Testicular Cancer

4. STAGING & PROGNOSIS

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) [28].

Table 1: TNM classification for testicular cancer (adapted from UICC, 2016, 8th edn.) [28]

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 [29]
** AJCC eighth edition considers hilar soft tissue invasion and epididymal invasion as pT2, while the discontinuous involvement of the spermatic cord is considered as pM1 [29]

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, 8^th edn.) [28]

In population-based patient series from developed countries, 75-80% of SGCT patients, and 55-64% of NSGCT patients had CS I disease at diagnosis [30,31]. True CS I, i.e. persistently elevated or increasing serum tumour marker levels after radical orchidectomy, was found in approximately 5% of NSGCT patients [30].

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

For CS I seminoma germ cell tumour (SGCT), primary tumour size and stromal invasion of the rete testis have been identified to be associated with relapse risk in a pooled analysis of retrospective data [32]. Absence of both factors was associated with a low risk of recurrence (6%) [35]. Whilst the original analysis was not supported by a subsequent retrospective report [33], some prospective series [34-36] have supported the prognostic significance of tumour size and stromal invasion of the rete testis. Two SRs assessed the prognostic value of both risk factors [37,38]. 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 be able to recommend the use of both risk factors to drive adjuvant treatment decisions [37,38].

For CS I NSGCT, invasion of the primary tumour into blood or lymphatic vessels, (i.e. lymphovascular invasion (LVI)), was strongly associated with the risk of relapse disease [39-41]. No other risk factors have the same level of validation for prognostic significance [42]. While interobserver agreement is variable, immunohistochemistry with vascular markers may improve detection of LVI [43]. The percentage of embryonal carcinoma within a tumour may enhance the positive predictive value (PPV) and negative predictive value (NPV) of LVI [40], but there is no definitive prognostic cut-off for percentage [40]. Risk of relapse at five years according to historical figures, for patients with LVI-positive tumours was 50% vs. 15% in patients with LVI-negative tumours.

Table 3: Pathological risk-factors for occult metastatic disease in clinical stage I testicular cancer

4.4. The International Germ Cell Cancer Collaborative Group (IGCCCG) classification for the prognostic risk groups of metastatic germ cell cancer

The 1997 IGCCCG defined a prognostic risk-factor system for metastatic GCT based on identification of clinically independent adverse factors [45]. The classification has been revalidated on a contemporary cohort of metastatic TGCT treated with cisplatin/etoposide based first-line chemotherapy [46].

Compared to the 1997 figures, the five-year progression-free survival (PFS) of NSGCT 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 metastases were confirmed as negative factors for PFS [46].

For SGCT, revalidation of the IGCCCG classification showed that the five-year PFS increased to 89% and 79% in good- and intermediate-risk patients with corresponding OS rates of 95% and 88%. Testicular lactate dehydrogenase (LDH) over 2.5 times the upper limit of normal (ULN) was identified as a possible adverse prognostic factor in regard to reduced three-year PFS, however overall three-year survival was not affected [47].

Table 4: Prognostic-based staging system for metastatic germ cell cancer (IGCCCG) [46,47]*

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