ABSTRACT
Background
Hepatic steatosis (HS) development and its risk factors in testicular germ cell tumor (TGCT) survivors have not been investigated.
Methods
The study was designed as a retrospective observational study. Patients with existing HS at diagnosis were excluded. Serial imaging was utilized to detect HS.
Results
A total of 106 TGCT survivors were included. HS developed in 57% (n = 61) during a median follow-up of 51.8 months (8.5–241.5); 77% (n = 47) of those had persistent HS. Patients who developed HS had a higher baseline body mass index (BMI) (median 26.5 vs. 23.6 kg/m2, p = 0.000). Higher baseline BMI [adjusted odds ratio (aOR): 1.35, (95% CI: 1.10–1.65) p = 0.004] and S0 stage [aOR: 3.87, (95% CI: 1.18–12.67), p = 0.025] were associated with a higher risk of HS development. The median time from the diagnosis of TGCT to the detection of HS was 44.7 months (29.5–59.8). Higher baseline BMI was associated with earlier development of HS both in all patients [hazard ratio (HR): 1.16, (95% CI: 1.04–1.30), p = 0.007] and patients treated with the BEP regimen [HR: 1.21, (95% CI: 1.01–1.47), p = 0.038].
Conclusion
HS may be considered a long-term complication in TGCT patients. The risk is associated with baseline BMI. Diagnosis and management of HS should be implemented in the survivorship care plan of TGCT survivors.
KEYWORDS: Testicular, germ cell tumor, survivor, hepatic steatosis, fatty liver, body mass index, BMI
GRAPHICAL ABSTRACT
1. Introduction
Testicular germ cell tumor (TGCT) is the most common cancer among young males between 15 and 40 years [1]. Approximately 75.000 new cases are diagnosed per year worldwide [2]. The cure rates are high with a 10-year overall survival rate exceeding 95% [3].
As TGCT patients are at a young age at the time of presentation and have high cure rates, the early detection and management of treatment-related long-term complications and follow-up are of utmost importance. Metabolic syndrome may be counted among the long-term complications observed among TGCT survivors, despite conflicting results in the studies [4,5]. On the other hand, hepatic steatosis (HS) and nonalcoholic fatty liver disease (NAFLD) are among the strongest indicators of metabolic syndrome [6]. NAFLD is a global alarming problem with an increase in incidence, from 20 cases per 1000 person-years in the year 2000 to 70 cases per 1000 person-years by 2015 [7]. It is an independent risk factor for cardiovascular and end-stage liver disease [8]. In addition to the association between HS and metabolic syndrome, chemotherapy is also counted among the causes of HS. A commonly used chemotherapeutic agent, cisplatin was reported to be among the rare causes of HS, albeit usually transient [9]. Chemotherapy-induced acute steatohepatitis is usually a reversible clinical entity after the cessation of anti-neoplastic treatment. However, persistent HS and steatohepatitis were also reported [10,11].
Given the aforementioned information, HS may be one of the long-term complications in TGCT survivors. However, to the best of our knowledge, this topic has not been investigated in medical literature. In this study, we retrospectively investigated HS prevalence and its potential association with metabolic syndrome and chemotherapy in TGCT survivors.
2. Methods
2.1. Patients and study design
The study was designed as a single-center, retrospective observational study. Follow-up patients with TGCT at Ankara University, Faculty of Medicine, Department of Medical Oncology, and those who had their last clinical visits between 1 January 2019 and 1 March 2023 were included. All patients had at least a 6-month follow-up period with serial imaging. Patients with testicular tumors other than germ cell origin and the ones who have secondary testicular germ cell or non-testicular germ cell tumors were excluded. Patients with a history of alcohol abuse, diabetes, dyslipidemia, hypertension, and HS at the time of tumor diagnosis were excluded. Demographic data such as age, smoking history, body mass index (BMI), primary tumor localization (left-right testicle), date of radical orchiectomy (also accepted as the exact date of diagnosis), tumor histology (seminoma and non-seminoma), presence of embryonal carcinoma, yolk sac carcinoma, choriocarcinoma, and teratoma components, tumor size, presence of lymphovascular and rete testis invasion, germ cell neoplasia in situ, T, N, M, and S stage, overall stage (according to AJCC 8th edition, 2017) [12–14], primary treatment (follow-up, one dose carboplatin, bleomycin-cisplatin-etoposide protocol (BEP), etoposide-ifosfamide-cisplatin protocol (VIP)), number of BEP treatment cycles, presence of retroperitoneal lymph node dissection (RPLND), and absence/presence of disease recurrence were all recorded. Primary treatment was defined as the management after orchiectomy, either as adjuvant for earlier stages or as definitive for initial stage 3, metastatic diseases. Pathological specimens and imaging results were assessed, and final reports were issued by the genitourinary pathologists and abdominopelvic imagers from the Department of Pathology and Department of Radiology of Ankara University, Faculty of Medicine.
