Testicular Metastasis from Renal Cell Carcinoma: A Systematic Review

Approximately one-third of renal cell carcinoma (RCC) is recognized in its metastatic stage. This systematic review aimed to summarize knowledge on the occurrence and treatment of testicular RCC metastasis. The literature search was performed by two authors independently, with the use of main electronic medical databases (Science Direct, Web of Science, and PubMed) until March 2023 to identify relevant articles that could potentially contribute to this review. Neither language nor publication dates were set as limits. Although we found a total of 51 case reports, only 31 of them contained all the required information. Testicular metastasis in patients with RCC suggests a late stage of the disease. Moreover, it usually does not present typical systemic or specific symptoms except for swelling and enlargement of the affected testis. Knowledge of the possibility of such variants of RCC metastases will allow a clinician to make an appropriate diagnosis and implement adequate treatment without delay, which is crucial in the management of neoplastic disease.


Introduction
Renal cell carcinoma (RCC) is the sixth most commonly diagnosed neoplasm and compromises 5% of all cancer diagnoses among men [1].It is often recognized incidentally in diagnostic imaging tests, as it can be asymptomatic for a prolonged time.RCC appears to be the reason why approximately 30% of cases are diagnosed with severe metastatic disease at the time of diagnosis [2].
Approximately 20-50% of RCC patients with localized disease progress to the metastatic stage (mRCC) [3][4][5] in which the most frequent sites of RCC metastasis are the lungs, skeletal system, liver, and brain [6].Testes are an extremely rare localization for RCC metastasis, and therefore, only a handful of cases have been described in the literature so far, with the first reported in 1946 [7].Most of them affected the testis ipsilaterally to primary kidney tumor placement and were prevalent more frequently on the left side [8].They can be found during or before the primary diagnosis of RCC and may initially resemble primary testicular cancer.Their differential diagnosis with metastases is impossible until tumor tissue from the testis is obtained by orchiectomy or biopsy and histopathological examination is performed.However, the list of reports on this subject still needs to be more significant.
According to the authors' best knowledge, there has been no such precise, systematic review or meta-analysis published that would evaluate mRCC in the testes.Therefore, this article aims to conduct a systematic review of the existing literature to familiarize clinicians with the possibility of this rare location of RCC metastases in the testes.This knowledge will facilitate a more careful evaluation of the patient, a faster appropriate diagnosis, and, consequently, individually adapted treatment.

Search Strategy
The literature search was performed by two authors independently (AP, SR), using the main electronic medical databases (Science Direct, Web of Science, and PubMed) until March 2023 to identify relevant articles that could potentially contribute to this review.The search strategy of this study included the following terms: "testicular renal cell carcinoma metastases".Non-English articles were translated if appropriate and no date range was introduced.The work was carried out in accordance with the guidelines of the Declaration of Helsinki.Due to the characteristics of this study, it was not necessary to obtain the opinion of the Bioethical Committee.Having obtained the full texts, a reference search was conducted to identify other potentially relevant articles that may have been overlooked in the electronic database.Preferred Reporting Items for Systematic Reviews and Metaanalyses [PRISMA] guidelines were strictly followed in performing this study [9] (Figure 1).primary testicular cancer.Their differential diagnosis with metastases is impossible until tumor tissue from the testis is obtained by orchiectomy or biopsy and histopathological examination is performed.However, the list of reports on this subject still needs to be more significant.
According to the authors' best knowledge, there has been no such precise, systematic review or meta-analysis published that would evaluate mRCC in the testes.Therefore, this article aims to conduct a systematic review of the existing literature to familiarize clinicians with the possibility of this rare location of RCC metastases in the testes.This knowledge will facilitate a more careful evaluation of the patient, a faster appropriate diagnosis, and, consequently, individually adapted treatment.

Search Strategy
The literature search was performed by two authors independently (AP, SR), using the main electronic medical databases (Science Direct, Web of Science, and PubMed) until March 2023 to identify relevant articles that could potentially contribute to this review.The search strategy of this study included the following terms: "testicular renal cell carcinoma metastases."Non-English articles were translated if appropriate and no date range was introduced.The work was carried out in accordance with the guidelines of the Declaration of Helsinki.Due to the characteristics of this study, it was not necessary to obtain the opinion of the Bioethical Committee.Having obtained the full texts, a reference search was conducted to identify other potentially relevant articles that may have been overlooked in the electronic database.Preferred Reporting Items for Systematic Reviews and Meta-analyses [PRISMA] guidelines were strictly followed in performing this study [9] (Figure 1).

