【多伦多大学】精准评估：提高PCa的TNM分期系统的适用性，会面临哪些挑战？

导读

精确评估前列腺癌的分期是对疾病进行管理的基础，但目前随着新型成像方式的发展，评估疾病分期的精确度更高了，此时可能出现分期迁移和分期改变等现象，在仍然使用原来的TNM分期系统的情况下，可能不利于疾病管理。来自多伦多大学Temerty医学院的Alejandro Berlin等人，分析了目前影响精确分期的现象、精确分期的重要性，提出了iTNM分期系统，也许会对你有所启发。

TNM Staging of Prostate Cancer: Challenges in Securing a Globally Applicable Classification

前列腺癌的TNM分期：确保分期系统在全球适用所面临的挑战[1]

Histological diagnosis along with disease extent (stage) are cardinal for decision-making in the management of cancer. Cancer stage is the synoptic description of the anatomical extent of disease. Stage may be recorded as clinical (pretreatment) classification or clinical stage, and pathological (postsurgical) classification or pathological stage. The clinical classification is determined via physical examination, imaging, endoscopy, and biopsy including surgical exploration and/or biomarkers for certain tumour types. Over time, physical examination has been eclipsed by the rapid adoption of increasingly sophisticated imaging modalities that augment our ability to precisely determine disease extent. The focus of this letter is on the clinical classification of prostate cancer (PCa) and the significance of newer diagnostic imaging techniques that enhance the accuracy of determination of disease extent in PCa.

组织学诊断和疾病程度（分期）是决定癌症管理的基础。癌症分期是对疾病在解剖学上的大概描述。分期可记录为临床（治疗前）分类或临床分期，以及病理（手术后）分类或病理分期。临床分类的确定方法有体格检查、成像、内镜检查和活检，包括手术探查和/或某种肿瘤的生物标志物。随着时间的推移，体格检查的重要性已经不如成像了，如今的成像方式日益复杂，快速地应用于医学，提高了精确确定疾病程度的能力。

本文的重点是前列腺癌（PCa）的临床分期，并讨论可以更准确确定PCa疾病程度的新型诊断成像技术的重要性。

Progress in and adoption of new methods to ascertain the extent of disease underscore the importance of understanding and precise communication of staging classifications. In this regard, it is essential to distinguish between two phenomena that challenge our appreciation of cancer staging. The first is stage migration, which refers to changes in the proportion of T, N, or M category within a defined population resulting from increased accuracy for evaluating the extent of disease while applying the original, predefined staging system. An example of this is nonpalpable disease (T1 category) for which a new imaging tool might reveal a conspicuous tumour with extraprostatic extension in the same patients (T3 category). Stage migration results in spurious variations in stage-specific outcomes, when in fact the overall individual outcomes are unchanged. Second, stage shift refers to actual changes in the patterns of disease presentation within a defined population (eg, as with the introduction of prostate-specific antigen [PSA] testing an increased proportion presented with early-stage PCa). Hence, stage shift is a desirable effect of cancer screening and early detection efforts, which should lead to improvements in disease outcomes. Both stage migration and stage shift have been observed in PCa.

随着能确定疾病程度的新方法的进展和应用，理解分期分类并进行精确描述也变得更加重要。在这一点上，有必要区分两种会挑战我们对癌症分期认识的现象。第一种现象是分期迁移（stage migration），指在应用原始的、预先定义的分期系统时，由于评估疾病程度的准确性提高，患者的T、N或M发生变化。举一个疾病分期为不可扪及疾病（T1期）的患者例子，如果新的影像学工具发现一个明显的肿瘤，伴包膜外扩散，那么该患者的疾病分期则变为T3期。分期迁移导致患者的疾病分期发生变化，但事实上不能算是真的发生了改变，患者本身的整体结局并没有改变。第二种现象是分期改变（stage shift），是指在一个确定的人群中，疾病的表现模式发生了实际变化（例如，随着前列腺特异性抗原[PSA]检测的引入，表现为早期PCa的患者比例增加）。因此，分期改变是癌症筛查和早期检测工作的一个理想效果，它应该可以促进疾病结局的改善。目前分期迁移和分期改变均可在PCa管理中观察到。

Evolving practices in PCa diagnosis and staging provide relevant contextualisation. Before the availability of PSA testing, PCa was detected via physical examination (digital rectal examination) or transurethral resection of the prostate (TURP) in symptomatic patients. Accordingly, increases in the granularity of T3 and T4 categories in the 3rd edition (1978) and 4th edition (1987) of the TNM classification were incorporated. Use of TURP in the management of benign prostatic hyperplasia led to introduction of the T1a/T1b categories in the 4th edition for cancers incidentally found in resected tissue. With the utilisation of PSA, shifts to lower disease stages were observed, including the detection of clinically inapparent cancers for which the new T1c category (nonpalpable disease identified via needle biopsies) was introduced in the 5th edition (1997), in parallel to increased granularity for the T2 subcategories since the 6th edition (2002). Subsequently, some investigators started to use transrectal ultrasound imaging to differentiate T1 and T2 categories; however, the impact of this modality on routine practice and staging has remained marginal.

