Congenital cryptorchidism or undescended testicle (TND) occurs in 3-5% of full-term male newborns and is considered the most common congenital genitourinary anomaly.1
The testicles do not migrate to the scrotum and remain in the inguinal canal or abdomen.2 Current guidelines recommend that the diagnosis of NDD be made between the 3rd and 6th month,3 in order to schedule surgical treatment for the 12th month. of the child’s life.4
Hormonal therapy with human chorionic gonadotropin (hCG) has been abandoned for many years, as it has had low success rates and many side effects.3 The treatment of choice is inguinal or scrotal orchidopexy and, preferably, it should be scheduled until the end of the first year and no later than 18 months of the child’s life.5
Orchiopexy has a high success rate and very low complication rates (1-3%) . Early surgical correction aims to prevent the long-term complications of cryptorchidism, which are (a) reduced fertility in adult life, (b) increased risk of testicular malignancy, (c) increased risk of testicular torsion, and (d) the psychological effects due to the appearance on the individual.6, 7
In the last five decades, there has been a progressive decrease in the age at which orchidopexy is proposed, as a result of evidence supporting early intervention to prevent testicular damage in untreated cryptorchidism.4 However, and contrary to According to current guidelines, the age distribution of the population undergoing orchidopexy remains diverse and suboptimal, with a higher mean age; The age of orchidopexy has a wide distribution in childhood and adolescence and two peaks that occur in the 2nd and 10th to 11th years of life.7-9
Congenital cryptorchidism is an established risk factor for testicular cancer: 5-10% of all patients with testicular neoplasms have a history of undescended testis (UNDT).
Historically, the connection of congenital cryptorchidism with testicular malignancies was recognized in the early 18th century, and since then, much research has followed and confirmed this suspicion.2
However, there remains notable variability in reported measures of association, with values ranging from 3-fold to 17-fold.10 The most recent meta-analysis was published in 2013 by Lip et al.
The pooled risk ratio for cancer presentation was 2.90 (95% CI, 2.21-3.82).2 Since then, the guidelines of several professional associations have been updated and numerous prospective and observational studies have followed. retrospectives. Both actions could have modified the estimated association. Thus, the application of a mathematical method that processes all bibliographic data, especially recently published prospective and retrospective observational studies, according to the principles of evidence-based medicine, would be useful to present an updated association.
The study was designed with special attention to the definitions of congenital cryptorchidism, orchidopexy in childhood, and the incidence of testicular cancer in adulthood.
| Methods |
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).11 Using a predefined strategy, a search was conducted in the PubMed and Scopus databases from inception to February 2023.
The formulation of the research question was adjusted to the PICO and FINER criteria of the Cochrane Manual of Systematic Reviews.12 A controlled vocabulary was applied with all phrases synonymous with congenital cryptorchidism and testicular cancer. More specifically, the Medical subject Headings (MeSH) and search terms that were used are the following: "undescended testis" OR "undescended testicles" OR "cryptorchidism" (Mesh), AND ["testicular neoplasms" (MeSH) OR {[ testicular* OR testicl*] AND [cancer* OR malignant* OR neoplasm* OR carcinoma* OR tumor* OR tumor*]}].
All observational studies written in English with human participants were included, with no restriction on study duration or year of publication. Unpublished data were not included in the analysis.
The inclusion criteria were the following (a) healthy men with nonsyndromic congenital cryptorchidism, (b) orchidopexy performed before 20 years of age, (c) location of testicular cancer ipsilateral or contralateral with the TND, and (d) cancer testicular in adulthood.
Furthermore, studies that met one of the following criteria were excluded (a) children with congenital or genetic syndromes – genitourinary and neuromuscular anomalies; (b) acquired TND, retractile testes, sliding (elevator) testes, and postoperative cryptorchidism; (c) patients with hormonal treatment of NDD or untreated cryptorchidism maintained in adult life, and (d) animal models.
Two researchers independently extracted data. They initially assessed titles and abstracts, and then assessed full-text articles for appropriateness. Any disagreement between the two researchers was resolved through discussion. The quality of the included studies was then assessed using the Newcastle-Ottawa Scale (NOS).