The routine clinical follow-up visits and serial imaging protocols in our clinic are based on either the National Comprehensive Cancer Network (NCCN) or European Society of Medical Oncology (ESMO) guidelines. Follow-up imaging reports of the patients from the time of diagnosis to the last follow-up were analyzed. The presence of HS reported in any imaging modality (computed tomography, ultrasonography, magnetic resonance imaging) was recorded. “Persistent hepatic steatosis” was defined as the clinical situation where HS was detected in every imaging study until the last imaging exam during the follow-up. The first and last detection dates of HS were recorded to analyze the median time to HS development and median duration of persistent HS. The patient selection strategy is detailed in Figure S1 (Supplementary).
Body mass index, hypertension, diabetes mellitus, dyslipidemia, and serum metabolic and lipid panel values were recorded at the time of first detection of HS.
The baseline characteristics were compared between the groups who developed HS and those who did not develop HS to investigate any risk factors for the development of HS. The baseline characteristics were also used to analyze their relationship with time-to-event (HS). The metabolic syndrome-associated parameters at the date of first detection of HS were presented to interpret any relevance with metabolic syndrome.
2.2. Statistical analysis
Continuous variables were given as median (minimum (min)-maximum (max)). Categorical variables were presented as percentages. Univariate analyses were performed using chi-square, Fisher exact, Student’s t, and Mann–Whitney U-tests, where needed. The statistically significant and clinically associated variables in the univariable analysis were included in the multivariable analysis. Multivariable analysis was performed using binary logistic regression analysis. Time-to-event data were estimated using the Kaplan–Meier method and compared using the log-rank test. The Cox regression method was used for univariable and multivariable analyses, and significant and clinically associated variables in univariable analysis were included in the multivariable analysis. All p-values were based on a 2-tailed test of significance (p = 0.05). All the statistical analyses were conducted using the software SPSS version 26 (SPSS Inc, USA).
3. Results
3.1. Baseline characteristics
A total of 158 patients with testicular cancer were detected. Eighteen (11.4%) patients were excluded because of existing HS at the diagnosis and 106 patients were selected as the study population (Figure S1, supplementary). Baseline characteristics of the whole study population are shown in Table 1. The median age was 26 (16–55), and smoking history was positive in 34.9% of the patients. The median BMI of the study population was found to be 25.2 (17.4–33.9). About 63.2% of the patients had non-seminoma tumors. The median tumor size was 3.5 cm (1–11.7) at diagnosis. Lymphovascular invasion was positive in 31.1% of the patients, whereas rete testis invasion was found in 19.8%. The proportion of stage 1 disease was 45.3%. Among patients with stage 3 disease, the risk group was “good” in 48.5%. Treatment and recurrence characteristics of the population are presented in Table 2. 67.9% of the patients had BEP chemotherapy after radical orchiectomy, with a median cycle of 3 (1–6). Retroperitoneal lymph node dissection (RPLND) was performed in 14.2% of the patients, either due to residual disease or as part of the adjuvant treatment. Recurrence was observed in 23.6% of the patients during clinical follow-up.
Table 1.
Characteristics of the study population and hepatic steatosis subgroups at the diagnosis [Pre-existing HS at the diagnosis was an exclusion criterion for the study. n = 18 (11.4%) of 158 patients had HS at the diagnosis and were excluded from the study. This table shows patient groups who developed or did not develop HS during the follow-up.].