PCa诊断和分期方面的不断发展促进了TNM分类系统的演变。在有PSA检测之前，PCa是通过体检（直肠指检）或对有症状的患者进行经尿道前列腺切除术（TURP）来发现的。因此，TNM分类第3版（1978年）和第4版（1987年）对T3和T4期进行了更细的划分。使用TURP治疗良性前列腺增生，导致在第四版中引入了T1a/T1b期，用于描述切除组织中偶然发现的癌症。PSA的应用使我们发现有些疾病的分期应改为更低，包括发现了临床上不明显的癌症，为此在第5版（1997年）中引入了新的T1c期（通过穿刺活检发现的不可触及的疾病），此外，自第6版（2002年）公布以来，T2期有了更细的划分。随后，一些研究者开始使用经直肠超声成像来区分T1和T2期，然而，这种方式对常规实践和分期的影响仍然很小。

Driven by settings in which most patients presented with stage I-II PCa (ie, T1 and T2), the use of prognostic groups (permutations of T category, PSA, and Gleason score) became a standard for guiding clinical and research activities; nevertheless, the distinction between stage I-II and stage III-IV PCa has remained highly relevant. It is worth noting that cancer stage serves many other purposes beyond its role in prognostication (further described in [[3]]). Together, these reasons underscore the importance of addressing the challenges and opportunities posed by progress in PCa imaging with regard to accurate and clear PCa staging.

在大多数患者为I-II期PCa（即T1和T2）的情况下，预后分组（结合T期、PSA和Gleason评分）成为指导临床和研究活动的标准；尽管如此，区分I-II期和III-IV期PCa仍然非常重要。值得注意的是，癌症分期除了在提供预后信息方面的作用外，还有许多其他作用（具体信息见参考文献[2]）。这些原因共同强调了，随着PCa影像学在准确评估PCa分期方面的进展，目前重要的是要解决PCa成像所带来的挑战，并抓住机遇。

The past two decades have been characterised by remarkable advances in PCa imaging. First, magnetic resonance imaging (MRI) has emerged as a superior modality for determining the local extent of PCa. Although the accuracy is not perfect, the improvement in resolution might also lead to changes in the assignment of T category and stage migration. Second, positron emission tomography (PET) with prostate-targeted tracers (eg, prostate-specific membrane antigen [PSMA]) has been increasingly used and approved in some jurisdictions for the staging of newly diagnosed PCa. Again, although the sensitivity of PET for nodal staging may not be optimal, it can demonstrate highly specific uptake in lymph nodes not detected via conventional imaging in a significant proportion of patients (20-45%, depending on the population) with conventionally defined localised disease. Similarly, approximately 10-25% of patients with presumed localised PCa with high-risk features may have distant metastatic disease detectable with PET tracers.

过去二十年来，PCa成像取得了显著的进步。首先，磁共振成像（MRI）成为优先选择的用来确定PCa局部范围的一种方式。虽然准确性并不完美，但分辨率有了改善，也可能使T分期有所改变，发生分期迁移。其次，使用前列腺靶向示踪剂（如前列腺特异性膜抗原[PSMA]）的正电子发射断层扫描（PET）已越来越多地用于对新诊断的PCa进行分期，并在一些地区得到批准。虽然PET对淋巴结分期的敏感性可能并不理想，但对于相当一部分通过常规手段识别的局部前列腺癌患者（20-45%，取决于患者人群），PET在常规成像未检测到的淋巴结中表现出高度特异性摄取。而且，在大约10-25%具有高风险特征、推测患有局部PCa的患者中，PET示踪剂可能会检测到远处转移性疾病。

Stage migration induced by imaging also has implications for the prognostic groups previously defined without MRI and PET imaging. Moreover, faulty annotation and inappropriate quantification of factors that affect prognosis (including stage) can introduce bias in analyses of outcomes and in prognostic subgroups. In addition, MRI is increasingly being used to guide the areas for sampling—so-called targeted biopsies—with consequent grade migration, potentially further jeopardising the performance of current risk stratification groups that are based on systematic biopsies. Taken together, these phenomena stress the need for clarity and consistency in the use of TNM classification as it continues to serve as a widely applicable relevant system against which proposed value-added advances should be adequately benchmarked and quantified.