The NOS is composed of eight items classified into three subgroups: sample selection, comparability of study groups, and outcome determination. Each study can score from 0 to 9 stars, with more stars indicating higher quality.13
| Statistic analysis |
The meta-analysis was performed with RevMan 5.4 edition software. The random defects model was applied to estimate the odds ratio (OR) for the categorical variables, with 95% confidence intervals (CI).
From a statistical point of view, given that three of the six studies in the meta-analysis were case-control studies, the calculation of the total odds ratio was the only appropriate option among the measures of association.
For the included cohort studies that expressed their data in hazard ratios and incidence ratios, ORs with 95% CIs were calculated by extracting the figures from published tabular data and converting the other measures of association into ORs.
Results are presented as mean ± SD. A p value < 0.05 was considered statistically significant. Heterogeneity between reports was estimated with the I-squared statistic. To visually assess ORs, heterogeneity, and potential publication bias, a forest plot and a funnel plot were constructed, respectively.14
| Results |
In total, 2176 studies were identified in the PubMed and Scopus databases. After screening the titles and abstracts, 2083 records were excluded, according to predetermined criteria.
The remaining 93 articles were retrieved and analyzed in full text. Finally, 6 studies were selected in this meta-analysis: three cohort studies and three case-control studies.
The studies were published between 1987 and 2018 and took place in Australia, Europe and the United States. The average Newcastle-Ottawa score was 8/9 for all included records.
The 6 selected studies included a total of 371,681 patients, 25,272 cases of congenital ODD treated surgically until adolescence and 1786 cases of testicular neoplasia.
Adjusted measures of association were estimated in all studies. The results of this meta-analysis demonstrate that congenital cryptorchidism treated surgically until adolescence is statistically significantly associated with the risk of testicular cancer.
The pooled odds ratio was estimated to be 3.99, 2.80-5.71 95% CI in a random defect model. Heterogeneity between studies was moderate, at 51%. A forest plot and graph were constructed to evaluate ORs and potential publication bias, respectively.
Visual evaluation of the funnel plot reveals a small asymmetry, suggesting the existence of some publication bias, although it is difficult to determine symmetry with only six studies.12
| Discussion |
The present meta-analysis demonstrates that congenital cryptorchidism surgically corrected up to 20 years of age is strongly associated with the risk of testicular cancer in adulthood.
Data regarding poorly descended laterality and the side of testicular cancer support that the risk of cancer remains higher for the contralateral, normally descended testis, although to a lesser extent than in the cryptorchid testis.
Early surgical intervention in the first year of life is more protective for the patient, since it prevents testicular damage on the affected side and reduces the overall risk of cancer.
In accordance with the literature, this study provides an estimate of the real association between congenital cryptorchidism surgically corrected until adolescence and adult testicular cancer. The pooled odds ratio for developing testicular cancer risk is almost four times higher.
In the data selection process, a few meta-analyses were found that estimated hazard ratios and ORs for the risk of testicular malignancy in adults. To begin, in 2010, Cook and colleagues applied a highly sensitive investigation of the literature and systematically reviewed 34 studies published between 1976 and 2008.
They reported that the risk of testicular cancer is more than four times higher in men with a history of ODD and the OR was 4.30.3.62-5.11 95% CI.21 Similar results were announced by Lip et al. in 2013. They reviewed 12 observational studies, published between 1987 and 2010, and estimated the risk of testicular cancer in adults: RR=2.90,2.21-3.82 95% CI.2
A meta-analysis by Banks et al followed in 2013, which presented the association of TND with testicular germ cell neoplasia (and not all histological types of testicular neoplasia).
They reviewed 36 observational studies from 1971 to 2007, and the pooled RR was 4.1 3.6-4.7 95% CI.27 Although all the results mentioned coincide with those of the present study, most of them did not focus on the treatment of ODD, whether it was surgical treatment or hormonal therapy or even no treatment at all.