Eligibility Assessment
The research selection and data extraction were split between A.P. and S.R. to allow independent double-checking of articles and data.The inclusion criteria required that studies involve testicular mRCC confirmed by histopathological examination to eliminate any misinterpretation of data due to false diagnosis.
Studies were excluded according to the following criteria: -Review articles and conference abstracts and studies void of any original data.-Works that provided incomplete or non-extractable data (such as lack of patient age (12), histological type (16), side of testicular metastasis (16), and side of primary RCC (16); information about the presence or absence of other metastatic sites at the time of diagnosis of testicular mRCC ( 16), information about follow-up management of the disease (14) or one impossible to extract.
The article was excluded if there was a minimum of one (or more) of the abovementioned reasons.
By contacting the authors of the original studies, any inconsistencies in the included studies were resolved.In each instance where information was not available, all reviewers contributed to the evaluation until consensus was achieved.

Data Extraction
The extraction of data from all studies that met the inclusion criteria for this systematic review was performed individually by two reviewers.The authors of the studies were contacted for clarification or additional information whenever discrepancies in the reported research were found.

Study Endpoints
The analysis is focused on the histological types of renal cell carcinoma with testicular metastasis.The secondary endpoint involved the association between the location of the metastatic tumor in the testes (contralateral vs. ipsilateral) and the location of the primary tumor in the kidney.The tertiary endpoint is concerned with the assessment of the incidence of testicular metastases as the first manifestation of advanced kidney cancer and the presence of other metastases at the stage of diagnosis of metastases in the testes.

Quality Assessment
The Joanna Briggs Institute's critical evaluation checklist for case reports was used to estimate the quality and reliability of the included studies [10].Eight domains were evaluated in the analysis: The presence of demographic characteristics of the patient, clear description of the patient's history presented as a timeline, current clinical condition of the patient, diagnostic tests or assessment methods and results, description of intervention and treatment procedures, identification of adverse events (harms) or unanticipated events, and case takeaway lesson.Each domain was determined in Table 1 with a subjective answer-'yes' if the information was present, 'no' if it was not provided in the text, 'unclear' when the domain information was not fully completed, or 'not applicable' if the domain was not related to the article.The significance level of the statistical tests in this analysis was set at α = 0.05.The p-value was calculated considering Holm's correction method for multiple comparisons.The relationships between the two nominal variables were estimated using Fisher's exact test and Pearson Chi-squared test.A measure of the strength of the relationship, V, was calculated in the case of df > 1.A comparison of the multiple observed proportions with the expected probabilities was performed using the Chi-squared test for goodness of fit.In the case of two independent groups with nonnormally distributed variables, the Mann-Whitney U two-sample rank-sum test was used to compare means.In terms of the effect size measurement, the rrank biserial was reported.A one-way Kruskal-Wallis ANOVA was used to estimate the differences between the three groups with nonnormally distributed variables.In terms of the effect size measurement, the ˆ 2 ordinal was reported.The central measure of the distribution was reported in the form of the median, and the variability of the distribution in the form of the first and third quartile, Mdn (Q1-Q3).The correlation between the two independent numerical variables (when a variable has at least one outlier) was calculated using the Spearman method.The p values were calculated by asymptotic t approximation.

Study Identification
The process of identifying studies is summarized in Figure 1.The initial search revealed 223 articles that would potentially meet the inclusion criteria.A total of 17 studies were duplicates and were excluded.After the initial screening of abstracts and titles, 206 were considered ineligible: The majority were reviews or reported irrelevant data, while 9 reports were unable to be retrieved.Forty-eight articles were analyzed by full text and, finally, 26 studies were included in this systematic review.

Characteristics of the Included Studies
The characteristics of the included studies are summarized in Table 2. Thirty-one cases were evaluated in this systematic review.The studies included in this research ranged in publication date from January 1984 to March 2023.The geographical distribution of the works was worldwide.The descriptive statistics of the variables on a continuous scale are shown in Table 3.The distributions of the categorical variables are shown in Table 4.

Study Identification
The Joanna Briggs Institute's critical appraisal checklist for case reports is summarized in Table 1.Nearly half of the articles contained descriptions of the demographic characteristics of the patients.Unclear data were present in approximately 30% overall, while a complete lack of information was in approximately 20%.In most of the articles, case history was explicitly described and depicted as a timeline.Only less than 10% gave unclear or nonchronologically ordered disease details.Similarly, in the largest number of articles, the current clinical condition of the patient was provided on presentation, except in around 15% of them.Data on diagnostic tests or assessment methods with clearly described results and a take-away lesson were present in approximately 90%.Adverse or unanticipated events were not commonly identified and described; they were absent in more than half of the publications and unclear in five.The post-intervention clinical condition was clearly provided in 70% of the articles, while it was unclear in three and lacking such data in five of them.

