Patients with testicular germ cell tumors (TGCT) have an increased risk for venous thromboembolism (VTE). We identified risk factors for VTE in this patient cohort and developed a clinical risk ...model.
In this retrospective cohort study at the Medical University of Graz we included 657 consecutive TGCT patients across all clinical stages. A predictive model for VTE was developed and externally validated in 349 TGCT patients treated at the University Hospital Zurich.
Venous thromboembolic events occurred in 34 (5.2%) patients in the Graz cohort. In univariable competing risk analysis, higher clinical stage (cS) and a retroperitoneal lymphadenopathy (RPLN) were the strongest predictors of VTE (p<0.0001). As the presence of a RPLN with more than 5cm in greatest dimension without coexisting visceral metastases is classified as cS IIC, we constructed an empirical VTE risk model with the following four categories (12-month-cumulative incidence): cS IA-B 8/463 patients (1.7%), cS IS-IIB 5/86 patients (5.9%), cS IIC 3/21 patients (14.3%) and cS IIIA-C 15/70 patients (21.4%). This risk model was externally validated in the Zurich cohort (12-month-cumulative incidence): cS IA-B (0.5%), cS IS-IIB (6.0%), cS IIC (11.1%) and cS IIIA-C (19.1%). Our model had a significantly higher discriminatory performance than a previously published classifier (RPLN-VTE-risk-classifier) which is based on the size of RPLN alone (AUC-ROC: 0.75 vs. 0.63, p = 0.007).
According to our risk stratification, TGCT patients with cS IIC and cS III disease have a very high risk of VTE and may benefit from primary thromboprophylaxis for the duration of chemotherapy.
To validate the utility of the chemokine ligand 12 (CXCL12) as prognostic marker in patients with localized and metastatic germ cell tumors (GCT).
CXCL12 expression was analyzed on a tissue ...microarray consisting of 750 tissue cores of different histological tumor components, Germ cell neoplasia in situ (GCNIS) and adjacent normal tissue of 263 testicular cancer patients using a semi-quantitative score. The association between CXCL12 expression and recurrence-free survival (RFS) as well as overall survival (OS) was assessed using Kaplan-Meier curves with log-rank tests.
CXCL12 expression was absent in all seminomas but was found in 52 of 99 (52.5%) non-seminomas. Follow-up was available for 260 patients of which 36 (13.8%) recurred. In patients with stage 1 non-seminoma GCT, CXCL12 expression was not associated with higher risk of disease recurrence (p = 0.270). In contrast, post chemotherapy RFS of patients with metastatic non-seminoma and positive CXCL12 expression was significantly shorter compared to CXCL12 negative patients (p = 0.003). OS differences were not statistically different between patients with CXCL12 positive or negative tumors for either localized or metastatic disease.
CXCL12 is almost exclusively expressed in non-seminoma. Pure seminoma, GCNIS and adjacent normal testicular tissue are CXCL12 negative. Our analysis suggests that patients with metastatic disease and a CXCL12-positive non-seminoma are at higher risk for disease recurrence after first-line chemotherapy and might thus be candidates for more intensive treatment and/or closer follow-up.
The prognostic utility of systemic inflammatory markers has so far not been investigated in patients with metastatic testicular germ cell tumours (GCTs).
International Germ Cell Cancer Cooperative ...Group (IGCCCG) risk groups and blood-based systemic inflammatory markers (haemoglobin, leukocytes, platelets (P), neutrophils (N), lymphocytes (L), C-reactive protein (CRP) and albumin) of 146 patients undergoing first-line chemotherapy for GCT were retrieved. In addition, N to L ratio (NLR), P to L ratio and the systemic immune-inflammation index (SII=N × P/L) were calculated. The prognostic ability of these markers for overall survival (OS) were assessed using regression analyses and Kaplan-Meier curves with log-rank tests.
In univariate Cox regression, low haemoglobin and albumin as well as high leukocytes, N, NLR, SII and CRP were associated with a shorter OS. In multivariable Cox regression analyses, high leukocyte (hazard ratio (HR) 1.274 (95% confidence interval (CI) 1.057-1.535); P=0.011) and N count (1.470 (1.092-1.980); P=0.011), higher NLR (84.5 (2.2-3193.4); P=0.017) and SII (12.15 (1.17-126.26); P=0.037) remained independent prognostic predictors for OS besides the IGCCCG risk groups.
