Testicular cancer is the most common cancer in young men, with an incidence in Sweden of 7.4/100,000 [1]. The incidence increases in Europe and several other parts of the world [2, 3]. Ninety-five percent of all testicular cancers are testicular germ cell tumours (TGCT), of which 55–60% are seminomas and 40–45% non-seminomas [4].

The cause of testicular cancer is not known, but some risk factors have been identified, including cryptorchidism, hypospadias, inguinal hernias, previous testicular cancer and family history of testicular cancer [4]. TGCT have a high heritability and genome-wide association studies have identified common variation associated with TGCT susceptibility, which is estimated to account for up to 44% of the disease heritability [5]. Furthermore, low birth weight and short gestational age seem to be associated with an increased risk of TGCT [6]. Some risk factors during adolescence and adulthood have also been described, such as having an occupation as a fire-fighter, working with aircraft maintenance [7] and marijuana smoking [8].

There are indications that the first steps of TGCT oncogenesis occur in utero and it has been hypothesised that cryptorchidism, hypospadias, poor semen quality and TGCT form part of a testicular dysgenesis syndrome with a common origin in fetal life [9, 10]. Both cryptorchidism and hypospadias have been associated with neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and intellectual disabilities (ID) and other behavioural/emotional disorders with onset in childhood [11, 12]. Furthermore, ASD, ADHD and ID share some of the risk factors of TGCT, for example, low birth weight [13, 14]. Moreover, a recent study by Liu et al. [15] investigated the prevalence of neurodevelopmental disorders in paediatric patients with intracranial germ cell tumours and found an association between ASD and pure germinomas.

Few studies have investigated the association between psychiatric disorders and TGCT. One previous study showed that patients with schizophrenia had a lower risk for testicular cancer [16].

The prognosis of TGCT is currently excellent, but some individuals present with a widely disseminated disease, requiring extensive treatment to be cured [4]. For other malignancies, patients with psychiatric disorders are more often diagnosed with advanced stage [17, 18]. Patients with severe psychiatric disorders may also have difficulties accepting cancer treatments [18]. One previous study of TGCT patients showed that a history of psychiatric disorders was associated with worse overall survival (OS) [19].

Our aim was to investigate if history of any neurodevelopmental or other psychiatric disorder is associated with increased risk of TGCT and increased mortality. We had two a priori hypotheses based on clinical observations. Firstly, we hypothesised that psychiatric disorders, specifically neurodevelopmental disorders such as ASD, ADHD and ID, are associated with an increased risk of developing TGCT. Secondly, we hypothesised that psychiatric disorders overall are associated with poorer TGCT prognosis.

Study design

We first used a nested case–control study design to assess the risk of TGCT. We then used a cohort study design to investigate the associations between a history of psychiatric disorders and prognosis among the TGCT patients (i.e. among the cases in the case–control study).

Study population

We included all patients diagnosed with TGCT in Sweden during the years 1992–2014 as cases (Fig. 1). The cases were identified from the Swedish Cancer Register using ICD-9 (186) and ICD-10 (C62), and ICD-O/3.2 (SNOMED/C24 codes, Table S1) and were individually matched for age and calendar period of diagnosis with 10 cancer-free controls each. The controls were identified from the Total Population Register. Mortality data were retrieved from the Swedish Cause of Death Register. TGCT-specific mortality was defined as death due to TGCT as a main or contributing cause of death.

First, we have a case–control design for the aetiological results and a case series (grey box), for the survival results. The number of patients and controls are indicated, and also stratified by subtype and history of psychiatric comorbidity or not. TGCT testicular germ cell tumour, NPR National Patient Register, LISA Longitudinal Integrated Database for Health Insurance and Labour Market Studies, SWENOTECA Sweden Norway Testicular Cancer Group.

Exposures

Data on history of psychiatric diagnoses were retrieved from the nationwide Swedish Patient Register. The Swedish Patient Register includes all in-patient care, and since 2001 also outpatient physician consultations including psychiatric care from both public and private caregivers. History of any psychiatric disorder was defined as having any ICD9 diagnosis of 290–319 (1992–1996) or any ICD10 diagnosis of F00-F99 (after 1997). Diagnoses of psychiatric disorders were identified up until six months prior to the TGCT diagnosis for the cases and index date for the controls. The psychiatric disorders were stratified according to subtype into six categories: Psychotic disorders, Mood and anxiety disorders, Sleep disorders, Eating and personality disorders, Neurodevelopmental disorders and Substance misuse (Table S2).

