Prostate Cancer

4. CLASSIFICATION AND STAGING SYSTEMS

4.1. Classification

The objective of a tumour classification system is to combine patients with a similar clinical outcome. This allows for discussion about prognosis with patients, the design of clinical trials on relatively homogeneous populations, the comparison of clinical and pathological data obtained from different hospitals across the world, and the development of recommendations for the treatment of these patient populations. Throughout these Guidelines the Union for International Cancer Control (UICC) 8^th edition (2017), the Tumour, Node, Metastasis (TNM) classification for staging of PCa (Table 4.1) [103] and the EAU risk group classification are used [104]. The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Changes in the diagnostic pathway, such as imaging (e.g., Magnetic Resonance Imaging [MRI], Prostate-Specific Membrane Antigen [PSMA] Positron Emission Tomography Computed Tomography [PET/CT] scan) and biopsy (e.g., increasing number of systematic biopsy cores, targeted biopsy) may cause a stage shift in risk classification systems [105].

Although the 2017 American Joint Committee on Cancer (AJCC) staging 8^th edition specifically states that clinical staging should be based on digital rectal examination (DRE) only, such an explicit comment is not made by the UICC. Since clinical stage as assessed by DRE only, it is included in the EAU (D’Amico) risk group classification, cT-stage should be based on DRE findings and not on imaging. Additional staging information based on imaging should be reported separately. A non-palpable PCa with bilateral positive biopsies and extra-prostatic extension (EPE) on MRI would therefore be categorized as cT1c with a separate report of MRI findings.

Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [103]

1 Metastasis no larger than 0.2 cm can be designated pNmi.2 When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most advanced category.

Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical TNM, except for clinical stage T1 and T2 substages. Pathological stages pT1a/b/c do not exist and histopathologically confirmed organ-confined PCas after RP are pathological stage pT2. The current UICC no longer recognise pT2 substages [103].

Of note: the EANM recently proposed a ‘miTNM’ (molecular imaging TNM) classification, taking into account PSMA PET/CT findings [106]. The prognosis of the miT, miN and miM substages is likely to be better than their T, N and M counterparts due to the ‘Will Rogers phenomenon’; the extent of this prognosis shift remains to be assessed as well as its practical interest and impact [107]. This reclassification is not endorsed by the UICC or the AJCC.

4.2. Gleason score and International Society of Urological Pathology 2019 grade

In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour architecture were distinguished, but in the 2005 and subsequent 2014 ISUP consensus meetings Gleason grades 1 and 2 were eliminated [108,109]. The 2005 ISUP modified Gleason score (GS) of biopsy-detected PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common (secondary) pattern, if two are present. If only one pattern is present, it needs to be doubled to yield the GS. For three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of its extent. In case intraductal carcinoma is present intermixed with invasive PCa, it should be incorporated in the GS based on its underlying architectural pattern [110]. In addition to reporting of the carcinoma features for each biopsy side, an overall (or global) GS based on the carcinoma-positive biopsies can be provided. The global GS takes into account the cumulative extent of each grade from all prostate biopsies (see Section 5.2.9.2). The 2014 and 2019 ISUP endorsed grading system limits the number of PCa grades, ranging them from 1 to 5 (see Table 4.2) [109,111].

Table 4.2: International Society of Urological Pathology 2014 grade (group) system

4.3. Clinically significant prostate cancer

The descriptor ‘clinically significant’ is widely used to differentiate PCa that may cause morbidity or death in a specific patient from types of PCa that do not. This distinction is particularly important as insignificant PCa that does not cause harm is so common [9]. Unless this distinction is made, such cancers are at high risk of being over-treated, with the treatment itself risking harmful side effects to patients. The over-treatment of insignificant PCas has also been criticised as a major drawback of PSA testing and early detection [112]. Although pathological factors are often used to delineate insignficant PCa, the definition of significant vs. insignificant is a balance between tumour and patient factors. High-risk PCa is significant in almost all men, except when life expectancy is limited. Low-risk PCa is insignificant in almost all men.

From a pathological point of view in large studies of RP specimens which showed only ISUP grade 1 disease, EPE (0.3%) [113] and biochemical recurrence (3.5%) were rare, and seminal vesicle (SV) invasion or lymph node (LN) metastasis did not occur at all [114,115]. International Society of Urological Pathology grade 1 disease at RP itself can therefore be considered clinically insignificant. Whilst ISUP grade 1 bears the hallmarks of cancer histologically, ISUP grade 1 at RP itself does not behave in a clinically malignant fashion [116]. It is important to note that the studies showing absence of metastasis in ISUP grade 1 were all done on RP specimens; ISUP grade 1 on biopsy is associated with low risk of developing metastasis and disease-specific death, due to under-sampling of a higher grade component. Finally, modifications in PCa grading, MRI and targeted biopsies led to a grade shift during the past 10–15 years; for instance the introduction of the ISUP 2005 led to 20% of pre-ISUP 2005 GS 6 tumours being upgraded to GS 7 or higher, which has to be taken into account when interpreting older studies [117].

The current standard practice of MRI-targeted and template biopsies has reduced diagnostic inaccuracy [118], however sampling error may still occur such that higher grade cancer could be missed. This should especially be considered if the prior MRI showed a suspicious lesion, but only ISUP grade 1 was found at biopsy. Another complexity in defining insignificant cancer is that ISUP grade 1 may progress to higher grades over time, becoming clinically significant at a later biopsy [119].

Therefore, although ISUP grade 1 itself can be described as clinically insignificant, it is important to take into account other factors, including age, imaging prior to biopsy and adequate sampling core number. When combined with low-risk clinical factors (see Table 4.3), ISUP grade 1 represents low-risk PCa, with its recommendation of preferred management being active surveillance (AS) or watchful waiting (WW) (see Sections 6.1.1.1 & 6.1.1.2). It should be noted, therefore, that defining ISUP grade 1 as insignificant cancer does not mean it should be ignored, but appropriately observed.

Epidemiological and autopsy data suggest that a proportion of ISUP grade 2 PCas would remain undetectable during a man’s life [120] and therefore may be over-treated. In current guidelines deferred treatment may be offered to select patients with intermediate-risk PCa [121], but clear evidence is lacking for appropriate selection criteria [122].

Recent papers have defined clinically significant cancer differently, commonly using ISUP grade 2 and above and even ISUP grade 3 and above, demonstrating the lack of consensus and evolution of its definition [123-126]. Some papers provide more than one definition within a single study [127,128]. Since there is insufficient data to relate modern histological grading to hard clinical endpoints, it is imperative that authors define and state it in their own studies what they believe csPCa is, including exactly how the disease was diagnosed.

Table 4.3: EAU risk groups for biochemical recurrence of localised and locally-advanced prostate cancer

GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.
* Based on digital rectal examination.
** Based on CT/bone scan.

4.4. Prognostic relevance of stratification

TNM staging is a schematic representation of anatomic tumour extent and pathological tumour grade is reflective of intrinsic features of tumour aggressiveness. EAU risk group classification, which is essentially based on D’Amico’s classification system for PCa, combines clinical information on tumour extent, PSA and pathology (Table 4.3) [104]. A more precise stratification of the clinically heterogeneous subset of intermediate-risk group patients could provide a better framework for their management [129,130]. Specifically the National Cancer Center Network (NCCN) Guidelines subdivide intermediate-risk disease into favourable intermediate-risk and unfavourable intermediate-risk, with unfavourable features including ISUP grade 3, and/or > 50% positive biopsy cores and/or at least two intermediate-risk factors [121]. However, as yet, the best stratification and optimal treatment remain controversial.

4.5. Guidelines for classification and staging systems