| Variable | Whole population: n = 106 (100%) | HS (+) n = 61 (57%) |
HS (-) n = 45 (42.5%) |
P* |
|---|---|---|---|---|
| Age, median(min-max) | 26 (16-55) | 30 (16-55) | 26 (16-54) | 0.133 |
| Smoking, n (%) | ||||
| Never | 69 (65.1) | 38 | 31 | 0.406 |
| Ex-smoker | 3 (2.8) | 3 | 0 | |
| Current | 34 (32.1) | 20 | 14 | |
| Smoking Packet/year, median(min-max) | 10 (3-40) | 10 (3-25) | 20 (4-40) | 0.022 |
| BMI, kg/m2, median (min-max) | 25,2 (17.4-33.9) | 26,5 (19-33.9) | 23,6 (17.4-30.4) | 0.000 |
| Primary localization, n (%) | ||||
| Left testicle | 56 (52.8) | 33 (54) | 23 (51.1) | 0.761 |
| Right testicle | 50 (47.2) | 28 (46) | 22 (48.9) | |
| Histology, n (%) | ||||
| Seminoma | 39 (36.8) | 28 (46) | 11 (24.4) | 0.019 |
| Non-seminoma | 67 (63.2) | 33 (54) | 34 (75.6) | |
| Embryonal carcinoma component, n (%) | ||||
| Present | 50 (47.2) | 27 (44.2) | 23 (51.1) | 0.485 |
| Absent | 56 (52.8) | 34 (55.8) | 22 (48.9) | |
| Yolk sac carcinoma component, n (%) | ||||
| Present | 32 (30.2) | 15 (24.5) | 17 (37.7) | 0.144 |
| Absent | 74 (69.8) | 46 (75.5) | 28 (62.3) | |
| Choriocarcinoma component, n (%) | ||||
| Present | 8 (7.5) | 4 (6.5) | 4 (8.8) | 0.720 |
| Absent | 98 (92.5) | 57 (93.5) | 41 (91.2) | |
| Teratoma component, n (%) | ||||
| Present | 33 (31.1) | 15 (24.5) | 18 (40) | 0.137 |
| Absent | 73 (68.9) | 46 (75.5) | 27 (60) | |
| Tumor size, cm, median (min-max) | 3,5 (1-11.7) | 3.5 (1-11) | 3.5 (1.2-11.7) | 0.729 |
| Lymphovascular invasion, n (%) | ||||
| Present | 33 (31.1) | 23 (37.7) | 10 (22.2) | 0.111 |
| Absent | 72 (37.9) | 38 (62.3) | 35 (77.8) | |
| Rete invasion, n (%) | ||||
| Present | 21 (19.8) | 15 (24.5) | 6 (13.3) | 0.218 |
| Absent | 85 (80.2) | 46 (75.5) | 39 (86.7) | |
| Germ cell neoplasia in situ, n (%) | ||||
| Present | 37 (34.9) | 22 (36) | 15 (33.3) | 0.838 |
| Absent | 669 (65.1) | 39 (64) | 30 (66.7) | |
| pT stage, n (%) | ||||
| 1 | 64 (60.4) | 36 (59) | 28 (62.2) | 0.931 |
| 2 | 39 (36.8) | 23 (37.7) | 16 (35.5) | |
| 3 | 3 (2.8) | 2 (3.3) | 1 (2.3) | |
| N stage, n (%) | ||||
| 0 | 50 (47.2) | 30 (49.1) | 20 (44.4) | 0.828 |
| 1 | 29 (27.4) | 17 (27.9) | 12 (26.7) | |
| 2 | 12 (11.3) | 7 (11.5) | 5 (11.1) | |
| 3 | 15 (14.2) | 7 (11.5) | 8 (17.8) | |
| M stage, n (%) | ||||
| 0 | 94 (88.7) | 55 (90.1) | 39 (86.7) | 0.758 |
| 1 | 12 (11.3) | 6 (9.9) | 6 (13.3) | |
| S stage, n (%) | ||||
| 0 | 44 (41.5) | 30 (49.2) | 14 (31.2) | 0.034 |
| 1 | 42 (39.6) | 25 (40.9) | 17 (37.8) | |
| 2 | 16 (15.1) | 5 (8.2) | 11 (24.4) | |
| 3 | 4 (3.8) | 1 (1.7) | 3 (6.6) | |
| Stage, n (%) | ||||
| 1 | 48 (45.3) | 30 (49.2) | 18 (40) | 0.257 |
| 2 | 25 (23.6) | 16 (26.2) | 9 (20) | |
| 3 | 33 (31.1) | 15 (24.6) | 18 (40) | |
| Risk group (for stage 3), n (%) | ||||
| Good | 16 (48.5) | 10 (66.7) | 6 (33.3) | 0.102 |
| Intermediate | 15 (45.5) | 5 (33.3) | 10 (55.6) | |
| Poor | 2 (6) | 0 (0) | 2 (11.1) |
HS: hepatic steatosis, BMI: body mass index.
The sıgnıfıcant p values (<0.05) were wrıtten bold.
Table 2.
Treatment and recurrence characteristics.
| Variable | Whole population, n = 106 | HS (+), n = 61 (57%) | HS (-), n = 45 (42.5%) | P* |
|---|---|---|---|---|
| Primary treatment, n (%) | ||||
| Follow-up | 25 (23.6) | 16 (26.2) | 9 (20) | 0.662 |
| Carboplatin (1 dose) | 8 (7.5) | 5 (8.2) | 3 (6.7) | |
| BEP | 72 (67.9) | 40 (65.6) | 32 (71.1) | |
| VIP | 1 (0.9) | 0 (0) | 1 (2.2) | |
| BEP cycle number, median (min-max) | 3 (1-6) | 3 (1-6) | 3 (1-6) | 0.704 |
| RPLND, n (%) | ||||
| Yes | 15 (14.2) | 6 (9.9) | 9 (20) | 0.165 |
| No | 91 (85.8) | 55 (90.1) | 36 (80) | |
| Recurrence, n (%) | ||||
| Yes | 25 (23.6) | 15 (24,6) | 10 (22.2) | 0.821 |
| No | 81 (76.4) | 46 (75.4) | 35 (77.8) | |
| Median follow-up, months, median (min-max) | 51.8 (8.5-241.5) | 55 (14.3-230.8) | 42,8 (1.5-241.5) | 0.135 |
HS: hepatic steatosis, BEP: bleomycin-cisplatin-etoposide VIP: etoposide-ifosfamide-cisplatin RPLND: retroperitoneal lymph node dissection.