In 2007, Walsh et al investigated the association between surgically corrected undescended testes and testicular cancer in adults, with particular attention to the age of orchiopexy.
They used a cut-off age of 10 to 11 years for surgical intervention and compared the evolution of testicular cancer. They included five observational studies in the meta-analysis, two of which were also included in the present meta-analysis, and supported that testicular malignancy is 1.6 to 7.5 times more likely to occur in men with a history of ODD.
After dichotomizing the data, they estimated that men in whom orchiopexy was delayed after the age of 10 to 11 years or not performed had a higher risk of developing testicular cancer, compared with patients in whom surgery was performed. performed in the prepubertal period, and the pooled OR was 5.80, 1.8-19.3 95% CI.22
Testicular cancer is one of the most common malignancies among adolescents and young adult men in economically developed countries. Its incidence has increased significantly in the last 50 years.21
The etiology of testicular cancer is considered multifactorial, and the associated causes are the following: hereditary factors, family history, abnormal genetic function of stem cells, chemical oncogenesis, human immunodeficiency virus (HIV) infection, age and race.
Trauma to the inguinal area, persistent orchitis, varicocele, and testicular microlithiasis are conditions that have been associated with testicular cancer in the past; However, these theories have been shown to be erroneous and have been abandoned.22, 23
The early onset of the neoplasia and considerable epidemiological evidence led to the recognition of the best-established risk factor: congenital cryptorchidism.
Historically, the connection of congenital cryptorchidism with testicular malignancies was suspected in the early 18th century, and since then, much research has followed and confirmed this suspicion.2
There are two theories that explain the mechanism by which cryptorchidism leads to carcinogenesis.
- The first theory, called the testicular dysgenesis hypothesis , suggests that both conditions share genetic, intrauterine, or environmental causal factors.24
- The second theory, called position theory , suggests that abnormal location of the undescended testicle predisposes to testicular cancer.25
Putting the pieces together, whether the common cause theory or the association of cause and defect is valid, congenital cryptorchidism is undoubtedly a part of the pathway that contributes to testicular malignancy.22
Despite this recognition, there remains notable variability in cancer risk measures, with published values varying between 3 and 17 times.10
There are several possible explanations for this variability, including uncertainty in the diagnosis of undescended testicles and testicular cancer, large variations in the incidence of ODD and cancer risk among different racial and ethnic groups, confusion in the definitions of cryptorchidism congenital, acquired cryptorchidism and retractile testes, flaws in research methods, differences in statistical methodologies, heterogeneity between samples and effects of each published study, and statistical bias.26
Orchiopexy reduces the overall risk of testicular cancer, and the earlier the surgical diversion is performed before puberty, the greater the protection for the child.26
Five studies in the current meta-analysis stratified groups of children based on age at orchiopexy and estimated risk of testicular cancer.
Schneuer et al applied a 5-year cut-off and found that 66% of patients in the sample underwent orchidopexy at age 16 years. Swerdlow et al compared an age cutoff of 10 years and found that only 5.6% of the sample had undergone surgery before that age.
Strader et al applied age limits of 10 and 14 years and found that 32.1% of patients had undergone orchiopexy before the age of 10 years, while 28.5% of them were over 14 years old. the time of the intervention.
Prener and collaborators used cut-off ages of 7 and 15 years, without further information on the number of cases in each group. All studies, except the last one, have shown that orchidopexy in the prepubertal age is more beneficial for the patient, and the earlier it is scheduled, the better for the child.15-20
The latest guidelines from several professional associations, such as the British Association of Pediatric Urologists, the American Urological Association, the European Society of Pediatric Urology Guidelines and the Nordic Consensus statement, recommend performing orchiopexy between 6 and 12 months of age. age (corrected gestational age) or, at the latest, 18 months. 3, 28-30 These guidelines are not universally followed.30 It is also estimated that for each subsequent six-month period that orchiopexy is delayed, there will be a 6% increase in the risk of testicular cancer.5 The protective role of orchiopexy early supports the position theory of carcinogenesis.22
The use of ultrasound is not recommended for the diagnosis of undescended testicle, nor for post-surgical follow-up.