Age of Testicular Diagnosis of mRCC vs. Testicular Metastasis as the First Clinical Manifestation of RCC
The results of the Mann-Whitney test performed, WMann-Whitney (2) = 133.00,p = 0.240, r ˆ_biserialˆrank = 0.27, n = 31, showed that there were no significant differences in age at diagnosis of testicular mRCC between patients with testicular metastases as the first clinical manifestation of RCC, Mdn = 65.50 (55.75-68.75)years, n = 10, and patients without testicular metastases as the first clinical manifestation of RCC, Mdn = 69.00(56.00-73.00)years, n = 21.
A graphical visualization of the variable distributions along with the test results can be found in Figure 2.

Age of Testicular mRCC Diagnosis vs.Time Period between Primary Kidney Tumor Diagnosis and Testicular Metastasis
The correlation analysis performed did not show a significant correlation between the age of testicular mRCC diagnosis and the time between the diagnosis of primary kidney tumor and testicular metastasis, ρ = 0.37, p = 0.109.

Age of Testicular mRCC Diagnosis vs.Time Period between Primary Kidney Tumor Diagnosis and Testicular Metastasis
The correlation analysis performed did not show a significant correlation between the age of testicular mRCC diagnosis and the time between the diagnosis of primary kidney tumor and testicular metastasis, = 0.37, p = 0.109.

Testicular mRCC Side in Relation to Kidney Primary RCC Side
The results of the Chi-square goodness-of-fit test performed (χ2 = 3.85, df = 1, p = 0.049) showed that among the study patients (N = 26), the number of patients with ipsilateral mRCC on the testicular side relative to the primary kidney RCC side (n = 18, 69.2%) was significantly higher than the group of patients with contralateral mRCC on the testicular side (n = 8, 30.8%).

T Stage of Primary RCC vs. Testicular Metastasis as the First Clinical Manifestation of RCC
The results of the independence test performed, V = 0.56, Fisher's p = 0.620, showed that there was no dependence on frequencies (percentages) between the T stage of the primary RCC site in the kidney and testicular metastasis as the first clinical manifestation of RCC.
A graphical visualization of the variable distributions along with the test results can be found in Figure 3.

Discussion
Patients with RCC develop metastases in 33% of cases, while 25% of them have metastatic disease at the time of diagnosis [35,36].
According to the results of the International mRCC Database Consortium (IMDC),

Discussion
Patients with RCC develop metastases in 33% of cases, while 25% of them have metastatic disease at the time of diagnosis [35,36].
According to the results of the International mRCC Database Consortium (IMDC), the median age at diagnosis with the mRCC is 60 years, while most of the patients are men (73%).According to our study, the median age of testicular mRCC diagnosis was 68 years.The correlation analysis performed showed no significant relations between the age of diagnosis of testicular mRCC and the time between diagnosis of primary kidney tumor and testicular metastasis.As reported in the previous study, the most common histopathological type is clear cell carcinoma, which occurs in 87% of cases of mRCC [37].Clear cell RCC also accounted for 87% of all reported cases in our analysis.Basement membrane (BM) and extracellular matrix (ECM) invasion seems to be a key underlying mechanism throughout tumor invasion results in metastasis.Matrix metalloproteinases and heparinase, which are expressed in RCC cells, are known to be responsible for the damage of the major components of the BM and ECM [38].RCC can affect many sites of the body, but the most common are the lungs (71%), lymph nodes (49%), bone (36%), liver (21%), adrenal (9%), brain (9%), pancreas (5%), pleura (4%), and thyroid (0.6%) [39].As mentioned above, RCC metastasis to the testis is extremely rare, hence it is not even mentioned in statistics.According to our study, in relation to the primary kidney tumor, more commonly, the ipsilateral testis (69.2%) was affected.Contralateral spreading to the testis was presented in 30.8% of cases.The metastasis was localized in the left gonad in 51.6% of all reported cases, and 3% of the patients had bilateral testicular metastases (Table 2).
RCC is said to spread mainly through blood vessels.The method of expansion of RCC cells into the testes is not certainly clear, but it is believed that they can descend to the gonad through the testicular vein in the case of ipsilateral mRCC or more regionally through the ipsilateral renal capsular veins, then to the Batson's plexus (the external vertebral venous plexus), contralateral renal capsular veins, and finally spermatic cord vessels and gonad in the case of contralateral mRCC [2].
The median time between primary kidney tumor diagnosis and testicular metastasis was 33.5 months.The relationship between renal tumor stage (T-category based on TNM classification) and time to diagnosis of testicular metastasis was also analyzed.The average time to diagnosis of metastasis for T1, T2, and T3 was 36 months, 21.5 months, and 15 months, respectively.
Prevalent clinical manifestations in patients with RCC (with and without metastases) are irritability with an incidence of 79%, pain and fatigue (71%), worry (71%), and disturbance of sleep (64%), while patients with mRCC more frequently report fatigue (82%), weakness and worry (65%), shortness of breath, and irritability (53%) [38].Symptoms directly caused by testicular metastasis of RCC are non-characteristic and nonspecific, manifesting as a palpable rigid mass in the scrotum.
Usually, such RCC metastatic manifestation is initially diagnosed as primary independent cancer of the testis, and suspicion of RCC is made on the staging level based on a CT scan, which reveals primary renal tumors.After testicular mRCC resection, the diagnosis is confirmed by its histopathological examination.The disease ought to be differentiated from gonadal germ cell tumor, which is generally the most common type of testis cancer, and testicular lymphoma occurring most frequently among men aged over 70 years [40].The standard management of testicular tumors is orchiectomy, which provides material for histopathological examination [41].A CT scan, performed before surgery, enables one to identify the primary location of the disease and other possible sites of metastases.Cytoreductive nephrectomy (CN) is palliative for the majority of patients with mRCC and systemic treatment is required.According to the outcomes of the CAR-MENA (NCT00930033) and SURTIME (NCT01099423) randomized clinical trials in mRCC patients with intermediate and poor prognosis IMDCs, the primary tumor needs to be treated with immunotherapy-based combination therapy ahead of time.Subsequent cy-toreductive nephrectomy may be performed in patients with a clinical response to systemic therapy.In patients ineligible for surgery, mRCC needs to undergo systemic treatment with vascular endothelial growth factor (VEGF) receptor inhibitors, tyrosine kinase inhibitors, and immunotherapies.Cytoreductive nephrectomy with complete resection of a single metastasis or three oligometastases may improve survival and delay systemic therapy, therefore, CN is preferred in patients with oligometastases when complete local treatment of the metastases can be achieved [31,42,43].
Among patients with nonresectable metastatic disease or disqualified for surgery due to poor general condition, embolization can control symptoms, including visible hematuria or flank pain [42].