3.2. Hepatic steatosis
The median follow-up of the patients was 51.8 months (8.5–241.5). Fifty-seven percent (n = 61) of the patients developed HS during the follow-up. The median time from diagnosis to development of HS was 44.7 months (29.5–59.8) (Figure 1(a)). Baseline and treatment-recurrence characteristics were compared as univariable and multivariable between HS (+) and HS (-) groups (Tables 2 and 3). In the univariable analysis, smoking history did not differ between groups. However, the median packet/year was significantly higher in the HS (-) group than in the HS (+) [10 (3–25) vs 20 (4–40), p = 0.022) among patients with smoking history. Median BMI was higher in the HS (+) group (26.5 (19–33.9) vs. 23.6 (17.4–30.4) kg/m2, p = 0.000) compared to the HS (-) group. After adjusting for variables in the multivariable analysis, higher BMI remained to be associated with a higher risk of HS development (Odds ratio (OR): 1.35, (95% confidence interval (CI): 1.10–1.65), p = 0.004) (Table 3). Non-seminoma histology was found to be higher in the HS (-) group (75.6% vs 54%, p = 0.019). Finally, the proportion of S stage 1-2-3 was higher in the HS (-) group in the univariable analysis and was a significant factor for lower risk of HS development in multivariable analysis (OR: 0.25, (95% CI: 0.07–0.84), p = 0.025) (Table 3). The baseline characteristics were used to analyze their relationship with time-to-event (HS) data as univariable and multivariable in all patients and in patients treated with the BEP regimen (Table 4. Expanded tables and analyses are presented in Table 1S and 2S). In all patients, BMI, histology, rete invasion, and lymphovascular invasion were statistically significant in univariable analyses. Multivariable analysis including these variables revealed that only baseline BMI was statistically significant [HR: 1.16, (95% CI: 1.04–1.30), p = 0.007], suggesting higher baseline BMI was associated with earlier HS development. In patients treated with the BEP regimen, age, BMI, histology, yolk sac component, rete invasion, lymphovascular invasion, S stage, and BEP cycle number were statistically significant in univariable analyses. Age [HR: 1.07 (95% CI: 1.00–1.14), p = 0.031] and BMI [HR: 1.21 (95% CI: 1.01–1.47), p = 0.038] remained significant in multivariable analysis, suggesting that older age and higher BMI at diagnosis are associated with earlier development of HS (Table 4).
Figure 1.
(a) Hepatic steatosis development. (b) Baseline BMI and hepatic steatosis development in all patients. (c) Baseline BMI and hepatic steatosis development in patients treated with BEP regimen.
Table 3.
Binary logistic regression analysis for risk factors of hepatic steatosis.
| Variable | Unadjusted OR (95% CI) | P | Adjusted OR* (95% CI) | P |
|---|---|---|---|---|
| Age (continuous variable) |
1.03 (0.98–1.08) | 0.135 | 1.04 (0.97–1.12) | 0.184 |
| BMI (continuous variable) |
1.34 (1.12–1.61) | 0.001 | 1.35 (1.10–1.65) | 0.004 |
| Smoking history (Present vs. absent) |
1.34 (0.59–3.03) | 0.492 | 0.93 (0.30–2.89) | 0.913 |
| Histology (Non-seminoma vs seminoma) |
0.38 (0.16–0.88) | 0.026 | 1.37 (0.36–5.17) | 0.637 |
| S stage (S1-2-3 vs S0) |
0.46 (0.20–1.04) | 0.064 | 0.25 (0.07–0.84) | 0.025 |
*A significant model (chi-square = 21.724, df = 5, p = 0.001), constant p = 0.003, BMI: body mass index, OR: Odds ratio.
The sıgnıfıcant p values (<0.05) were wrıtten bold.
Table 4.
