Impact for prognosis and clinical decision
A focus on seminoma stage I is relevant since it is the most common single stage or histology of TGCT—it may account for up to 80% of seminomas and 40% of all testicular cancers[9]. Thus, having two staging criteria may have implications in clinical practice or clinical trial design: should we embrace the changes (AJCC) or ignore them (UICC)? Should adjuvant treatment be decided according to staging subcategory (i.e. higher risk could mean more aggressive treatment)? Should follow-up protocols take the new subcategories into consideration and have more intense schedules in higher risk patients, even though, ultimately, survival would be similar? These clinically meaningful questions remain unanswered, creating additional anxiety on patients and their family.
A fundamental notion is that the overall prognosis in stage I seminoma is exceptionally good[4]—confirmed in our retrospective analysis, with few recurrences recorded (3) and a 5-year overall survival rate of 100%, regardless of subcategorization, with a median follow-up time ~6 years. The occurrence of few events may be a limitation (i.e. low rate recurrence or death), indicating high curability rate even after recurrence. Retrospective data has emerged suggesting the 3 cm cut-off was significantly associated with metastatic status at presentation, but only if LVI or spermatic cord invasion (SCI) were present[10], which are known independent high-risk features. This conclusion is not applicable to pT1 stage, since LVI is, per definition, at least pT2, and SCI is pT3[2, 3]. The three recurrences identified (3 out of 17 surveillance patients, 17.6%), are within the estimated 15-20% risk of recurrence for stage I seminoma without adjuvant treatment[11].
Another clinical concern is adjuvant treatment selection. Already in daily routine, again, use the presence of RTI and tumor size > 4 cm can be taken into account in order to establish an individual recurrence risk and help choose treatment over surveillance[4]. Interestingly, size ≥ 3 cm, the current AJCC pT1b subcategory, in the univariate analysis, was significantly associated with RTI (P<0.0001) and EN (P=0.023). This may indicate that increasing size is related to adverse pathological features, a coherent finding, and yet its clinical relevance is unknown at this time and should be a focus of future research. Additionally, two recurrences were identified in the pT1a group (vs 1 in pT1b), with neither case showing RTI, which underscores the need to have better biomarkers to predict recurrence (in seemingly classical low risk patients).
Some considerations are justified regarding patients with a tumor size ≥ 3 cm but ≤ 4 cm, which were almost half of the pT1b group (44.8%, Table 1). Following the 8th edition AJCC criteria, they would be considered at higher risk of recurrence (vs pT1a) and yet below the classically considered higher risk size of 4 cm. Observing the combinations of no RTI/RTI and tumor size ≤ 4 cm and > 4 cm (Table 2) one can realize that even within the pT1b category, different risk groups can be identified. This is in accordance with a nomogram that suggested risks of recurrence depending on how many risk factors were present: none, 12%, presence of either one, 16% and in the presence of both, a 32% risk of recurrence[12]. RTI is explicitly considered by AJCC as a pathological feature that does not change staging (based on large contemporary cohorts data)[2]. Thus, the clinical significance of RTI remains controversial[7]. Combining our experience, in particular and as mentioned before, the observed significant association between RTI and increased tumor size (P<0.0001, Table 1), with large retrospective data whose importance is recognized in international guidelines[4, 11], RTI may have a role in clinical practice. Actually, RTI could be, in the future, included for staging purposes as an adverse feature within the pT1b subclassification, such as a suffix pT1b(0) for no RTI (lower risk) vs pT1b(1) for RTI (higher risk)—like the precedent in melanoma M1 disease staging with (0) indicating normal lactate dehydrogenase (LDH) and (1) indicating elevated LDH[2]. This change could enable the evaluation of its significance prospectively, essentially as the decision to create pT1a vs pT1b subclassifications based on a size cut-off.
Analysis of potential bias
This is an exploratory retrospective analysis of current criteria applied to a population that was treated regardless of them, therefore the interpretation of results is considerably limited, although it may offer glimpses into future directions, namely clinical or basic research aims of focus.
The follow-up time may be insufficient to detect enough events (recurrence or death) in a small population, which is a limitation in stage I seminoma studies[13]. Nevertheless, the study that suggested the 3 cm cut-off (and now the basis for seminomas’ pT1a vs pT1b cut-off in AJCC’s) used a 3-year recurrence risk[14], thus considering that our population has over 5 years of follow-up we believed it would be appropriate to proceed with the analysis. We focused on stage I seminoma in order to obtain a more homogenous population.
Our population was treated from 2005 onwards, and at that time one of the popular adjuvant treatment options was RT, that could explain the relevant percentage of treated patients with this technique (43.1% of the population, vs 8.6% chemotherapy and 29.3% surveillance), and may help explain the few recurrences, although, retrospectively, some patients may have been over- treated according to current trends of thinking[15]. The patients that recurred (2 in pT1a group and 1 in pT1b group, all undergoing surveillance protocol) were effectively treated, and their current status is no evidence of disease.
Additionally, some pathological data were missing due to suboptimal evaluation conditions of the material under analysis.
Despite much focus is rightly placed on late toxicities, we were not able to gather meaningful clinical data regarding these issues.