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]
# As updated in the UICC 8th Edition Errata [28b]

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.)  [28]

In population-based patient series from developed countries, 75-80% of seminoma germ cell tumour (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

4.3.1. Seminoma

Primary testicular tumor size and stromal invasion of the rete testis have been considered the prognostic risk factors associated with relapse in CS I (SGCT). Two SRs assessed the prognostic value of both risk factors [32,33]. While tumour size (continuous or dichotomised) and rete testis invasion (RTI) 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 justify the use of both risk factors to drive adjuvant treatment decisions in routine practice.

Recently, two large series re-assessed prognostic risk factors in CS I SCGT patients under surveillance [34,35]. A multi-institutional retrospective series including 1,016 patients and an additional validation cohort of 285 patients identified primary testicular tumour size (size < 2 cm, 2-5 cm, and > 5), RTI (pagetoid + stromal invasion) and lymphovascular invasion (LVI) to be associated with risk of relapse [34]. A three-tier risk stratification was compiled, including a small proportion of high-risk patients (2.3%) with tumour size > 5 cm and both RTI and LVI present who had a five-year cumulative probability of relapse of 44%.

A large prospective series from Denmark [35] including 924 patients with central pathology review identified invasion of the testicular hilum (rete testis and hilar soft tissue), LVI, and elevated β-HCG and LDH prior to orchiectomy as independent predictors of relapse. In contrast to previous studies, tumour size was not identified as a risk factor. A six-tier risk stratification was developed and the estimated five-year probability of relapse ranged from 6% in patients without risk factors to 62% in patients with all four risk factors, which was 22% of the patient population. Both series demonstrated that the vast majority of patients with CS I SGCT are cured by orchiectomy alone as the overall relapse rate was 14.7% and 16%, supporting “active surveillance” (AS) as the preferred adjuvant strategy for all CS I seminoma patients irrespective of risk factors.

4.3.2. NSGCT

For CS I NSGCT, invasion of the primary tumour into blood or lymphatic vessels, (i.e., lymphovascular invasion [LVI]), has long been described to be strongly associated with the risk of relapse [39-41]. According to historical figures, relapse risk for patients with LVI-positive tumours was 50% vs. 15% in patients with LVI-negative tumours.

A recent Danish study of more than 400 patients with central pathology review suggested tumour size, invasion of the hilar soft tissue and presence of embryonal carcinoma as additional risk factors [36]. Depending on the combination of factors, relapse risk ranged from < 5% to > 85%.

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 [37]. The classification has been revalidated on a contemporary cohort of metastatic TGCTs treated with cisplatin/etoposide based first-line chemotherapy [38].

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 [38].

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 [39].

Table 3: Prognostic-based staging system for metastatic germ cell cancer (IGCCCG) [37]*

* 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.