Systemic inflammatory markers might have prognostic utility for patients with metastatic GCT. The planned IGCCCG update could be an opportunity to test these markers in a larger data set.
Introduction and objectives
In several urogenital cancers, organ-preserving surgery represents the preferred treatment approach, but in patients with testicular germ cell tumors (tGCTs), radical ...orchiectomy represents the standard of care. This study aimed to summarize published case series assessing oncological and functional outcomes after testis-sparing surgery (TSS) in patients with tGCTs.
Materials and methods
A systematic literature review and individual patient data meta-analysis were conducted of published cases with tGCT treated with TSS.
Results
Of 2,333 reports, we included 32 reports providing data on 285 patients, including 306 testicles treated with TSS. Adjacent germ cell neoplasia in situ (GCNIS) was described in 43%. Hypogonadism and infertility after TSS were diagnosed in 27% and 18%. In patients undergoing adjuvant testicular radiotherapy, hypogonadism was diagnosed in 40%. Patients treated with adjuvant testicular radiotherapy after TSS exhibited a significantly lower incidence of local recurrence (2% vs. 50%,
p
< 0.001). Distant metastases after TSS were observed in 2%.
Conclusion
The current data questions the benefits of TSS in tGCT patients. If at all, TSS should only be offered to well-informed patients with a singular testicle, excellent compliance, a singular tumor less than 2 cm located at the lower pole of the testicle, and normal preoperative endocrine function. Unless patients plan to father a child within a short time frame, adjuvant testicular radiotherapy should be recommended after TSS. Radical orchiectomy remains the standard of care, but future studies may support the use of TSS in selected men.
Background
Sertoli cell tumors (SCTs) of the testes are rare, and the literature provides only weak evidence concerning their clinical course and management. The objective of this study was to ...summarize evidence on SCTs’ clinical presentation, clinicopathological risk factors for malignancy, treatment options, and oncological outcomes.
Materials and Methods
Data sources included Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and Web of Science. Published case reports, case series, and cohorts were included. Data on clinicopathological variables, treatment of local or metastatic disease, site of metastasis, or survival were extracted from each study considered in this paper, and associations between clinicopathological variables and metastatic disease were analyzed. Whenever feasible, data on individual patients were collected.
Results
Of the 435 patients included, only one (<1%) showed local recurrence after testis‐sparing surgery (TSS). Three patients underwent adjuvant retroperitoneal lymphadenectomy. Fifty patients presented with metastases, located in the retroperitoneal lymph nodes (76%), lungs (36%), and bones (16%); median time to recurrence was 12 months. Risk factors for metastatic disease included age, tumor size, necrosis, tumor extension to the spermatic cord, angiolymphatic invasion, and mitotic index. Patients with metastases had a median life expectancy of 20 months. In six patients, metastasectomy resulted in complete remission.
Conclusion
Our findings suggest that few local recurrences result after TSS, and no adjuvant therapy can be regarded as a standard of care. Several risk factors are predictive of metastatic disease. Surgery leads to remission in metastatic disease, whereas systemic treatment alone does not result in long‐term remission.
Implications for Practice
Testicular Sertoli cell tumors usually present without metastatic disease and show low local recurrence rates after testis‐sparing surgery; no adjuvant therapy option can be regarded as a standard of care. Patients with risk factors should undergo staging investigations. Those with metastatic disease have poor prognoses, and metastasectomy may be offered in selected cases.
Considering the rarity of Sertoli cell tumors, there are unanswered questions about optimal treatment for patients with localized or metastatic disease. This review of the literature presents the available information on clinical presentation, treatment options, and patient outcomes, as well as clinicopathological risk factors associated with metastatic disease.
Conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) may both be successfully used as salvage treatment for patients with metastatic germ cell tumors (GCTs) who experience ...progression with first-line treatment.