成像引起的分期迁移也对未经MRI和PET成像定义的预后分组有影响。此外，错误的解释和对影响预后的因素（包括分期）的不适当量化，会使结局分析和预后亚组中出现偏倚。此外，MRI越来越多地用来指导取样区域--所谓的靶向活检--随之而来的分期迁移，可能会进一步对目前基于系统活检的风险分层分组产生不良影响。综上所述，这些现象强调了需要使用明确且一致的TNM分类系统，因为它仍然是一个广泛适用的、有价值的系统，应该对提出的增值进展进行适当的基准和量化。

The optimal use of imaging technologies in newly diagnosed PCa has not been elucidated or uniformly adopted. While MRI and/or PET are considered standard practice in some settings, a significant proportion of the world has limited or no access to either of these imaging modalities. The fundamental goal of the TNM classification has been to provide a universally applicable system with a sensible balance between ideal, useful, and practical. It is becoming apparent that the massive differences in patterns of presentation and gaps in diagnostic imaging availability result in significant noncomparability of clinical stage recorded across the globe, even within high-resource settings.

如何在新诊断的PCa中进行最佳的成像，目前尚不清楚，也没有统一的操作。虽然认为在某些情况下MRI和/或PET是标准实践，但在世界上很大一部分地区，这些成像方式的可获得性是有限的，甚至无法获得这些成像方式。TNM分类的基本目标是提供一个普遍适用的系统，在理想、有用和实用之间取得合理的平衡。越来越明显的是，由于表现形式的巨大差异和诊断性成像可获得性的差距，全球范围内记录的临床分期有很大的不可比性，即使是在医学资源丰富的地区。

A possible solution is to advocate for modification of the current framework by adopting an additional dimension for the classification system. We propose a pilot iTNM classification with an “i” prefix that denotes when a T, N, or M category is derived via modern imaging modalities, as has been suggested for PSMA PET. In this way, a wider spectrum of practices could be encompassed and accommodated while retaining validity and applicability across settings and allowing amelioration of the effect of stage migration on outcome assessments. At the same time, we recommend that major groups support multi-institutional efforts, such as the European Association of Urology-coordinated PIONEER and OPTIMA consortiums, with sharing of high-quality data (eg, prognostic factors, treatment details, and outcomes) to help in redefining stage and prognostic groupings according to this new classification for the direct benefit of all patients with PCa.

一个可能的解决方案是主张修改目前的框架，为分类系统增加一个维度。建议试行iTNM分期系统，其中“i”这个前缀表示T、N或M类别是通过现代成像方式得出的，比如建议的PSMA PET。这样可以涉及并适应更广泛的实践，同时保留有效性和跨环境的适用性，并减少分期迁移对结局评估的不良影响。此外，建议主要团体支持多机构的努力，如欧洲泌尿外科学会协调的PIONEER和OPTIMA联盟，共享高质量的数据（如预后因素、治疗细节和结局），以帮助我们根据这种新的分类重新定义分期和预后分组，使所有PCa患者直接获益。

Stage migration is an inevitable consequence of progress, but failure to address it proactively hinders our ability to precisely classify and communicate disease extent, ascertain changes in patterns of presentation, and limits our capability to effectively quantify the impact that advances may invariably have on treatment decisions and potentially on disease outcomes. Although this problem may appear daunting, we suggest that it presents us with an opportunity to marry the improving precision of diagnostics with first principles in PCa staging that foster opportunities for data-driven learning, perhaps refining the risks associated with PCa stage and grade, while allowing crosspollination across different actors and settings.

分期迁移是进步的必然结果，但如果不主动解决这个问题，就会阻碍我们对疾病程度进行精确分类和交流，阻碍我们确定疾病表现模式的变化，并使我们无法有效评估获得的进步可能对治疗决策和疾病结局有何影响。尽管这个问题可能较难解决，但我们认为它为我们提供了一个机会，将精确度不断提高的诊断方法与PCa分期的第一原则结合起来，提供数据驱动的学习机会，也许可以降低与PCa分期和分级相关的风险，同时允许在不同的参与者和环境中进行交流。