Study Limitations
Owing to the casuistic nature of the problem, our systematic review is focused on the case reports or case series evaluation.Moreover, because of the large-scale studies shortage in literature, we were not able to perform a meta-analysis.

Conclusions
Our review outlines the possibility of the rare metastatic variant appearance of RCC in clinical practice.Generally, such disease is highly probable to manifest in a patient who approaches a urological clinic without systemic or specific symptoms with a suspicion of a primary testicular tumor, confirmed on ultrasound.Standard management is typically based on orchiectomy and postoperative histopathological examination, which reveals the primary severe disease (mRCC).Perceiving even the subtlest cancer symptoms enables one to promptly suspect, recognize, and prevent the tumor from spreading.Symptoms of RCC often appear in advanced metastatic disease, which makes it impossible for early disease identification and proper treatment implementation.We want to emphasize the importance of knowledge of rare manifestations of RCC metastases, such as testicular mRCC, so that a severe cancer process in the patient's body, especially when the primary disease is clinically silent, is quickly and adequately recognized.In addition, it will also contribute to faster implementation of surgical and systemic treatments.

Figure 1 .
Figure 1.The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart.

Figure 1 .
Figure 1.The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart.

Figure 2 .
Figure 2. Distribution of age at diagnosis of testicular mRCC between patients with testicular metastases as the first clinical manifestation of RCC and patients without testicular metastases as the first clinical manifestation of RCC.

Figure 2 .
Figure 2. Distribution of age at diagnosis of testicular mRCC between patients with testicular metastases as the first clinical manifestation of RCC and patients without testicular metastases as the first clinical manifestation of RCC.

Figure 3 .
Figure 3. Distribution of time between diagnosis of primary kidney tumor and testicular metastasisin months by T stage of primary RCC site in kidney with the results of the differences between the groups (the pT4 group with fewer than two data points has been omitted).

Figure 3 .
Figure 3. Distribution of time between diagnosis of primary kidney tumor and testicular metastasisin months by T stage of primary RCC site in kidney with the results of the differences between the groups (the pT4 group with fewer than two data points has been omitted).

Table 1 .
The risk of bias analysis based on the Joanna Briggs Institute's critical appraisal tool.

Table 2 .
Characteristics of the cases included in the database in chronological order.mRCC-metastatic renal cell carcinoma; N/A-not available; p-histopathological, tki-tyrosine kinase inhibitor.

Table 3 .
The descriptive statistics of the variables.mRCC-metastatic Renal Cell Carcinoma.

Table 4 .
The distributions of the categorical variables.mRCC-metastatic Renal Cell Carcinoma.