Data on 1,984 patients with GCTs who experienced progression after at least three cisplatin-based cycles and were treated with either cisplatin-based CDCT or carboplatin-based HDCT chemotherapy were collected from 38 centers or groups worldwide. Of 1,984 patients, 1,594 (80%) were eligible, and among the eligible patients, 1,435 (90%) could reliably be classified into one of the following five prognostic categories based on prior prognostic classification: very low (n = 76), low (n = 257), intermediate (n = 646), high (n = 351), and very high risk (n = 105). Within each of the five categories, the progression-free survival (PFS) and overall survival (OS) after CDCT and HDCT were compared using the Cox model adjusted for significant distributional differences between important variables.
Overall, 773 patients received CDCT, and 821 patients received HDCT. Both treatment modalities were used with similar frequencies within each prognostic category. The hazard ratio for PFS was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for OS was 0.65 (95% CI, 0.56 to 0.75), favoring HDCT. These results were consistent within each prognostic category except among low-risk patients, for whom similar OS was observed between the two treatment groups.
This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.
MiR-371a-3p predicts the presence of a macroscopic non-teratomatous germ cell tumour (GCT). We hypothesised that miR-371a-3p can also detect recurrence during active surveillance (AS) of stage I GCT.
...We prospectively collected serum samples of 33 men. Relative expression of serum miR-371a-3p levels was determined at each follow-up visit using real-time quantitative reverse transcription-polymerase chain reaction.
Recurrence was detected using standard follow-up investigations in 10/33 patients (30%) after a median of 7 months. Directly after orchiectomy, miR-371a-3p levels were not elevated in any of the 15 patients with available post-orchiectomy samples. However, all ten recurring patients exhibited increasing miR-371a-3p levels during follow-up, while miR-371a-3p levels remained non-elevated in all but one patient without recurrence. MiR-371a-3p detected recurrences at a median of 2 months (range 0-5) earlier than standard follow-up investigations.
MiR-371a-3p levels immediately post orchiectomy are not predictive for recurrences and unfortunately cannot support decision-making for AS vs. adjuvant treatment. However, miR-371a-3p detects recurrences reliably and earlier than standard follow-up investigations. If this can be confirmed in larger cohorts, monitoring miR-371a-3p could replace surveillance imaging in seminomatous GCT and reduce the amount of imaging in non-seminomatous GCT. Earlier detection of disease recurrence may also reduce the overall treatment burden.
Purpose
Testicular granulosa cell tumors (tGrCT) are rare sex cord-stromal tumors. This review aims to synthesize the available evidence regarding the clinical presentation and clinicopathological ...characteristics, treatment and outcomes.
Methods
We conducted a systematic literature search using the most important research databases. Whenever feasible, we extracted the data on individual patient level.
Results
From 7863 identified records, we included 88 publications describing 239 patients with tGrCT. The majority of the cases were diagnosed with juvenile tGrCT (166/239, 69%), while 73/239 (31%) patients were diagnosed with adult tGrCT. Mean age at diagnosis was 1.5 years (± 5 SD) for juvenile tGrCT, and 42 years (± 19 SD) for adult tGrCT. Information on primary treatment was available in 231/239 (97%), of which 202/231 (87%) were treated with a radical orchiectomy and 20/231 (9%) received testis sparing surgery (TSS). Local recurrence after TSS was observed in 1/20 (5%) cases. Metastatic disease was never observed in men with juvenile tGrCT but in 7/73 (10%) men with adult tGrCT. In 5/7 men with metastatic tGrCT, metastases were diagnosed at initial staging, while 2/7 patients developed metastases after 72 and 121 months of follow-up, respectively. Primary site of metastasis is represented by the retroperitoneal lymph nodes, but other sites including lungs, liver, bone and inguinal lymph nodes can also be affected. In comparison with non-metastatic adult tGrCT, men with metastatic adult tGrCT had significantly larger primary tumors (70 vs 24 mm,
p
0.001), and were more likely to present with angiolymphatic invasion (57% vs 4%,
p
0.002) or gynecomastia (29% vs 3%,
p
0.019). In five out of seven men with metastatic disease, resection of metastases or platinum-based chemotherapy led to complete remission.
Conclusion
Juvenile tGrCT represent a benign entity whereas adult tGCTs have metastatic potential. Tumor size, presence of angiolymphatic invasion or gynecomastia represent risk factors for metastatic disease. The published literature supports the use of testis sparing surgery but there is only limited experience with adjuvant therapies. In the metastatic setting, the reviewed literature suggests that aggressive surgical and systemic treatment might cure patients.
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