contrast enhanced CT scan of the abdomen and pelvis for assessment of tumor parameters.

All the patients underwent either partial nephrectomy or radical nephrectomy according to the pre-op clinical stage of the patient. In patients with metastasis, cytoreductive nephrectomy was performed. Post-operatively, the pathological staging was assessed with the help of final histopathological report in terms of histological stage, histological type, nuclear grade, and lymph node positivity.

Both groups were compared using a two-tailed t-test for continuous variables, and a chi-square or Fisher’s exact test for categorical variables and the level of significance (α) was accepted at 0.05 (95% confidence interval). p value <0.05 was considered significant.

Results

There were 91 patients in the pre-COVID era group and 93 patients in the COVID era group.

The mean age of the patients was comparable in both groups, 52.36 ± 13.56 years in pre-COVID era group and 54.13 ± 13.58 years in COVID era group (p = 0.381). The sex distribution was also comparable in both groups, but renal masses were encountered more commonly in male patients. There were 77.41% male patients in COVID era and 64.84 % male patients in pre-COVID era (p: 0.071) (Tables 1 and 2)

Table 1 Demographic data of patients in pre-COVID and COVID era patients
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Table 2 Gender distribution of patients in pre-COVID and COVID era patients
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The mean size of the renal masses was statistically significantly higher in the COVID era as compared to the pre-COVID era (7.10 ± 3.83 cm, 5.84 ± 3.03 cm, p = 0.017).

The clinical presentation of patients in both groups was evaluated. Abdominal pain was the most common presenting complaint in patients in the pre-COVID as well as COVID era, and it was comparable in both groups (p = 0.263). Incidence of hematuria as a presenting complaint was also comparable in both groups (p = 0.054). Both the groups had comparable number of patients with various other forms of clinical presentations like fever, weakness, and limb pain (p = 0.171). A higher number of asymptomatic patients were diagnosed with renal masses in pre-COVID era as compared to COVID era (p = 0.022). In COVID era, 13 (13.97%) patients were diagnosed as having renal masses at the time of evaluation for COVID. There were more asymptomatic patients in the pre-COVID era as compared to COVID era (27.47% vs. 5.37%, p = 0.045) (Table 3).

Table 3 Pre-operative staging, clinical presentation, and post-operative staging, histopathology of patients, post-op nuclear grade on histopathology, lymph node status, and metastasis in pre-COVID and COVID era patients
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Pre-operative clinical staging (T stage) was statistically significantly higher in the patients in COVID era as compared to pre-COVID era (p = 0.041). The lymph node status was comparable in both groups (p = 0.291). The presence of metastasis was seen in 7 patients in the COVID era whereas only 1 patient had metastasis in the pre-COVID era (p = 0.042); these patients underwent cytoreductive nephrectomy (Table 3).

Post-operative pathological T staging was also significantly higher in the COVID era as compared to pre-COVID era (p value = 0.027). The nuclear grades were also statistically significantly higher in COVID era as compared to pre-COVID era (p = 0.007) (Table 3).

The histopathological sub-types of the renal malignancy were similar in both the groups (p = 0.054). There were 51.7% cases of locally advanced RCC (T3a) in COVID era as against only 28.5% cases in pre-COVID era. There were no cases with sarcomatoid differentiation in pre-COVID era, but there were 8 cases with sarcomatoid differentiation in COVID era (Table 3).

Partial nephrectomy was done in 24 in COVID era vs. 32 in pre-COVID era whereas radical nephrectomy was done in 69 patients in COVID era vs. 59 in pre-COVID era, which was comparable (p = 0.373) (Table 4).

Table 4 Comparison of type of surgery done in pre-COVID and COVID era patients
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Discussion

During COVID-19 pandemic, the management of renal malignancies posed a great challenge for urologists, oncologists, and all other health professionals. In COVID times the material resources, personal protective equipment was limited. There was uncertainty regarding the diagnostic tests for COVID-19 patients, and moreover there were false positives and false negatives, so that one cannot be sure about whether any asymptomatic patient was infected or not.

In present study, it was observed that the patients presenting to health facilities in the COVID era had higher T staging, greater tumor size, and more aggressive disease in terms of renal malignancy. This could be attributed to the delay in presentation to the hospitals. This delay was due to fear of getting COVID infection in the hospitals, difficulty in traveling due to lockdown, and as most of the hospitals were converted to COVID hospitals, the availability of basic services was also affected. There were also financial effects of COVID on the patients in terms of loss of jobs and expenditures in the treatment of COVID.

It has been observed in literature that active surveillance for small renal masses in elderly patients is a valid option as majority of SRM corresponds to slow growing lesions, so there is a possibility to offer the same in all age patients in this COVID times to delay the treatment. For large or local advanced tumors, prompt intervention is warranted, since these cases can progress in few weeks. Even in the patients having renal vein thrombosis or IVC thrombosis, the best approach is to perform surgery if resectability is there [18]. There is a subset of patients in which the decision between AS and Surgery during COVID is confusing; these are cT1b and T2a. For most of these patients, the surgical approach seems more appropriate, but it is observed that for some selected pT1b, it is possible to postpone the surgeries for 60–90 days since the growth kinetics of T1b/T2 tumors seems similar to SMR [19]

The patients who visit the health facilities at COVID times should be stratified according to the clinical stage of the disease so as to know that whether the patient needs aggressive management or if the patient can undergo active surveillance so that the patient is prevented from undue hospital visits during COVID, overloading of the health facilities can be prevented, and the patients who require active management are treated properly.