The diagnosis is based on clinical history and physical examination.4 In the included studies, the selection of cases and control patients was based on hospital records, diagnoses coded with the International Classification of Diseases (ICD) system, questionnaires and telephone interviews. There was no mention of any follow-up of patients after cancer diagnosis.
Data on maldescended laterality and side of testicular cancer are controversial. There is evidence to support that the risk of testicular cancer in the opposite descended testicle increases in men with unilateral cryptorchidism, although to a lesser extent than in the ipsilateral testicle.25 On the other hand, there are studies that have not demonstrated an increased risk of cancer testicular in the normally descended testis and also suggest that this risk is similar to that of the general male population.26
In the current meta-analysis, only half of the included studies present data on the laterality of the descended testicle and the risk of malignancy. More specifically, Prener et al estimated that the risk of testicular cancer in the contralateral descended testis is similar to that of the cryptorchid testis,17 while Strader et al and Forman et al mention that the extent of the risk is considerably lower on the unaffected side. 18,19 These observations support the hypothesis that congenital cryptorchidism and testicular cancer share common causal factors and provide information in favor of the common cause theory.25 Finally, the limitations of this meta-analysis are worth mentioning.
- The first limitation is that three of the six included studies were case-control studies. The retrospective characteristics of these studies have a negative effect on data quality.
- Second, the measures of association used in each study were not adjusted in the statistical process.
- Third, a moderate heterogeneity of 51% was estimated with the I-squared statistic. Any type of variability between studies in a systematic review and meta-analysis could be called heterogeneity.
Specifically, the studies in this meta-analysis were conducted during a period between 1987 and 2018 and took place around the world, in the United States, the United Kingdom, Sweden, Denmark, and Australia. Inevitably, these studies put together would differ. All these different nationalities of the participants increase the clinical variability of our study. Furthermore, there is an evident methodological diversity in the studies due to the variability in the study design and the probable risk of bias in all of them.
Consequently, statistical heterogeneity is a consequence of the clinical and methodological variability of the included articles, as well as due to chance. The moderate heterogeneity shows that the interpretation of the results must be done with caution. However, we believe that the heterogeneity is partially balanced by the strengths of this meta-analysis, which are the clearly defined PICO question, the carefully extracted data, and the inclusion of only eligible studies. Furthermore, since only English-language studies were included in the data extraction, the so-called Tower of Babel bias must be taken into account in the meta-analysis.
Last but not least, publication bias must be taken into account in any meta-analysis. More specifically, the funnel plot reveals a small asymmetry, suggesting the existence of some publication bias, although it is difficult to determine symmetry with only six studies contributing to the funnel plot.
On the other hand, it is believed that the limitations and heterogeneity could be balanced by the strengths of the present meta-analysis, which are the clearly defined PICO question, the strict evaluation of the quality of the studies and the quality of the results. The strict inclusion and exclusion criteria, the defined search strategy and the random defect model applied in the meta-analysis. Therefore, accidental exclusion of relevant and important epidemiological data is considered unlikely. 31, 32
| Conclusions |
The results of the meta-analysis verify, with an updated estimate, the well-established association of congenital cryptorchidism with the risk of developing testicular cancer in adulthood, with special attention to surgical treatment until adolescence.
The extensive literature review achieved greater clarity on the suggested age for orchidopexy and its benefits, as well as the laterality of the undescended testis, and highlighted knowledge gaps.
The aforementioned findings offer clinicians updated information about young patients undergoing orchidopexy, in order to better advise them and their families. The moderate heterogeneity and potential publication bias of the included studies should be taken into account when counseling patients and their families.
More prospective studies, with high-quality evidence, are needed to investigate the clinical characteristics of congenital cryptorchidism, the age limits of orchiopexy, compliance with the recommended age for orchiopexy, the laterality of cancer and testicular cancer, the tumor histology and recommended follow-up.
All associations should be further investigated with specific meta-analyses, in order to clarify the mechanisms contributing to carcinogenesis.