Univariable and multivariable cox-regression analysis for time to hepatic steatosis development (all patients and patients treated with BEP regimen) (expanded tables and analyses are presented in Table 1S and 2S).
| Univariable |
Multivariable |
|||
|---|---|---|---|---|
| Variable | HR (95% CI) | P* | HR (95% CI) | P* |
| ALL PATIENTS | ||||
| BMI (continuous variable) |
1.14 (1.03–1.25) | 0.007 | 1.16 (1.04–1.30) | 0.007 |
| Histology (Non-seminoma vs seminoma) |
0.56 (0.33–0.95) | 0.032 | 0.37 (0.34–1.30) | 0.244 |
| Lymphovascular invasion Present vs absent |
1.79 (1.06–3.04) | 0.029 | 1.07 (0.50–2.29) | 0.847 |
| Rete invasion Present vs absent |
2.40 (1.29–4.45) | 0.005 | 2.23 (0.97–5.09) | 0.056 |
| PATIENTS TREATED WITH BEP REGIMEN | ||||
| Age at the diagnosis (continuous variable) | 1.03 (1.00–1.07) | 0.014 | 1.07 (1.00–1.14) | 0.031 |
| BMI at the diagnosis (continuous variable) |
1.12 (1.00–1.26) | 0.040 | 1.21 (1.01–1.47) | 0.038 |
| Histology Non-seminoma vs seminoma |
0.31 (0.15–0.62) | 0.001 | 0.82 (0.23–2.94) | 0.770 |
| Yolk sac component Absent vs present |
2.20 (1.04–4.66) | 0.039 | 2.13 (0.51–8.85) | 0.294 |
| Lymphovascular invasion Present vs absent |
2.24 (1.17–4.27) | 0.014 | 0.82 (0.24–2.75) | 0.757 |
| Rete invasion Present vs absent |
2.22 (1.03–4.76) | 0.039 | 0.56 (0.16–1.93) | 0.362 |
| S stage 1 vs 0 2 vs 0 3 vs 0 |
0.44 (0.22–0.88) 0.25 (0.08–0.76) 0.14 (0.01–1.12) |
0.022 0.016 0.064 |
0.38 (0.11–1.24) 0.68 (0.07–6.37) 0.14 (0.01–1.68) |
0.112 0.736 0.124 |
| BEP cycle number (continuous variable) |
0.72 (0.54–0.98) | 0.039 | 0.67 (0.35–1.27) | 0.226 |
BMI: body mass index, BEP: bleomycin-cisplatin-etoposide, HR: hazard ratio.
The sıgnıfıcant p values (<0.05) were wrıtten bold.
The clinical characteristics of 61 patients with HS at the time of the initial detection of HS are presented in Table 5. The median age was 33 (17–56) at the time of the HS detection. The median BMI was 27.4 (22.2–42.4). Among these 61 patients, 14.7% had been diagnosed with hypertension, 8.2% with diabetes mellitus, and 37.7% with dyslipidemia during follow-up from diagnosis of germ cell tumor to development of HS. Median fasting blood glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were within normal limits. About 11.5% of the patients with HS had elevated liver transaminase levels. Seventy-seven percent (n = 47) of the patients who developed HS had persistent HS (they had HS in all serial imaging reports during follow-up). The median duration of HS in all patients with HS was 26 months (2–212).
Table 5.
Clinical characteristics at the date of first hepatic steatosis detection.
| Variable | n = 61 |
|---|---|
| Age, median(min-max) | 33 (17–56) |
| BMI, kg/m2, median(min-max) | 27.4 (22.2–42.4) |
| HT, n (%) DM, n (%) Dyslipidemia, n (%) |
9 (14.7) 5 (8.2) 23 (37.7) |
| Fasting blood glucose, mg/dL, median(min-max) | 88.5 (73–180) |
| Lipid profile (median min-max) | |
| Total cholesterol, mg/dL HDL, mg/dL LDL, mg/dL Triglyceride, mg/dL |
183 (113–349) 40 (26–67) 103 (48–235) 148 (44–544) |
| Elevated liver transaminases, n (%) | 7 (11.5) |
BMI: body mass index, HT: hypertension, DM: diabetes mellitus, HDL: high-density lipoprotein, LDL: low-density lipoprotein.
4. Discussion
In this study, we describe and characterize the HS development among TGCT survivors. To the best of our knowledge, this is the first study in the literature that assesses this issue. We found that 57% of the patients developed HS, and 77% of those had persisted HS. Higher baseline BMI was associated with both HS development risk and earlier occurrence.
The estimated worldwide prevalence of NAFLD in adults is 25% and 20.7% in young adults of mean age 24; a BMI in the overweight or obese range is positively associated with HS [15]. Studies about the prevalence of NAFLD in Türkiye reported varying results according to age [16]. In a local study of individuals with a mean age of 39, the prevalence of NAFLD was 19.8% [16]. Another study revealed a prevalence of 23.2% in young adults with a mean age of 20.5 [17]. In a large study with 8120 healthy individuals, the <30-year-old group had a 23% prevalence of NAFLD, and the 30–40-year-old group had a prevalence of 38.7% [18]. In our study, the median age at the diagnosis was 26, and none of the patients had HS at the time of diagnosis in our patient group according to the exclusion criteria. Fifty-seven percent of the patients developed HS at a median age of 33. Although we do not have a control group in the study, we found that the HS prevalence is higher among TGCT survivors than in the general and Turkish populations according to age. Additionally, older age in patients treated with the BEP regimen was associated with earlier development of HS, which is consistent with the literature that shows an increased prevalence of NAFLD by age [18].