Although a wide range of psychiatric disorders can be considered neurodevelopmental, we used the term neurodevelopmental disorders to describe this using DSM-5, i.e. ASD (299 or F84 according to ICD9 or ICD10, respectively), ADHD (314 or F90) and ID (317-319 or F70-79). According to DSM-5, communication disorders, specific learning disorders and motor disorders are also classified as neurodevelopmental disorders [20], but data on these disorders were not available.

Covariates

Sociodemographic data were extracted from LISA, the Longitudinal Integrated Database for Health Insurance and Labour Market Studies at Statistics Sweden. The information was retrieved one year prior to the index year for the majority of cases and controls. Level of education was classified into three categories: 9 or less years of school, 10–12 years of school, or more than 12 years of school.

Clinical stage was defined according to Royal Marsden, modified [21]. Details of clinical stage were available from years 2000 and onwards and were identified from the Swedish Testicular Cancer Register held by the SWENOTECA-group. Patients in the study were treated according to the guidelines in the SWENOTECA protocols [22].

History of cryptorchidism was defined as having undergone a surgical correction and the information on operation of cryptorchidism was retrieved from the register of procedures, which is part of the National Patient Register. History of any unspecified congenital malformation was also retrieved from the National Patient Register (Table S2). Data on specific congenital malformations (e.g. hypospadias and unoperated cryptorchidism) was not available.

Statistical analyses

We used conditional logistic regression (conditioned for age and calendar year) to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association of psychiatric diagnoses with TGCT, overall and stratified by histopathological subgroup (seminoma and non-seminoma). We constructed a multivarible model adjusting for education, congenital malformations and cryptorchidism.

Thereafter, we used Kaplan–Meier failure curves and cumulative incidence functions to visualise the differences in mortality. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI to assess the association between psychiatric comorbidity and all-cause and TGCT-specific mortality. We constructed two multivariable models, in the first model we adjusted for age, index year and education, the second model was further adjusted for cancer stage. In a sensitivity analysis educational level was left out of the model, and the results remained essentially unchanged. Due to limited statistical power, since there were few deaths, it was not possible to separately analyse mortality for different subtypes of psychiatric disorders. Follow-up started on the date of diagnosis, and ended on the date of death or administrative censoring (December 31, 2018) in all-cause mortality analyses. In analyses of TGCT-specific mortality, patients were followed from date of diagnosis until death with the underlying cause of death recorded as TGCT as the outcome event, with censoring at death due to other causes, or to administrative end of follow-up (December 31, 2017). Statistical analyses were performed using the SAS 9.4 (SAS Institute, Cary, NC) software.

We included 6166 TGCT patients, of whom 2591 were diagnosed with non-seminoma and 3575 with seminoma, and 61,660 matched controls (Table 1). As expected, history of cryptorchidism was more prevalent among patients than controls.

Risk of TGCT in patients with psychiatric disorders

A history of any psychiatric disorder overall was present in 8.8% of the patients and 8.3% of the controls indicating no significant increased risk of TGCT (OR 1.06; 95% CI 0.96–1.17, Table 2). Comparing TGCT overall to controls revealed no statistically significant differences in proportions of psychiatric disorders. This was also the case for the subgroup of non-seminoma patients.

However, neurodevelopmental disorders were seen among 1.1% of the seminoma patients and among 0.7% of their controls and psychotic disorders were seen among 0.6% of the seminoma patients and among 1.0% of their controls. History of a neurodevelopmental disorder was associated with an increased risk of seminoma (OR 1.54; 95% CI 1.09–2.19) whereas a history of a psychotic disorder was associated with a decreased risk of seminoma (OR 0.62; 95% CI 0.40–0.96) (Table 2).

Age at diagnosis

Median age at diagnosis was 29 years for non-seminoma patients overall and 23 years for non-seminoma patients with neurodevelopmental disorders (Wilcoxon–Mann–Whitney test p < 0.001, Table S3).