Mano et al. studied 1278 patients of renal cell cancer to assess the impact of delay in surgery on survival. They found that for tumors less than 4 cm, the surgical waiting time (SWT) did not affect the outcomes, while for larger tumors, a SWT >3 months decreased the overall survival but did not affect the recurrence rates or cancer-specific survival (CSS). They concluded that in patients with T1b and higher tumors, the surgical waiting time (SWT) had an impact [20]. Bourgade et al. established that there was no impact on disease-specific survival even if the treatment was delayed up to 2 years for these small renal masses (<4cm size) [21]. Becker et al., in their series of small renal masses, reported no change in survival for a delay in nephrectomy of >3 months [22]. Based on above studies, asymptomatic patients with small renal masses can be kept on surveillance and curative therapy can be deferred for 6 months without risk of progression. Larger masses and those with symptoms should be treated, as a delay of >3 months would affect survival. For elderly or sick patients, the watchful waiting (WW) is the best approach, avoiding image or laboratory tests [23].

In our study, majority of the patients that presented in COVID era were symptomatic, with very few cases presenting as renal mass identified in routine screening. More patients in COVID era presented with hematuria during COVID era than in pre-COVID era. This indicated that more symptomatic and large masses presented to medical facility for treatment. This would have been probably because of less routine health check-up in COVID era and some patients opting to defer medical health visit due to fear of COVID. More of symptomatic patients presented with the fear of malignancy. This clearly indicated higher stage and symptomatic presentation of renal malignancy in COVID era.

Majority of patients in COVID era underwent radical nephrectomy—with 62.36% cases undergoing minimal invasive radical nephrectomy as opposed to 45.05 % cases during pre-COVID era. 11.8% of renal malignancy patients underwent open radical nephrectomy as opposed to 7.69% of cases in pre-COVID era (p = 0.37). This was majority due to locally advanced renal malignancy with renal vein or inferior vena cava thrombosis in COVID era. 47.2% of cases underwent partial nephrectomy in pre-COVID era as against only 25.81% cases in COVID era (p = 0.37). This indicates shift of more radical surgeries in COVID era, which is probably due to more advanced cases in COVID era as against small renal mass diagnosed during routine health check-up in the pre-COVID era.

In our study, there were more metastatic patients in COVID era as compared to pre-COVID era (n=7, n=1, p= 0.04), which can be attributed to delay in diagnosis and delay in seeking medical help due to COVID restrictions and fear.

As there was not much literature available regarding informed consent for cancer treatment during the COVID-19, we emphasized on use of a proper informed consent for the patients getting operated during this time of COVID era stating that the treatment was with due risk of COVID infection involved as many COVID patients were asymptomatic and the COVID tests were also not much reliable.

At the same time, it is being suggested that minimally invasive surgeries should be used whenever possible; it should also be considered that rigorous extra attention is being given to avoid the spreading SARS-CoV-2 through aerosols that can occur during the installation and evacuation of pneumo-peritoneum, during use of harmonic scalpels, removal of trocars, specimen extraction in laparoscopic and robotic surgeries, or the use of electric scalpel in open surgeries [24].

Dedicated surgical rooms and personal protective equipment should be used while operating. Upfront cytoreduction and/or resection of metastasis for patients with metastatic RCC must be discouraged. Metastatic patients configure a heterogeneous group of patients. Also, patients with intermediate or poor risks usually do not benefit with initial surgical approach, these patients are treated with immunotherapy as well as targeted therapy which should not be postponed due to COVID pandemic [25]. Additionally, there is no certainty when pandemic will finish, being casual to interrupt or postpone the initiation of systemic therapies for these group of patients may lead to high risk of progression.

Follow-up protocols following a curative therapy should be tailored according to the final histopathological report and can be increased to 3 to 6 months. The follow-up interval can be extended, with physical examinations done every 6 months and blood investigations with imaging reported telephonically at 3 months [23].

Our study also has limitations. It was based on scarce literature regarding RCC and COVID-19. Probably, this proposed risk-based recommendations, may be in some grade, influenced the authors’ personal biases. This was a single-center analysis, and we need to perform larger studies to have a better outcome analysis.

Conclusions

There was a clear shift in the clinical as well as histological stage in patients of renal malignancies in COVID era as compared to pre-COVID era with more symptomatic patients with higher stage. Fear of COVID infection overshadowed the management of other diseases such as renal malignancies which led to delay in management leading to disease progression. In future if such a situation arises, we need to stratify the patients according to their stage and clinical presentation so as we can give them the best management considering the constraints in medical facilities due to any pandemic.