HS is known to have a strong association with metabolic syndrome. Metabolic syndrome has also been shown to be among the long-term complications seen in TGCT survivors [19]. The increased incidence of metabolic syndrome identified in long-term survivors appears to be most likely associated with lower testosterone levels in these patients [20]. In a cohort of 255 TGCT survivors (median age, 38.7 years; at a mean of 7.8 years after anti-cancer treatment), metabolic syndrome risk increased by 1.9 compared to healthy controls where hypogonadism and chemotherapy were the main risk factors [4]. Moreover, a recent study reported that high BMI was associated with both primary and secondary low testosterone levels in TGCT survivors [21]. A different study comprising 486 survivors showed that metabolic syndrome frequency was not significantly different from the control group. However, survivors were found to have a higher prevalence of hypertension, higher LDL levels, and BMI [5]. In a study of 336 TGCT survivors, low testosterone levels showed a strong correlation with hyperglycemia, hypercholesterolemia, hypertriglyceridemia, inflammatory processes, procoagulant state, and obesity. Despite these findings, testosterone replacement therapy in a randomized double-blind study did not improve metabolic health in TGCT survivors. However, replacement was associated with a modest decrease in fat mass after 12 months compared to placebo [22]. Although these studies suggest metabolic syndrome as a long-term complication of TGCT, the results are somewhat conflicting. In our study, metabolic syndrome-related clinical characteristics of the patients who developed HS at the date of HS development do not suggest a strong relationship between HS and metabolic syndrome among TGCT survivors. We found the median BMI as 27.4 kg/m2 (22.2–42.4) at the time of detection of HS. This median BMI at the detection of HS was similar to BMI at the diagnosis of TGCT [25.2 kg/m2 (17.4–33.9)]. Yet, a higher baseline BMI was significantly associated with the risk of HS development and earlier occurrence. Despite the effect of BMI, a smaller proportion of the patients who developed HS had hypertension (14%), diabetes (8.7%), and dyslipidemia (37.7%). Median fasting blood glucose, total cholesterol, LDL, HDL, and triglyceride levels were within normal limits in these patients. These results may suggest that HS development among TGCT survivors may have multifactorial etiologies such as high BMI, chemotherapy effect, and hypogonadism besides metabolic syndrome.
Metabolic syndrome has been associated with testicular damage. An interesting study revealed that the presence of liver steatosis was associated with germinal epithelial loss, with a positive correlation between the degree of parenchymal steatosis and the severity of germinal epithelial loss [23]. It is not known whether HS is the cause or the result of germinal epithelial loss. Based on our findings, we may speculate that loss of germinal epithelial loss may be the underlying cause of HS development since we did not include the patients with HS at the time of diagnosis.
The liver has a complex organization and functions in the intermediate metabolism of nutrient molecules and for the clearance of toxic agents. Chemotherapy use is a challenge for tight regulation in physiology and proper function of the liver. Most drugs are lipophilic, which causes them to be easily taken by the liver. Various toxic effects may be observed, which can mimic all types of acute and chronic hepatobiliary diseases, including HS. Cisplatin commonly may cause increased aminotransferases, and rarely steatosis and cholestasis [9]. In a comparative analysis of primary treatment of TGCT, primary chemotherapy was associated with long-term risks of hypogonadism and metabolic syndrome [24]. Chemotherapy-induced acute steatohepatitis is usually reversible after cessation of the treatment. However, persistent steatosis and steatohepatitis may not be uncommon clinical situations [10,11]. In our study, the median time for HS development was 44.7 months, and 77% of those were persistent HS. However, we did not find chemotherapy or BEP cycle numbers as risk factors for HS development. Yet, more than 75% of the patients in our study received chemotherapy, which may contribute to the development of HS.
Our study showed that S stage 0 was associated with an increased risk of HS development compared to S stage 1-2-3. This result may reflect that HS development is a complication for survivors. However, whether tumor markers themselves (AFP, beta-hCG, LDH) may be modulators in lipid metabolism and HS development remains to be investigated [25].
As cardiovascular diseases are among the long-term complications for TGCT survivors, baseline and follow-up lipid profile testing and counseling regarding cardiovascular risk factors are recommended and patients are encouraged to adopt a healthy lifestyle, including a heart-healthy diet, regular exercise, and weight loss when needed [26]. On the other hand, surveillance imaging is typically not recommended beyond 5 years in asymptomatic patients, and further management is recommended according to the survivorship care plan [26]. Since HS is a risk factor for cardiovascular and chronic liver diseases and the median time of HS development was 44.7 months, surveillance and detection of HS should be incorporated into the survivorship care plan of TGCT patients. As a suggestion, yearly hepatic ultrasonography may be recommended along with other survivorship examinations such as metabolic parameters.
