Testicular Cancer

4. STAGING & CLASSIFICATION SYSTEMS

4.1. Staging

The 2016 Tumour, Node, Metastasis (TNM) classification of the International Union Against Cancer (UICC) is recommended to assess the anatomical extent of the disease (Table 1) [25].

Table 1: TNM classification for testicular cancer (adapted from UICC, 2016, 8th edn.) [25]

N indicates the upper limit of normal.
LDH = lactate dehydrogenase; hCG = human chorionic gonadotrophin; AFP = alpha-fetoprotein.
1 Except for pTis and pT4, where radical orchidectomy is not always necessary for classification purposes, the extent of the primary tumour is assessed in the radical orchidectomy specimen; see pT. In other circumstances, TX is used if no radical orchidectomy has been performed.
+ The current “Carcinoma in situ” nomenclature is replaced by GCNIS.
* AJCC eighth edition subdivides T1 Pure Seminoma by T1a and T1b depending on size no greater than 3 cm or greater than 3 cm in greatest dimension .26
** AJCC eighth edition considers the hilar soft tissue invasion and epididymal invasion as pT2, while the discontinuous involvement of the spermatic cord is considered as pM1 .26

4.2. The Union for International Cancer Control prognostic groups

According to the 2016 TNM classification, the following prognostic groups are defined:

Table 2: Prognostic groups for testicular cancer (UICC, 2016, 8th edn.) [25]

Stage IA:
Patients have primary tumours limited to the testis and epididymis, with no evidence of microscopic vascular or lymphatic invasion by tumour cells on microscopy, no sign of metastases on clinical examination or imaging, and post-orchidectomy serum tumour marker levels within normal limits. Marker decline in patients with CS I disease should be assessed until normalisation occurs on two consecutive measurements.

Stage IB:
Patients have a more locally invasive primary tumour, but no sign of metastatic disease.

Stage IS:
Patients have persistently elevated (and usually increasing) serum tumour marker levels after orchidectomy, indicating the presence of subclinical metastatic disease (or possibly a second GCT in the contralateral testis).

In population-based patient series from developed countries, 75-80% of seminoma patients, and 55%-64% of non-seminomatous germ cell tumour (NSGCT) patients had stage I disease at diagnosis [27,28]. True stage IS, i.e. persistently elevated or increasing serum tumour marker levels after orchidectomy, was found in approximately 5% of non-seminoma patients [27].

4.3. Risk factors for relapse in clinical stage I testicular cancer

In clinical stage (CS) I seminoma testis, primary testicular tumour size and stromal invasion of the rete testis have been identified to be associated with the risk of relapse in a pooled analysis of retrospective data [29]. Absence of both factors indicated a low risk of recurrence (6%) [30]. Whilst the original analysis was not supported by a further retrospective report [31], some prospective series [32-34] supported the prognostic significance of tumour size and stromal invasion of the rete testis. Two systematic reviews (SRs) assessed the prognostic value of both risk factors [35,36]. While tumour size (continuous or dichotomised) and rete testis invasion were associated with a higher risk of relapse, both SRs highlighted the low quality of the studies included and concluded that the level of evidence was too low to recommend the use of both risk factors to drive adjuvant treatment decisions [35,36].

For CS I non-seminoma testis, invasion of the primary tumour into blood or lymphatic vessels, i.e. lymphovascular invasion (LVI), was strongly associated with the risk of relapse disease [37-39]. While interobserver agreement is limited, immunohistochemistry might improve detection of LVI [40]. The percentage of embryonal carcinoma within a tumour may enhance the positive predictive value (PPV) and negative predictive value (NPV) of LVI [38], but there is no definitive prognostic cut-off for percentage [38]. Risk of relapse at five years for LVI-positive tumours was 50% versus 15% in LVI-negative tumours.

4.4. The International Germ Cell Cancer Collaborative classification for the prognostic risk groups of metastatic testicular cancer

The 1997 IGCCCG defined a prognostic risk-factor system for metastatic GCT based on identification of clinically independent adverse factors [41]. The classification has been revalidated on a contemporary cohort of metastatic testicular GCT treated with cisplatin/etoposide based first-line chemotherapy [42].

Compared to the 1997 figures, the five-year progression-free survival (PFS) of non-seminoma testis patients was unchanged for good- and intermediate-risk, but significantly improved for poor-risk patients (from 41% to 54%). The five-year overall survival (OS) was substantially better for all groups. In addition to the traditional components of the IGCCCG risk-prognostic groups previously described, older age (linear association) and lung metastasis were confirmed as negative factors for PFS [42].

With seminoma, the five-year PFS increased to 89% and 79% in good- and intermediate-risk patients with the corresponding OS rates of 95% and 88%. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good-prognosis patients with LDH above 2.5 times the upper limit of normal (ULN) had a three-year PFS of 80% and a three-year OS of 92% (comparable to intermediate prognosis patients at 78% and 93% respectively), vs. 92% and 97% (in the group with lower LDH) [43].

Table 3: Prognostic-based staging system for metastatic germ cell cancer (IGCCCG) [42,43]*

* Pre-chemotherapy serum tumour markers should be assessed immediately prior to the administration of chemotherapy (same day).
AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase; PFS = progression-free survival.