Our study has some limitations. Firstly, the study has inherent limitations of its retrospective nature. Ideally, the study would include metabolic syndrome-related data at the diagnosis of germ cell tumors for optimal comparison. Comparing metabolic syndrome-related data of the HS (+) group and the matched HS (-) group at the time of HS detection would be highly valuable and informative. Unfortunately, we do not have this information due to the retrospective nature of our study. Another limitation of our study is the absence of a control group. Young age and long survival of this patient group necessitate large-scale, well-designed long-term prospective studies. We do not have waist circumferences and serum testosterone levels of our patients in this current study. The use of radiology as the sole indicator of the presence of HS may be another potentially significant limitation. Determination of HS by different imaging methods and different observers is among the limitations of the study to provide standardization. Long-term metabolic effects of HS including liver fibrosis, and cardiovascular disease, as well as the effect of HS on overall survival, may be studied in future prospectively designed studies.
5. Conclusions
HS may be an important but ignored, long-term complication among patients with a history of TGCT. The BMI at diagnosis is a significant indicator of HS development, yet developmental mechanisms may be complex and multifactorial. Better-designed prospective studies, which also take into account molecular aspects of the process, will be helpful to shed more light on the causes and consequences of HS in this patient group. Since HS itself is associated with significant morbidity and mortality such as cardiovascular and chronic liver diseases, diagnosis and management of HS during follow-up of TGCT survivors are of utmost importance.
Supplementary Material
Funding Statement
This paper was not funded.
Article highlights
Hepatic steatosis (HS) (fatty liver) development among TGCT survivors has not been investigated.
Fifty-seven percent of TGCT survivors developed HS.
Median time to HS development was 44.7 months.
Seventy-seven percent of patients who developed HS had persistent HS.
Higher baseline BMI and S0 stage were associated with a higher risk of HS development.
Higher baseline BMI was associated with earlier development of HS.
Diagnosis and management of HS should be implemented in the survivorship care plan of TGCT survivors.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Author contributions
All authors contributed to the study’s conception and design. Erman Akkus, Başak Gülpınar, and Evren Süer collected the data. Erman Akkus and Yüksel Ürün performed analysis and interpretation of the data. The first draft of the manuscript was written by Erman Akkus and Ali Devrim Karaosmanoğlu. All authors commented on and revised previous versions of the manuscript. All authors read and approved the final manuscript.
Data availability statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethical disclosure
Ethical approval was obtained from the Clinical Research Ethics Committee of Ankara University Faculty of Medicine (Number: İ09-639-23) in compliance with the Helsinki Declaration. The study analyzed retrospective, anonymous clinical data of the patients. Informed consent of the patients was not required, and waiver/exemption was granted by the Ethics Committee.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2025.2467613
References
- 1.Chia VM, Quraishi SM, Devesa SS, et al. International trends in the incidence of testicular cancer, 1973–2002. Cancer Epidemiol Biomarkers Prev. 2010;19(5):1151–1159. doi: 10.1158/1055-9965.EPI-10-0031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bray F, Richiardi L, Ekbom A, et al. Trends in testicular cancer incidence and mortality in 22 European countries: continuing increases in incidence and declines in mortality. Int J Cancer. 2006;118(12):3099–3111. doi: 10.1002/ijc.21747 [DOI] [PubMed] [Google Scholar]
- 3.Travis LB, Beard C, Allan JM, et al. Testicular cancer survivorship: research strategies and recommendations. J Natl Cancer Inst. 2010;102(15):1114–1130. doi: 10.1093/jnci/djq216 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Willemse PM, Burggraaf J, Hamdy NA, et al. Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors. Br J Cancer. 2013;109(1):60–67. doi: 10.1038/bjc.2013.226 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• of considerable interest.
- 5.Zaid MA, Gathirua-Mwangi WG, Fung C, et al. Clinical and genetic risk factors for adverse metabolic outcomes in north American testicular cancer survivors. J Natl Compr Canc Netw. 2018;16(3):257–265. doi: 10.6004/jnccn.2017.7046 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• of considerable interest.
- 6.Almeda-Valdés P, Cuevas-Ramos D, Aguilar-Salinas CA.. Metabolic syndrome and non-alcoholic fatty liver disease. Ann Hepatol. 2009;8(Suppl 1):S18–24. doi: 10.1016/S1665-2681(19)31822-8 [DOI] [PubMed] [Google Scholar]
- 7.Le MH, Le DM, Baez TC, et al. Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons. J Hepatol. 2023;79(2):287–295. doi: 10.1016/j.jhep.2023.03.040 [DOI] [PubMed] [Google Scholar]
- 8.Tomeno W, Imajo K, Takayanagi T, et al. Complications of non-alcoholic fatty liver disease in extrahepatic organs. Diagnostics (Basel). 2020;10(11):912. doi: 10.3390/diagnostics10110912 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ramadori G, Cameron S. Effects of systemic chemotherapy on the liver. Ann Hepatol. 2010;9(2):133–143. doi: 10.1016/S1665-2681(19)31651-5 [DOI] [PubMed] [Google Scholar]
- 10.Paternostro R, Sieghart W, Trauner M, et al. Cancer and hepatic steatosis. ESMO Open. 2021;6(4):100185. doi: 10.1016/j.esmoop.2021.100185 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vigano L, De Rosa G, Toso C, et al. Reversibility of chemotherapy-related liver injury. J Hepatol. 2017;67(1):84–91. doi: 10.1016/j.jhep.2017.02.031 [DOI] [PubMed] [Google Scholar]
- 12.International Germ Cell Cancer Collaborative Group . International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol. 1997;15(2):594–603. doi: 10.1200/JCO.1997.15.2.594 [DOI] [PubMed] [Google Scholar]
- 13.Gillessen S, Sauvé N, Collette L, et al. Predicting Outcomes in Men with Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results from the IGCCCG Update Consortium. J Clin Oncol. 2021;39(14):1563–1574. doi: 10.1200/JCO.20.03296 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Beyer J, Collette L, Sauvé N, et al. Survival and New Prognosticators in Metastatic Seminoma: Results from the IGCCCG-Update Consortium. J Clin Oncol. 2021;39(14):1553–1562. doi: 10.1200/JCO.20.03292 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Abeysekera KWM, Fernandes GS, Hammerton G, et al. Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study. Lancet Gastroenterol Hepatol. 2020;5(3):295–305. doi: 10.1016/S2468-1253(19)30419-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kaya E, Yılmaz Y. Non-alcoholic fatty liver disease: A growing public health problem in Turkey. Turk J Gastroenterol. 2019;30(10):865–871. doi: 10.5152/tjg.2019.18045 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kaya E, Demir D, Alahdab YO, et al. Prevalence of hepatic steatosis in apparently healthy medical students: a transient elastography study on the basis of a controlled attenuation parameter. Eur J Gastroenterol Hepatol. 2016;28(11):1264–1267. doi: 10.1097/MEG.0000000000000681 [DOI] [PubMed] [Google Scholar]
- 18.Değertekin B, Tozun N, Demir F, et al. The Changing Prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) in Turkey in the Last Decade. Turk J Gastroenterol. 2021;32(3):302–312. doi: 10.5152/tjg.2021.20062 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Amiri A, Krumpolec P, Mego M, et al. Habitual physical activity modulates cardiometabolic health in long-term testicular cancer survivors. Support Care Cancer. 2023;31(9):539. doi: 10.1007/s00520-023-08000-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Efstathiou E, Logothetis CJ. Review of late complications of treatment and late relapse in testicular cancer. J Natl Compr Canc Netw. 2006;4(10):1059–1070. doi: 10.6004/jnccn.2006.0088 [DOI] [PubMed] [Google Scholar]
- 21.Kim GY, Conduit C, O’Haire S, et al. Association between low total serum testosterone and body mass index in Australian survivors of testicular cancer: a retrospective analysis. Basic Clin Androl. 2024;34(1):14. doi: 10.1186/s12610-024-00230-5 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• of considerable interest
- 22.Kreiberg M, Jørgensen N, Juul A, et al. A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention). Clin Genitourin Cancer. 2022;20(5):404–414. doi: 10.1016/j.clgc.2022.04.017 [DOI] [PubMed] [Google Scholar]; • of interest.
- 23.López-Lemus UA, Garza-Guajardo R, Barboza-Quintana O, et al. Association Between Nonalcoholic Fatty Liver Disease and Severe Male Reproductive Organ Impairment (Germinal Epithelial Loss): Study on a Mouse Model and on Human Patients. Am J Mens Health. 2018;12(3):639–648. doi: 10.1177/1557988318763631 [DOI] [PMC free article] [PubMed] [Google Scholar]; • of interest.
- 24.Pierorazio PM, Cheaib JG, Patel HD, et al. Comparative Effectiveness of Surveillance, Primary Chemotherapy, Radiotherapy and Retroperitoneal Lymph Node Dissection for the Management of Early Stage Testicular Germ Cell Tumors: A Systematic Review. J Urol. 2021;205(2):370–382. doi: 10.1097/JU.0000000000001364 [DOI] [PubMed] [Google Scholar]
- 25.Xu P, Xu CF, Wan XY, et al. Association between serum alpha-fetoprotein levels and fatty liver disease: a cross-sectional study. World J Gastroenterol. 2014;20(33):11865–11870. doi: 10.3748/wjg.v20.i33.11865 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Oldenburg J, Berney DM, Bokemeyer C, et al. Testicular seminoma and non-seminoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up☆. Ann Of Oncol. 2022;33(4):362–375. doi: 10.1016/j.annonc.2022.01.002 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.